DIAMINO HETEROCYCLIC CARBOXAMIDE COMPOUND

Description

TECHNICAL FIELD

[0001] The present invention relates to diamino heterocyclic carboxamide compounds useful as active ingredients in pharmaceutical compositions, particularly pharmaceutical compositions for cancer therapy.

BACKGROUND ART

[0002] Lung cancer is caused by disordered growth of tracheal, bronchial and/or alveolar cells as a result of losing their normal functions. The number of people who die of lung cancer is the largest of the total of cancer deaths (17%), and worldwide about 1.3 million people die of lung cancer each year.

[0003] Treatment for lung cancer is divided into three major categories: surgical operation (surgical therapy), anticancer agent (chemotherapy) and radioactive irradiation (radiation therapy), but the effectiveness of treatment will vary depending on the tissue type of lung cancer. For example, although a definite diagnosis of lung cancer is made by a pathologist based on his cytohistopathological diagnosis on a microscope specimen, small cell lung cancer, which constitutes about 20% of lung cancer cases, has often reached an advanced stage at the time of discovery because it generally has a high grade of malignancy and will rapidly grow and spread and will often metastasize to other organs. For this reason, chemotherapy and/or radiation therapy is often used for treatment of this cancer, but the prognosis is poor because small cell lung cancer will often recur although it is relatively sensitive to these therapies. On the other hand, in the case of non-small cell lung cancer, which constitutes the remainder of about 80%, surgical therapy is considered for use until a certain stage, but there is little opportunity to use surgical operation in the subsequent stages where chemotherapy and/or radiation therapy is mainly used for treatment.

[0004] Thus, in either type of lung cancer, chemotherapy is an important option for treatment.

[0005] ALK (Anaplastic Lymphoma Kinase) is a receptor tyrosine kinase and is a protein having a transmembrane region in the middle part, flanked by a tyrosine kinase region on the carboxyl-terminal side and an extracellular region on the amino-terminal side. It has previously been reported that full-length ALK is expressed in several types of cancer cells of ectodermal origin (e.g., neuroblastoma, glioblastoma, breast cancer, melanoma) (Non-patent Document 1). In some cases of human malignant lymphoma, it has also been reported that the ALK gene is fused with another gene (e.g., NPM gene, CLTCL gene, TFG gene, TPM3 gene, ATIC gene, and TPM4 gene) as a result of chromosomal translocation, and thereby produces an oncogenic fusion tyrosine kinase (Science, vol. 263, p. 1281, 1994; Blood, vol. 86, p. 1954, 1995; Blood, vol. 95, p. 3204, 2000; Blood, vol. 94, p. 3265, 1999; Oncogene, vol. 20, p. 5623, 2001). Also in the case of inflammatory myofibroblastic tumor, it is known that the ALK gene is fused with another gene (e.g., CARS gene, SEC31L1 gene, and RanBP2 gene) as a result of chromosomal translocation, and thereby produces a fusion tyrosine kinase (Laboratory Investigation, a journal of technical methods and pathology, vol. 83, p. 1255, 2003; International Journal of Cancer, vol. 118, p. 1181, 2006; Medicinal Research Reviews, vol. 28, p. 372, 2008). Most of partner molecules to be fused with ALK have a complex-forming domain, and the generated fusion products per se also appear to form complexes. This complex formation would induce uncontrol of ALK tyrosine kinase activity and abnormal activation of intracellular signals, thereby causing canceration (Cellular and Molecular Life Science, vol. 61, p. 2939, 2004; Nature Reviews Cancer, vol. 8, p. 11, 2008).

[0006] Moreover, recent reports have indicated the presence of a TPM4-ALK fusion protein in esophageal cancer by proteomics analysis procedures (World Journal of Gastroenterology, vol. 12, p. 7104, 2006; Journal of Molecular Medicine, vol. 85, p. 863, 2007), Further, a fusion gene between EML4 (echinoderm microtubule associated protein like-4) and ALK was confirmed in specimens from lung cancer patients, and it was also reported that this EML4-ALK fusion gene has tumorgenicity and is a causal gene of cancer, and that inhibitors against its kinase activity suppress the growth of various cells where the EML4-ALK fusion protein is expressed (Patent Document 1 and Non-patent Document 2). These documents further show that inhibitors of the EML4-ALK fusion protein are useful as therapeutic agents for lung cancer in EML4-ALK polynucleotide-positive lung cancer patients. Further, in lung cancer, the presence of many variants of EML4-ALK has been proved (Patent Document 1; Annals of surgical oncology, vol. 17, p. 889, 2010; Molecular Cancer Research, vol. 7, p. 1466, 2009; Clinical Cancer Research, vol. 15, p. 3143, 2009; Cancer, vol. 115, p. 1723, 2009; Clinical Cancer Research, vol. 14, p. 6618, 2008; Clinical Cancer Research, vol. 14, p. 4275, 2008), and the presence of TFG-ALK (Cell, vol. 131, p. 1190, 2007) and KIF5B-ALK (Clinical Cancer Research, vol. 15, p. 3143, 2009) has been reported. Furthermore, it is known that there have been cases in which EML4-ALK is expressed in lung cancer patients as well as colon cancer patients and breast cancer patients (Molecular Cancer Research, vol. 7, p. 1466, 2009).

[0007] Moreover, Patent Document 1 shows the following compounds A to D (each being known as an ALK inhibitor) as examples of compounds having inhibitory activity against the EML4-ALK fusion protein, and it also discloses the actual values of their inhibitory activity against the EML4-ALK fusion protein. However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

Their respective chemical names are: 4-[(3'-bromo-4'-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (also called WHI-P154) for compound A; N-[2-(3-chlorophenyl)ethyl]-2-[(1[4-(trifluoromethoxy)phenoxy]acetyl}amino)methyl]-1,3-thiazole-4-carboxamide for compound B; 5-chloro-N⁴-[2-(isopropylsulfonyl)phenyl]-N²-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (also called TAE684) for compound C; and 2-[(5-bromo-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]-N-methylbenzenesulfonamide for compound D.

[0008] Moreover, in ALK fusion protein-expressing lymphoma cells, a compound having ALK inhibitory activity, WHI-P154 (compound A shown above), has been reported to inhibit cell growth and induce apoptosis (Non-patent Document 3). However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0009] Likewise, TAE684 (compound C shown above) is known as an inhibitor of a fusion protein from a fusion gene between NPM gene and ALK gene.

[0010] TAE684 structurally differs from the compounds of the present invention in that the center ring sandwiched between two -NH groups is a chloro-substituted pyrimidine ring.

[0011] Moreover, TAE684 has been reported to inhibit the spread of anaplastic large cell lymphoma (ALCL) by its inhibitory activity against the NPM-ALK fusion protein (Non-patent Document 4). On the other hand, although it is described that compounds including TAE684 have inhibitory activity against focal adhesion kinase (FAK) and are thereby useful for preventing and/or treating non-small cell lung cancer and small cell lung cancer, there is no information about actual therapeutic effects on these lung cancers (Patent Document 2). Furthermore, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0012] Further reports were issued showing that ELM4-ALK is expressed in non-small cell lung cancer cells (NCI-H2228), that TFG-ALK is expressed in non-small cell lung cancer patients, and that TAE684 inhibits the growth of non-small cell lung cancer cells (NCI-H2228) (Patent Document 1 and Non-patent Documents 5 and 6).

[0013] Further, it is reported that the compound below has Syk inhibitory activity and is useful as an active ingredient in agents for preventing or treating a disease in which Syk is involved, such as allergy, inflammation, immune disease, thrombus, and cancer (Patent Document 3).

(For the symbols in the formula, refer to the publication.)

[0014] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested, and there is no specific disclosure about therapeutic effects on cancer.

[0015] Further, it is reported that the compound below has inhibitory activity against protein kinase C and is useful as an active ingredient in agents for preventing or treating a disease in which protein kinase C is involved, such as diabetic complication, ischemia, inflammation, and cancer (Patent Document 4).

(For the symbols in the formula, refer to the publication.)

[0016] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested, and there is no specific disclosure about therapeutic effects on cancer.

[0017] Further, it is reported that the compound below has inhibitory activity against the kinase activity of EML4-ALK fusion protein and mutant EGFR protein and is useful as an active ingredient in therapeutic agents for cancer including lung cancer, etc (Patent Document 5).

(In the formula, -X- is 1,3,5-triazine-2,4-diyl or quinazoline-2,4-diyl which may be substituted. For other symbols in the formula, refer to the publication.)

[0018] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0019] Further, it is reported that the compound below has inhibitory activity against various kinases including ALK and is useful for treating cell proliferative disease (Patent Document 6).

(For the symbols in the formula, refer to the publication.)

[0020] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0021] Further, it is reported that the compound below has inhibitory activity against ALK and/or c-Met and is useful for treating proliferative disease (Patent Document 7).

(For the symbols in the formula, refer to the publication.)

[0022] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0023] Further, it is reported that the compound below has inhibitory activity against various kinases including ALK and is useful for treating hyperproliferative disease and angiogenic disease (Patent Document 8).

(For the symbols in the formula, refer to the publication.)

[0024] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0025] Further, it is reported that the compound below has inhibitory activity against various kinases including IGF-1R and ALK and is useful for treating cancer (Patent Document 9).

(For the symbols in the formula, refer to the publication.)

[0026] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0027] Further, it is reported that the compound below has Syk inhibitory activity and is useful for treating allergy, autoimmune disease, cancer, and abnormal myeloid cell growth (Patent Document 10).

(For the symbols in the formula, refer to the publication.)

[0028] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested, and there is no specific disclosure about therapeutic effects on cancer.

[0029] Further, it is reported that the compound below has inhibitory activity against Aurora-B kinase and is useful for treating cancer, infectious disease, inflammation, and autoimmune disease (Patent Document 11).

(For the symbols in the formula, refer to the publication.)

[0030] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested.

[0031] Further, it is reported that the compound below has STAT6 activation inhibitory activity and Th2 cell differentiation inhibitory activity and is useful for treating respiratory disease, asthma, and chronic obstructive pulmonary disease (Patent Document 12).

(For the symbols in the formula, refer to the publication.)

[0032] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested, and there is no specific disclosure about therapeutic effects on cancer.

[0033] Further, it is reported that the compound below has PKC inhibitory activity and is useful for treating allergy, inflammation, diabetes, cancer and the like (Patent Document 13).

(For the symbols in the formula, refer to the publication.)

[0034] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested, and there is no specific disclosure about therapeutic effects on cancer.

[0035] Further, it is reported that the compound below has inhibitory activity against PLK-1 and PLK-3 and is useful for treating cancer, cell proliferative disease, virus infection disease, autoimmune disease, and neurodegenerative disease (Patent Document 14).

(For the symbols in the formula, refer to the publication.)

[0036] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested.

[0037] Further, it is reported that the compound below has HSP-90 inhibitory activity and is useful for treating cell proliferative disease, cancer, inflammation, arthritis, and angiogenic disease (Patent Document 15).

(For the symbols in the formula, refer to the publication.)

[0038] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested.

[0039] Further, it is reported that the compound below has ALK, c-Met and Mps1 kinase inhibitory activity and is useful for treating hyperproliferative disease, cancer, and angiogenic disease (Patent Document 16).

(For the symbols in the formula, refer to the publication.)

[0040] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0041] Further, it is reported that the compound below has inhibitory activity against Syk and Jak and is useful for treating heart disease, inflammation, autoimmune disease, and cell proliferative disease (Patent Document 17).

(For the symbols in the formula, refer to the publication.)

[0042] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested.

[0043] Further, it is reported that the compound below has IKK inhibitory activity and is useful for treating inflammation, immunopathy, cancer, neurodegenerative disease, age-related disease, heart disease, and dysbolism (Patent Document 18).

(For the symbols in the formula, refer to the publication.)

[0044] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention. Furthermore, the inhibitory activity against the kinase activity of EML4-ALK fusion protein is neither disclosed nor suggested.

[0045] Further, it is reported that the compound below has inhibitory activity against various kinases including ALK and is useful for treating cell proliferative disease and cancer (Patent Document 19).

(For the symbols in the formula, refer to the publication.)

[0046] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0047] Further, it is reported that the compound below has ALK, ROS, IGF-1R and InsR kinase inhibitory activity and is useful for treating cell proliferative disease (Patent Document 20).

(For the symbols in the formula, refer to the publication.)

[0048] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

[0049] Further, it is reported that the compound below has ALK, ROS, IGF-1R and InsR kinase inhibitory activity and is useful for treating cell proliferative disease (Patent Document 21).

(For the symbols in the formula, refer to the publication.)

[0050] However, there is no specific disclosure about the diamino heterocyclic carboxamide compounds according to the present invention.

CITATION LIST

PATENT DOCUMENTS

[0051] 

Patent Document 1: European Patent Publication No. EP 1914240

Patent Document 2: International Publication No. WO 2004/080980

Patent Document 3: International Publication No. WO 00/75113

Patent Document 4: International Publication No. WO 00/76980

Patent Document 5: International Publication No. WO 2009/008371

Patent Document 6: International Publication No. WO 2008/073687

Patent Document 7: International Publication No. WO 2008/051547

Patent Document 8: International Publication No. WO 2009/032703

Patent Document 9: International Publication No. WO 2009/020990

Patent Document 10: Japanese Patent Publication No. 2008-13499

Patent Document 11: International Publication No. WO 2008/077885

Patent Document 12: International Publication No. WO 2004/002964

Patent Document 13: International Publication No. WO 2009/012421

Patent Document 14: International Publication No. WO 2009/040399

Patent Document 15: International Publication No. WO 2008/024974

Patent Document 16: International Publication No. WO 2009/032694

Patent Document 17: International Publication No. WO 2009/136995

Patent Document 18: International Publication No. WO 2009/089042

Patent Document 19: International Publication No. WO 2009/143389

Patent Document 20: International Publication No. WO 2009/126514

Patent Document 21: International Publication No. WO 2009/126515

NON-PATENT DOCUMENTS

[0052] 

Non-patent Document 1: International Journal of Cancer, vol. 100, p. 49, 2002

Non-patent Document 2: Nature, vol. 448, no. 2, p. 561, 2007

Non-patent Document 3: Laboratory Investigation, vol. 85, p. 1544, 2005

Non-patent Document 4: Proceedings of the National Academy of Science, vol. 104, no. 1, p. 270, 2007

Non-patent Document 5: Cell, vol. 131, p. 1190, 2007

Non-patent Document 6: Proceedings of the National Academy of Science, vol. 104, no. 50, p. 19936, 2007

SUMMARY OF INVENTION

TECHNICAL PROBLEMS

[0053] The present invention provides a compound which is useful as an active ingredient in pharmaceutical compositions, particularly pharmaceutical compositions for cancer therapy, and which can be used more safely as an active ingredient in pharmaceutical compositions.

SOLUTION TO PROBLEMS

[0054] As a result of extensive and intensive studies on compounds useful as active ingredients in pharmaceutical compositions for cancer therapy, the inventors of the present invention have found that the diamino heterocyclic carboxamide compound of the present invention has excellent inhibitory activity against the kinase activity of EML4-ALK fusion proteins, and is useful as an active ingredient in pharmaceutical compositions for cancer therapy. This finding led to the completion of the present invention.

[0055] Namely, the present invention relates to a compound of formula (I) or a salt thereof, as well as a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and an excipient.

(wherein the symbols are as defined below:

[0056] -X-: a group of formula (II)

[0057] A: chloro, ethyl or isopropyl;

R¹:

(1) phenyl in which the carbon at the 4-position is substituted with -W-Y-Z and the carbon at the 3-position may be substituted with a group selected from the group consisting of halogen, R⁰⁰ and -O-R⁰⁰;
-W-: a bond, piperidine-1,4-diyl, or piperazine-1,4-diyl;
-Y-: a bond;
Z: a non-aromatic heterocyclic ring which may be substituted with one or more R⁰⁰;

R²:

(i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of -N(C_1-6 linear or branched alkyl)₂, C_1-6 linear or branched alkyl, -COO- C_1-6 linear or branched alkyl, -OH, -COOH, -CONH-R^ZB and morpholinyl, or

(ii) a non-aromatic heterocyclic ring which may be substituted with one or more groups selected from the group consisting of C_1-6 linear or branched alkyl, -CO- C_1-6 linear or branched alkyl, oxo, -CO-R^ZB and benzyl;

R^ZB: phenyl which may be substituted with a group selected from the group consisting of halogen and -O-linear or branched C_1-6 alkyl;

R³: -H.

[0058] Unless otherwise specified, when symbols used in one chemical formula are also used in another chemical formula, the same symbols have the same meanings.

[0059] The present invention also relates to an inhibitor against the kinase activity of EML4-ALK fusion protein, which comprises a compound of formula (I) or a salt thereof.

[0060] Moreover, the present invention also relates to a pharmaceutical composition for cancer therapy, which comprises a compound of formula (I) or a salt thereof. It is to be noted that the pharmaceutical composition includes a therapeutic agent for cancer, which comprises a compound of formula (I) or a salt thereof.

[0061] Moreover, the present invention also relates to a pharmaceutical composition comprising a compound of formula (1) or a salt thereof and a pharmaceutical excipient; a pharmaceutical composition for use in a method for preventing and treating cancer, lung cancer, non-small lung cancer, small cell lung cancer, EML4-ALK fusion polynucleotide-positive cancer, EML4-ALK fusion polynucleotide-positive lung cancer, or EML4-ALK fusion polynucleotide-positive non-small lung cancer, comprising a compound of formula (I) or a salt thereof , a compound of formula (1) or a salt thereof for use in a method as an inhibitor against the kinase activity of EML4-ALK fusion protein; a compound of formula (I) or a salt thereof for use in a method for the prevention and treatment of cancer .

ADVANTAGEOUS EFFECT OF INVENTION

[0062] The compound of formula (I) or a salt thereof has inhibitory activity against the kinase activity of EML4-ALK fusion protein, as well as growth inhibitory activity against EML4-ALK fusion protein-dependent cells, and can be used as an active ingredient in pharmaceutical compositions for preventing and/or treating cancer, such as lung cancer in one embodiment, non-small cell lung cancer or small cell lung cancer in another embodiment, ALK fusion polynucleotide-positive cancer in yet another embodiment, ALK fusion polynucleotide-positive lung cancer in yet another embodiment, ALK fusion polynucleotide-positive non-small cell lung cancer in yet another embodiment, ALK fusion protein-positive cancer in yet another embodiment, ALK fusion protein-positive lung cancer in yet another embodiment, ALK fusion protein-positive non-small cell lung cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive lung cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive non-small cell lung cancer in yet another embodiment, EML4-ALK fusion protein-positive cancer in yet another embodiment, EML4-ALK fusion protein-positive lung cancer in yet another embodiment, or EML4-ALK fusion protein-positive non-small cell lung cancer in yet another embodiment.

DESCRIPTION OF EMBODIMENTS

[0063] The present invention will now be described in more detail below.

[0064] As used herein, the term "halogen" means F, Cl, Br or I.

[0065] The term "lower alkyl" refers to linear or branched alkyl containing 1 to 6 carbon atoms (hereinafter abbreviated as "C_1-6"). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. Another embodiment is C_1-4 alkyl, and yet another embodiment is methyl, ethyl or isopropyl.

[0066] The term "lower alkenyl" refers to a monovalent group of a C_2-6 linear or branched hydrocarbon chain having at least one double bond. Examples include vinyl, propenyl, isopropenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, etc. Another embodiment is isopropenyl.

[0067] The term "cycloalkyl" refers to an optionally bridged C_3-10 saturated cyclic hydrocarbon group, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, adamantyl, etc. Other examples include those partially unsaturated, such as cyclopentenyl, cyclohexenyl, cyclooctadienyl, bicyclo[3.1.1]heptenyl, etc.

[0068] The term "cyclic amino" refers to a monovalent group of a 3- to 8-membered monocyclic non-aromatic cyclic amine which has at least one nitrogen atom and may further have the same or different one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein at least one nitrogen atom has a binding hand. Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, homopiperazinyl, morpholinyl, oxazepanyl, thiomorpholinyl, thiazepanyl, and the like. Alternatively, another embodiment is a monovalent group of a 5- or 6-membered monocyclic non-aromatic cyclic amine. Yet another embodiment is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. It should be noted that such a ring may be bridged, as exemplified by 2,5-diazabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl and the like, or may have an unsaturated bond in part of the ring, as exemplified by dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, tetrahydropyrazyl, or the like.

[0069] The term "non-aromatic heterocyclic ring" refers to a monovalent group of a 3- to 10-membered monocyclic non-aromatic heterocyclic ring which has 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, azocanyl, piperazinyl, homopiperazinyl, morpholinyl, oxazepanyl, thiomorpholinyl, thiazepanyl, tetrahydropyranyl, tetrahydrofuryl, dioxanyl, dioxolanyl, tetrahydrothienyl, tetrahydrothiopyranyl, and the like. Another embodiment is a monovalent group of a 5- or 6-membered monocyclic non-aromatic heterocyclic ring. It should be noted that such a ring may be bridged, as exemplified by 2,5-diazabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl or the like, or may have an unsaturated bond in part of the ring, as exemplified by dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, tetrahydropyrazyl or the like.

[0070] The term "aromatic heterocyclic ring" refers to a monovalent group of a 5- to 10-membered monocyclic aromatic heterocyclic ring which has 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, thienyl, furyl, 1,2,4-oxadiazolyl and the like. Another embodiment is pyridyl, imidazolyl, or pyrazolyl. Yet another embodiment is pyridyl.

[0071] The term "ALK fusion polynucleotide" refers to a fusion polynucleotide in which the ALK gene is fused with another gene and thereby expresses an oncogenic fusion tyrosine kinase. Examples include EML4-ALK fusion polynucleotide, TFG-ALK fusion polynucleotide, KIF5-ALK fusion polynucleotide, NPM-ALK fusion polynucleotide, CLTCL-ALK fusion polynucleotide, TPM3-ALK fusion polynucleotide, TPM4-ALK fusion polynucleotide, ATIC-ALK fusion polynucleotide, CARS-ALK fusion polynucleotide, SEC31L1-ALK fusion polynucleotide, RanBP2-ALK fusion polynucleotide and the like.

[0072] The term "ALK fusion protein" refers to a fusion tyrosine kinase produced by expression of ALK fusion polynucleotide.

[0073] The term "EML4-ALK fusion polynucleotide" refers to a fusion polynucleotide in which the ALK gene is fused with the EML4 gene and thereby expresses an oncogenic ALK fusion protein, including variants thereof, such as EML4-ALK fusion polynucleotide v1 (polynucleotide of SEQ ID NO: 1 of Patent Document 1), EML4-ALK fusion polynucleotide v2 (polynucleotide of SEQ ID NO: 6 of Patent Document 1) and EML4-ALK fusion polynucleotide v3 (polynucleotide of SEQ ID NO: 129 of Patent Document 1), as well as various variants (Annals of surgical oncology, vol. 17, p. 889, 2010, Molecular Cancer Research, vol. 7, p. 1466, 2009, Clinical Cancer Research, vo. 15, p. 3143, 2009, Cancer, vol. 115, p. 1723, 2009, Clinical Cancer Research, vol. 14, p. 6618, 2008, Clinical Cancer Research, vol. 14, p. 4275, 2008, etc.).

[0074] The term "EML4-ALK fusion protein" refers to a fusion tyrosine kinase created by expression of EML4-ALK fusion polynucleotide.
A compound of formula (I) or a salt thereof wherein -X- in formula (I) represents a group of formula (II) means a compound of formula (V) or a salt thereof.

[0075] The phrase "may be substituted" is intended to mean "unsubstituted" or "having 1 to 5 substituents." When substituted with a plurality of groups, these groups may be the same or different from each other.

[0076] The phrase "is (are) substituted" or "substituted" is intended to mean "having 1 to 5 substituents." When substituted with a plurality of groups, these groups may be the same or different from each other.

[0077] The phrase "lower alkyl which may be substituted with one or more halogens" refers to, for example, lower alkyl which may be substituted with the same or different 1 to 7 halogens. Another embodiment is lower alkyl which may be substituted with 1 to 5 halogens. Yet another embodiment is lower alkyl which may be substituted with 1 to 3 halogens.

[0078] The phrase "lower alkenyl which may be substituted with one or more halogens" refers to, for example, lower alkenyl which may be substituted with 1 to 3 halogens.

[0079] Some embodiments of the compounds of formula (I) or a salt thereof are given below.

(1) Compounds of formula (I) or a salt thereof, wherein

(1-4) -X- is a group of formula (II), and A is chloro, ethyl or isopropyl,

(1-5) -X- is a group of formula (II), and A is chloro,

(1-6) -X- is a group of formula (II), and A is ethyl or isopropyl,

(1-7) -X- is a group of formula (II), and A is ethyl, or

(1-8) -X- is a group of formula (II), and A is isopropyl.

(2) Compounds of formula (I) or a salt thereof, wherein

(2-2) R¹ is phenyl in which the carbon at the 4-position is substituted with -W-Y-Z and the carbon at the 3-position may be substituted with a group selected from the group consisting of halogen, R⁰⁰, and -O- R⁰⁰, R⁰⁰ is lower alkyl which may be substituted with one or more halogens, -Y- is a bond, and Z is a non-aromatic heterocyclic ring which may be substituted with one or more R⁰⁰,

(2-3) R¹ is phenyl in which the carbon at the 4-position is substituted with a group selected from the group consisting of 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-(1-methylpiperidin-4-yl)piperazin-1-yl, 4-methylpiperazin-1-yl and 4-isopropylpiperazin-1-yl and the carbon at the 3-position may be substituted with a group selected from the group consisting of fluoro, methyl, trifluoromethyl and methoxy,

(2-4) R¹ is phenyl in which the carbon at the 4-position is substituted with 4-(4-methylpiperazin-1-yl)piperidin-1-yl and the carbon at the 3-position may be substituted with a group selected from the group consisting of methyl, trifluoromethyl and methoxy,

(2-5) R¹ is phenyl in which the carbon at the 4-position is substituted with 4-methylpiperazin-1-yl and the carbon at the 3-position may be substituted with a group selected from the group consisting of fluoro and methoxy,

(2-6) R¹ is 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(2-7) R¹ is 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(2-8) R¹ is 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}-3-(trifluoromethyl)phenyl,

(2-9) R¹ is 3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(2-10) R¹ is 4-(4-methylpiperazin-l-yl)phenyl,

(2-11) R¹ is 3-fluoro-4-(4-methylpiperazin-1-yl)phenyl,

(2-12) R¹ is 3-methoxy-4-(4-methylpiperazin-1-yl)phenyl,

(2-13) R¹ is 3-methyl-4-{4-(1-methylpiperidin-4-yl)piperazin-1-yl}phenyl, or

(2-14) R¹ is 4-(4-isopropylpiperazin-1-yl)-3-methylphenyl.

(3) Compounds of formula (I) or a salt thereof, wherein

(3-1) R² is

(i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of -N(lower alkyl)₂, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-R^ZB, and morpholinyl, or

(ii) a non-aromatic heterocyclic ring which may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-R^ZB, and benzyl,

(3-2) R² is cycloalkyl which may be substituted with one or more groups selected from the group consisting of -N(lower alkyl)₂, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-R^ZB, and morpholinyl,

(3-3) R² is a non-aromatic heterocyclic ring which may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-R^ZB, and benzyl,

(3-4) R² is

(i) cyclohexyl which may be substituted with one or more groups selected from the group consisting of -N(lower alkyl)₂, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-R^ZB, and morpholinyl,

(ii) piperidinyl which may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-R^ZB, and benzyl, or

(iii) tetrahydropyranyl,

(3-5) R² is cyclohexyl which may be substituted with one or more groups selected from the group consisting of -N(lower alkyl)₂, lower alkyl, -COO-lower alkyl, -OH, - COOH, -CONH-R^ZB, and morpholinyl,

(3-6) R² is piperidinyl which may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-R^ZB, and benzyl,

(3-7) R² is tetrahydropyranyl,

(3-8) R² is 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl, or tetrahydropyran-4-yl,

(3-9) R² is 4-hydroxycyclohexyl,

(3-10) R² is 4-hydroxy-4-methylcyclohexyl, or

(3-11) R² is tetrahydropyran-4-yl.

(4) Compounds of formula (I) or a salt thereof, wherein R³ is -H.

(5) Compounds, in which any combination of two or more of (1) to (4) shown above is applied. Examples of embodiments of the combination include:

(5-1) Compounds or a salt thereof, in which (1) and (4) shown above are applied,

(5-2) Compounds or a salt thereof, in which (1), (2), and (4) shown above are applied,

(5-3) Compounds or a salt thereof, in which (1), (2), (3), and (4) shown above are applied,

(5-6) Compounds or a salt thereof, in which (1-4), (2-2), (3-1), and (4) shown above are applied,

(5-7) Compounds or a salt thereof, in which (1-4), (2-3), (3-1), and (4) shown above are applied,

(5-8) Compounds or a salt thereof, in which (1-4), (2-3), (3-8), and (4) shown above are applied, and

(5-9) Compounds or a salt thereof, in which any consistent combination of two or more selected from the group consisting of (1-5), (1-7), (1-8), (2-6), (2-7), (2-8), (2-9), (2-10), (2-11), (2-12), (2-13), (2-14), (3-9), (3-10), (3-11) and (4) shown above is applied.

Other embodiments of the compound of formula (I) or a salt thereof are given below.

(6) Compounds of formula (I) or a salt thereof, wherein

(6-2) -X- is a group of formula (II), and A is ethyl or isopropyl,

(6-3) -X- is a group of formula (II), and A is ethyl, or

(6-4) -X- is a group of formula (II), and A is isopropyl.

(7) Compounds of formula (I) or a salt thereof, wherein

(7-2) R¹ is phenyl in which the carbon at the 4-position is substituted with -W-Y-Z and, as another substituent, the carbon at the carbon at the 3-position may be substituted with R⁰⁰ or -O- R⁰⁰, -W- is piperidine-1,4-diyl (attached via the nitrogen atom to phenyl to which - W- is attached) or a bond, -Y- is a bond, and -Z is piperazin-1-yl in which the nitrogen atom at the 4-position may be substituted with lower alkyl,

(7-3) R¹ is phenyl in which the carbon at the 4-position is substituted with 4-(4-methylpiperazin-1-yl)piperidin-1-yl and, as another substituent, the carbon at the 3-position may be substituted with methyl, trifluoromethyl, methoxy, or ethoxy,

(7-4) R¹ is 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-5) R¹ is 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}-3-(trifluoromethyl)phenyl,

(7-6) R¹ is 3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-7) R¹ is 3-ethoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-8) R¹ is 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-9) R¹ is phenyl in which the carbon at the 4-position is substituted with 4-methylpiperazin-1-yl or 4-isopropylpiperazin-1-yl and, as another substituent, the carbon at the 3-position may be substituted with methyl, trifluoromethyl, or methoxy,

(7-10) R¹ is 3-methyl-4-(4-methylpiperazin-1-yl)phenyl,

(7-11) R¹ is 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl,

(7-12) R¹ is 3-methoxy-4-(4-methylpiperazin-1-yl)phenyl,

(7-13) R¹ is 4-(4-methylpiperazin-1-yl)phenyl,

(7-14) R¹ is 4-(4-isopropylpiperazin-1-yl)-3-methylphenyl,

(7-15) R¹ is phenyl in which the carbon at the 3-position is substituted with -SO₂-R⁰⁰,

(7-16) R¹ is 3-(methylsulfonyl)phenyl,

(7-21) R¹ is 2-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-23) R¹ is 4-morpholin-4-ylphenyl,

(7-24) R¹ is 4-(1-methylpiperidin-4-yl)phenyl,

(7-25) R¹ is 4-{4-(cyclopropylmethyl)piperazin-1-yl}-3-(trifluoromethyl)phenyl, or

(7-26) R¹ is 4-{3-(dimethylamino)pyrrolidin-1-yl}-3-(trifluoromethyl)phenyl.

(8) Compounds of formula (I) or a salt thereof, wherein

(8-1) R² is cycloalkyl substituted with -OH and lower alkyl,

(8-2) R² is cyclohexyl substituted with -OH and lower alkyl,

(8-3) R² is cyclohexyl in which the carbon at the 4-position is substituted with -OH and lower alkyl,

(8-4) R² is cyclohexyl in which the carbon at the 4-position is substituted with -OH and methyl,

(8-5) R² is cycloalkyl substituted with -OH,

(8-6) R² is cyclohexyl substituted with -OH,

(8-7) R² is 4-hydroxycyclohexyl,

(8-8) R² is a non-aromatic heterocyclic ring which may be substituted with lower alkyl,

(8-9) R² is tetrahydropyranyl which may be substituted with lower alkyl, or piperidinyl which may be substituted with lower alkyl,

(8-10) R² is tetrahydropyran-4-yl,

(8-11) R² is piperidin-4-yl in which the nitrogen atom at the 1-position may be substituted with lower alkyl,

(8-12) R² is 1-methylpiperidin-4-yl, or

(8-13) R² is piperidin-4-yl.

(9) Compounds of formula (I) or a salt thereof, wherein R³ is -H.

(10) Compounds of (6-3) shown above or a salt thereof.

(11) Compounds of (7-4), (7-5), (7-6), (7-7), (7-8), (7-10), (7-13), or (7-14) shown above or a salt thereof.

(12) Compounds of (8-4), (8-7), (8-10), or (8-13) shown above or a salt thereof.

(13) Compounds, in which

(13-1) any combination of two or more of (6) to (9) shown above is applied, or a salt thereof, or

(13-2) any combination of two or more of (9) to (12) shown above is applied, or a salt thereof.

[0080] Examples of specific compounds falling within the present invention include the following compounds.

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-2-yl)piperidin-1-yl]phenyl}amido)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-isopropyl-3-[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.

6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, or

6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, or a salt thereof.

[0081] Examples of specific compounds falling within the present invention include those selected from Compound groups P and Q shown below.
Compound group P:

a group consisting of 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide.

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(cis-4-hydxoxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide,

3-({3-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-ylamino)pyrazine-2-carboxamide,

6-ethyl-3-{[4-(4-methylpiperazin-2-yl)phenyl]amino}-5-{tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, and

6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)pipendin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, as well as salts of these compounds.

Compound group Q:

a group consisting of 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(1-methyl-1H-indazol-6-yl)amino]pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(4-morpholin-4-ylphenyl)amino]pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide,

5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

3-({4-[4-(cyclopropylmethyl)piperazin-1-yl]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide,

3-({4-[3-(dimethylamino)pyrrolidin-1-y1]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide,

6-ethyl-5-[(cis-4-ethyl-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-ethyl-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(cis-4-hydroxy-4-isopropylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxy-4-isopropylcyclohexyl)amino]-3-({3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, and

6-ethyl-3-(3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(1-methylpiperidin-4-yl)amino]pyrazine-2-carboxamide, as well as salts of these compounds.

[0082] The compounds of formula (I) may have tautomers and/or geometrical isomers (including cis-trans isomers of compounds having a saturated ring group such as a cycloalkyl group), depending on the type of their substituents. Even when the compounds of formula (I) appear herein only in one isomer form, the present invention encompasses the other isomers, and also encompasses separated isomers or mixtures thereof.

[0083] Further, since some compounds of formula (I) have an asymmetric carbon atom or axial asymmetry, optical isomers based on this asymmetry may also exist. The present invention also encompasses separated optical isomers of the compounds of formula (I) or mixtures thereof.

[0084] Likewise, salts of the compounds of formula (I) are pharmaceutically acceptable salts of the compounds of formula (I). The compounds of formula (I) may form acid or base addition salts, depending on the type of their substituents. Specific examples include acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or with organic acids (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like), salts with inorganic bases (e.g., sodium, potassium, magnesium, calcium, aluminum, and the like) or with organic bases (e.g., methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like), salts with various amino acids and amino acid derivatives (e.g., acetylleucine, and the like), as well as ammonium salt, etc.

[0085] Moreover, the present invention also encompasses the compounds of formula (I) and salts thereof in the form of various hydrates, solvates, and crystalline polymorphic substances. The present invention also encompasses the compounds labeled with various radioactive or non-radioactive isotopes.

[0086] The compounds of formula (I) and pharmaceutically acceptable salts thereof can be prepared by applying various known synthesis methods on the basis of characteristics derived from their skeletal structure or the type of their substituents. In some cases, depending on the type of functional group, it is technically effective to replace such a functional group with an appropriate protecting group (a group which can be easily converted into the original functional group) at the starting material stage or at the intermediate stage. Examples of such a protecting group include those described in Greene and Wuts, "Greene's Protective Groups in Organic Synthesis (fourth edition, 2007)" and so on, which may be selected and used as appropriate, depending on reaction conditions. In such a method, after introduction of the protecting group and subsequent reaction, the protecting group may be removed if necessary to obtain a desired compound.

[0087] Likewise, a prodrug of the compound of formula (I) can be prepared by introducing a specific group at the starting material stage or at the intermediate stage, as in the case of the above protecting group, or by subjecting the obtained compound of formula (I) to further reaction. The reaction may be accomplished by applying conventional esterification, amidation, dehydration or other techniques known to those skilled in the art.

[0088] Explanation will be given below of typical processes for preparing the compounds of formula (I). Each process may also be accomplished by reference to the documents cited in this explanation. It should be noted that the processes of the present invention are not limited to the examples illustrated below.

(Preparation Process 1) (not part of the invention)

[0089] 

(In the formula, -L_A represents a leaving group, and examples include lower alkylsulfanyl.)

[0090] This process is intended to prepare the compound of the present invention (I-a) by reacting compound (1a) with compound (2).

[0091] In this reaction, compounds (1a) and (2) are used in equal amounts or one of them is used in an excessive amount. A mixture of these compounds is stirred in a solvent inert to the reaction or in the absence of a solvent under cooling to reflux conditions, preferably at 0°C to 200°C, generally for 0.1 hours to 5 days. The reaction may be performed using a microwave reaction system, because it is advantageous for smooth reaction in some cases. A solvent used for this purpose is not particularly limited, as long as it is inert to the reaction, and examples include aromatic hydrocarbons (e.g., benzene, toluene, xylene), ethers (e.g., diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane), halogenated hydrocarbons (e.g., 1,2-dichloroethane, chloroform), alcohols (e.g., methanol, ethanol, 2-propanol), 1-methyl-2-pyrrolidinone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), acetonitrile, and mixtures thereof. The reaction may be performed in the presence of an organic base (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or the like) or an inorganic base (e.g., potassium carbonate, sodium carbonate, potassium hydroxide, or the like), because it is advantageous for smooth reaction in some cases.

[0092] When the reaction is performed in the presence of such a base as shown above, depending on the properties or the like of starting compounds, the desired reaction is impossible or difficult to proceed, for example, due to decomposition or the like of the starting compounds. In this case, the reaction may be performed in the presence of a mineral acid (e.g., hydrochloric acid, hydrobromic acid, and the like), an organic acid (e.g., acetic acid, propionic acid, and the like) or a sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid, and the like), because it is advantageous for smooth reaction in some cases. Further, when -L_A is lower alkylsulfanyl, the S atom may be oxidized with various oxidizing agents such as Oxone®, m-chloroperbenzoic acid (mCPBA) and peracetic acid to convert the lower alkylsulfanyl into lower alkylsulfinyl or lower alkylsulfonyl and then the lower alkylsulfinyl or lower alkylsulfonyl may be reacted with compound (2), because it is advantageous for smooth reaction in some cases.

[Documents]

[0093] S. R. Sandler and W. Karo, "Organic Functional Group Preparations," second edition, vol. 1, Academic Press Inc., 1991

[0094] The Chemical Society of Japan, "Fifth Series of Experimental Chemistry," vol. 14 (2005) (MARUZEN Co., Ltd., Japan)

(Preparation Process 2)

[0095] 

(In the formula, -L_B represents a leaving group, and examples include a halogen (e.g., F, Cl), a sulfonyloxy group (e.g., methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy), lower alkylsulfanyl, and lower alkylsulfonyl.)

[0096] This process is intended to prepare the compound of the present invention (I-b) by reacting compound (1b) with compound (2).

[0097] In this reaction, the procedure of Preparation Process 1 may be applied.

(Starting Material Synthesis 1) (not part of the invention)

[0098] 

(In the formula, -L_C represents a leaving group, and examples include a halogen (e.g., F, Cl) and a sulfonyloxy group (e.g., methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy); R^A represents acyl, benzyl, lower alkyl, or -H; and M represents an alkali metal.)

[0099] This process is intended to prepare compound (1a) by reacting compound (5), which is obtained by reacting compound (3) with compound (4), with compound (6) and thereafter subjecting to deprotection reaction to remove R^A.

[0100] In the reaction which gives compound (5), the procedure of Preparation Process 1 may be applied. In the reaction which gives compound (1a), the procedure of Preparation Process 1 may be applied and the reaction may be performed using compound (6) or a reagent which produces compound (6) in the system, and thereafter deprotection reaction may be conducted under reaction conditions which are selected as appropriate from, for example, reaction conditions described in Greene and Wuts, "Greene's Protective Groups in Organic Synthesis (fourth edition, 2007)." Examples of compound (6) include sodium acetate and sodium methoxide. It is to be noted that compound (1a) can also be prepared by performing the reaction using a hydrogen peroxide solution in place of compound (6) and thereafter performing acid treatment with hydrochloric acid or the like.

(Starting Material Synthesis 2)

[0101] 

[0102] This process is intended to prepare compound (1b) by reacting compound (7) with compound (4).

[0103] In this reaction, the procedure of Preparation Process 1 may be applied.

[0104] The compound of formula (I) is isolated and purified as a free compound or as a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorphic substance thereof. A pharmaceutically acceptable salt of the compound of formula (I) may also be prepared by being subjected to conventional salt-forming reaction.

[0105] Isolation and purification may be accomplished by applying conventional chemical operations such as extraction, fractional crystallization, various types of fractionation chromatography, etc.

[0106] Various isomers can be prepared by selecting appropriate starting compounds or can be separated on the basis of differences in the physical and chemical properties of isomers. For example, optical isomers can be derived into optically pure isomers by conventional optical resolution techniques (e.g., fractional crystallization resulting in a diastereomer salt with an optically active base or acid, chromatography on a chiral column or the like, and the like). They can also be prepared from appropriate optically active starting compounds.

[0107] The compounds of formula (I) were confirmed for their pharmacological activity in the following tests. Unless otherwise specified, the test examples shown below may be accomplished by a method described in EP 1914240 or any publicly-known method and, when using commercially available reagents, kits, or the like, may be accomplished in accordance with the instructions attached to these commercially available products. It is to be noted that the term "EML4-ALK fusion protein v1" refers to a polypeptide of the amino acid sequence represented by SEQ ID NO: 2 of Patent Document 1, and the term "EML4-ALK fusion protein v3" refers to a polypeptide of the amino acid sequence represented by SEQ ID NO: 130 of Patent Document 1.

Test Example 1: Evaluation of inhibitory activity against the kinase activity of EML4-ALK fusion protein

[0108] A recombinant retrovirus was created from expression plasmid FLAG-EML4-ALKv1/pMX-iresCD8 in which cDNA for EML4-ALK fusion protein v1 was integrated, and injected into mouse lymphoid cell line BA/F3 cells. Using a magnetic bead reagent for cell separation and a purification column (anti-CD8 monoclonal antibody immobilized on magnetic beads and a MiniMACS purification column; both are products of Miltenyi Biotec Inc.), cell surface CD8-expressing cells were purified to establish EML4-ALK fusion protein v1-expressing BA/F3 cells. From the cells, EML4-ALK fusion protein v1 was purified and subjected to kinase activity evaluation. EML4-ALK fusion protein v1 was investigated for its phosphorylation activity toward a peptide substrate by using a kinase activity detection kit (HTRF KinEASE-TK; Cisbio Inc.). Test compounds were each added to a reaction solution containing the enzyme protein to give 8 final concentrations from 1000 nM to 0.3 nM, followed by addition of ATP and reaction for 1 hour. The ATP concentration used was 100 µM. Another reaction solution was prepared to contain the enzyme protein but no test compound (in which the solvent DMSO alone was added at 0.4% in place of the test compound), followed by reaction in the same manner with or without ATP addition. In the absence of the test compound, the phosphorylation count without ATP addition and with ATP addition was assumed to be 100% inhibition and 0% inhibition, respectively. The concentration causing 50% inhibition (IC₅₀) was calculated for each test compound by the logistic regression method.

[0109] As a result, some compounds of the present invention were found to have inhibitory activity against the kinase activity of EML4-ALK fusion protein v1. Table 1 shows the IC₅₀ values obtained for some compounds of the present invention. Ex denotes Example No. In the table below, Compound X denotes a racemic form of the compound of Example 174 shown in International Publication No. WO 2009/136995 (rac-2-{[(1R,2S)-2-aminocyclohexyl]amino}-4-{[4'-(morpholin-4-yl)biphenyl-4-yl]amino}pyrimidine-5-carboxamide), and Compound Y denotes the compound of Examples 26-22 shown in International Publication No. WO 00/76980 (S-{[2-(dimethylamino)ethyl]amino}-6-ethyl-3-[(3-methylphenyl)amino]pyrazine-2-carboxamide).

[Table 1] (# not part of the invention)

Ex	IC50(nM)	Ex	IC50(nM)	Ex	IC50(nM)
86#	17	383#	0.23	534	1.0
110#	0.99	387	0.26	538	2.3
284#	8.9	388	0.17	544	1.9
325	5.3	391	0.22	545	11
328#	76	392	0.21	546	7.8
340	0.37	399#	0.94	547	1.5
341	2.8	406#	0.34	549	2.1
343	2.1	426	0.49	550	11
347#	1.7	459	0.26	553	1.4
354	0.77	466	0.93	554	4.5
355	0.33	490	3.1	558	2.2
357	17	491	2.8	Compound X	220
370	0.65	493	2.6	Compound Y	>1000
377	0.24	494	4.1
378	0.26	512	1.5

Test Example 2: Evaluation of growth inhibitory activity against EML4-ALK fusion protein-dependent cells

[0110] EML4-ALK fusion protein v1-expressing BA/F3 cells can grow in the absence of IL-3. In other words, they are cells that EML4-ALK fusion protein v1-dependently grow.

[0111] In a 96-well plate (Iwaki), BA/F3 cells expressing EML4-ALK fusion protein v1 were seeded at 500 cells per well in RPMI1640 medium (Invitrogen) containing 10% fetal bovine serum, followed by addition of a test compound (final concentration: 10 µM to 0.1 nM). As a negative control, DMSO used as a solvent of the test compound was added. Then, the cells were cultured under 5% CO₂ at 37°C for 2 days. A cell counting reagent (AlmarBlue; Biosource) was added, and the cells were cultured for 150 minutes, followed by measurement of fluorescence intensity with a luminometer (Safire; Tecan) in accordance with instructions attached to the reagent. Assuming that the value measured for the medium alone and the value measured for the negative control were 100% inhibition and 0% inhibition, respectively, the inhibition rate was calculated for each compound to thereby determine the concentration causing 50% inhibition (IC₅₀ value) by the logistic regression method.

[0112] As a result, some compounds of the present invention showed growth inhibitory activity against BA/F3 cells expressing EML4-ALK fusion protein v1. Table 2 shows the IC₅₀ values obtained for some compounds of the present invention. Ex denotes Example No. In the table below, Compound X and Compound Y respectively denote the compounds described in Test Example 1.

[Table 2] (# not part of the invention)

Ex	IC50(nM)	Ex	IC50(nM)	Ex	IC50(nM)
86#	68	383#	5.9	534	24
110#	64	387	10	538	7.7
284#	85	388	4.1	544	27
325	20	391	6.5	545	25
328#	76	392	6.3	546	23
340	9.5	399#	11	547	5.7
341	11	406#	9.8	549	14
343	11	426	11	550	39
347#	17	459	8.1	553	4.7
354	8.6	466	9.3	554	14
355	9.2	490	18	558	16
357	60	491	16	Compound X	821
370	4.9	493	19	Compound Y	>1000
377	6.9	494	42
378	6.1	512	19

[0113] From the results of Test Examples 1 and 2 shown above, it was confirmed that the compounds of the present invention had inhibitory activity against the kinase activity of EML4-ALK fusion protein v1 and growth inhibitory activity against EML4-ALK fusion protein v1-expressing BA/F3 cells. On the other hand, Compounds X and Y described in Test Example 1 were confirmed to have extremely weak inhibitory activity against the kinase activity of EML4-ALK fusion protein v1 and growth inhibitory activity against EML4-ALK fusion protein v1-expressing BA/F3 cells, compared with the compounds of the present invention.

Test Example 3: Antitumor test (in vivo) on EML4-ALK fusion protein-dependent cells

[0114] Expression plasmid EML4-ALKv1/pMXS in which cDNA for EML4-ALK fusion protein v1 was integrated was trasfected into 3T3 fibroblast cells by the phosphate calcium method to thereby establish EML4-ALK fusion protein v1 expressing 3T3 cells. 3 × 10⁶ cells of EML4-ALK fusion protein v1 expressing 3T3 cells suspended in PBS were inoculated subcutaneously by injection to the back of 5 weeks old male Balb/c nude mice (Charles River Japan, Inc.). After 7 days of the inoculation, the administration of test compound was initiated. The test was conducted in the solvent group and the compound group, 4 animals per group. The test compound was suspended in a solvent composed of 0.5% methylcellulose and administered orally at a dose of 10 mg/kg. Administrations were performed once a day for 5 days, and body weight and tumor size were measured every other day. Tumor volume was calculated using the following formula.

[0115] Assuming that the tumor volume of the solvent group on the day of starting and the day of finishing administration of the test compound was 100% inhibition and 0% inhibition, respectively, the inhibition rate of the test compound was calculated. When regression of tumor volume is induced from the day of starting administration, the tumor volume on the day of starting administration and the state in which the tumor disappeared were assumed to be 0% regression and 100% regression, respectively, and the rate of regression of the test compound was calculated.

[0116] As a result, it was confirmed that among the compounds of the present invention, there were compounds that inhibited growth of tumor of EML4-ALK fusion protein v1 expressing 3T3 cells and compounds that induced regression of tumor of EML4-ALK fusion protein v1 expressing 3T3 cells. Table 3 shows the inhibition rate of some compounds of the present invention. It is to be noted that in the table below, the numerical values specified with "(regression)" each indicate a rate of regression. Ex denotes Example No.

[Table 3]

Ex	(%)
370	81
378	92
392	28 (regression)
426	81
466	54 (regression)
546	79
549	67 (regression)
553	63
558	37 (regression)

[0117] Thus, when orally administered, the compounds of the present invention inhibited tumor growth in mice inoculated with EML4-ALK fusion protein v1 expressing 3T3 cells or induced regression of tumor, thereby confirming that the compounds of the present invention had oral activity.

Test Example 4: Antitumor test (in vivo) on EML4-ALK fusion protein-dependent cells

[0118] The antitumor effects on EML4-ALK fusion protein-dependent cells can also be confirmed by use of human non-small cell lung cancers cell line NCI-H2228 cells (cells derived from EML4-ALK fusion polynucleotide-positive lung cancer patients (EML4-ALK fusion protein v3-dependent cells)) in place of the EML4-ALK fusion protein v1 expressing 3T3 cells of Test Example 3, as shown below.

[0119] 3 × 10⁶ cells of NCI-H2228 cells suspended in 50% Matrigel (Invitrogen) were inoculated subcutaneously by injection to the back of 5 weeks old male NOD/SCID mice (Charles River Japan, Inc.). After 3 weeks of the inoculation, the administration of test compounds was initiated. The test was conducted in the solvent group and test compound groups, 6 animals per group. The test compounds were each dissolved in a solvent composed of 10% 1-methyl-2-pyrrolidinone (SIGMA-ALDRICH Inc.)/90% polyethylene glycol 300 (Fluka Inc.) and administered orally at a dose of 1 mg/kg. Administrations were performed once a day for 14 days, and body weight and tumor size were measured every other day. Tumor volume was calculated using the following formula.

[0120] Assuming that the tumor volume of the solvent group on the day of starting and the day of finishing administration was 100% inhibition and 0% inhibition, respectively, the inhibition rate was calculated for each compound.

[0121] As a result, it was confirmed that among the compounds of the present invention, there were compounds that inhibited growth of tumor of NCI-H2228 cells. For example, the compound of Example 549 inhibited growth of tumor of NCI-H2228 cells by 69%.

[0122] Thus, when orally administered, the compounds of the present invention inhibited tumor growth in mice inoculated with human non-small cell lung cancer cell line NCI-H2228 cells, thereby confirming that the compounds of the present invention had oral activity.

[0123] On the other hand, when Compounds X and Y described in Test Example 1 were administered, no significant growth inhibition against NCI-H2228 cells (tumor) was shown, compared with the solvent group. The significance test was conducted by Student's t-test.

[0124] In view of the foregoing, in Test Examples 1 and 2, the compounds of the present invention were confirmed to have inhibitory activity against the kinase activity of EML4-ALK fusion protein, as well as growth inhibitory activity against EML4-ALK fusion protein-dependent cells. Further, in Test Examples 3 and 4, the compounds of the present invention were also confirmed to have an antitumor effect on EML4-ALK fusion protein-dependent cells (tumor) based on the above actions. These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and/or treating cancer, such as lung cancer in one embodiment, non-small cell lung cancer or small cell lung cancer in another embodiment, ALK fusion polynucleotide-positive cancer in yet another embodiment, ALK fusion polynucleotide-positive lung cancer in yet another embodiment, ALK fusion polynucleotide-positive non-small cell lung cancer in yet another embodiment, ALK fusion protein-positive cancer in yet another embodiment, ALK fusion protein-positive lung cancer in yet another embodiment, ALK fusion protein-positive non-small cell lung cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive lung cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive non-small cell lung cancer in yet another embodiment, EML4-ALK fusion protein-positive cancer in yet another embodiment, EML4-ALK fusion protein-positive lung cancer in yet another embodiment, or EML4-ALK fusion protein-positive non-small cell lung cancer in yet another embodiment.

[0125] So far, as to the ALK gene, the presence of various types of active point mutation and overexpression associated with gene amplification have been confirmed in cells derived from neuroblastoma patients (Nature, vol. 455, p. 971, 2008; Cancer Research, vol. 68, p. 3389, 2008). Further, it is known that a compound having inhibitory activity against the kinase activity of ALK protein shows an antitumor effect on cells derived from mutant ALK polynucleotide-positive cancer patients and cells derived from cancer patients with overexpression of ALK polynucleotide (Cancer Research, vol. 68, p. 3389, 2008). These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and/or treating neuroblastoma, such as mutant ALK polynucleotide-positive cancer in one embodiment, cancer with overexpression of ALK polynucleotide in another embodiment, mutant ALK polynucleotide-positive neuroblastoma in yet another embodiment, or neuroblastoma with overexpression of ALK polynucleotide in yet another embodiment.

[0126] The compounds of formula (I) were also confirmed for their pharmacological activity in the following tests. Unless otherwise specified, the test examples shown below may be accomplished in a known manner and, when using commercially available reagents and/or kits, may be accomplished in accordance with the instructions attached to these commercially available products.

Test Example 5: Evaluation of inhibitory activity against the kinase activity of RET protein

[0127] A partial protein of only a kinase domain of RET protein was purchased from Carna Biosciences Inc., Japan. The phosphorylation activity toward a peptide substrate was investigated using an EZ reader (Caliper). Test compounds were each mixed with a protein solution to give 8 final concentrations from 100 nM to 0.03 nM, followed by addition of a mixed liquid of ATP and substrate peptide (Caliper) and reaction for 30 minutes. The ATP concentration used was 100 µM. A reaction liquid which contained protein but no test compound (in which the solvent DMSO alone was added at 0.8% in place of the test compound) was prepared, followed by reaction in the same manner with or without ATP addition. In the absence of the test compound, the phosphorylation peptide peak without ATP addition and with ATP addition was assumed to be 100% inhibition and 0% inhibition, respectively. The test compound concentration causing 50% inhibition (IC₅₀ value) was calculated by the logistic regression method.

[0128] As a result, some compounds of the present invention showed inhibitory activity against the kinase activity of RET protein. Table 4 shows the IC₅₀ values obtained for some compounds of the present invention. Ex denotes Example No.

[Table 4]

Ex	IC50(nM)	Ex	IC50(nM)	Ex	IC50(nM)
565	1.1	571	1.1	577	3.4
566	0.95	572	1.3	578	1.5
567	1.7	573	1.0	579	1.1
568	1.5	574	1.0	580	3.6
569	1.0	575	1.3	581	2.9
570	2.3	576	1.3	582	1.1

[0129] RET (Rearranged during transfection) is a receptor tyrosine kinase and is a protein having a transmembrane region in the middle part, flanked by a tyrosine kinase region on the carboxyl-terminal side and an extracellular region on the amino-terminal side.

[0130] From the results of Test Example 5, it was confirmed that the compounds of the present invention had inhibitory activity against the kinase activity of RET protein. So far, as to the RET gene, active point mutation has been confirmed in cells or cancer tissue specimens derived from non-small cell lung cancers, small cell lung cancer, thyroid cancer, adrenal pheochromocytoma, colon cancer, and pancreatic cancer, and fusion with H4, H4L, PRKAR1A, NCOA4, GOLGA5, HTIF1, TIF1G, TKTN1, RFG9, ELKS, PCM1, RFP, and HOOK3 genes has been confirmed in cells or cancer tissue specimens derived from thyroid cancer, ovarian cancer, and mesothelioma (point mutation in non-small cell lung cancer: Nature Genetics, 2007, 39, 347-351; point mutation in small cell lung cancer: Japanese Journal of Cancer Research, 1995, 86, 1127-1130; fusion and point mutation in thyroid cancer: Endocrine Reviews, 2006, 27, 535-560; point mutation in adrenal tumor: Journal of Clinical Endocrinology and Metabolism, 1996, 81, 2041-2046; point mutation in colon cancer: Science, 2006, 314, 268-274; point mutation in pancreatic cancer: Cancer Research, 2005, 65, 11536-11544; fusion in ovarian cancer: International Journal of Surgical Pathology, 2009, 17, 107-110; fusion in mesothelioma: Cancer letters, 2008, 265, 55-66). Further, it is known that a compound having inhibitory activity against the kinase activity of RET protein shows an antitumor effect on cells derived from mutant RET polynucleotide-positive cancer patients and cells derived from fusion RET polynucleotide-positive cancer patients (Endocrine Reviews, 2006, 27, 535-560). These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and/or treating thyroid cancer, such as adrenal pheochromocytoma in one embodiment, colon cancer in another embodiment, pancreatic cancer in yet another embodiment, ovarian cancer in yet another embodiment, mesothelioma in yet another embodiment, mutant RET polynucleotide-positive cancer in yet another embodiment, mutant RET polynucleotide-positive lung cancer in yet another embodiment, mutant RET polynucleotide-positive non-small cell lung cancer in yet another embodiment, mutant RET polynucleotide-positive small cell lung cancer in yet another embodiment, mutant RET polynucleotide-positive thyroid cancer in yet another embodiment, mutant RET polynucleotide-positive adrenal pheochromocytoma in yet another embodiment, mutant RET polynucleotide-positive colon cancer in yet another embodiment, mutant RET polynucleotide-positive pancreatic cancer in yet another embodiment, RET fusion polynucleotide-positive cancer in yet another embodiment, RET fusion polynucleotide-positive thyroid cancer in yet another embodiment, RET fusion polynucleotide-positive ovarian cancer in yet another embodiment, or RET fusion polynucleotide-positive mesothelioma in yet another embodiment.

Test Example 6: Evaluation of inhibitory activity against the kinase activity of ROS protein

[0131] A partial protein of only a kinase domain of ROS protein was purchased from Carna Biosciences Inc., Japan, and tests were conducted as in Test Example 5, except that the ATP concentration in the mixed solution of ATP and substrate peptide (Caliper) was 50 uM.

[0132] As a result, some compounds of the present invention showed inhibitory activity against the kinase activity of ROS protein. Table 5 shows the IC₅₀ values obtained for some compounds of the present invention. Ex denotes Example No.

[Table 5]

Ex	IC50(nM)	Ex	IC50(nM)	Ex	IC50(nM)
565	0.40	571	0.86	577	1.9
566	0.86	572	0.37	578	0.51
567	0.23	573	0.78	579	0.58
568	1.0	574	1.3	580	0.29
569	0.65	575	1.6	581	0.41
570	0.51	576	1.9	582	1.2

[0133] ROS (v-Ros avian UR2 sarcoma virus oncogene homolog 1) is a receptor tyrosine kinase and is a protein having a transmembrane region in the middle part, flanked by a tyrosine kinase region on the carboxyl-terminal side and an extracellular region on the amino-terminal side.

[0134] From the results of Test Example 6, it was confirmed that the compounds of the present invention had inhibitory activity against the kinase activity of ROS protein. So far, as to the ROS gene, fusion with the FIG gene, the SLC34A2 gene, and the CD74 gene has been confirmed in cells or cancer tissue specimens derived from non-small cell lung cancers and glioblastoma (Biochimica et Biophysica Acta (BBA) Reviews on Cancer, 2009, 1795, 37-52). Further, since it is known that siRNA which inhibits molecule expression of cell lines derived from SLC34A2-ROS fusion polynucleotide-positive cancer patients shows an antitumor effect on the cell lines (Cell, 2007, 131, 1190-1203), it can be expected that a compound having inhibitory activity against the kinase activity of ROS protein shows an antitumor effect on ROS fusion polynucleotide-positive cancer. These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and/or treating glioblastoma, such as ROS fusion polynucleotide-positive cancer in one embodiment, ROS fusion polynucleotide-positive lung cancer in another embodiment, ROS fusion polynucleotide-positive non-small cell lung cancer in yet another embodiment, or ROS fusion polynucleotide-positive glioblastoma in yet another embodiment.

Test Example 7: Evaluation of inhibitory activity against the kinase activity of FLT3 protein

[0135] A partial protein of only a kinase domain of FLT3 protein was purchased from Carna Biosciences Inc., Japan, and tests were conducted as in Test Example 5.

[0136] As a result, some compounds of the present invention showed inhibitory activity against the kinase activity of FLT3 protein. Table 6 shows the IC₅₀ values obtained for some compounds of the present invention. Ex denotes Example No.

[Table 6]

Ex	IC50(nM)	Ex	IC50(nM)	Ex	IC50(nM)
565	0.44	571	0.39	577	0.41
566	0.51	572	0.34	578	0.56
567	0.46	573	0.37	579	0.36
568	0.50	574	0.36	580	0.4.9
569	0.35	575	0.72	581	0.52
570	0.66	576	0.51	582	0.37

[0137] FLT3 (Fms- like tyrosine kinase 3) is a receptor tyrosine kinase and is a protein having a transmembrane region in the middle part, flanked by a tyrosine kinase region on the carboxyl-terminal side and an extracellular region on the amino-terminal side.

[0138] From the results of Test Example 7, it was confirmed that the compounds of the present invention had inhibitory activity against the kinase activity of FLT3 protein. So far, as to the FLT3 gene, active point mutation and internal tandem duplication mutation in the juxtamembrane region (FLT3-ITD) have been confirmed in cells derived from acute myelocytic leukemia patients, and fusion with the SPTBN1 gene has been confirmed in cells derived from atypical chronic myelocytic leukemia patients (active point mutation and internal tandem duplication in the juxtamembrane region in acute myelocytic leukemia: Current Pharmaceutical Design, 2005, 11, 3449-3457; fusion in atypical chronic myelocytic leukemia: Experimental Hematology, 2007, 35, 1723-1727). Further, it is known that a compound having inhibitory activity against the kinase activity of FLT3 protein shows an antitumor effect on cells derived from mutant FLT3 polynucleotide-positive cancer patients and cells derived from SPTBN1-FLT3 fusion polynucleotide-positive cancer patients (Current Pharmaceutical Design, 2005, 11, 3449-3457; Experimental Hematology, 2007, 35, 1723-1727). These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and/or treating acute myelocytic leukemia, such as atypical chronic myelocytic leukemia patients in one embodiment, mutant FLT3 polynucleotide-positive cancer in another embodiment, mutant FLT3 polynucleotide-positive acute myelocytic leukemia in yet another embodiment, FLT3 fusion polynucleotide-positive cancer in yet another embodiment, or FLT3 fusion polynucleotide-positive atypical chronic myelocytic leukemia in yet another embodiment.

Test Example 8: Kinase inhibition profiling

[0139] The inhibition rates against 78 types of tyrosine kinases (ABL, ARG, BTK, BMX, ITK, TEC, TXK, FRK, BLK, LCK, HCK, LYN, FGR, FYN, SRC, YES, BRK, SRM, CSK, CTK, FER, FES, ACK, TNK1, HER4, EGFR, HER2, JAK1, TYK2, JAK2, JAK3, ROS, ALK, LTK, IRR, INSR, IGF1R, DDR1, DDR2, MUSK, TRKA, TRKB, TRKC, TYRO3, AXL, MER, MET, RON, RET, FGFR4, FGFR1, FGFR2, FGFR3, FLT4, KDR, FLT1, FLT3, FMS, KIT, PDGFRa, PDGFRb, TIE2, EphA1, EphA2, EphA8, EphA7, EphA6, EphA4, EphA3, EphA5, EphB4, EphB3, EphB1 EphB2, FAK, PYK2, SYK, ZAP70) were calculated for each test compound at 5 nM. Activity measurement was made by Carna Biosciences Inc., Japan, and the data were analyzed as follows: assuming that the average signal of control wells containing all reaction components was 0% inhibition and the average signal in the absence of the enzyme was 100% inhibition, the inhibition rate was calculated for each test substance from the average signal of two test wells.

[0140] As a result, at a concentration of 5 nM, some compounds of the present invention showed 50% or more inhibitory activity against 7 types of kinases including ALK, RET, ROS and FLT3 and, hence, appear to be highly selective for specific kinases and to have fewer fears about safety, which fears are induced by inhibition of non-target kinases responsible for side effects.

[0141] A pharmaceutical composition which comprises one or more compounds of formula (I) or pharmaceutically acceptable salts thereof as an active ingredient can be prepared in a conventional manner by using a pharmaceutical excipient, a pharmaceutical carrier or other additives commonly used in the art.

[0142] Any mode of administration may be used, either oral administration in the dosage form of tablets, pills, capsules, granules, powders, solutions or the like, or parenteral administration in the dosage form of injections (e.g., intraarticular, intravenous, intramuscular, and the like), suppositories, eye drops, eye ointments, percutaneous solutions, ointments, percutaneous patches, transmucosal solutions, transmucosal patches, inhalants or the like.

[0143] Solid compositions used for oral administration include tablets, powders, granules, and the like. In these solid compositions, one or more active ingredients are mixed with at least one inert excipient, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or magnesium aluminometasilicate, or the like. The compositions may also comprise inert additives, for example, lubricants (e.g., magnesium stearate and the like), disintegrating agents (e.g., carboxymethyl starch sodium and the like), stabilizers, and/or solubilizers, as in the usual cases. Tablets or pills may be coated with sugar coating or a gastric or enteric film, if necessary.

[0144] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and comprise commonly-used inert diluents such as purified water or ethanol. These liquid compositions may comprise, in addition to inert diluents, auxiliaries (e.g., solubilizers, wetting agents, suspending agents, and the like), sweeteners, flavors, aromatics, and/or antiseptics.

[0145] Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents include injectable distilled water or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oils (e.g., olive oil and the like), as well as alcohols (e.g., ethanol and the like) or Polysorbate 80 (pharmacopoeia name), and the like. These compositions may further comprise isotonizing agents, antiseptics, wetting agents, emulsifiers, dispersants, stabilizers or solubilizers. They are sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation with disinfectants or by irradiation. Alternatively, they may be formulated into a sterile solid composition and reconstituted for use by being dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0146] Formulations for external use include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and the like. They comprise commonly-used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions or the like. Examples of ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerine monostearate, stearyl alcohol, cetyl alcohol, Lauromacrogol, sorbitan sesquioleate, and the like.

[0147] Transmucosal formulations such as inhalants or transnasal formulations are used in solid, liquid or semi-solid form and can be prepared in a conventionally known manner. For example, such formulations may be supplemented as appropriate with known excipients and further with pH adjustors, antiseptics, surfactants, lubricants, stabilizers, thickeners and so on. For their administration, an appropriate device for inhalation or insufflation may be used. For example, using a known device (e.g., a metered-dose inhalation device and the like) or a nebulizer, the compound(s) may be administered alone or as a powder of a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalators or the like may be for single or multiple administration use, and dry powders or powder-containing capsules may be used in such devices. Alternatively, they may be in the form of pressurized aerosol sprays or the like which use an appropriate propellant, for example, a preferred gas such as chlorofluoroalkane, hydrofluoroalkane, carbon dioxide, or the like.

[0148] In general, for oral administration, the daily dosage is desirably about 0.001 to 100 mg/kg, preferably 0.005 to 30 mg/kg, and more preferably 0.01 to 10 mg/kg body weight, given as a single dose or in 2 to 4 divided doses. For intravenous administration, the daily dosage is desirably about 0.0001 to 10 mg/kg body weight, given in one or several doses per day. Likewise, for transmucosal formulations, the daily dosage is about 0.001 to 100 mg/kg body weight, given in one or several doses per day. The dosage may be determined as appropriate for each case in consideration of symptom, age, sex and so on.

[0149] The compounds of formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases against which the compounds of formula (I) would be effective. In general, when an antitumor agent is administered alone during chemotherapy for tumor, particularly malignant tumor, the antitumor agent has a limit in its effect in terms of side effects and the like, and thus often fails to produce a sufficient antitumor effect. For this reason, in clinical cases, multidrug therapy is used in which two or more drugs with different mechanisms of action are combined. By combining antitumor agents with different mechanisms of action, this combination therapy aims to reduce side effects and/or enhance the desired antitumor effect, for example, 1) to reduce the number of non-sensitive cell population, 2) to prevent or delay the development of drug resistance, 3) to disperse toxicity by combination of drugs with different toxicity levels, and the like. In such combination therapy, drugs may be administered simultaneously or separately in succession or at desired time intervals. Formulations for simultaneous administration may be in either mixed or separate form.

[0150] Drugs which can be combined include chemotherapeutics (e.g., alkylating agent, antimetabolite, and the like), immunotherapeutic agents, hormonal therapeutic agents, and cell growth factor inhibitors, more specifically drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, irinotecan, vinorelbine, bevacizumab, pemetrexed and the like.

EXAMPLES

[0151] How to prepare the compounds of formula (1) will be further explained in more detail by way of the following examples. It should be noted that the present invention is not limited to the compounds shown in the following examples. In addition, how to prepare the starting compounds is shown in preparation examples. Processes for preparing the compounds of formula (I) are not limited only to those actually shown in the following examples, and the compounds of formula (I) may also be prepared by any combination of these processes or by any process obvious to those skilled in the art.

[0152] In the examples, preparation examples and tables shown below, the following abbreviations are used as needed.
Rex: Preparation Example No., Ex: Example No., Structure: chemical structural formula, Data: physical and chemical data (FAB+: FAB-MS[M+H]⁺, ESI+: ESI-MS[M+H]⁺, APCI/ESI+: APCI/ESI-MS[M+H]⁺ (APCI/ESI means simultaneous measurement of APCI and ESI), FAB-: FAB-MS[M-H]^-, ESI-: ESI-MS[M-H]^-, APCI-: APCI-MS[M-H]^-, ¹H-NMR (CDCl₃): δ (ppm) of ¹H-NMR peaks in chloroform-d, ¹H-NMR(CD3OD): δ (ppm) of ¹H-NMR peaks in methanol-d, ¹H-NMR(CDCl3+CD3OD): δ (ppm) of ¹H-NMR peaks in a mixed solution of chloroform-d and methanol-d, ¹H-NMR(DMSO-d₆): δ (ppm) of ¹H-NMR peaks in DMSO-d₆, XRD: diffraction angle 2θ(°) of main peak in powder X ray diffraction measurement, HCl: which means that the intended product was obtained as hydrochloride, 2HCl: which means that the intended product was obtained as a dihydrochloride, TsOH: which means that the intended product was obtained as a p-toluene sulfonic acid salt, HFM: which means that the intended product was obtained as a hemifumaric acid salt, FM: which means that the intended product was obtained as a fumaric acid salt, Me: methyl, Et: ethyl, nPr: normalpropyl, iPr: isopropyl, cPr: cyclopropyl, cHex: cyclohexyl, Ph: phenyl, Bn: benzyl, Boc: tert-butyloxycarbonyl, Ac: acetyl. Syn: preparation process (indicating that the intended compound was prepared from corresponding starting materials as in the indicated Preparation Example or Example). In the tables shown in Preparation Examples or Examples, there are cis-trans isomers and their configurations are undecided, but as to compounds that show a single configuration of one of cis and trans, no indication of configuration is made in their chemical structural formulas and, instead, the symbol "*" is given to their preparation example Nos. or example Nos. Compounds that are give the same number following the symbol "*" indicate that one of the compounds is a cis form and the other is a trans form.

[0153] The measurement of powder X ray diffraction was performed using RINT-TTR II under the following conditions; tube: Cu, tube current: 300 mA, tube voltage: 50 kV, sampling width: 0.020°, scan rate: 4°/min, wavelength: 1.54056 Å, range of diffraction angle measured (2θ): 2.5 to 40°. It is to be noted that the powder X ray diffraction should not strictly be understood, because, due to the nature of powder X ray diffraction data, crystal lattice space and overall pattern are important in determination of crystal identity, and the relative intensity may vary in some degree depending on the direction of crystal growth, particle size, and measurement conditions.

Preparation Example 4

[0154] A mixture of 4-methyl-3-nitrobenzoic acid (1.97 g) and thionyl chloride (6 mL) was heated under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure, followed by an azeotropic process with toluene to give a red-brown oil. To a mixture of the red-brown oil and THF (25 mL), diethylamine (2.6 mL) was added under ice cooling and stirred at room temperature for 5 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give N,N-diethyl-4-methyl-3-nitrobenzamide (2.61 g) as a brown oil.

Preparation Example 41

[0155] To a mixture of 2-methoxy-4-nitrobenzenesulfonylchloride (600 mg) and THF (5 mL), a mixture of piperidine (406 mg) and THF (1 mL) was added and stirred at room temperature for 12 hours. After addition of 10 % hydrochloric acid, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1-[(2-methoxy-4-nitrophenyl)sulfonyl]piperidine (714 mg) as a yellow solid.

Preparation Example 48

[0156] A mixture of 2-fluoro-5-nitrobenzoic acid (600 mg) and thionyl chloride (2 mL) was heated under reflux for 15 hours. The reaction liquid was concentrated under reduced pressure, followed by an azeotropic process with toluene to give a yellow crystal. To a mixture of the yellow crystal and THF (11 mL), triethylamine (0.47 mL) and isopropylamine (0.29 mL) were added under ice cooling and stirred at room temperature for 5 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a yellow crystal. To a mixture of the yellow crystal (723 mg) and methanol (8 mL) and water (3 mL), ammonium chloride (2.05 g) and zinc powder (2.09 g) were added, and the mixture was heated under reflux for 3 hours. After filtration of the reaction suspension through celite, the filtrate was concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 5-amino-2-fluoro-N-isopropylbenzamide (527 mg) as a light brown crystal.

Preparation Example 160

[0157] To a mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.0 g) and DMF (15 mL), thionyl chloride (1 mL) was added at room temperature and stirred for 20 minutes. The reaction liquid was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:n.-hexane) to give 3,5-dichloro-6-ethylpyrazine-2-carbonitrile (608 mg) as a slightly yellow oil.

Preparation Example 194

[0158] To a solution of a mixture of methyl 5-chloro-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxylate (Preparation Example 193) (20 mg) and THF (2 mL), O-methylhydroxylamine hydrochloride (14 mg) was added. To the reaction liquid, lithium hexamethyldisilazide (0.39 mL, 1M THF solution) was added under ice cooling and stirred for 20 minutes. The reaction liquid was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate, and then the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 5-chloro-N-methoxy-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (21 mg) as a yellow powder.

Preparation Example 240

[0159] To a mixture of 1-(2-iodo-4-nitrophenyl)-4-methylpiperazine (Preparation Example 241) (406 mg), toluene (3 mL) and water (3 mL), sodium carbonate (496 mg), phenylboronic acid (157 mg) and tetrakis(triphenylphosphine)palladium (68 mg) were added in an argon atmosphere and stirred overnight at 110°C. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol) to give 1-methyl-4-(5-nitrobiphenyl-2-yl)piperazine (348 mg) as a yellow brown oil.

Preparation Example 244

[0160] To a mixture of N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]acetamide (433 mg) and DMF (5 mL), 63% sodium hydride in oil (66 mg) was added under ice cooling and stirred at room temperature for 1 hour. The reaction liquid was ice cooled again, and methyl iodide (0.11 mL) was added and stirred at room temperature for 4 hours. The reaction liquid was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]acetamide (200 mg) as an orange solid.

Preparation Example 246

[0161] To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL), ethyllithium (0.5 M benzene-cyclohexane solution) (56.8 mL) was added at -78°C and stirred over 4 hours until it reached -50°C. After addition of water (150 mL), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 30:1) and further purified (eluent; n-hexane:ethyl acetate = 2:1 to 1:1) to give tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 246) (0.202 g), which was a low-polarity product, as a white solid and tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 248), which was a high-polarity product, as a colorless syrup.

Preparation Example 247

[0162] To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 246) (0.202 g) and dioxane (2 mL), 26% hydrogen chloride-dioxane (1.1 mL) was added under ice cooling and stirred at room temperature for 12 hours. The solvent was distilled off to give 4-amino-1-ethylcyclohexanol hydrochloride (0.140 g) as a white viscous solid.

Preparation Example 249

[0163] To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 248) (0.256 g) and dioxane (2 mL), 26% hydrogen chloride-dioxane (1.4 mL) was added under ice cooling and stirred at room temperature for 17 hours. The precipitated solid was collected by filtration to give 4-amino-1-ethylcyclohexanol hydrochloride (0.152 g) as a white solid.

Preparation Example 250

[0164] To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL), isopropyllithium (0.7 M pentane solution) (40.3 mL) was added at -78°C and stirred over 4 hours until it reached -50°C. After addition of water (150 mL), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate = 3:1) and further purified (eluent; chloroform:methanol = 30:1) to give tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 250) (0.854 g), which was a low-polarity product, as a white solid and tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 252) (0.179 g), which was a high-polarity product, as a yellow oil.

Preparation Example 251

[0165] To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 250) (0.392 g) and dioxane (3 mL), 26% hydrogen chloride-dioxane (2.0 mL) was added under ice cooling and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.190 g) as a white solid.

Preparation Example 253

[0166] To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 252) (0.179 g) and dioxane (1.5 mL), 26% hydrogen chloride-dioxane (0.9 mL) was added under ice cooling and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.086 g) as a white solid.

Preparation Example 287

[0167] To a mixture of propane-2-thiol (3.30 mL), potassium carbonate (6.60 g) and DMF (40 mL), 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction liquid was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene (6.60 g) as a yellow oil.

Preparation Example 291

[0168] To a mixture of 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene (Preparation Example 287) (6.60 g) and chloroform (150 mL), m-chloroperbenzoic acid (18.0 g) was added and stirred at 50°C for 12 hours. After the reaction liquid was cooled, saturated aqueous sodium hydrogen carbonate and 5% aqueous sodium sulfite were added, and the reaction liquid was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 2-(isopropylsulfonyl)-4-methyl-1-nitrobenzene (7.41 g) as a yellow solid.

Preparation Example 292

[0169] To a mixture of 2-(isopropylsulfonyl)-4-methyl-1-nitrobenzene (Preparation Example 291) (7.41 g) and acetic acid (70 mL), iron powder (5.43 g) was added and stirred at 80°C for 3 hours. Thereafter, insoluble materials in the reaction liquid were removed, and the solvent was distilled off under reduced pressure. After addition of ethyl acetate (150 mL) and removal of insoluble materials, the residue was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether to give 2-(isopropylsulfonyl)-4-methylaniline (3.86 g) as a light yellow solid.

Preparation Example 298

[0170] To a mixture of 55% sodium hydride in oil (733 mg) and DMF (20 mL), a mixture of 3-(methylsulfonyl)aniline (1.44 g) and THF (20 mL) were added under ice cooling and stirred for 30 minutes under ice cooling. After dropwise addition of a mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxamide (2.0 g) and DMF (30 mL) over 15 minutes, the reaction liquid was further stirred under ice cooling for 15 minutes. After addition of 10% aqueous citric acid (300 mL) and extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was concentrated, and the precipitated solid was collected by filtration and dried to give 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (1.95 g) as a light yellow solid.

Preparation Example 299

[0171] To a mixture of 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (Preparation Example 298) (1.95 g) and DMSO (30 mL), potassium carbonate (1.81 g) and 30% hydrogen peroxide solution (2.65 mL) were added and stirred at 50°C for 1.5 hours. The reaction liquid was ice-cooled, and 1M hydrochloric acid (25 mL) and thereafter water (150 mL) were added and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water to give 2-(methylsulfanyl)-4-{[3-(methylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (1.40 g) as a light yellow solid.

Preparation Example 304

[0172] To a mixture of 4-chloro-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (Preparation Example 303) (51 mg) and methanol (1 mL), sodium methoxide (11 mg) was added under ice cooling and stirred overnight at room temperature. Water was added to the reaction liquid, and the solid was collected by filtration to give 4-methoxy-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (41 mg).

Preparation Example 311

[0173] To a mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 306) (500 mg), dichloromethane (40 mL) and methanol (40 mL), a mixture of Oxone® (922 mg) and water (10 mL) was added and stirred at room temperature for 18 hours. To the reaction liquid, chloroform and water were added, and the precipitated solid was collected by filtration and washed with water to give 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (234 mg) as a light yellow solid.

Preparation Example 339

[0174] To a mixture of 4-methoxy-6-[(6-methoxy-pyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (Preparation Example 337) (0.35 g) and water (2.2 mL), concentrated hydrochloric acid (2.2 mL) was added and stirred at 80°C for 1.5 hours. After the reaction liquid was cooled, 1M aqueous sodium hydroxide was added so that the reaction liquid became almost neutral, and then the resulting solid was collected by filtration to give 4-[(6-methoxy-pyridin-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (0.34 g).

Preparation Example 342

[0175] To a mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid (1.50 g) and dichloromethane (15 mL), oxalyl chloride (1.20 mL) and DMF (0.015 mL) were added under ice cooling and stirred 30 minutes under ice cooling and 2 hours at room temperature. The solvent was distilled off under reduced pressure, followed by an azeotropic process with toluene. The resulting residue was dissolved in THF, followed by dropwise addition of 40% aqueous methylamine at -10°C. After the dropwise addition was completed, the reaction liquid was concentrated, and water was added. The resulting solid was collected by filtration and washed with water to give a white solid. The solid was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off. To a mixture of the resulting residue and dioxane (20 mL), 3-(methylsulfonyl)aniline hydrochloride (432 mg) and N,N-diisopropylethylamine (0.73 mL) were added and stirred at 100°C for 4 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 100:0 to 30:1) to give 4-chloro-N-methyl-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (445 mg) as a white solid.

Preparation Example 346

[0176] To a mixture of 4-chloro-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidine-5-carboxamide (Preparation Example 344) (0.68 g) and sodium acetate (0.80 g), DMF (7 mL) was added and stirred at 100°C for 6 hours. After the reaction liquid was returned to room temperature, water was added, and the resulting solid was collected by filtration to give 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (0.71 g).

Preparation Example 349

[0177] To 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (Preparation Example 346) (0.71 g), ethanol (14 mL) and THF (14 mL) were added, and 1M aqueous sodium hydroxide (6 mL) was added and stirred at room temperature for 1 hour. Then, 1M hydrochloric acid (6 mL) was added, and the precipitated solid was collected by filtration and dried to give 2-(methylsulfanyl)-6-oxo-4-(quinolin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide (0.63 g).

Preparation Example 353

[0178] A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (600 mg), 3-(methylsulfonyl)aniline (467 mg), N,N-diisopropylethylamine (0.48 mL) and dioxane (18 mL) was stirred in a sealed tube at 170°C for 17 hours. After cooling, the mixture was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was washed with chloroform, and the solid was collected by filtration and dried to give 5-chloro-6-ethyl--3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (412 mg) as a yellow solid.

Preparation Example 364

[0179] To a mixture of 4-chloro-6-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (Preparation Example 359) (194 mg) and DMF (5 mL), sodium acetate (257 mg) was added and stirred at 100°C for 5 hours. After the reaction liquid was cooled, ethyl acetate and water were added, and the precipitated powder was collected by filtration and dried to give a light yellow solid. To a mixture of the solid, ethanol (5 mL), methanol (20 mL) and THF (5 mL), 1M aqueous sodium hydroxide (3 mL) was added and stirred at room temperature for 1 hour, at 60° C for 1 hour, and at 80° C for 1 hour. After the reaction liquid was cooled, 1M hydrochloric acid (3 mL) was added, and the reaction liquid was extracted with chloroform-isopropanol. Silica gel was added to the organic layer, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol = 100:0 to 20:1) to give a crude product. This crude product was washed with a small amount of methanol to give 4-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (27 mg) as a yellow solid.

Preparation Example 397

[0180] To a mixture of 5-chloro-6-ethyl-3-{[4-(methylsulfanyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 394) (92 mg) and acetic acid (2.5 mL), sodium tungstate dihydrate (29 mg) and 30% hydrogen peroxide solution (0.15 mL) were added and stirred at room temperature for 30 minutes. After water and ethyl acetate were added to the reaction liquid, 1M aqueous sodium hydroxide was added and stirred for 30 minutes, and the reaction liquid was partitioned. After drying over anhydrous sodium sulfate, the organic layer was filtered and concentrated. The resulting residue was washed with ethyl acetate to give 5-chloro-6-ethyl-3-{[4-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (103 mg).

Preparation Example 398

[0181] To a mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (2.64 g) and pyridine (30 mL), mesyl chloride (2.45 mL) was added under ice cooling. After stirring at room temperature for 5 hours, pyridine was distilled off under reduced pressure, and the resulting residue was partitioned using ethyl acetate and water. The resulting organic layer was washed with 10% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give a light brown syrup. To the light brown syrup, ethanol (60 mL) and THF (30 mL) were added, and then 10% palladium on carbon (0.7 g) was added and stirred at room temperature for 14 hours under 3 atmospheric pressure of hydrogen. After filtration through celite, the filtrate was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 100:0 to 40:1). The resulting crude product was washed with diisopropyl ether to give 3,5-di-chloro-6-isopropylpyrazine-2-carboxamide (632 mg) as a white solid.

Preparation Example 399

[0182] To a mixture of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (4.00 g) and methanol (50 mL), ammonium formate (10.2 g) and water (5 mL) were added and stirred for 1 hour until they were completely dissolved. Then, 10% palladium on carbon (2.0 g) was added and stirred at room temperature for 65 hours. After insoluble materials were separated by filtration through celite, the solvent was distilled off, and chloroform was added to the resulting residue, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to give tert-butyl (4-amino-1-methylcyclohexyl)carbamate (3.73 g) as a colorless syrup.

Preparation Example 400

[0183] To a mixture of tert-butyl (4-amino-1-methylcyclohexyl)carbamate (Preparation Example 399) (3.73 g) and ethanol (30 mL), 4M hydrogen chloride in ethyl acetate (30 mL) was added under ice cooling and stirred at room temperature for 20 hours. The precipitated solid was collected by filtration and washed with ethyl acetate to give 1-methylcyclohexane-1,4-diamino dihydrochloride (2.10 g) as a white solid.

Preparation Example 412

[0184] To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.16 g), 4-bromo-3-methoxy-1-nitrobenzene (2.63 g) and DMF (31.6 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.50 g) and potassium carbonate (4.24 g) were added and stirred at 80° C for 4 hours. After this mixture was concentrated under reduced pressure, water and ethyl acetate were added, and insoluble materials were filtered through celite. The organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate = 1:0 to 2:1) to give tert-butyl 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.21 g) as a yellow solid.

Preparation Example 413

[0185] To a mixture of tert-butyl 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (Preparation Example 412) (2.21 g), ethanol (40 mL) and THF (20 mL), 10% palladium on carbon (1.0 g) was added and stirred at room temperature for 3 hours under a hydrogen atmosphere at normal pressure. After filtration through celite, the filtrate was distilled off under reduced pressure to give tert-butyl 4-(4-amino-2-methoxy-phenyl)piperidine-1-carboxylate (1.97 g) as a gray solid.

Preparation Example 417

[0186] A mixture of 5-chloro-6-(1-hydroxy-1-methylethyl)-3-{[4-(4-methylpyrazin1-yl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 416) (430 mg) and acetic acid (10 mL) was stirred at 120°C for 5 hours. After the reaction liquid was cooled, the solvent was distilled off, and water and saturated aqueous sodium hydrogen carbonate were added to neutralize. After extraction with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was washed with diisopropyl ether to give 5-chloro-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (265 mg) as an orange solid.

Preparation Example 430

[0187] To a mixture of 7-nitro-2H-1,4-benzoxazine-3(4H)-one (2.0 g), benzyltriethylammonium chloride (470 mg), potassium carbonate (4.27 g) and acetonitrile (60 mL), 1-bromo-2-chloroethane (1.28 mL) was added and stirred at 75°C for 3 hours. After the reaction liquid was cooled, saturated aqueous sodium hydrogen carbonate was added, and the reaction liquid was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazine-3(4H)-one (1.92 g) as a yellow powder.

Preparation Example 432

[0188] To a mixture of 4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazine-3(4H)-one (Preparation Example 430) (1.08 g), potassium carbonate (0.87 g) and acetonitrile (10.8 mL), 1-methylpiperazine (1.39 mL) was added and stirred at 80°C for 48 hours. After the reaction liquid was cooled, saturated aqueous sodium hydrogen carbonate was added, and the reaction liquid was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 100:0 to 20:1) to give 4-[2-(4-methylpiperazin-1-yl)ethyl]-7-nitro-2H-1,4-benzoxazine-3(4H)-one (690 mg) as a yellow liquid.

Preparation Example 440

[0189] A mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (1.10 g), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)aniline (Preparation Example 436) (1.58 g), N,N-diisopropylethylamine (0.80 mL) and dioxane (31 mL) was stirred at 100°C for 135 hours. After cooling, water was added, followed by extraction with ethyl acetate. Further, insoluble materials were separated by filtration, and the insoluble materials were dissolved in methanol and thereafter mixed with the organic layer. The solvent was distilled off under reduced pressure, followed by drying to give a brown solid. A mixture of the brown solid and acetic acid (30 mL) was stirred at 120°C for 5 hours. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate was added, and the precipitated solid was collected by filtration and washed with water. The resulting solid was purified by basic silica gel column chromatography (eluent: chloroform) to give 5-chloro-6-isopropenyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide (0.99 g) as a yellow solid.

Preparation Example 444

[0190] After a mixture of palladium acetate (188 mg), 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine) (781 mg), cesium carbonate (4.09 g) and THF (20 mL) was stirred for 30 minutes, a mixture of 1-bromo-3-methoxy-5-nitrobenzene (1.94 g), 1-methylpiperazine (2.76 mL) and THF (20 mL) was added and heated under reflux for 14 hours. After cooling, the reaction liquid was diluted with ethyl acetate, and insoluble materials were separated by filtration. After extraction with 2M hydrochloric acid from the filtrate, the resulting aqueous layer was basified with 50% aqueous potassium hydroxide and then extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 100:0 to 20:1) to give 1-(3-methoxy-5-nitrophenyl)-4-methylpiperazine (1.01 g) as an orange syrup.

Preparation Example 454

[0191] To a mixture of tert-butyl 4-(4-amino-2-methoxy-phenyl)piperidine-1-carboxylate (Preparation Example 413) (4.25 g) and THF (100 mL), sodium hydrogen carbonate (1.28 g) and water (30 mL) were added, followed by dropwise addition of benzyl chloroformate (1.98 mL) under ice cooling and stirring overnight. After addition of water and extraction with ethyl acetate, the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate = 2:1) to give tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (4.92 g) as a colorless amorphous.

Preparation Example 455

[0192] A mixture of tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (Preparation Example 454) (4.92 g), trifluoroacetic acid (10 mL) and 1,2-dichloroethane (50 mL) was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure, and after addition of saturated aqueous sodium hydrogen carbonate, the residue was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was solidified by addition of diethyl ether to give benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate (3.24 g) as a white solid.

Preparation Example 464

[0193] To a mixture of benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate (Preparation Example 455) (1.52 g) and 1,2-dichloroethane (70 mL), formalin (3.62 mL) and sodium triacetoxyborohydride (1.42 g) were added and stirred overnight at room temperature. After addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform:methanol saturated aqueous ammonia = 100:0:0 to 10:1:0.1) to give benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (1.26 g) as a white solid.

Preparation Example 467

[0194] To a mixture of 7-amino-4-[3-(4-methylpiperazin-1-yl)propyl]-2H-1,4-benzoxazine-3(4H)-one (Preparation Example 435) (300 mg) and THF (9 mL), gradual dropwise addition of borane-tetrahydrofuran complex (3.0 mL, 1M THF solution) was conducted under ice cooling under an argon atmosphere. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour and further stirred at 70°C for 3 hours. After methanol (10 mL) was gradually added to the reaction liquid under ice cooling, 1M hydrochloric acid (5 mL) and thereafter 1M aqueous sodium hydroxide (10 mL) were added and stirred at room temperature for 1 hour. After dilution with water, the reaction liquid was extracted with ethyl acetate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; chloroform :methanol = 100:0 to 20:1) to give 4-[3-(4-methylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-7-amine (120 mg).

Preparation Example 468

[0195] To a mixture of benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (Preparation Example 464) (1.26 g), ethanol (20 mL) and THF (10 mL), 5% palladium on carbon (0.38 g) was added and stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. After filtration through celite, the filtrate was distilled off under reduced pressure to give 3-methoxy-4-(1-methylpiperidin-4-yl)aniline (0.80 g) as a light pink solid.

Preparation Example 472

[0196] To a mixture of 2-[methyl(3-nitrophenyl)amino]ethanol (780 mg) and dichloromethane (20 mL), triethylamine (0.66 mL) and mesyl chloride (0.37 mL) were added sequentially under ice cooling and stirred for 3 hours. Water was added to the reaction liquid, and the organic layer was separated and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (1.0 g) as a yellow solid.

Preparation Example 473

[0197] A mixture of 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (Preparation Example 472) (1.0 g), 1-methylpiperazine (1.61 mL) and NMP (5 mL) was reacted at 130°C for 30 minutes using a microwave reaction system. The reaction liquid was diluted with water, extracted with a mixed solvent of chloroform and methanol (10:1), and then washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia = 10:1:0.1) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-3-nitroaniline (890 mg) as a yellow oil.

Preparation Example 502

[0198] To a mixture of 8-(2-methoxy-5-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (Preparation Example 495) (795 mg) and dioxane (16 mL), 4M hydrochloric acid (6.8 mL) was added and stirred overnight at 80°C. The reaction liquid was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the concentrate. The concentrate was extracted with chloroform and then washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane) to give 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (296 mg).

Preparation Example 503

[0199] To a mixture of 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (Preparation Example 502) (296 mg), 1-methylpiperazine (0.20 mL) and 1,2-dichloroethane (11 mL), sodium triacetoxyborohydride (385 mg) was added and stirred overnight at room temperature. After addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol =100:0 to 10:1) to give 1-[1-(2-methoxy-5-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.40 g) as a brown oil.

Preparation Example 516

[0200] To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane (4.15 g) was added and stirred at 80°C for 20 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol =100:0 to 100:1) to give 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (5.13 g) as a yellow solid.

Preparation Example 545

[0201] To a mixture of 5-chloro-6-(2-hydroxypropan-2-yl)-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 544) (300 mg) and trifluoroacetic acid (3 mL), triethylsilane (0.55 mL) was added under ice cooling and stirred under ice cooling for 10 minutes and at room temperature for 22 hours. After the reaction liquid was concentrated, the residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 20:1:0.1) to give a crude product. The crude product was washed with diisopropyl ether to give 5-chloro-6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (219 mg) as an orange solid.

[0202] Tables 7 to 47 show the chemical structures of the compounds prepared in the above preparation examples, and the chemical structures of the compounds of preparation examples prepared by the same manner as shown in the above preparation examples using corresponding starting materials. Tables 48 to 84 show the preparation processes and physical and chemical data of these preparation examples compounds.

Example 4

[0203] A mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 294) (200 mg), 1-(aminomethyl)-N,N-dimethylcyclohexylamine (409 mg) and NMP (1 mL) was heated at 180°C for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated crystal was collected by filtration and washed with ethyl acetate to give a white solid. To the white solid, a mixed solvent of ethanol and water was added, heated and then cooled, and the precipitated solid was collected by filtration to give 2-({[1-(dimethylamino)cyclohexyl]methyl}amino)-4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (136 mg) as a white solid.

Example 19

[0204] A mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 294) (200 mg), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (1.12 g) and NMP (1 mL) was heated at 180°C for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 20:1) to give a white amorphous. To a mixture of the white amorphous, ethyl acetate (10 mL) and ethanol (5 mL), 4M hydrogen chloride in ethyl acetate (5 mL) was added under ice cooling and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration and dried to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-[(piperidin-2-ylmethyl)amino]-1,6-dihydropyrimidine-5-carboxamide hydrochloride (126 mg) as a white solid.

Example 29

[0205] To a mixture of tert-butyl 3-[(5-carbamoyl-4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-2-yl)amino]piperidine-1-carboxylate (Example 28) (299 mg) and ethyl acetate (3 mL), 4M hydrogen chloride in ethyl acetate (2.7 mL) was added under ice cooling and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide dihydrochloride (194 mg) as a white solid.

Example 31

[0206] To a mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide dihydrochloride (Example 29) (67 mg) and pyridine (1.3 mL), mesyl chloride (0.10 mL) was added under ice cooling and stirred for 1 hour. After ethanol was added to the reaction system, the reaction system was concentrated. The resulting residue was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate, and the organic layer was dried. The organic layer was concentrated, followed by an azeotropic process with toluene. The resulting residue was solidified with ethyl acetate-hexane. The resulting solid was recrystallized from ethanol to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-{[1-(methylsulfonyl)piperidin-3-yl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (43 mg).

Example 37

[0207] A mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 311) (234 mg), 1-(aminomethyl)cyclohexaneamine (172 mg) and NMP (2 mL) was stirred at 80°C for 30 minutes. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated solid was collected by filtration. This solid was heated with ethanol-water and washed to give 2-{[(1-aminocyclohexyl)methyl]amino}-4-{[3-(methylcarbamoyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (215 mg) as a white solid.

Example 84

[0208] A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 353) (150 mg), 1-(aminomethyl)cyclohexaneamine (163 mg) and NMP (1 mL) was heated at 180°C for 20 minutes using a microwave reaction system. The reaction liquid was cooled, and ethyl acetate and water were added and stirred for 30 minutes. Thereafter, the precipitated powder was collected by filtration. This powder was heated with ethanol-water (1:1) and washed to give 5-{[(1-aminocyclohexyl)methyl]amino}-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (112 mg) as a white solid.

Example 146

[0209] A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg), 3-chloro-4-methylsulfonylaniline (374 mg) and NMP (1 mL) was stirred at 230°C for 1 hour using a microwave reaction system. Thereafter, trans-4-aminocyclohexanol (524 mg) was added to the reaction liquid and stirred at 190°C for 30 minutes using a microwave reaction system. After cooling, the reaction liquid was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 10:0 to 30:1) to give a crude product. This product was heated with ethanol and washed to give a light yellow solid. To the light yellow solid, ethyl acetate was added and heated, and insoluble materials were separated by filtration and the filtrate was concentrated. After the filtrate was concentrated, the residue was heated and washed with ethanol to give 3-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (39 mg) as a light yellow solid.

Example 159

[0210] To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (298 mg), chloroform (40 mL) and acetonitrile (10 mL), N-chlorosuccinimide (108 mg) was added and stirred at 70°C for 8 hours. After the reaction liquid was cooled, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol = 10:0 to 10:1). The resulting crude product was solidified from chloroform and collected by filtration. The resulting solid was heated with ethyl acetate and washed with ethyl acetate to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{(3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (189 mg) as a white solid.

Example 181

[0211] To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL), N-bromosuccinimide (69 mg) was added and stirred at room temperature for 2 hours. To the reaction liquid, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol = 10:0 to 10:1). The resulting crudeproduct was solidified with ethyl acetate and washed with ethyl acetate to give 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (130 mg) as a light yellow solid.

Example 190

[0212] To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL), N-iodosuccinimide (87 mg) was added and stirred at room temperature for 2 hours. To the reaction liquid, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol = 10:0 to 10:1). The resulting crude product was solidified with ethyl acetate and washed with ethyl acetate to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-iodo-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (153 mg) as a light yellow solid.

Example 196

[0213] A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 353) (8.8 mg), 1-methyl-piperidin-3-ylamine (8.0 mg) and NMP (0.5 mL) was heated at 190°C for 30 minutes using a microwave reaction system. After the reaction liquid was cooled, the organic layer was distilled off under reduced pressure, and the residue was separated and purified by HPLC (column: SunFire® C18, 5 µm, 19 mm x 100 mm, solvent: MeOH/0.1% HCOOH-H₂O = 10/90 (0 min)-10/90 (1 min)-95/5 (9 min)-95/5 (12 min), flow rate: 25 mL/min) to give (6-ethyl-5-[(1-methylpiperidin-3-yl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (2.4 mg).

Example 302

[0214] To a mixture of 5-[(4-amino-4-methylcyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}-6-propylpyrazine-2-carboxamide (Example 301) (89 mg) and dichloromethane (5 mL), formalin (0.30 mL) and sodium triacetoxyborohydride (82 mg) were added and stirred at room temperature for 1.5 hours. After the reaction liquid was diluted with chloroform, it was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After the drying agent was separated by filtration, silica gel was added, and the solvent was distilled off, followed by purification of the residue by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia = 10:0:0 to 10:1:0.1). The resulting residue was washed with ethyl acetate to give 5-{[4-(dimethylamino)-4-methylcyclohexyl]amino}-3-{[3-(methylsulfonyl)phenyl]amino}-6-propylpyrazine-2-carboxamide (31 mg) as a light yellow solid.

Example 309

[0215] To a mixture of 6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-[(4-methyl-3-nitrophenyl)amino]pyrazine-2-carboxamide (Example 308) (242 mg) and methanol (10 mL), 5% palladium on carbon (25 mg) was added and stirred under a hydrogen atmosphere at room temperature for 4 hours. After filtration of the reaction liquid, the filtrate was concentrated under reduced pressure to give 3-[(3-amino-4-methylphenyl)amino]-6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]pyrazine-2-carboxamide (162 mg) as a green solid.

Example 310

[0216] To a mixture of 3-[(3-amino-4-methylphenyl)amino]-6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]pyrazine-2-carboxamide (Example 309) (150 mg), THF (2 mL) and DMF (2 mL), N,N-diisopropylethylamine (49 mg) and acrylic acid chloride (34 mg) were added under ice cooling and stirred for 30 minutes. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 3-{[3-(acryloylamino)-4-methylphenyl]amino}-6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]pyrazine-2-carboxamide (48 mg) as a light yellow powder.

Example 343

[0217] To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Example 342) (205 mg), ethanol (20 mL) and THF (10 mL), 10% palladium on carbon (100 mg) was added under a hydrogen atmosphere and stirred at room temperature for 18 hours. After the catalyst was separated by filtration, the solvent was distilled off, and the residue was purified by basic silica gel column chromatography (eluent: chloroform). The resulting yellow solid was washed with ethyl acetate to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (136 mg) as a yellow solid.

Example 381

[0218] To a mixture of tert-butyl 4-[4-({3-carbamoyl-5-ethyl-6-[(trans-4-hydroxycyclohexyl)amino]pyrazin-2-yl}amino)-2-methoxyphenyl]piperidine-1-carboxylate (Example 382) (270 mg) and ethyl acetate (10 mL), 4M hydrogen chloride in ethyl acetate (4 mL) was added under ice cooling and stirred at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate and chloroform were added to the residue. The precipitated solid was collected by filtration and dried to give 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(3-methoxy-4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide (85 mg) as a light yellow solid.

Example 405

[0219] To a mixture of 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide (Example 358) (43 mg) and dichloroethane (1 mL), pyridine (0.01 mL) and acetic anhydride (0.01 mL) were added under ice cooling and stirred at room temperature for 20 minutes. After addition of saturated aqueous sodium hydrogen carbonate, the reaction liquid was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the organic layer was concentrated, and the resulting residue was solidified with ethyl acetate-hexane to give 3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (26 mg) as a white solid.

Example 436

[0220] To a mixture of methyl 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylate (Example 435) (126 mg), THF (2 mL) and methanol (2 mL), 10 % aqueous sodium hydroxide (1 mL) was added and heated under reflux for 2 hours. To the reaction liquid, 10 % hydrochloric acid was added to give a pH of about 7, and the resulting solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 436) (47 mg), which was a low-polarity product, as a light yellow white powder and 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 437) (59 mg), which was a high-polarity product, as a light yellow powder.

Example 438

[0221] To a mixture of 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 436) (62 mg), o-anisidine (42 mg) and DMF (2 mL), 1-hydroxy-1H-benzotriazole monohydrate (46 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg) were added and stirred at room temperature for 7 hours. The reaction liquid was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 6-ethyl-5-({4-[(2-methoxy-phenyl)carbamoyl]cyclohexyl}amino)-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazine-2-carboxamide (33 mg) as a yellow powder.

Example 495

[0222] A mixture of 6-chloro-3-{[3-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-4-methoxyphenyl]amino}-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (Example 482) (0.80 g), acetic acid (4 mL) and water (4 mL) was stirred at 80°C for 3 hours. To the reaction liquid, concentrated hydrochloric acid (1 mL) was added and stirred at 80°C for 2 hours. The reaction liquid was cooled and concentrated under reduced pressure, and then chloroform was added, followed by washing with saturated aqueous sodium hydrogen carbonate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol = 10:1 to 30:1) to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (0.74 g) as a yellow amorphous.

Example 499

[0223] To a mixture of 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Example 495) (0.346 mg), N-methylpiperazine (0.12 mL) and 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (225 mg) was added and stirred at room temperature for 5 hours. After addition of saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia = 100:0:0 to 20:1:0.1) to give a crude product. The crude product was solidified with ethyl acetate-diisopropyl ether and then washed with ethyl acetate to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-methoxy-3-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (39 mg) as a light yellow solid.

Example 508

[0224] A mixture of 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 181) (50 mg), cyclopropylboronic acid (18 mg), tetrakistriphenylphosphine palladium (24 mg), potassium carbonate (71 mg), dioxane (2.5 mL) and water (0.5 mL) was stirred at 115°C overnight. After cooling, the reaction liquid was partitioned using chloroform, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying, the organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia = 100:0:0 to 10:1:0.1). The resulting residue was solidified with ethyl acetate-hexane to give 6-cyclopropyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (10 mg) as a yellow solid.

Example 534

[0225] To a mixture of 5-[(1-benzylpiperidin-4-yl)amino]-6-ethyl-3-({3-methyl-4-[4(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (Example 507) (1.31 g), ethanol (26 mL) and acetic acid (13 mL), palladium hydroxide (0.65 g) was added and stirred under a hydrogen atmosphere at room temperature for 3 days. After the catalyst was separated by filtration, the solvent was concentrated and partitioned using chloroform and saturated aqueous sodium hydrogen carbonate. The organic layer was concentrated to give 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-ylamino)pyrazine-2-carboxamide (0.73 g) as a light yellow solid.

[0226] Tables 85 to 164 show the chemical structures of the compounds prepared in the above examples, and the chemical structures of the examples compounds prepared by the same manner as shown in the above examples using corresponding starting materials. Tables 165 to 183 show the preparation processes and physical and chemical data of these examples compounds.

[Table 7]

Rex	Structure	Rex	Structure
1		8
2		9
3		10
4		11
5		12
6		13
7		14

[Table 8]

Rex	Structure	Rex	Structure
15		22
16		23
17		24
18		25
19		26
20		27
21		28

[Table 9]

Rex	Structure	Rex	Structure
29		36
30		37
31		38
32		39
33		40
34		41
35		42

[Table 10]

Rex	Structure	Rex	Structure
43		50
44		51
45		52
46		53
47		54
48		55
49		56

[Table 11]

Rex	Structure	Rex	Structure
57		64
58		65
59		66
60		67
61		68
62		69
63		70

[Table 12]

Rex	Structure	Rex	Structure
71		78
72		79
73		80
74		81
75		82
76		83
77		84

[Table 13]

Rex	Structure	Rex	Structure
85		92
86		93
87		94
88		95
89		96
90		97
91		98

[Table 14]

Rex	Structure	Rex	Structure
99		106
100		107
101		108
102		109
103		110
104		111
105		112

[Table 15]

Rex	Structure	Rex	Structure
113		120
114		121
115		122
116		123
117		124
118		125
119		126

[Table 16]

Rex	Structure	Rex	Structure
127		134
128		135
129		136
130		137
131		138
132		139
133		140

[Table 17]

Rex	Structure	Rex	Structure
141		148
142		149
143		150
144		151
145		152
146		153
147		154

[Table 18]

Rex	Structure	Rex	Structure
155		162
156		163
157		164
158		165
159		166
160		167
161		168

[Table 19]

Rex	Structure	Rex	Structure
169		176
170		177
171		178
172		179
173		180
174		181
175		182

[Table 20]

Rex	Structure	Rex	Structure
183		190
184		191
185		192
186		193
187		194
188		195
189		196

[Table 21]

Rex	Structure	Rex	Structure
197		204
198		205
199		206
200		207
201		208
202		209
203		210

[Table 22]

Rex	Structure	Rex	Structure
211		218
212		219
213		220
214		221
215		222
216		223
217		224

[Table 23]

Rex	Structure	Rex	Structure
225		232
226		233
227		234
228		235
229		236
230		237
231		238

[Table 24]

Rex	Structure	Rex	Structure
239		246 *1
240		247 *2
241		248 *1
242		249 *2
243		250 *3
244		251 *4
245		252 *3

[Table 25]

Rex	Structure	Rex	Structure
253 *4		260
254		261
255		262
256		263
257		264
258		265
259		266

[Table 26]

Rex	Structure	Rex	Structure
267		274
268		275
269		276
270		277
271		278
272		279
273		280

[Table 27]

Rex	Structure	Rex	Structure
281		288
282		289
283		290
284		291
285		292
286		293
287		294

[Table 28]

Rex	Structure	Rex	Structure
295		302
296		303
297		304
298		305
299		306
300		307
301		308

[Table 29]

Rex	Structure	Rex	Structure
309		317
310		318
311		319
312		320
313		321
314		322
315		323
316		324

[Table 30]

Rex	Structure	Rex	Structure
325		333
326		334
327		335
328		336
329		337
330		338
331		339
332		340

[Table 31]

Rex	Structure	Rex	Structure
341		348
342		349
343		350
344		351
345		352
346		353
347		354

[Table 32]

Rex	Structure	Rex	Structure
355		363
356		364
357		365
358		366
359		367
360		368
361		369
362		370

[Table 33]

Rex	Structure	Rex	Structure
371		379
372		380
373		381
374		382
375		383
376		384
377		385
378		386

[Table 34]

Rex	Structure	Rex	Structure
387		395
388		396
389		397
390		398
391		399
392		400
393		401
394		402

[Table 35]

Rex	Structure	Rex	Structure
403		411
404		412
405		413
406		414
407		415
408		416
409		417
410		418

[Table 36]

Rex	Structure	Rex	Structure
419		426
420		427
421		428
422		429
423		430
424		431
425		432

[Table 37]

Rex	Structure	Rex	Structure
433		440
434		441
435		442
436		443
437		444
438		445
439		446

[Table 38]

Rex	Structure	Rex	Structure
447		454
448		455
449		456
450		457
451		458
452		459
453		460

[Table 39]

Rex	Structure	Rex	Structure
461		468
462		469
463		470
464		471
465		472
466		473
467		474

[Table 40]

Rex	Structure	Rex	Structure
475		482
476		483
477		484
478		485
479		486
480		487
481		488

[Table 41]

Rex	Structure	Rex	Structure
489		496
490		497
491		498
492		499
493		500
494		501
495		502

[Table 42]

Rex	Structure	Rex	Structure
503		509
504		510
505		511
506		512
507		513
508		514

[Table 43]

Rex	Structure	Rex	Structure
515		521
516		522
517		523
518		524
519		525
520		526

[Table 44]

Rex	Structure	Rex	Structure
527		532
528		533
529		534
530		535
531		536

[Table 45]

Rex	Structure	Rex	Structure
537		542
538		543
539		544
540		545
541		546

[Table 46]

Rex	Structure	Rex	Structure
547		552
548		553
549		554
550		555
551		556

[Table 47]

Rex	Structure
557
558
559
560
561
562

[Table 48]

Rex	Syn	Data
1	Rex299	ESI-: 402
2	Rex298	ESI-: 420
3	Rex292	1H-NMR (CDCl3): 1.11 (3H, br-s), 1.21 (3H, br-s), 2.17 (3H, s), 3.28 (2H, br-s), 3.51 (2H, br-s), 3.66 (2H, br-s), 6.66-6.68 (2H, m), 7.03 (1H, dd, J = 0.8Hz, 8.0Hz).
4	Rex4	EI: 236
5	Rex299	ESI-: 388
6	Rex298	ESI-: 406
7	Rex292	1H-NMR (CDCl3): 1.50-1.65 (6H, m), 2.16 (3H, s), 3.36 (2H, br-s), 3.71 (4H, m), 6.66-6.69 (2H, m), 7.02 (1H, d, J = 7.6Hz).
8	Rex4	EI: 248
9	Rex299	1H-NMR (DMSO-d6): 1.48-1.59 (6H, m), 2.30 (3H, s), 2.41 (3H, s), 3.33 (2H, br-s), 3.54 (2H, br-s), 7.02 (1H, dd, J = 1.2Hz, 8.0Hz),7.28 (1H, d, J = 8.0Hz), 7.47 (1H, d, J = 4.0Hz), 7.99 (1H, d, J = 1.2Hz), 9.16 (1H, d, J = 4.4Hz), 12.68 (1H, s), 12.84 (1H, s).
10	Rex298	ESI-: 418
11	Rex292	1H-NMR (CDCl3): 1.24 (6H, d, J = 6.8Hz), 2.19 (3H, s), 3.70 (2H, br-s), 4.23-4.29 (1H, m), 5.85 (1H, br-s), 6.97 (1H, dd, J = 1.6Hz, 7.6Hz), 7.06 (1H, d, J = 7.6Hz), 7.13(1H, d, J = 1.6Hz).
12	Rex4	1H-NMR (CDCl3): 1.29 (6H, d, J = 6.4Hz), 2.65 (3H, s), 4.25-4.34 (1H, m), 5.99 (1H, br-s), 7.42 (1H, d, J = 8.0Hz), 7.94 (1H, dd, d = 2.0Hz, 8.0Hz), 8.30 (1H, d, J = 1.6Hz).

[Table 49]

Rex	Syn	Data
13	Rex299	1H-NMR (DMSO-d6): 1.14 (6H, d, J = 6.4Hz), 2.31 (3H, s), 2.43 (3H, s), 4.06-4.11 (1H, m), 7.31 (1H, d, J = 8.0Hz), 7.47 (1H, d, J = 4.4Hz), 7.54 (1H, dd, J = 1.6Hz, 8.0Hz), 8.14 (1H, d, J = 7.6Hz), 8.47 (1H, d, J = 1.6Hz), 9.17 (1H, d, J = 4.4Hz), 12.69 (1H, s), 12.84 (1H, s).
14	Rex298	ESI-: 392
15	Rex299	1H-NMR (DMSO-d6): 2.31 (3H, s), 2.44 (3H, s), 2.76 (3H, d, J = 4.4Hz), 7.31 (1H, d, J = 8.0Hz), 7.47 (1H, d, J = 4.4Hz), 7.52 (1H, dd, J = 1.6Hz, 8.0Hz), 8.36 (1H, d, J = 4.8Hz), 8.49 (1H, d, J = 1.6Hz), 9.19 (1H, d, J = 4.4Hz), 12.70 (1H, s), 12.85 (1H, s).
16	Rex298	ESI-: 364
17	Rex299	ESI-: 424
18	Rex298	ESI-: 442
19	Rex299	ESI-: 436
20	Rex298	ESI-: 454
21	Rex292	1H-NMR (CDCl3): 3.00 (3H, d, J = 4.9Hz), 3.94 (2H, m), 6.44 (1H, m), 6.58 (1H, dd, J = 2.4Hz, 8.5Hz), 6.64 (1H, d, J = 2.4Hz), 7.67 (1H, d, J = 8.5Hz).
22	Rex4	1H-NMR (CDCl3): 3.07 (3H, d, J = 4.9Hz), 6.15 (1H, m), 7.82 (1H, d, J = 8.3Hz), 8.17 (1H, dd, J = 2.2Hz, 8.3Hz),8.29 (1H, d, J = 2.2Hz).
23	Rex299	ESI-: 366
24	Rex298	ESI-: 384
25	Rex292	1H-NMR (CDCl3): 1.05 (3H, t, J = 7.1Hz), 1.24 (3H, t, J = 7.1Hz), 3.18 (2H, q, J = 7.1Hz), 3.35 (1H, m), 3.83 (3H, m), 6.56 (1H, dd, J = 2.2Hz, 8.1Hz), 6.67 (1H, d, J = 2.2Hz), 7.03 (1H, d, J = 8.1Hz).

[Table 50]

Rex	Syn	Data
26	Rex4	1H-NMR (CDCl3): 1.09(3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1Hz), 3.06-3.21 (2H, m), 3.35-3.44 (1H, m), 3.76-3.85 (1H, m), 7.74 (1H, d, J = 8.3Hz), 8.18 (1H, dd, J = 2.2Hz, 8.3Hz), 8.29 (1H, d, J = 2.2Hz).
27	Rex299	ESI-: 408
28	Rex298	ESI-: 426
29	Rex292	1H-NMR (CDCl3): 1.08 (6H, d, J = 6.4Hz), 2.21 (1H, s), 3.40-3.47 (1H, m), 4.21 (1H, d, J = 6.8Hz), 7.14-7.18 (1H, m).
30	Rex299	1H-NMR (DMSO-d6): 0.86-0.96(6H, m), 2.43 (1H, s), 3.15-3.20 (1H, m), 3.35 (3H, s), 7.43-7.70 (4H, m), 8.23 (1H, s), 9.18 (1H, s), 12.79 (1H, s), 13.06(1H, s).
31	Rex298	ESI-: 428
32	Rex299	1H-NMR (DMSO-d6): 2.32-2.54 (9H, m), 7.33-7.70 (4H, m), 8.52 (1H, s), 9.18 (1H, s), 12.81 (1H, s), 13.09 (1H, s).
33	Rex298	ESI-: 400
34	Rex299	1H-NMR (DMSO-d6): 1.45-1.59 (6H, m), 2.54 (3H, s), 3.12 (2H, m), 3.56-3.63 (2H, m), 7.28-7.30 (1H, m), 7.38-7.41 (1H, m), 7.58-7.59 (1H, m), 7.99-7.99 (1H, m), 9.16-9.17 (1H, m), 12.85 (1H, br-s), 13.13 (1H, br-s).
35	Rex298	ESI-: 438
36	Rex292	1H-NMR (CDCl3): 1.25 (6H, d,J = 6.6Hz), 3.94 (2H, m), 4.20-4.32 (1H, m), 6.22 (1H, m), 6.55-6.58 (1H, m), 6.63 (1H, d, J = 2.2Hz), 7.61 (1H, dd, J = 1.2Hz, 8.3Hz).

[Table 51]

Rex	Syn	Data
37	Rex4	1H-NMR (CDCl3): 1.30 (6H, d,J = 6.6Hz), 4.28-4.36 (1H, m), 5.90 (1H, m), 7.78 (1H, d, J = 8.5Hz), 8.16 (1H, dd, J = 2.2Hz, 8.3Hz), 8.28 (1H, d, J = 2.2Hz).
38	Rex299	1H-NMR(DMSO-d6): 1.14 (6H, d, J = 6.6Hz), 2.56 (3H, s), 4.01-4.02 (1H, m), 7.36-7.37 (2H, m), 7.58-7.59 (1H, m), 7.94-7.95 (1H, m), 8.24-8.26 (1H, m), 9.17 (1H, m), 12.85 (1H, br-s), 13.14 (1H, br-s).
39	Rex298	ESI-: 412
40	Rex292	1H-NMR (CDCl3): 1.43-1.50 (2H, m), 1.57-1.63 (4H, m), 3.11-3.13 (4H, m), 3.84 (1H, s), 6.16-6.25 (2H, m), 7.62-7.66 (1H, m).
41	Rex41	1H-NMR (CDCl3): 1.54-1.63 (6H, m), 3.25 (4H, t, J = 5.6Hz), 4.04 (1H, s), 7.83 (1H, d, J = 0.2Hz), 7.88 (1H, dd, J = 0.2Hz, 8.8Hz), 8.07 (1H, d,J = 8.8Hz).
42	Rex299	ESI-: 452
43	Rex298	1H-NMR (DMSO-d6): 1.44-1.50 (6H, m), 3.30-3.04 (4H, m), 3.10 (1H, s), 3.85 (1H, s), 7.46-7.48 (1H, m), 7.55-7.56 (1H, m), 7.64-7.66 (1H, m), 7.93 (1H, br-s), 9.53 (1H, br-s).
44	Rex292	1H-NMR (CDCl3): 1.09 (6H, t, J = 7.2Hz), 2.28 (4H, q, J = 7.2Hz), 3.84 (1H, s), 6.17-6.23 (2H, m), 7.67-7.71 (1 H, m).
45	Rex41	1H-NMR (CDCl3): 1.13 (6H, t, J = 7.2Hz), 3.37 (4H, q, J = 7.2Hz), 4.04 (3H, s), 7.82 (1H, d, J = 2.8Hz), 7.87 (1H, dd, J = 2.8Hz, 8.8Hz), 8.12 (1H, d, J = 8.8Hz).
46	Rex299	ESI-: 440
47	Rex298	ESI-: 458

[Table 52]

Rex	Syn	Data
48	Rex48	1H-NMR (CDCl3): 1.26 (6H, d, J = 6.4Hz), 3.66 (2H, br-s), 4.25-4.31 (1H, m), 6.57 (1H, br-s), 6.69-6.73 (1H, m), 6.89 (1H, dd, J = 8.4Hz, 11.6Hz), 7.35 (1H, dd, J = 3.2Hz, 6.8Hz).
49	Rex299	1H-NMR (DMSO-d6): 1.14 (6H, d,J = 6.4Hz), 2.39 (3H, s), 4.01-4.06 (1H, m), 7.24 (1H, t, J = 9.2Hz), 7.49-7.53 (2H, m), 7.88 (1H, dd, J = 2.8Hz, 6.4Hz), 8.18 (1H, d, J = 8.0Hz), 9.16 (1H, d, J = 4.4Hz), 12.74 (1H, s), 12.96 (1H, s).
50	Rex298	1H-NMR (DMSO-d6): 1.14 (6H, d, J = 6.8Hz), 2.41 (3H, S), 4.01-4.07 (1H, m), 7.24 (1H, t, J = 9.2Hz), 7.62-7.66 (1H, m), 7.82-7.84 (1H, m), 7.87 (1H, s), 8.14 (1H, s), 8.15 (1H, m), 9.38 (1H, s).
51	Rex48	1H-NMR (CDCl3): 1.50-1.65 (6H, m), 3.28 (2H, br-s), 3.63 (2H, br-s), 3.71 (2H, br-s), 6.61-6.65 (2H, m), 6.86 (1H, t, J = 7.6Hz).
52	Rex299	1H-NMR (DMSO-d6): 1.44-1.61 (6H, m), 2.45 (3H, s), 3.21 (2H, br-s), 3.59 (2H, br-s), 7.26 (1H, t, J = 8.8Hz), 7.49-7.53 (2H, m), 7.63 (1 H, dd, J = 2.4Hz, 6.4Hz), 9.14 (1H, d, J = 4.4Hz), 12.72 (1H, s), 12.89 (1H, s).
53	Rex298	1H-NMR (DMSO-d6): 1.45-1.62 (6H, m), 2.33 (3H, s), 3.22 (2H, m), 3.59 (2H, br-s), 7.26 (1H, t, J = 8.8Hz), 7.57-7.62 (2H, m), 7.86 (1H, s), 8.13 (1H, s), 9.35 (1H, s).
54	Rex299	1H-NMR (DMSO-d6): 2.45 (3H, s), 3.26 (2H, br-s), 3.53 (2H, t, J = 4.8Hz), 3.63 (4H, br-s), 7.28 (1H, t, J = 8.8Hz), 7.51-7.57 (2H, m), 7.65 (1H, dd, J = 2.8Hz, 6.0Hz), 9.14 (1H, d, J = 4.4Hz), 12.73 (1H, s), 12.89 (1H, s).

[Table 53]

Rex	Syn	Data
55	Rex298	1H-NMR (DMSO-d6): 2.41 (3H, s), 3.27 (2H, m), 3.54 (2H, t, J = 4.8H), 3.64 (4H, br-s), 7.28 (1H, t, J = 8.8Hz), 7.61-7.64 (2H, m), 7.88 (1H, br-s), 8.14 (1H, br-s), 9.38 (1H, s).
56	Rex292	1H-NMR (CDC3): 1.08 (3H, t, J = 7.2Hz), 1.23 (3H, t, J = 7.2Hz), 3.24 (2H, q, J = 7.2Hz), 3.55 (2H, m), 3.70 (2H, br-s), 6.56 (1H, dd, J = 3.2Hz, 5.6Hz), 6.62 (1H, m), 6.85 (1H, t, J = 8.8Hz).
57	Rex299	1H-NMR (DMSO-d6): 1.01 (3H, t, J = 7.2Hz), 1.13 (3H, t, J = 7.2Hz), 2.45 (3H, s), 3.17 (2H, q, J = 7.2Hz), 3.44 (2H, m), 7.26 (1 H, t, J = 8.8Hz), 7.46 (1H, m), 7.52 (1H, d, J = 4.4Hz), 7.67 (1H, dd, J = 2.8Hz, 6.0Hz), 9.15 (1H, d, J = 4.4Hz), 12.73 (1H, s), 12.94 (1H, s).
58	Rex298	1H-NMR (DMSO-d6): 1.02 (3H, t, J = 7.2Hz), 1.13 (3H, t, J = 7.2Hz), 2.40 (3H, s), 3.18 (2H, q, J = 7.2Hz), 3.45 (2H, q, J = 7.2Hz), 7.27 (1H, t, J = 9.2Hz), 7.58-7.61 (2H, m), 7.87 (1H, br-s), 8.14 (1H, br-s), 9.35 (1H, s).
59	Rex292	1H-NMR (CDCl3): 1.05 (6H, d, J = 6.4Hz), 3.27-3.49 (1H, m), 3.90 (1H, s), 4.55 (1H, d, J = 6.4Hz), 6.62-6.28 (2H, m), 7.65-7.69 (1H, m).
60	Rex41	1H-NMR (CDCl3): 1.08 (6H, t, J = 6.8Hz), 3.48 (1H, q, J = 7.6Hz), 4.11 (1H, s), 4.75 (1H, d, J = 7.6Hz), 7.88 (1H, d, J = 2.0Hz), 7.94 (1H, dd, J = 2.0Hz, 8.4Hz), 8.12 (1H, d, J = 8.4Hz).
61	Rex299	1H-NMR (DMSO-d6): 0.94-0.99 (6H, m), 3.18-3.24 (1H, m), 2.49 (1H, s), 3.92 (1H, s), 7.06-7.08 (1H, m), 7.20-7.23 (1H, m), 7.39-7.40 (1H, m), 7.61-7.69 (2H, m), 9.20 (1H, br-s), 12.88 (1H, br-s), 13.28 (1H, br-s).

[Table 54]

Rex	Syn	Data
62	Rex298	ESI-: 444
63	Rex292	1H-NMR (CDCl3): 1.40-1.46 (2H, m), 1.62-1.67 (4H, m), 2.96-2.99 (4H, m), 3.97 (1H, br-s), 7.06-7.10 (2H, m), 7.15-7.18 (1H, m).
64	Rex41	1H-NMR (CDCl3): 1.45-1.71 (7H, m), 3.06 (4H, t, J = 5.6Hz), 7.46-7.52 (1H, m), 8.00-8.04 (1H, m), 8.43-8.46 (1H, m).
65	Rex299	ESI-: 440
66	Rex298	1H-NMR (DMSO-d6): 1.31-1.38 (4H, m), 1.51-1.55 (7H, m), 2.44 (1H, s), 2.83-2.92 (7H, m), 7.56-7.58 (2H, m), 8.14-8.26 (3H, m), 9.77 (1H, br-s).
67	Rex292	1H-NMR (CDCl3): 1.43-1.45 (2H, m), 1.64 (4H, m), 2.22 (1H, s), 3.21 (2H, m), 3.66-3.76 (4H, m), 6.48-6.51 (2H, m), 6.94 (1H, d, J = 8.0Hz).
68	Rex4	1H-NMR (CDCl3): 1.43-1.87 (6H, m), 2.42 (3H, s), 3.13-3.15 (2H, m), 3.69-3.83 (2H, m), 7.32 (1H, d, J = 8.4Hz), 8.07-8.11 (2H, m).
69	Rex299	ESI-: 400
70	Rex298	ESI-: 418
71	Rex292	1H-NMR (CD3OD): 2.23 (3H, s), 2.84 (3H, s), 6.50-6.55 (2H, m), 7.14 (1H, d, J = 8.4Hz).
72	Rex4	1H-NMR (CDCl3): 2.54 (3H, s), 3.04 (3H, d, J = 4.8Hz), 5.80 (1H, br-s), 7.49 (1H, d, J = 8.4Hz), 8.04-8.12 (1H,m).
73	Rex299	ESI-: 346
74	Rex298	ESI-: 364
75	Rex292	1H-NMR (CDCl3): 1.54-1.62 (6H, m), 3.20-3.23 (2H, m), 3.62-3.64 (1H, m), 3.77 (5H, m), 6.20 (1H, d, J = 2.0Hz), 6.27 (1H, dd, J = 2.0Hz, 8.1Hz), 7.02 (1H, d, J = 8.1Hz).
76	Rex299	ESI-: 416

[Table 55]

Rex	Syn	Data
77	Rex298	ESI-: 434
78	Rex292	1H-NMR (CDCl3): 1.45-1.47 (2H, m), 1.65 (4H, m), 2.17 (3H, s), 3.18-3.21 (2H, m), 3.59-3.66 (3H, m), 3.78-3.82 (1H, m), 6.49 (1H, d, J = 2.7Hz), 6.60 (1H, dd, J = 2.7Hz, 8.3Hz), 6.97 (1H, d, J = 8.3Hz).
79	Rex4	1H-NMR (CDCl3): 1.48-1.54 (2H, m), 1.70 (4H, m), 2.42 (3H, s), 3.16-3.20 (2H, m), 3.73-3.80 (2H, m), 7.39 (1H, d, J = 8.5Hz), 8.05 (1H, d, J = 2.2Hz), 8.12 (1H, dd, J = 2.2Hz,8.5Hz).
80	Rex299	ESI-: 400
81	Rex298	ESI-: 418
82	Rex292	1H-NMR (CDCl3): 2.31 (3H, s), 2.98 (3H, d, J = 4.9Hz), 3.60 (2H, m), 5.69 (1H, m), 6.64 (1H, dd, J = 2.7Hz, 8.1Hz), 6.70 (1H, d, J = 2.7Hz), 6.98 (1H, d, J = 8.1 Hz).
83	Rex299	ESI-: 346
84	Rex298	ESI-: 364
85	Rex48	1H-NMR (CDCl3): 2.97 (3H, d, J = 4.8Hz), 4.03 (2H, br-s), 5.76 (1H, br-s), 6.77 (1H, dd, J = 2.4Hz, 8.0Hz), 6.90 (1H, d, J = 2.4Hz), 7.33 (1H, d, J = 8.0Hz).
86	Rex299	1H-NMR (DMSO-d6): 2.51 (3H, s), 2.73 (3H, d, J = 4.4Hz), 7.48 (1H, d, J = 8.4Hz), 7.63-7.65 (2H, m), 8.22 (1H, d, J = 1.6Hz), 8.38 (1H, d, J = 4.8Hz), 9.18 (1H, d, J = 4.4Hz), 12.89 (1H, s), 13.27 (1H, s).
87	Rex298	1H-NMR (DMSO-d6): 2.45 (3H, s), 2.73 (3H, d, J = 4.8Hz), 7.48 (1H, d, J = 8.4Hz), 7.88 (1H, d, J = 8.8Hz), 7.89 (1H, s), 8.12 (1H, d, J = 2.0Hz), 8.17 (1H, s), 8.38 (1H, m), 9.62 (1H, s).

[Table 56]

Rex	Syn	Data
88	Rex48	1H-NMR (CDCl3): 3.01 (3H, dd, J = 1.2Hz, 5.2Hz), 3.69 (2H, br-s), 6.70-6.74 (1H, m), 6.77 (1H, br-s), 6.90 (1H, dd, J = 8.4Hz, 11.6Hz), 7.38 (1H, dd, J = 3.2Hz, 6.4Hz).
89	Rex299	1H-NMR (DMSO-d6): 2.49 (3H, s), 2.77 (3H, d, J = 4.4Hz), 7.26 (1H, t, J = 8.8Hz), 7.53-7.58 (2H, m), 7.95 (1H, dd, J = 2.8Hz, 6.4Hz), 8.24 (1H, br-s), 9.16 (1H, d, J = 4.4Hz), 12.75 (1H, s), 12.96 (1H, s).
90	Rex298	1H-NMR (DMSO-d6): 2.40 (3H, s), 2.77 (3H, d, J = 4.8Hz), 7.26 (1H, t, J = 10.0Hz), 7.64-7.68 (1H, m), 7.87 (1H, br-s), 7.92 (1H, dd, J = 2.4Hz, 6.4Hz), 8.14 (1H, br-s), 8.21 (1H, br-s), 9.39 (1H, br-s).
91	Rex292	1H-NMR (CDCl3): 2.55 (3H, s), 3.91 (3H, s), 6.22-6.30 (2H, m), 7.65-7.69 (1H, m).
92	Rex41	1H-NMR (CDCl3): 2.66 (3H, d, J = 5.2Hz), 4.11 (3H, s), 4.84 (1H, d, J = 5.2Hz), 7.89 (1H, d, J = 2.0Hz), 7.94 (1H, dd, J = 2.0Hz, 8.8Hz), 8.12 (1H, d, J = 8.8Hz).
93	Rex299	ESI-: 398
94	Rex298	ESI-: 416
95	Rex292	1H-NMR (CDCl3): 2.97 (3H, d, J = 4.6Hz), 3.90 (3H, s), 3.96 (2H, m), 6.20 (1H, d, J = 2.2Hz), 6.34 (1H, dd, J = 2.2Hz, 8.5Hz), 7.66 (1 H, m), 8.04 (1H, d, J = 8.5Hz).
96	Rex4	1H-NMR (CDCl3): 3.04 (3H, d, J = 4.9Hz), 4.09 (3H, s), 7.74 (1H, m), 7.84 (1H, d, J = 2.2Hz), 7.93 (1H, dd, J = 2.2Hz, 8.5Hz), 8.39 (1H, d, J = 8.5Hz).
97	Rex299	ESI-: 362

[Table 57]

Rex	Syn	Data
98	Rex298	ESI-: 380
99	Rex48	1H-NMR (CDCl3): 0.83-0.88 (1H, m), 1.42-1.65 (5H, m), 3.15 (2H, dd, J = 9.2Hz, 15.2Hz), 3.64-3.76 (2H, m), 4.01 (2H, br-s), 6.78 (1H, dd, J = 2.4Hz, 8.4Hz), 6.90 (1H, d, J = 2.8Hz), 7.05 (1H, d, J = 8.4Hz).
100	Rex299	1H-NMR (DMSO-d6): 1.37-1.59 (6H, m), 2.54 (3H, s), 3.06-3.11 (2H, m), 3.51-3.62 (2H, m), 7.40 (1H, d, J = 8.4Hz), 7.61-7.66 (2H, m), 8.27 (1H, d, J = 2.0Hz), 9.18 (1H, d, J = 4.0Hz), 12.89 (1H, s), 13.28 (1H, s).
101	Rex298	1H-NMR (DMSO-d6): 1.37-1.59 (6H, m), 2.45 (3H, s), 3.06-3.11 (2H, m), 3.52-3.62 (2H, m), 7.40 (1H, d, J = 8.0Hz), 7.90 (1H, br-s), 7.92 (1H, m), 8.16 (1H, br-s), 8.19 (1H, d, J = 2.0Hz), 9.62 (1H, s).
102	Rex353	ESI-: 346
103	Rex353	ESI-: 454
104	Rex353	ESI-: 346
105	Rex353	ESI-: 346
106	Rex299	1H-NMR (DMSO-d6): 2.53 (3H, s), 2.72 (3H, d, J = 4.4Hz), 7.41 (1H, d, J = 8.8Hz), 7.48-7.56 (2H, m), 8.36 (1H, d, J = 4.6Hz), 9.16 (1H, d, J = 3.7Hz), 12.80 (1H, s), 13.10 (1H, s).
107	Rex298	1H-NMR (DMSO-d6): 2.43 (3H, s), 2.73 (3H, d, J = 4.6Hz), 7.41 (1H, d, J = 8.5Hz), 7.65 (1H, dd, J = 2.7Hz, 8.8Hz), 7.77 (1H, d, J = 2.4Hz), 7.88 (1H, s), 8.14 (1H, s), 8.35 (1 H, d, J = 4.6Hz), 9.43 (1H, s).

[Table 58]

Rex	Syn	Data
108	Rex353	1H-NMR (CDCl3): 1.29 (3H, t, J = 7.6Hz), 2.87 (2H, q, J = 7.3Hz), 3.04 (3H, s), 5.56 (1H, br-s), 6.25 (1H, br-s), 7.34 (1H, d, J = 8.8Hz), 7.74 (1H, br-), 7.81 (1H, dd, J = 2.9Hz, 8.8Hz), 7.93 (1H, d, J = 2.7Hz), 10.95 (1H, br-s).
109	Rex353	1H-NMR (CDCl3): 1.31 (3H, t, J = 7.6Hz), 2.89 (2H, q, J = 7.3Hz), 3.03 (3H, d, J = 4.9Hz), 4.04 (3H, s), 5.53 (1H, br-s), 6.12 (1H, br-s), 7.28 (1H, m), 7.49 (1H, s), 7.74 (1H, br-s), 8.58 (1H, d, J = 8.3Hz), 11.43 (1H, br-s).
110	Rex292	1H-NMR (CDCl3): 2.18 (3H, s), 2.98 (3H, d, J = 4.9Hz), 3.88 (2H, m), 5.97 (1H, m), 6.64 (1H, d, J = 8.1 Hz), 7.44 (1H, dd, J = 2.0Hz, 8.3Hz), 7.51 (1H, m).
111	Rex4	1H-NMR (CDCl3): 2.64(3H, s), 3.05 (3H, d, J = 4.9H), 6.17 (1H, m), 7.67 (1H, dd, J = 2.0Hz, 8.3Hz), 7.76 (1H, d, J = 2.0Hz), 8.00 (1H, d, J = 8.3Hz).
112	Rex353	ESI-: 346
113	Rex353	ESI-: 400
114	Rex292	1H-NMR (CDCl3): 2.21 (3H, s), 2.99 (3H, d, J = 4.9Hz), 3.70 (2H, m), 5.72 (1H, m), 6.71-6.77 (2H, m), 7.00-7.04 (1H, m).
115	Rex353	1H-NMR (CDCl3): 1.30 (3H, t, J = 7.3Hz), 2.42 (3H, s), 2.87 (2H, q, J = 7.3Hz), 3.02 (3H, d, J = 4.9Hz), 5.50 (1H, m), 5.75 (1H, m), 7.09-7.11 (1H, m), 7.75 (1H, m), 8.16-8.18 (1H, m), 10.74 (1H, m).
116	Rex353	ESI-: 366
117	Rex353	ESI-: 325

[Table 59]

Rex	Syn	Data
118	Rex292	1H-NMR (CDCl3): 2.98 (3H, d, J = 4.9Hz), 3.85 (2H, br-s), 6.06 (1H, br-s), 6.98-7.01 (2H, m), 7.25-7.29 (1H, m).
119	Rex353	1H-NMR (CDCl3): 1.31 (3H, t, J = 7.6Hz), 2.92 (2H, q, J = 7.3Hz), 3.05 (3H, d, J = 4.9Hz), 5.57 (1H, br-s), 6.13 (1H, br-s), 7.18 (1H, m), 7.52 (1H, m), 7.73 (1H, s), 8.87 (1H, d, J = 8.5Hz), 11.15 (1H, br-s).
120	Rex292	1H-NMR (CDCl3): 3.00 (3H, d, J = 4.9Hz), 4.19 (2H, br-s), 5.92 (1H, br-s), 6.80 (1H, dd, J = 1.7Hz, 7.6Hz), 6.87 (1H, dd, J = 1.7Hz, 7.6Hz), 7.08 (1H, d, J = 7.6Hz).
121	Rex4	1H-NMR (CDCl3): 3.06 (3H, s), 5.57 (1H, br-s), 6.04 (1H, br-s), 7.42 (1H, d, J = 8.1H), 7.74 (1H, dd, J = 1.5Hz, 7.6H), 7.83 (1H, dd, J = 2.0Hz, 8.1Hz).
122	Rex353	1H-NMR (CDCl3): 1.31 (3H, t, J = 7.6Hz), 2.91 (2H, q, J = 7.3Hz), 3.04 (3H, d, J = 4.9Hz), 5.56 (1H, br-s), 5.95 (1H, br-s), 7.21 (1H, m), 7.34 (1H, m), 7.74 (1H, br-s), 8.56 (1H, m), 11.40 (1H, br-s).
123	Rex299	1H-NMR (DMSO-d6): 2.84 (3H, s), 7.21 (2H, t, J = 9.6H), 7.52 (1H, t, J = 9.6Hz), 7.53 (2H, s), 7.64 (1H, d, J = 4.0Hz), 8.22 (2H, d, J = 9.2Hz), 9.24 (1H, d, J = 4.0Hz), 12.92 (1H, br-s), 13.73 (1H, s).
124	Rex298	ESI-: 343
125	Rex353	ESI-: 325
126	Rex353	ESI-: 398
127	Rex353	ESI+: 334

[Table 60]

Rex	Syn	Data
128	Rex353	1H-NMR (DMSO-d6): 1.24 (3H, t, J = 7.6Hz), 2.89 (2H, q, J = 7.3Hz), 4.53 (2H, s), 6.92 (1H, d, J = 8.5Hz), 7.11-7.16 (2H, m), 8.02 (1H, br-s), 8.25 (1H, br-s), 10.78 (1H, br-s), 11.06 (1H, br-s).
129	Rex353	ESI-: 265
130	Rex353	ESI-: 350
131	Rex353	ESI-: 289
132	Rex353	ESI+: 488
133	Rex353	1H-NMR (CDCl3): 1.31 (3H, t, J = 7.2Hz), 2.64 (6H, s), 2.91 (2H, q, J = 7.2H), 4.30 (1H, br-s), 5.60 (1H, br-s), 7.56 (1H, br-s), 7.77 (1H, m), 7.95 (1H, d, J = 8.0Hz), 11.12 (1H, br-s).
134	Rex353	1H-NMR (CDCl3): 1.30 (3H, t, J = 7.2Hz), 2.89 (2H, q, J = 7.6Hz), 2.99 (3H, s), 5.59 (1H, br-s), 6.60 (1H, br-s), 7.53 (1H, dd, J = 2.4H, 9.2Hz), 7.60 (1H, d, J = 8.8Hz), 7.75 (1H, br-s), 7 96 (1H, d, J = 2.4Hz), 10.95(1H, s).
135	Rex353	ESI+: 368
136	Rex353	ESI+: 364
137	Rex292	1H-NMR (CDCl3): 2.44(3H, s), 2.50 (3H, s), 6.79 (1H, dd, J = 2.4Hz, 8.4Hz), 7.06 (1H, d, J = 8.4Hz), 7.25 (1H, d, J = 2.4Hz).
138	Rex353	ESI-: 382
139	Rex292	1H-NMR (CDCl3): 3.15-3.17 (4H, m), 3.70-3.72 (4H, m), 3.85 (3H, s), 4.13 (2H, br-s), 6.19 (1H, d, J = 2.0Hz), 6.23 (1H, dd, J = 2.0Hz, 8.4Hz), 7.01 (1H, d, J = 8.4Hz).
140	Rex41	1H-NMR (CDCl3): 3.28-3.30 (4H, m), 3.72-3.74 (4H, m), 4.06 (3H, s), 7.86 (1H, d, J = 2.0Hz), 7.89 (1H, dd, J = 2.0Hz, 8.4Hz), 8.80 (1H, d, J = 8.4Hz,).

[Table 61]

Rex	Syn	Data
141	Rex353	ESI-: 454
142	Rex353	1H-NMR (DMSO-d6): 1.24 (3H, t, J = 7.6Hz), 2.79 (2H, q, J = 7.3Hz), 4.56 (2H, s), 6.84 (1H, d, J = 8.5Hz), 6.98 (1H, dd, J = 2.4Hz, 8.5Hz), 7.46 (1H, d, J = 2.2Hz), 8.01 (1H, br-s), 8.24 (1H, br-s), 10.65 (1H, br-s), 11.11 (1H, br-s).
143	Rex353	ESI+: 317
144	Rex353	1H-NMR (DMSO-d6): 1.24 (3H, t, J = 7.6Hz), 2.78 (2H, q, J = 7.3Hz), 4.20-4.24 (4H, m), 6.81-6.89 (2H, m), 7.29 (1H, d, J = 2.4Hz), 7.98 (1H, br-s), 8.21 (1H, br-s), 10.98 (1H, br-s).
145	Rex48	1H-NMR (CDCl3): 3.36 (3H, s), 3.53 (2H, t, J = 5.1 Hz), 3.61 (2H, m), 4.01 (2H, br-s), 6.14 (1H, br-s), 6.76 (1H, dd, J = 2.0Hz, 8.3Hz), 6.91 (1H, d, J = 2.2Hz), 7.33 (1H, d, J = 8.3Hz).
146	Rex353	1H-NMR (CDCl3): 1.31 (3H, t, J = 7.6Hz), 2.90 (2H, q, J = 7.3Hz), 3.39 (3H, s), 3.58 (2H, m), 3.64 (2H, m), 5.79 (1H, br-s), 6.38 (1H, br-s), 7.52 (1H, d, J = 3.7Hz), 7.75 (1H, br-s), 7.87 (1H, dd, J =2.0Hz, 8.3Hz), 11.05 (1H, br-s).
147	Rex353	1H-NMR (CDCl3): 1.24-1.59 (9H, m), 2.90 (2H, q, J = 7.6Hz), 3.10-3.17 (4H, m), 3.95 (3H, s), 5.59 (1H, br-s), 7.13 (1H, d, J = 8.8Hz), 7.63 (1H, d, J = 8.4Hz), 7.75-7.81 (3H, m), 11.16 (1H, br-s).
148	Rex353	1H-NMR (CDCl3): 1.25 (3H, t, J = 7.6Hz), 2.60 (3H, s), 2.92 (2H, q, J = 7.6Hz), 5.59 (1H, br-s), 7.28 (1H, m), 7.73 (1H, br-s), 7.75 (1H, m), 8.44 (1H, d, J = 2.0Hz), 10.99 (1H, br-s).
149	Rex353	1H-NMR (CDCl3): 1.21-1.34 (3H, m), 2.82-2.92 (5H, m), 5.61 (1H, br-s), 7.51 (1H, d, J = 6.8Hz), 7.72-7.75 (1H, m), 7.87 (1H, d, J = 6.8Hz), 8.42 (1H, d, J = 2.8Hz), 10.99 (1H, br-s).

[Table 62]

Rex	Syn	Data
150	Rex353	ESI+: 364
151	Rex353	1H-NMR (CDCl3): 1.25 (3H, t, J = 7.6Hz), 2.92 (3H, q, J = 7.6Hz), 5.63 (1H, br-s), 7.53 (1H, dd, J = 3.6Hz, 6.9Hz), 7.76 (1H, br-s), 7.90 (1H, d, J = 6.0Hz), 8.78 (1H, d, J = 3.6Hz), 11.27 (1H, br-s).
152	Rex353	ESI+: 329
153	Rex353	1H-NMR (CDCl3): 1.34 (3H, t, J = 7.6Hz), 2.95 (2H, q, J = 7.6Hz), 5.65 (1H, br-s), 7.74 (1H, dd, J = 2.0Hz, 9.2Hz), 7.79 (1H, br-s), 8.02 (1H, d, J = 9.2Hz), 9.28 (1H, d, J = 2.0Hz), 11.25 (1H, br-s).
154	Rex353	1H-NMR (CDCl3): 1.30 (3H, t, J = 7.6Hz), 2.86 (2H, q, J = 7.6Hz), 3.79 (3H, s), 5.49 (1H, m), 6.44 (1H, d, J = 3.2Hz), 7.01 (1H, d, J = 3.2Hz), 7.15 (1H, dd, J = 0.2Hz, 8.4Hz), 7.54 (1H, d, J = 8.4Hz), 7.74 (1H, m), 7.98 (1H, s), 10.84 (1H, m).
155	Rex292	1H-NMR (CDC3): 2.84 (3H, s), 3.37 (2H, br-s), 3.99 (1H, br-s), 6.62 (1H, d, J = 8.4Hz), 6.82 (1H, dd, J = 2.8Hz, 8.4Hz), 6.86 (1H, d, J = 2.8Hz).
156	Rex353	1H-NMR (CDCl3): 1.28 (3H, t, J = 7.6Hz), 2.85 (2H, q, J = 7.6Hz), 2.91 (3H, d, J = 4.8Hz), 4.32 (1H, br-s), 5.51 (1H, br-s), 6.73 (1H, d, J = 8.4Hz), 7.66-7.70 (3H, m), 10.50 (1H, br-s).
157	Rex292	1H-NMR (DMSO-d6): 1.67-1.78 (2H, m), 2.07 (2H, m), 3.03-3.27 (8H, m), 3.73 (3H, s), 3.90-4.16 (3H, m), 5.79 (2H, br-s), 6.29 (1H, d, J = 8.5Hz), 6.50-6.54 (2H, m).
158	Rex503	ESI+: 338
159	Rex353	ESI+: 491
160	Rex160	1H-NMR (CDCl3): 1.35(3H, t, J = 7.6Hz), 3.02 (2H, q, J=7.6Hz).
161	Rex353	ESI+: 375

[Table 63]

Rex	Syn	Data
162	Rex292	ESI+: 276
163	Rex444	ESI+: 306
164	Rex353	ESI+: 459
165	Rex353	ESI+: 376
166	Rex353	1H-NMR (CDCl3): 1.28(3H, t, J = 7.6Hz), 2.84 (2H, q, J = 7.6Hz), 3.46-3.48 (4H, m), 3.83-3.85 (4H, m), 5.55 (1H, br-s), 6.67 (1H, d, J = 8.8Hz), 8.43 (1H, d, J = 2.4Hz), 10.45 (1H, br-s).
167	Rex292	ESI+: 276
168	Rex444	ESI+: 306
169	Rex353	ESI+: 459
170	Rex353	ESI+: 552
171	Rex353	1H-NMR (CDCl3): 1.28 (3H, t, J = 7.2Hz), 2.84 (2H, q, J = 7.2Hz), 3.12-3.14 (4H, m), 3.86-3.88 (4H, m), 5.51 (1H, br-s), 6.91 (1H, dd, J = 2.4Hz, 7.2Hz), 7.55 (1H, dd, J = 2.4Hz, 7.2Hz), 7.71 (1H, br-s), 10.58 (1H, br-s).
172	Rex353	1H-NMR (CDCl3): 1.28 (3H, t, J = 7.6Hz), 2.31 (3H, s), 2.36 (3H, s), 2.84 (2H, q, J = 7.6Hz), 2.92-2.94 (4H, m), 5.48 (1H, br-s), 7.02 (1H, d, J = 8.8Hz), 7.34 (1H, d, J = 2.4Hz), 7.55 (1H, dd, J = 2.7Hz, 8.5Hz), 7.71 (1H, br-s), 10.60 (1H, br-s).
173	Rex353	1H-NMR (CDCl3): 1.28 (3H, t, J = 7.6Hz), 1.68-1.74 (6H, m), 1.92-1.95 (2H, m), 2.29-2.36 (7H, m), 2.50-2.65 (8H, m), 2.84 (2H, q, J = 7.6Hz), 3.13-3.16 (2H, m), 5.54 (1H, br-s), 6.98 (1H, d, J = 6.5Hz), 7.33 (1H, d, J = 2.6Hz), 7.51 (1H, d, J = 2.7Hz), 7.71 (1H, br-s), 10.58 (1H, br-s).

[Table 64]

Rex	Syn	Data
174	Rex353	1H-NMR (CDCl3): 1.29 (3H, t, J = 7.3Hz), 2.37 (3H, s), 2.62 (4H, m), 2.85 (2H, q, J = 7.3Hz), 3.03 (4H, m), 5.53 (1H, br-s), 7.05 (1H, d, J = 8.8Hz), 7.51 (1H, dd, J = 2.7Hz, 8.8Hz), 7.72 (1H, d, J = 2.4Hz), 10.70 (1H, br-s).
175	Rex353	1H-NMR(CDCl3):1.28(t,J=7.2Hz,3H),1.49(s,9H),2.84( q,J=7.2Hz,2H),3.09(m,4H),3.58(m,4H),5.62(br-s,1H),6.92(d,J=9.2Hz,2H),7.54(d,J=9.2Hz,2H),7.7 1(br-s,1H),10.60(s,1H).
176	Rex292	1H-NMR (CDCl3): 1.60 (2H, br-s), 2.04-2.17 (4H, m), 2.91-2.94 (4H, m), 6.80 (1H, dd, J = 2.8Hz, 8.4Hz), 6.91 (1H, d, J = 2.8Hz), 7.17 (1H, d, J = 8.4H).
177	Rex516	1H-NMR (CDCl3): 2.13-2.22 (4H, m), 3.18-3.20 (4H, m), 7.36 (1H, d, J = 8.8Hz), 8.35 (1H, dd, J = 2.4Hz, 9.2Hz), 8.53 (1H, d, J = 2.4Hz).
178	Rex353	ESI-: 462
179	Rex353	ESI+: 400
180	Rex292	1H-NMR (CDCl3): 0.16-0.20 (2H, m), 0.55-0.59 (2H, m), 0.97 (1H, m), 2.40 (2H, d, J = 6.4Hz), 2.75 (2H, m), 2.96 (4H, m), 3.72 (2H, m), 6.79 (1H, dd, J = 2.8Hz, 8.4Hz), 6.89 (1H, d, J = 2.8Hz), 7.24 (1H, d, J = 8.4Hz).
181	Rex516	EI: 329
182	Rex353	ESI+: 483
183	Rex292	1H-NMR (CDCl3): 1.80-1.88 (1H, m), 2.06-2.14 (1H, m), 2.24 (6H, s), 2.85-3.20 (5H, m), 3.65 (2H, br-s), 6.78 (1H, dd, J = 2.9Hz, 8.5Hz), 6.90 (1H, d, J = 2.7Hz), 7.14 (1H, d, J = 8.5Hz).

[Table 65]

Rex	Syn	Data
184	Rex516	1H-NMR (CDCl3): 1.90-1.97 (1H, m), 2.21-2.29 (1H, m), 2.32 (3H, s), 2.77-2.82 (1H, m), 3.43-3.53 (1H, m), 3.62-3.67 (3H, m), 6.79 (1H, d, J = 9.5Hz), 8.16 (1H, dd, J = 2.7Hz, 9.5Hz), 8.53 (1H, d, J = 2.7Hz).
185	Rex353	1H-NMR (CDCl3): 1.29 (3H, t, J = 7.3Hz), 1.84-1.89 (1H, m), 2.12-2.16 (1H, m), 2.26 (6H, s), 2.83-2.89 (3H, m), 3.20-3.41 (4H, m), 5.57 (1H, br-s), 7.09 (1H, d, J = 8.8Hz), 7.71-7.82 (3H, m), 10.68 (1H, br-s).
186	Rex353	1H-NMR (CDCl3): 1.10-1.15 (3H, m), 1.30 (3H, t, J = 7.3Hz), 2.45-2.52 (2H, m), 2.85-2.97 (10H, m), 5.57 (1H, br-s), 7.37-7.39 (1H, m), 7.73 (1H, br-s), 7.87-7.88 (2H, m), 10.86 (1 H, br-s).
187	Rex292	1H-NMR (CDCl3): 1.04 (6H, d, J = 6.3Hz), 2.28-2.33 (2H, m), 2.81 (2H, dd, J = 2.0Hz, 9.0Hz), 3.02-3.07 (2H, m), 3.69 (2H, br-s), 6.78 (1H, dd, J = 2.7Hz, 8.5Hz), 6.89 (1H, d, J = 2.9Hz), 7.15 (1H, d, J = 8.5Hz).
188	Rex516	1H-NMR (CDCl3): 1.10(3H, s), 1.11 (3H, s), 2.48-2.53 (2H, m), 3.08-3.13 (2H, m), 3.22 (2H, d, J = 10.7Hz), 7.22 (1H, d, J = 9.0Hz), 8.29 (1H, dd, J = 2.7Hz, 9.0Hz), 8.50 (1H, d, J = 2.7Hz).
189	Rex353	1H-NMR (CDCl3): 1.05-1.09 (6H, m), 1.22-1.46 (3H, m), 2.34-2.40 (2H, m), 2.71-3.76 (6H, m), 5.57 (1H, br-s), 7.32 (1H, d, J = 8.5Hz), 7.74 (1H, br-s), 7.85-7.88 (2H, m), 10.85 (1H, br-s).

[Table 66]

Rex	Syn	Data
190	Rex292	1H-NMR (CDCl3): 1.41 (3H, s), 1.42 (3H, s), 2.68 (3H, s), 2.87-2.90 (2H, m), 2.81 (2H, dd, J = 2.0Hz, 9.0Hz,2H),3.00(m,2H),3.23(m,2H),3.81 (br-s), 6.80 (1H, dd, J = 2.9Hz, 8.5Hz), 6.88 (1H, d, J = 2.9Hz), 7.24 (1H, d, J = 7.8Hz).
191	Rex516	1H-NMR (CDCl3): 1.15 (3H, s), 1.16 (3H, s), 2.36 (3H, s), 2.46-2.50 (2H, m), 2.79-2.85 (2H, m), 3.19 (2H, dd, J = 2.7Hz, 9.0Hz), 7.22-7.24 (1H, m), 8.30 (1H, dd, J = 2.7H, 9.0Hz), 8.50 (1H, d, J = 2.7Hz).
192	Rex353	1H-NMR (CDCl3): 1.11 (6H, m), 1.30 (3H, t, J = 7.3Hz), 2.33-2.44 (5H, m), 2.67-2.79 (2H, m), 2.85-2.91 (4H, m), 5.54 (1H, br-s), 7.33 (1H, d, J = 8.3Hz), 7.73 (1H, br-s), 7.85-7.87 (2H, m), 10.85 (1H, br-s).
193	Rex353	ESI+: 362
194	Rex194	ESI+: 377
195	Rex353	ESI+: 389
196	Rex353	ESI+: 403
197	Rex353	1H-NMR (CDCl3): 1.30 (3H, t, J = 7.6Hz), 1.48 (9H, s), 2.76-2.91 (6H, m), 3.55 (4H, m), 5.57 (1H, br-s), 7.31 (1H, d, J = 8.8Hz), 7.74 (1H, br-s), 7.86-7.90 (2H, m), 10.89 (1H, br-s).
198	Rex353	1H-NMR (CDCl3): 1.28 (3H, t, J = 7.6Hz), 1.48 (9H, s), 2.32 (3H, s), 2.82-2.88 (6H, m), 3.56 (4H, t, J = 4.9Hz), 5.52 (1H, br-s), 6.98 (1H, d, J = 8.5Hz), 7.36 (1H, d, J = 2.7Hz), 7.55 (1H, dd, J = 2.7Hz, 8.5Hz), 7.72 (1H, br-s), 10.62 (1H, br-s).

[Table 67]

Rex	Syn	Data
199	Rex516	1H-NMR(CDCl3):0.99(s,6H),1.29(t,J=5.6Hz,2H),1.59-1.67(m,2H),2.46(s,2H),2.67(m,2H),3.67(br-s,2H),6.77(dd,J=2.9Hz,8.5Hz,1H),6.89(d,J=2.7Hz, 1H),7.16(d,J=6.5Hz,1H).
200	Rex194	ESI+: 417
201	Rex194	ESI+: 476
202	Rex292	1H-NMR (CDCl3): 1.81-1.85 (2H, m), 1.99-2.03 (2H, m), 2.18-2.21 (4H, m), 2.79-2.84 (2H, m), 3.01-3.04 (2H, m), 3.12-3.34 (4H, m), 3.66-3.69 (2H, m), 9.92 (1H, dd, J = 2.4Hz, 8.0Hz), 6.98 (1H, d, J = 2.4Hz), 7.24 (1H, d, J = 8.0Hz).
203	Rex516	EI : 343
204	Rex353	ESI+: 497
205	Rex353	ESI-: 437
206	Rex353	ESI-: 472
207	Rex292	1H-NMR (CDCl3): 0.81 (3H, d, J = 6.4Hz), 1.48 (3H, d, J = 6.6Hz), 2.68 (2H, q, J = 11.0Hz), 2.81 (2H, d, J = 4.9Hz), 2.93 (1H, dd, J = 2.9Hz, 12.9Hz), 3.17 (1H, br-s), 3.29-3.44 (2H, m), 3.87 (2H, br-s), 6.83 (1H, dd, J = 2.7Hz, 8.5H), 6.89 (1H, d, J = 2.7Hz), 7.29 (1H, d, J = 8.3Hz).
208	Rex516	1H-NMR (CDCl3): 0.79 (3H, d, J = 6.3Hz), 1.04 (3H, d, J = 6.4Hz), 2.16-2.21 (2H, m), 2.28-2.34 (4H, m), 2.44-2.50 (1H, m), 2.86-2.90 (2H, m), 7.56 (1H, d, J = 8.8Hz), 8.40 (1H, dd, J = 2.7Hz, 8.8Hz), 8.55 (1H, d, J = 2.7Hz).
209	Rex353	ESI+: 471
210	Rex292	EI: 219
211	Rex516	EI: 249
212	Rex353	ESI+: 403

[Table 68]

Rex	Syn	Data
213	Rex292	1H-NMR (CDCl3): 1.52-1.55 (2H, m), 2.01 (2H, dt, J = 4.4Hz, 8.4Hz), 2.12-2.16 (2H, m), 2.84-2.94 (6H, m), 6.87 (1H, dd, J = 2.4Hz, 8.4Hz), 6.94 (1H, d, J = 2.4Hz), 7.10-7.21 (4H, m), 7.29 (1H, d, J = 8.4Hz).
214	Rex516	1H-NMR (CDCl3): 1.52-1.55 (2H, m), 2.01 (2H, dt, J = 4.4Hz, 12.8Hz), 2.12-2.16 (2H, m), 2.84-3.31 (6H, m), 6.86-6.89 (1H, m), 6.95 (1H, m), 7.10-7.19 (4H, m), 7.30 (1H, d, J = 8.4Hz).
215	Rex353	ESI-: 528
216	Rex353	ESI+: 403
217	Rex292	EI: 344
218	Rex516	EI: 374
219	Rex353	ESI-: 526
220	Rex292	1H-NMR (CDCl3): 2.34 (3H, s), 2.51 (4H, t, J = 4.8Hz), 3.17 (4H, t, J = 4.8Hz), 3.63 (2H, br-s), 6.58 (2H, s).
221	Rex516	1H-NMR (CDCl3): 2.38 (3H, s), 2.58 (4H, m), 3.36 (4H, t, J = 4.8Hz), 8.15 (2H, s).
222	Rex353	ESI-: 441
223	Rex292	1H-NMR (CDCl3): 1.41-1.53 (10H, m), 1.69 (2H, t, J = 7.1Hz), 2.86 (2H, s), 3.10 (2H, t, J = 6.8Hz), 3.59 (2H, br-s), 6.77 (1H, d, J = 2.7H, 8.5Hz), 6.90 (1H, dd, J = 2.5Hz, 9.5Hz), 7.08 (1H, d, J = 8.8Hz).
224	Rex516	1H-NMR (CDCl3): 1.42-1.57 (10H, m), 1.85 (2H, t, J = 7.1 Hz), 3.33 (2H, s), 3.61 (2H, t, J = 7.0Hz), 6.77 (1H, d, J = 9.5Hz), 8.14 (1H, dd, J = 2.7Hz, 9.5Hz), 8.53 (1H, d, J = 2.9Hz).

[Table 69]

Rex	Syn	Data
225	Rex353	1H-NMR (CDCl3): 1.28 (3H, t, J = 7.6Hz), 1.43-1.55 (10H, m), 2.32 (3H, s), 1.75 (2H, t, J = 7.1Hz), 2.85 (2H, q, J = 7.6Hz), 3.06 (2H, s), 3.32 (2H, t, J = 6.8Hz), 5.50 (1H, br-s), 7.02 (1H, d, J = 9.0Hz), 7.69-7.71 (2H, m), 7.80 (1H, d, J = 2.7Hz), 10.61 (1H, br-s).
226	Rex353	1H-NMR (CDCl3): 1.29 (3H, t, J = 7.6Hz), 1.49 (9H, s), 2.85 (2H, q, J = 7.6Hz), 2.98 (4H, m), 3.61 (4H, t, J = 5.1Hz), 3.90 (3H, s), 5.52 (1H, br-s), 6.87 (1H, d, J = 8.5Hz), 7.14 (1H, dd, J = 2.4Hz, 8.5Hz), 7.38 (1H, d, J = 2.2Hz), 7.73 (1H, br-s), 10.70 (1H, br-s).
227	Rex353	ESI+: 370
228	Rex413	ESI-: 343
229	Rex412	1H-NMR (CDCl3): 1.50 (9H, s), 2.37 (2H, m), 3.63-3.65 (2H, m), 4.06 (2H, m), 5.66 (1H, m), 7.44 (1H, d, J = 8.3Hz), 8.35 (1H, dd, J = 2.2Hz, 8.3Hz), 8.54 (1H, d, J = 2.2Hz).
230	Rex353	1H-NMR (CDCl3): 1.30 (3H, t, J = 7.3Hz), 1.49 (9H, s), 1.60-1.78 (2H, m), 2.81 (2H, m), 2.88 (2H, q, J = 7.3Hz), 3.00-3.06 (1H, m), 4.24 (1H, m), 5.56 (1H, m), 7.37 (1H, d, J = 8.5Hz), 7.74 (1H, m), 7.85 (1H, dd, J = 2.4Hz, 8.5Hz), 7.92 (1H, d, J = 2.4Hz), 10.90 (1H, br-s).
231	Rex353	ESI+: 403
232	Rex353	ESI+: 392
233	Rex353	ESI+: 390
234	Rex292	1H-NMR (CDCl3): 2.18 (3H, s), 2.38 (3H, s), 2.58 (4H, br-s), 2.83 (4H, br-s), 3.63 (2H, br-s), 6.35 (1H, dd, J = 2.8Hz, 8.4Hz), 6.98 (1H, d, J = 8.4Hz), 7.81 (1H, d, J = 2.8H), 8.66 (1H, br-s).

[Table 70]

Rex	Syn	Data
235	Rex353	ESI+: 432
236	Rex292	1H-NMR (CDCl3+CD3OD): 2.42 (3H, s), 2.69 (4H, br-s), 2.86 (4H, br-s), 3.05 (3H, s), 6.44 (1H, dd, J = 2.8Hz, 8.4Hz), 6.87 (1H, d, J=2.8Hz), 7.08 (1H, d, J = 8.8Hz).
237	Rex516	1H-NMR (CDCl3): 2.39 (3H, s), 2.64 (4H, br-s), 2.97 (4H, t, J = 4.8Hz), 3.19 (3H, s), 7.28 (1H, d, J = 8.8Hz), 7.53 (1H, br-s), 7.97 (1H, dd, J = 2.4Hz, 8.4Hz), 8.31 (1H, d, J = 2.4Hz).
238	Rex353	ESI+: 468
239	Rex292	1H-NMR (CDCl3): 2.35 (3H, s), 2.45 (4H, br-s), 2.85 (4H, t, J = 4.8Hz), 3.54 (2H, br-s), 6.62-6.65 (2H, m), 6.92 (1H, d, J = 9.2Hz), 7.29 (1H, t, J = 7.6Hz), 7.36 (2H, t, J = 7.6Hz), 7.57 (2H, d, J = 7.2Hz).
240	Rex240	1H-NMR (CDCl3): 2.27 (3H, s), 2.34 (4H, br-s), 2.99 (4H, t, J = 4.8Hz), 7.01 (1H, d, J = 9.2Hz), 7.35 (1H, t, J = 7.2Hz), 7.44 (2H, t, J = 7.2Hz), 7.58 (2H, d, J = 7.2Hz), 8.08 (1H, d, J = 2.8Hz), 8.14 (1H, dd, J = 2.8Hz, 9.2Hz).
241	Rex516	ESI+: 348
242	Rex353	ESI+: 451
243	Rex292	1H-NMR (CDCl3): 1.91 (3H, s), 2.34 (3H, s), 2.55 (4H, br-s), 2.87 (4H, m), 3.22 (3H, s), 3.64 (2H, br-s), 6.47 (1H, s), 6.66 (1H, d, J = 8.8Hz), 6.95 (1H, d, J = 8.4Hz).
244	Rex244	1H-NMR (CDCl3): 1.98 (3H, s), 2.35 (3H, s), 2.56 (4H, t, J = 4.8Hz), 3.18 (4H, dd, J = 3.6Hz, 5.6Hz), 3.26 (3H, s), 7.05 (1H, d, J = 9.2Hz), 7.98 (1H, d, J = 2.4Hz), 8.14 (1H, dd, J = 2.4Hz, 8.8Hz).

[Table 71]

Rex	Syn	Data
245	Rex353	ESI+: 446
246	Rex246	1H-NMR (CDCl3): 0.90 (3H, t, J = 7.8Hz), 1.40-1.55 (15H, m), 1.61-1.64 (2H, m), 1.78-1.82 (2H, m), 3.39 (1H, m), 4.42 (1H, m).
247	Rex247	1H-NMR (CD3OD): 0.90 (3H, t, J = 7.6Hz), 1.30-1.54 (6H, m), 1.62-1.65 (3H, m), 2.52-2.58 (1H, m).
248	Rex246	1H-NMR (CDCl3): 0.91 (3H, t, J = 7.6Hz), 1.32-1.49 (13H, m), 1.54 (2H, q, J = 7.6Hz), 1.60-1.66 (2H, m), 1.88-1.93 (2H, m), 3.59 (1H, m), 4.55 (1H, m).
249	Rex249	1H-NMR (CD3OD): 0.89 (3H, t, J = 7.6Hz), 1.20-1.31 (2H, m), 1.38-1.45 (2H, m), 1.55 (2H, q, J = 7.6Hz), 1.68-1.81 (4H, m), 2.70-2.75 (1H, m).
250	Rex250	1H-NMR (CDCl3): 0.91 (6H, d, J = 6.8Hz), 1.43-1.49 (11H, m), 1.51-1.63 (5H, m), 1.81-1.83 (2H, m), 3.37 (1H, m), 4.41 (1H, m).
251	Rex251	1H-NMR (DMSO-d6): 0.82 (6H, d, J = 6.8Hz), 1.24-1.31 (2H, m), 1.43-1.53 (3H, m), 1.65-1.67 (4H, m), 2.85-2.89 (1H, m), 3.87 (1H, m), 7.88 (2H, m).
252	Rex250	1H-NMR (CDCl3): 0.92 (6H, d, J = 6.8Hz), 1.43-1.45 (11H, m), 1.52-1.55 (2H, m), 1.64-1.76 (3H, m), 1.88-1.92 (2H, m), 3.68 (1H, m), 4.53 (1H, m).
253	Rex253	1H-NMR (DMSO-d6): 0.83 (6H, d, J = 6.8Hz), 1.25-1.32 (2H, m), 1.48 (2H, m), 1.62-1.68 (3H, m), 1.82-1.88 (2H, m), 3.17 (1H, m), 3.92 (1H, m), 7.84 (2H, m).
254	Rex353	ESI+: 453

[Table 72]

Rex	Syn	Data
255	Rex292	1H-NMR (CDCl3): 1.48 (9H, s), 1.85-1.93 (2H, m), 2.23 (3H, s), 2.93-3.02 (4H, m), 3.45-3.59 (6H, m), 6.47 (1H, d, J = 8.3Hz), 6.53 (1H, s), 6.86 (1H, d, J = 8.3Hz).
256	Rex353	1H-NMR (CDCl3): 1.28 (3H, t, J = 7.3Hz), 1.49 (9H, s), 1.91-1.96 (2H, m), 2.31 (3H, s), 2.84 (2H, q, J = 7.3Hz), 3.00-3.08 (4H, m), 3.56-3.61 (4H, m), 5.50 (1H, br-s), 7.01-7.04 (1H, m), 7.34 (1H, s), 7.52 (1H, m), 7.71 (1H, br-s), 10.60 (1H, br-s).
257	Rex292	1H-NMR (CD3OD): 1.49 (9H, s), 2.02-2.20 (6H, m), 2.37 (3H, s), 2.77-2.86 (2H, m), 3.27-3.34 (6H, m), 3.48-3.65 (6H, m), 3.96 (1H, t, J = 15.4Hz), 7.18-7.23 (3H, m).
258	Rex503	1H-NMR (CDCl3): 1.47 (9H, s), 1.69-1.90 (6H, m), 2.35 (3H, s), 2.61-2.80 (7H, m), 3.30-3.33 (2H, m), 3.42-3.50 (4H, m), 6.96 (1H, d, J = 8.3Hz), 8.00-8.03 (2H, m).
259	Rex516	ESI+: 235
260	Rex292	1H-NMR (CDCl3): 1.63 (2H, m), 2.03-2.94 (21H, m), 3.63 (2H, br-s), 6.34 (1H, d, J = 8.4Hz), 6.93 (1H, d, J = 8.4Hz), 7.81 (1H, s), 8.61 (1H, br-s).
261	Rex503	1H-NMR (CDCl3): 1.64-1.73 (2H, m), 2.12 (2H, d, J = 12.8Hz), 2.24 (3H, s), 2.29-2.38 (1H, m), 2.31 (3H, s), 2.50 (4H, br-s), 2.66 (4H, br-s), 2.75 (2H, t, J = 12.4Hz), 3.15 (2H, d, J = 12.0Hz), 7.16 (1H, d, J = 8.8Hz), 7.92 (1H, dd, J = 2.8Hz, 8.8Hz), 8.07 (1H, br-s), 9.16 (1H, d, J = 2.4Hz).
262	Rex516	1H-NMR (CDCl3): 2.29 (3H, s), 2.68 (4H, t, J = 6.0Hz), 3.27 (4H, t, J = 6.0Hz), 7.23 (1H, d, J = 8.8Hz), 7.97 (1H, dd, J = 2.4Hz, 8.8Hz), 8.16 (1H, br-s), 9.22 (1H, br-s).

[Table 73]

Rex	Syn	Data
263	Rex353	ESI+: 515
264	Rex292	1H-NMR (CDCl3): 1.63 (2H, m), 1.89 (3H, s), 1.97 (2H, m), 2.56-3.21 (19H, m), 3.61 (2H, br-s), 6.47 (1H, d, J = 2.8Hz), 6.61 (1H, dd, J = 2.8Hz, 8.4Hz), 6.91 (1H, d, J = 8.8Hz).
265	Rex244	1H-NMR (CDCl3): 1.62 (2H, m), 1.96 (3H, s), 2.00 (2H, m), 2.29 (3H, s), 2.36 (1H, m), 2.48 (4H, br-s), 2.48 (4H, br-s), 2.61 (4H, br-s), 2.86 (4H, m), 3.48 (3H, s), 3.51 (2H, t, J = 10.8Hz), 7.03 (1H, d, J = 9.2Hz), 7.96 (1H, d, J = 2.8Hz), 8.11 (1H, dd, J = 2.8Hz, 9.2Hz).
266	Rex353	ESI+: 529
267	Rex292	1H-NMR (CDCl3): 0.62-0.66 (2H, m), 0.91-0.96 (2H, m), 2.35 (1H, m), 2.35 (3H, s), 2.57 (4H, br-s), 2.96 (4H, s), 3.42 (2H, br-s), 6.08 (1H, d, J = 2.4Hz), 6.46 (1H, dd, J = 2.4Hz, 8.4Hz), 6.88 (1H, d, J = 8.4Hz).
268	Rex240	1H-NMR (CDCl3): 0.83 (2H, m), 1.09 (2H, m), 2.15 (1H, m), 2.38 (3H, s), 2.62 (4H, br-s), 3.21 (4H, br-s), 6.99 (1H, d, J = 8.4Hz), 7.68 (1H, d, J = 2.8Hz), 7.99 (1H, dd, J = 2.4Hz, 8.8Hz).
269	Rex353	ESI+: 415
270	Rex292	EI :251
271	Rex516	EI:281
272	Rex353	ESI-: 433
273	Rex353	ESI+: 482
274	Rex292	1H-NMR (CD3OD): 2.54 (3H, s), 2.57 (3H, s), 2.90-2.94 (4H, m), 2.99-3.02 (4H, m), 6.80 (1H, dd, J = 2.4Hz, 8.8Hz), 7.09 (1H, d, J = 8.8Hz), 7.22 (1H, d, J = 2.4Hz).

[Table 74]

Rex	Syn	Data
275	Rex516	1H-NMR (CDCl3): 2.39 (3H, s), 2.60 (4H, m), 3.04 (3H, d, J = 4.8Hz), 3.12-3.15 (4H, m), 7.17 (1H, d, J = 8.8Hz), 8.23 (1H, dd, J = 2.4Hz, 8.8Hz), 8.80 (1H, d, J = 2.4Hz).
276	Rex353	ESI+: 432
277	Rex292	1H-NMR (CD3OD): 1.69-1.71 (2H, m), 1.92-1.95 (2H, m), 2.35 (3H, s), 2.55 (3H, s), 2.57-2.82 (9H, m), 3.14 (2H, m), 3.31 (2H, m), 3.34 (6H, s), 6.86-6.88 (1H, m), 7.20-7.22 (2H, m).
278	Rex503	1H-NMR (CDCl3): 1.71-1.80 (2H, m), 1.96-1.99 (2H, m), 2.30 (3H, s), 2.49-2.64 (9H, m), 2.80 (6H, s), 2.84 (2H, m), 3.57-3.60 (2H, m), 7.31 (1H, d, J = 9.2Hz), 8.30 (1H, dd, J = 2.8Hz, 9.2Hz), 8.71 (1H, d, J = 2.8Hz).
279	Rex516	1H-NMR (CDCl3): 2.69-2.72 (4H, m), 2.86 (6H, s), 3.47-3.50 (4H, m), 7.39 (1H, d, J = 8.8Hz), 8.36 (1H, dd, J = 2.4Hz, 8.8Hz), 8.71 (1H, d, J = 2.4H).
280	Rex353	ESI+: 565
281	Rex292	1H-NMR (CDCl3): 2.48 (3H, s), 2.98 (4H, m), 3.31 (7H, m), 6.90 (1H, dd, J = 2.8Hz, 8.4Hz), 7.21 (1H, d, J = 2.8Hz), 7.27 (1 H, d, J = 8.4Hz).
282	Rex516	EI: 328
283	Rex353	ESI+: 468
284	Rex292	1H-NMR (CDCl3): 2.88 (3H, s), 2.96 (3H, s), 3.14 (3H, s), 3.19-3.56 (8H, m), 7.09 (1H, s), 7.29 (2H, m).
285	Rex516	1H-NMR (CDCl3): 2.34 (3H, s), 2.49-2.51 (4H, m), 2.88 (3H, s), 3.13-3.16 (2H, m), 3.15 (3H, s), 3.38 (2H, m), 6.64 (1H, d, J = 8.8Hz), 8.14-8.18 (2H, m).

[Table 75]

Rex	Syn	Data
286	Rex353	ESI+: 446
287	Rex287	EI: 211
288	Rex291	ESI+: 244
289	Rex292	FAB+: 214
290	Rex287	EI: 211
291	Rex291	FAB+: 244
292	Rex292	FAB+: 214
293	Rex298	ESI+: 401
294	Rex299	ESI+: 383
295	Rex298	ESI+: 415
296	Rex298	ESI+: 415
297	Rex299	ESI+: 397
298	Rex298	ESI-: 371
299	Rex299	ESI-: 353
300	Rex298	ESI-: 371
301	Rex299	ESI-: 354
302	Rex299	ESI+: 397
303	Rex298	ESI+: 310
304	Rex304	ESI+: 306
305	Rex298	ESI+: 352
306	Rex299	FAB+: 334
307	Rex298	ESI+: 338
308	Rex298	ESI+: 330,332
309	Rex298	ESI+: 366
310	Rex299	ESI+: 348
311	Rex311	FAB+: 350
312	Rex299	ESI-: 318
313	Rex298	ESI+: 374
314	Rex299	ESI+: 56
315	Rex298	ESI+: 387
316	Rex298	ESI+: 401

[Table 76]

Rex	Syn	Data
317	Rex339	ESI+: 292
318	Rex304	ESI+: 326,328
319	Rex339	ESI-: 310
320	Rex299	APCI-: 367
321	Rex299	ESI-: 381
322	Rex298	APCI-: 400
323	Rex298	ESI-: 336
324	Rex298	ESI+: 364
325	Rex299	ESI+: 384
326	Rex298	ESI+: 388
327	Rex299	APCI-: 368
328	Rex298	ESI+: 392
329	Rex298	ESI+: 404
330	Rex298	ESI+: 326
331	Rex299	ESI-: 318
332	Rex298	ESI+: 388
333	Rex298	ESI+: 427
334	Rex299	ESI-: 344
335	Rex299	ESI-: 386
336	Rex299	ESI-: 373
337	Rex304	ESI+: 322
338	Rex299	ESI-: 407
339	Rex339	ESI+: 308
340	Rex346	ESI+: 412
341	Rex349	ESI+: 370
342	Rex342	ESI+: 387, 389
343	Rex342	FAB+: 369
344	Rex298	ESI+: 346
345	Rex298	ESI+: 372
346	Rex346	ESI+: 370
347	Rex346	ESI+: 396

[Table 77]

Rex	Syn	Data
348	Rex349	ESI+: 354
349	Rex349	ESI+: 328
350	Rex298	ESI+: 372
351	Rex298	ESI+: 407, 409
352	Rex298	ESI+: 330
353	Rex353	ESI+: 355
354	Rex299	ESI+: 389, 391
355	Rex346	ESI+: 396
356	Rex298	ESI+: 330
357	Rex346	ESI+: 354
358	Rex349	ESI+: 354
359	Rex298	ESI+: 310, 312
360	Rex353	ESI+: 308, 310
361	Rex346	ESI+: 354
362	Rex349	ESI+: 312
363	Rex349	ESI+: 312
364	Rex364	ESI+: 292
365	Rex298	ESI+: 364
366	Rex346	ESI+: 388
367	Rex298	ESI+: 364
368	Rex346	ESI+: 388
369	Rex349	ESI+: 346
370	Rex349	ESI+: 346
371	Rex298	ESI+: 372
372	Rex346	ESI+: 396
373	Rex349	ESI+: 354
374	Rex298	ESI+: 296
375	Rex298	ESI+: 374
376	Rex298	ESI+: 330
377	Rex298	ESI+: 330
378	Rex298	ESI+: 398

[Table 78]

Rex	Syn	Data
379	Rex353	FAB+: 327
380	Rex346	ESI+: 422
381	Rex346	ESI-: 396
382	Rex346	ESI+: 320
383	Rex346	ESI+: 354
384	Rex346	ESI+: 354
385	Rex349	ESI+: 380
386	Rex349	ESI+: 356
387	Rex349	ESI+: 278
388	Rex349	ESI+: 312
389	Rex349	ESI+: 312
390	Rex353	ESI+: 278
391	Rex353	ESI+: 369, 371
392	Rex353	ESI+: 361, 363
393	Rex353	ESI+: 323
394	Rex353	ESI+: 323
395	Rex353	ESI+: 292
396	Rex397	ESI+: 355
397	Rex397	ESI+: 355
398	Rex398	ESI+: 234, 236
399	Rex399	ESI+: 229
400	Rex400	ESI+: 129
401	Rex353	ESI+: 328
402	Rex353	ESI-: 343
403	Rex353	ESI+: 317
404	Rex353	ESI+: 333
405	Rex353	ESI+: 328
406	Rex516	ESI+: 335
407	Rex292	ESI+: 305
408	Rex353	ESI+: 322
409	Rex353	ESI+: 368

[Table 79]

Rex	Syn	Data
410	Rex353	ESI+: 348
411	Rex353	ESI+: 361
412	Rex412	FAB+: 335
413	Rex413	ESI+: 306
414	Rex353	ESI+: 375
415	Rex353	ESI+: 405
416	Rex353	ESI+: 405
417	Rex417	ESI+: 387
418	Rex353	ESI+: 458
419	Rex353	ESI+: 433
420	Rex353	ESI+: 375
421	Rex516	ESI+: 349
422	Rex292	ESI+: 319
423	Rex353	ESI+: 488, 490
424	Rex353	ESI+: 443
425	Rex353	ESI+: 460
426	Rex516	ESI+: 373
427	Rex353	ESI+: 405
428	Rex353	ESI+: 362
429	Rex353	ESI+: 360
430	Rex430	EI: 256, 258
431	Rex430	EI: 270, 272
432	Rex432	ESI+: 321
433	Rex432	ESI+: 335
434	Rex292	ESI+: 291
435	Rex292	ESI+: 305
436	Rex292	ESI+: 343
437	Rex353	FAB+: 489 491
438	Rex454	ESI-: 409
439	Rex353	ESI+: 405
440	Rex440	ESI+: 538

[Table 80]

Rex	Syn	Data
441	Rex455	ESI+: 311
442	Rex353	ESI+: 443
443	Rex353	ESI+: 374
444	Rex444	ESI+: 252
445	Rex292	ESI+: 222
446	Rex353	ESI+: 355, 357
447	Rex353	ESI+: 405
448	Rex464	ESI+: 408
449	Rex468	ESI+: 274
450	Rex353	ESI+: 457
451	Rex516	ESI+: 305
452	Rex292	ESI+: 275
453	Rex353	ESI+: 458
454	Rex454	ESI+: 441
455	Rex455	ESI+: 341
456	Rex516	ESI+: 290
457	Rex292	ESI+: 260
458	Rex353	ESI+: 443
459	Rex516	ESI+: 379
460	Rex292	ESI+: 349
461	Rex353	ESI+: 405
462	Rex454	ESI+: 441
463	Rex455	APCI/ESI+: 341
464	Rex464	ESI+: 355
465	Rex464	ESI+: 438
466	Rex467	ESI+: 277
467	Rex467	ESI+: 291
468	Rex468	ESI+: 221
469	Rex468	ESI+: 304
470	Rex353	ESI+: 404, 406
471	Rex353	ESI+: 487, 489

[Table 81]

Rex	Syn	Data
472	Rex472	ESI+: 275
473	Rex473	APCI/ESI+: 279
474	Rex292	APCI/ESI+: 249
475	Rex516	APCI/ESI+: 237
476	Rex353	APCI/ESI+: 432, 434
477	Rex292	APCI/ESI+: 207
478	Rex454	FAB+: 411
479	Rex455	ESI+: 311
480	Rex464	ESI+: 325
481	Rex468	ESI+: 191
482	Rex464	ESI+: 408
483	Rex464	ESI+: 438
484	Rex468	ESI+: 274
485	Rex353	ESI+: 409
486	Rex468	ESI+: 304
487	Rex353	ESI+: 404
488	Rex353	ESI+: 374
489	Rex353	ESI+: 487
490	Rex353	ESI+: 457
491	Rex353	APCI/ESI+: 390, 392
492	Rex502	EI:220
493	Rex503	ESI+: 419
494	Rex455	ESI+: 319
495	Rex444	ESI+:295
496	Rex464	ESI+: 333
497	Rex292	ESI+: 265
498	Rex292	ESI+: 303
499	Rex444	ESI+: 279
500	Rex353	APCI/ESI+: 486, 488
501	Rex353	ESI+: 420
502	Rex502	APCI/ESI+: 251

[Table 82]

Rex	Syn	Data
503	Rex503	APCI/ESI+: 335
504	Rex292	APCI/ESI+: 305
505	Rex353	APCI/ESI+: 406
506	Rex353	APCI/ESI+: 433
507	Rex353	APCI/ESI+: 420
508	Rex353	APCI/ESI+: 419
509	Rex353	APCI/ESI+: 488
510	Rex502	APCI/ESI+: 235
511	Rex503	APCI/ESI+: 319
512	Rex292	APCI/ESI+: 239
513	Rex353	ESI+: 472
514	Rex432	ESI+: 308
515	Rex432	ESI+: 322
516	Rex516	ESI+: 279
517	Rex292	ESI+: 249
518	Rex516	ESI+: 295
519	Rex292	APCI/ESI+: 265
520	Rex353	ESI+: 404
521	Rex353	ESI+: 420
522	Rex292	ESI+: 292
523	Rex292	ESI+: 278
524	Rex353	ESI+: 475, 477
525	Rex353	ESI+: 488, 490
526	Rex353	ESI+: 502, 504
527	Rex353	ESI+: 474, 476
528	Rex353	ESI+: 474
529	Rex353	ESI+: 461
530	Rex467	ESI+: 278
531	Rex353	ESI+: 461, 463
532	Rex353	ESI+: 460, 462
533	Rex430	EI: 270, 272

[Table 83]

Rex	Syn	Data
534	Rex432	ESI+: 335
535	Rex292	ESI+: 305
536	Rex353	ESI+: 488, 490
537	Rex432	ESI+: 322
538	Rex292	ESI+: 292
539	Rex353	ESI+: 475, 477
540	Rex353	ESI+: 532, 534
541	Rex516	ESI+: 319
542	Rex292	ESI+: 289
543	Rex545	ESI+: 389
544	Rex353	ESI+: 435
545	Rex545	APCI/ESI+: 419
546	Rex417	ESI+: 470
547	Rex353	APCI/ESI+: 488
548	Rex353	1H-NMR (CDCl3):1.28(3H, t, J = 7.3Hz), 2.36(3H, S), 2.62 (4H, br-s), 2.85 (2H, q, J = 7.6Hz), 3.10 (4H, br-s), 5.50(1H, br-s), 6.91-6.99 (1H, m), 7.25 (1H, br-s), 7.53 (1H, d, J = 14.4Hz), 7.71 (1H, br-s), 10.71 (1H, br-s)
549	Rex353	ESI+: 506
550	Rex545	ESI+: 490
551	Rex516	ESI+:319
552	Rex292	ESI+:289
553	Rex353	ESI+: 472
554	Rex516	1H-NMR (CDCl3) :1.71-2.17 (6H, m), 2.35 (4H, m), 2.72-2.75 (4H, m), 2.99-3.02 (2H, m), 3.30-3.32 (4H, m), 6.87-6.92 (1H, m), 7.87-7.99 (2H, m)
555	Rex292	ESI+: 293

[Table 84]

Rex	Syn	Data
556	Rex353	1H-NMR (CDCl3): 1.26-1.32 (3H, m), 1.56-1.65 (2H, m), 1.84-1.97 (4H, m), 2.30 (4H, m), 2.72-3.09 (12H, m), 5.49 (1H, br-s), 6.90-6.95 (1H, m), 7.17-7.29 (1H, m), 7.52-7.56 (1H, m), 7.71 (1H, br-s), 10.71 (1H, br-s)
557	Rex516	1H-NMR (CDCl3): 1.59 (2H, m), 1.82-1.85 (2H, m), 1.93-1.98 (2H, m), 2.27 (4H, br-s), 2.75 (4H, t, J = 4.6Hz), 2.91-2.94 (2H, m), 3.24-3.26 (4H, m), 3.95 (3H, s), 6.87 (1H, d, J = 9.0Hz), 7.70 (1H, d, J = 2.4Hz), 7.85 (1H, dd, J = 2.7, 9.0Hz)
558	Rex292	1H-NMR (CDCl3): 1.65-2.00 (8H, m), 2.29 (4H, br-s), 2.75-2.76 (4H, m), 2.93-3.03 (6H, m), 3.83 (3H, s), 6.23-6.26 (2H, m), 6.76 (1H, d, J = 8.1 Hz)
559	Rex353	1H-NMR (CDCl3): 1.57-1.98 (11H, m), 2.29 (5H, m), 2.78 (4H, br-s), 2.94-2.96 (2H, m), 3.09 (4H, br-s), 3.71 (1H, br-s), 3.90 (3H, s), 5.56 (1H, br-s), 6.91 (1H, d, J = 8.5H), 7.13 (1H, dd, J = 2.4, 8.5Hz), 7.36 (1H, d, J = 2.4Hz), 7.41 (1H, br-s), 10.76 (1H, br-s)
560	Rex545	ESI+: 502
561	Rex353	ESI+: 423
562	Rex545	1H-NMR (CDCl3): 1.26 (6H, d, J = 6.8Hz), 2.37 (3H, S), 2.62 (4H, br-s), 3.10 (4H, br-s), 3.40-3.47 (1H, m), 5.52 (1H, br-s), 6.91-6.96 (1H, m), 7.24-7.26 (1H, m), 7.53 (1H, dd, J = 2.7, 14.6Hz), 7.69 (1H, br-s), 10.70 (1H, br-s)

[Table 85] (# not part of the invention)

Ex	Structure
1#
2#
3#
4#
5#
6#

[Table 86] (# not part of the invention)

Ex	Structure
7#
8#
9#
10#
11#
12#
13#

[Table 87] (# not part of the invention)

Ex	Structure
14#
15#
16#
17#
18#
19#

[Table 88] (# not part of the invention)

Ex	Structure
20#
21#
22#
23#
24#
25#
26#

[Table 89] (# not part of the invention)

Ex	Structure
27#
28#
29#
30#
31#
32#
33#

[Table 90] (# not part of the invention)

Ex	Structure
34#
35#
36#
37#
38#
39#
40#

[0334] (# not part of the invention)

[Table 91] (# not part of the invention)

Ex	Structure
41#
42#
43#
44#
45#
46#
47#

[Table 92] (# not part of the invention)

Ex	Structure
48#
49#
50#
51#
52#
53#
54#

[Table 93] (# not part of the invention)

Ex	Structure
55#
56#
57#
58#
59#
60#
61#

[Table 94] (# not part of the invention)

Ex	Structure
62#
63#
64#
65#
66#
67#
68#

[Table 95] (# not part of the invention)

Ex	Structure
69#
70#
71#
72#
73#
74#
75#

[Table 96] (# not part of the invention)

Ex	Structure
76#
77#
78#
79#
80#
81#
82#

[Table 97] (# not part of the invention)

Ex	Structure
83#
84#
85#
86#
87#
88#
89#

[Table 98] (# not part of the invention)

Ex	Structure
90#
91#
92#
93#
94#
95#
96#
97#

[Table 99] (# not part of the invention)

Ex	Structure
98#
99#
100#
101#
102#
103#
104#

[Table 100] (# not part of the invention)

Ex	Structure
105#
106#
107#
108#
109#
110#
111#
112#

[Table 101] (# not part of the invention)

Ex	Structure
113#
114#
115#
116#
117#
118#
119#

[Table 102] (# not part of the invention)

Ex	Structure
120#
121#
122#
123#
124#
125#
126#

[Table 103] (# not part of the invention)

Ex	Structure
127#
128#
129#
130#
131#
132#
133#

[Table 104] (# not part of the invention)

Ex	Structure
134#
135#
136#
137#
138#
139#
140#

[Table 105] (# not part of the invention)

Ex	Structure
141#
142#
143#
144#
145#
146#
147#
148#

[Table 106] (# not part of the invention)

Ex	Structure
149#
150#
151#
152#
153#
154#
155#
156#

[Table 107] (# not part of the invention)

Ex	Structure
157#
158#
159#
160#
161#
162#
163#
164#
165#

[Table 108] (# not part of the invention)

Ex	Structure
166#
167#
168#
169#
170#
171#
172#
173#

[Table 109] (# not part of the invention)

Ex	Structure
174#
175#
176#
177#
178#
179#
180#
181#
182#

[Table 110] (# not part of the invention)

Ex	Structure
183#
184# *5
185# *5
186#
187#
188#
189#
190#
191#

[Table 111] (# not part of the invention)

Ex	Structure
192#
193#
194#
195#
196#
197#
198#
199#

[Table 112] (# not part of the invention)

Ex	Structure
200#
201#
202#
203#
204#
205#
206#
207#

[Table 113] (# not part of the invention)

Ex	Structure
208#
209#
210#
211#
212#
213#
214#
215#

[Table 114] (# not part of the invention)

Ex	Structure
216#
217#
218#
219#
220#
221#
222#

[Table 115] (# not part of the invention)

Ex	Structure
223#
224#
225#
226#
227#
228#
229#

[Table 116] (# not part of the invention)

Ex	Structure
230#
231#
232#
233#
234#
235#
236#
237#

[Table 117] (# not part of the invention)

Ex	Structure
238#
239#
240#
241#
242#
243#
244#
245#

[Table 118] (# not part of the invention)

Ex	Structure
246#
247#
248#
249#
250#
251#
252#
253#

[Table 119] (# not part of the invention)

Ex	Structure
254#
255#
256#
257#
258#
259#
260#
261#

[Table 120] (# not part of the invention)

Ex	Structure
262#
263#
264#
265#
266#
267#
268#
269#

[Table 121] (# not part of the invention)

Ex	Structure
270#
271#
272#
273#
274#
275#
276#
277#

[Table 122] (# not part of the invention)

Ex	Structure
278#
279#
280#
281#
282# *
283#
284#
285#

[Table 123] (# not part of the invention)

Ex	Structure
286#
287#
288#
289#
290#
291#
292#
293#
294#

[Table 124] (# not part of the invention)

Ex	Structure
295#
296#
297#
298#
299#
300#
301# *
302# *
303#

[Table 125] (# not part of the invention)

Ex	Structure
304#
305#
306#
307#
308#
309#
310#
311#
312#

[Table 126] (# not part of the invention)

Ex	Structure
313#
314# *
315#
316# *
317# *
318# *
319#
320#
321#

[Table 127] (# not part of the invention)

Ex	Structure
322#
323#
324#
325
326#
327#
328#
329#
330#

[Table 128] (# not part of the invention)

Ex	Structure
331#
332#
333#
334#
335#
336# *
337#
338#

[Table 129] (# not part of the invention)

Ex	Structure
339#
340
341
342#
343
344#
345#
346

[Table 130] (# not part of the invention)

Ex	Structure
347#
348#
349#
350#
351#
352#

[Table 131] (# not part of the invention)

Ex	Structure
353#
354
355
356#
357
358
359
360#

[Table 132] (# not part of the invention)

Ex	Structure
361#
362
363#
364#
365#
366#
367#

[Table 133] (# not part of the invention)

Ex	Structure
368#
369#
370
371#
372#
373#
374#

[Table 134] (# not part of the invention)

Ex	Structure
375
376#
377
378
379#
380#
381
382#

[Table 135] (# not part of the invention)

Ex	Structure
383#
384#
385#
386#
387
388
389

[Table 136] (# not part of the invention)

Ex	Structure
390
391
392
393#
394
395#
396
397

[Table 137] (# not part of the invention)

Ex	Structure
398#
399#
400#
401#
402
403#
404#
405#

[Table 138] (# not part of the invention)

Ex	Structure
406#
407
408
409
410#
411#
412#

[Table 139] (# not part of the invention)

Ex	Structure
413#
414#
415#
416
417
418#
419
420#

[Table 140] (# not part of the invention)

Ex	Structure
421
422
423#
424#
425
426
427#
428#

[Table 141] (# not part of the invention)

Ex	Structure
429
430#
431#
432#
433
434#
435
436 *6

[Table 142] (# not part of the invention)

Ex	Structure
437 *6
438 *7
439 *7
440#
441#
442#
443

[Table 143] (# not part of the invention)

Ex	Structure
444
445#
446
447#
448
449#
450#

[Table 144] (# not part of the invention)

Ex	Structure
451
452#
453#
454#
455#
456#
457#

[Table 145] (# not part of the invention)

Ex	Structure
458#
459
460
461#
462
463
464#

[Table 146] (# not part of the invention)

Ex	Structure
465#
466
467#
468
469
470#
471#
472#

[Table 147] (# not part of the invention)

Ex	Structure
473#
474
475#
476#
477#
478#
479#
480#

[Table 148] (# not part of the invention)

Ex	Structure
481#
482#
483#
484#
485#
486#
487#

[Table 149] (# not part of the invention)

Ex	Structure
488
489#
490 *8
491 *8
492
493 *9
494 *9

[Table 150] (# not part of the invention)

Ex	Structure
495#
496#
497#
498#
499#
500#

[Table 151] (# not part of the invention)

Ex	Structure
501#
502#
503#
504#
505#
506#
507

[Table 152]

Ex	Structure
508#
509#
510#
511#
512
513#

[Table 153] (# not part of the invention)

Ex	Structure
514
515#
516#
517#
518
519#

[Table 154] (# not part of the invention)

Ex	Structure
520#
521#
522#
523#
524#
525#
526#

[Table 155] (# not part of the invention)

Ex	Structure
527#
528#
529#
530#
531#
532#
533#

[Table 156] (# not part of the invention)

Ex	Structure
534
535
536#
537#
538
539
540#

[Table 157] (# not part of the invention)

EX	STRUCTURE
541#
542#
543#
544
545
546
547

[Table 158]

EX	STRUCTURE
548
549
550
551
552
553

[Table 159]

EX	STRUCTURE
554
555
556
557
558

[Table 160] (# not part of the invention)

EX	STRUCTURE
559
560#
561#
562
563#
564

[Table 161]

EX	STRUCTURE
565
566
567
568
569

[Table 162]

EX	STRUCTURE
570
571
572
573
574

[Table 163]

EX	STRUCTURE
575
576
577
578
579

[Table 164]

EX	STRUCTURE
580
581
582

[Table 165]

Ex	Syn	Data
1	Ex4	ESI+: 451
2	Ex4	ESI+: 463
3	Ex4	ESI+: 477
4	Ex4	ESI+: 491
5	Ex4	ESI+: 493
6	Ex4	ESI+: 509
7	Ex4	ESI+: 423
8	Ex4	ESI+: 449
9	Ex4	ESI+: 477
10	Ex4	FAB+: 450
11	Ex4	FAB+: 450
12	Ex4	FAB+: 449
13	Ex4	ESI+: 449
14	Ex4	ESI+: 449
15	Ex4	ESI+: 449
16	Ex4	ESI+: 436
17	Ex4	ESI+: 436
18	Ex4	ESI+: 436
19	Ex19	ESI+: 449
20	Ex4	ESI+: 435
21	Ex4	ESI+: 435
22	Ex4	ESI+: 463
23	Ex37	ESI+: 639
24	Ex4	ESI+: 435
25	Ex4	ESI+: 435
26	Ex4	ESI+: 421
27	Ex4	ESI+: 421
28	Ex37	ESI+: 535
29	Ex29	ESI+: 435
30	Ex405	FAB+: 477
31	Ex31	FAB+: 513
32	Ex4	ESI+: 477
33	Ex4	ESI+: 477
34	Ex4	ESI+: 372
35	Ex4	FAB+: 436
36	Ex4	ESI+: 400
37	Ex37	ESI+: 414
38	Ex4	ESI+: 428
39	Ex4	ESI+: 449
40	Ex4	ESI+: 463
41	Ex4	ESI+: 437
42	Ex4	ESI+: 436
43	Ex4	ESI-: 400
44	Ex4	ESI+: 463
45	Ex4	ESI+: 449
46	Ex4	ESI+: 464
47	Ex4	ESI+: 392
48	Ex4	ESI+: 450
49	Ex4	ESI+: 426
50	Ex4	ESI+: 468
51	Ex4	ESI+: 454
52	Ex4	ESI+: 489
53	Ex4	FAB+: 388
54	Ex4	FAB+: 450
55	Ex4	ESI+: 449
56	Ex4	ESI+: 470
57	Ex4	ESI+: 456
58	Ex4	ESI+: 468
59	Ex4	ESI+: 442
60	Ex4	ESI+: 414
61	Ex4	ESI+: 484
62	Ex4	ESI+: 470
63	Ex4	ESI+: 492
64	Ex4	ESI+: 504
65	Ex4	ESI+: 448
66	Ex4	ESI+: 490

[Table 166]

Ex	Syn	Data
67	Ex4	ESI+: 408
68	Ex4	ESI+: 434
69	Ex4	FAB+: 382
70	Ex4	FAB+: 409
71	Ex4	ESI+: 381
72	Ex4	FAB+: 410
73	Ex4	ESI+: 478
74	Ex4	ESI+: 506
75	Ex4	ESI+: 518
76	Ex4	ESI+: 492
77	Ex4	ESI+: 464
78	Ex4	ESI+: 502
79	Ex4	ESI+: 476
80	Ex4	ESI+: 482
81	Ex4	ESI+: 456
82	Ex4	ESI+: 428
83	Ex4	ESI+: 469, 471
84	Ex84	ESI+: 447
85	Ex84	ESI+: 433
86	Ex84	ESI+: 434
87	Ex4	ESI+: 434
88	Ex4	ESI+: 392
89	Ex84	ESI+: 400
90	Ex4	ESI+: 372
91	Ex4	ESI+: 520
92	Ex4	ESI+: 508
93	Ex4	ESI+: 488
94	Ex4	ESI+: 434
95	Ex4	ESI+: 462
96	Ex4	ESI+: 446
97	Ex4	ESI+: 472
98	Ex4	ESI+: 474
99	Ex4	ESI+: 460
100	Ex4	ESI+: 392
101	Ex84	FAB+: 419
102	Ex84	FAB+: 475
103	Ex84	FAB+: 448
104	Ex4	ESI+: 426
105	Ex4	ESI+: 426
106	Ex4	ESI+: 434
107	Ex4	ESI+: 422
108	Ex84	ESI+: 433
109	Ex84	ESI+: 448
110	Ex84	ESI+: 448
111	Ex84	FAB+: 406
112	Ex146	ESI+: 420
113	Ex4	ESI+: 436
114	Ex4	ESI+: 358
115	Ex4	ESI+: 392
116	Ex4	ESI+: 392
117	Ex84	ESI+: 423
118	Ex4	ESI+: 494
119	Ex4	ESI+: 508
120	Ex4	ESI+: 482
121	Ex4	ESI+: 428
122	Ex4	ESI+: 484
123	Ex4	ESI+: 468
124	Ex4	ESI+: 414
125	Ex4	ESI+: 468
126	Ex4	ESI+: 18
127	Ex4	ESI+: 486
128	Ex4	ESI+: 482
129	Ex4	ESI+: 522
130	Ex4	ESI+: 480
131	Ex4	FAB+: 508
132	Ex4	ESI+: 468

[Table 167]

Ex	Syn	Data
133	Ex4	FAB+: 414
134	Ex4	ESI+: 522
135	Ex4	FAB+: 534
136	Ex4	FAB+: 444
137	Ex4	ESI+: 498
138	Ex4	ESI+: 482
139	Ex4	FAB+: 428
140	Ex4	ESI+: 536
141	Ex4	ESI+: 460
142	Ex4	ESI+: 432
143	Ex4	ESI+: 488
144	Ex4	ESI+: 474
145	Ex4	ESI+: 460
146	Ex146	ESI+: 468
147	Ex84	ESI+: 486
148	Ex84	ESI+: 448
149	Ex84	ESI+: 434
150	Ex84	ESI+: 427
151	Ex84	ESI+: 535
152	Ex84	ESI+: 427
153	Ex84	ESI+: 427
154	Ex4	ESI+: 448
155	Ex84	ESI+: 447
156	Ex84	ESI+: 443
157	Ex84	ESI+: 433
158	Ex84	ESI+: 433
159	Ex159	ESI+: 440
160	Ex84	ESI+: 427
161	Ex84	ESI+: 481
162	Ex84	ESI+: 427
163	Ex84	ESI+: 447
164	Ex84	ESI+: 406
165	Ex146	ESI+: 448
166	Ex84	ESI+: 434
167	Ex84	ESI+: 461
168	Ex84	ESI+: 497
169	Ex84	ESI+: 461
170	Ex84	ESI+: 448
171	Ex84	FAB+: 431
172	Ex84	FAB+: 447
173	Ex4	FAB-: 405
174	Ex84	FAB-: 404
175	Ex84	FAB+: 479
176	Ex84	FAB+: 413
177	Ex84	ESI+: 454
178	Ex146	ESI+: 407
179	Ex84	ESI+: 454
180	Ex159	ESI+: 488
181	Ex181	ESI+: 484, 486
182	Ex84	ESI+: 357
183	Ex84	ESI+: 441
184	Ex84	ESI+: 469
185	Ex84	ESI+: 469
186	Ex84	ESI+: 441
187	Ex84	ESI+: 427
188	Ex84	ESI+: 346
189	Ex84	ESI+: 431
190	Ex190	ESI+: 532
191	Ex84	ESI+: 371
192	Ex146	APCI/ESI+: 371
193	Ex84	ESI+: 434
194	Ex84	ESI+: 434
195	Ex196	ESI+: 419
196	Ex196	ESI+: 433
197	Ex196	ESI+: 447
198	Ex196	ESI+: 447

[Table 168]

Ex	Syn	Data
199	Ex196	ESI+: 461
200	Ex196	ESI+: 515
201	Ex196	ESI+: 523
202	Ex196	ESI+: 447
203	Ex196	ESI+: 475
204	Ex196	ESI+: 491
205	Ex196	ESI+: 433
206	Ex196	ESI+: 433
207	Ex196	ESI+: 418
208	Ex196	ESI+: 448
209	Ex196	ESI+: 448
210	Ex196	ESI+: 496
211	Ex196	ESI+: 405
212	Ex196	ESI+: 405
213	Ex196	ESI+: 419
214	Ex196	ESI+: 495
215	Ex196	ESI+: 495
216	Ex196	ESI+: 419
217	Ex196	ESI+: 447
218	Ex196	ESI+: 420
219	Ex196	ESI+: 434
220	Ex196	ESI+: 438
221	Ex196	ESI+: 391
222	Ex196	ESI+: 405
223	Ex196	ESI+: 473
224	Ex196	ESI+: 447
225	Ex196	ESI+: 447
226	Ex196	ESI+: 449
227	Ex196	ESI+: 463
228	Ex196	ESI+: 515
229	Ex196	ESI+: 523
230	Ex196	ESI+: 433
231	Ex196	ESI+: 433
232	Ex196	ESI+: 433
233	Ex196	ESI+: 433
234	Ex196	ESI+: 433
235	Ex196	ESI+: 434
236	Ex196	ESI+: 434
237	Ex196	ESI+: 436
238	Ex196	ESI+: 448
239	Ex196	ESI+: 448
240	Ex196	ESI+: 447
241	Ex196	ESI+: 447
242	Ex196	ESI+: 420
243	Ex196	ESI+: 420
244	Ex196	ESI+: 405
245	Ex196	ESI+: 406
246	Ex196	ESI+: 462
247	Ex196	ESI+: 476
248	Ex196	ESI+: 447
249	Ex196	ESI+: 462
250	Ex196	ESI+: 463
251	Ex196	ESI+: 448
252	Ex196	ESI+: 433
253	Ex196	ESI+: 447
254	Ex196	ESI+: 434
255	Ex196	ESI+: 379
256	Ex196	ESI+: 393
257	Ex196	ESI+: 407
258	Ex196	ESI+: 421
259	Ex196	ESI+: 421
260	Ex196	ESI+: 421
261	Ex196	ESI+: 407
262	Ex196	ESI+: 380
263	Ex196	ESI+: 394
264	Ex196	ESI+: 408

[Table 169]

Ex	Syn	Data
265	Ex196	ESI+: 394
266	Ex196	ESI+: 410
267	Ex196	ESI+: 394
268	Ex196	ESI+: 438
269	Ex196	ESI+: 419
270	Ex196	ESI+: 481
271	Ex196	ESI+: 406
272	Ex196	ESI+: 434
273	Ex196	ESI+: 421
274	Ex196	ESI+: 394
275	Ex196	ESI+: 442
276	Ex196	ESI+: 413
277	Ex196	ESI+: 426
278	Ex196	ESI+: 456
279	Ex196	ESI+: 427
280	Ex196	ESI+: 528
281	Ex84	ESI+: 427
282	Ex84	ESI+: 455
283	Ex84	ESI+: 370
284	Ex84	ESI+: 567
285	Ex84	ESI+: 463
286	Ex84	ESI+: 483
287	Ex84	ESI+: 447
288	Ex84	ESI+: 443
289	Ex84	ESI+: 463
290	Ex84	ESI+: 535
291	Ex84	ESI+: 427
292	Ex84	ESI+: 396
293	Ex84	ESI+: 414
294	Ex84	ESI+: 525
295	Ex84	ESI+: 549
296	Ex146	ESI+: 448
297	Ex84	ESI+: 433
298	Ex84	ESI+: 407
299	Ex84	ESI+: 378
300	Ex84	ESI+: 404
301	Ex84	ESI+: 461
302	Ex302	ESI+: 489
303	Ex84	ESI+: 424
304	Ex84	ESI+: 396
305	Ex84	ESI+: 412
306	Ex84	ESI+: 407
307	Ex84	ESI+: 547
308	Ex84	ESI+: 429
309	Ex309	ESI+: 399
310	Ex310	ESI+: 453
311	Ex84	ESI+: 549
312	Ex84	ESI+: 428
313	Ex84	ESI+: 496
314	Ex84	ESI+: 494
315	Ex84	ESI+: 427
316	Ex84	ESI+: 480
317	Ex84	ESI+: 466
318	Ex84	ESI+: 494
319	Ex84	ESI+: 401
320	Ex84	ESI+: 447
321	Ex84	ESI+: 440
322	Ex302	ESI+: 468
323	Ex146	ESI+: 502
324	Ex84	ESI+: 440
325	Ex84	ESI+: 454
326	Ex84	ESI+: 526
327	Ex84	ESI+: 414
328	Ex84	ESI+: 410
329	Ex84	ESI+: 441
330	Ex84	ESI+: 414

[Table 170]

Ex	Syn	Data
331	Ex84	ESI+: 409
332	Ex84	ESI+: 508
333	Ex84	ESI+: 385
334	Ex84	ESI+: 482
335	Ex84	ESI+: 480
336	Ex84	ESI+: 468
337	Ex84	ESI+: 453
338	Ex84	ESI+: 512
339	Ex84	ESI+: 484
340	Ex84	ESI+: 567
341	Ex84	ESI+: 537
342	Ex84	ESI+: 466
343	Ex343	ESI+: 468
344	Ex84	ESI+: 512
345	Ex159	ESI+: 546
346	Ex381	ESI+: 446
347	Ex84	ESI+: 454
348	Ex84	ESI+: 581
349	Ex84	ESI+: 581
350	Ex84	ESI+: 570
351	Ex146	ESI+: 549
352	Ex84	ESI+: 449
353	Ex84	ESI+: 463
354	Ex84	ESI+: 522
355	Ex84	ESI+: 484
356	Ex84	ESI+: 539
357	Ex84	ESI+: 441
358	Ex381	ESI+: 439
359	Ex84	ESI+: 439
360	Ex84	ESI+: 636
361	Ex84	ESI+: 469
362	Ex84	ESI+: 468
363	Ex84	ESI+: 538
364	Ex84	ESI+: 560
365	Ex84	ESI+: 455
366	Ex84	ESI+: 476
367	Ex84	ESI+: 455
368	Ex84	ESI+: 442
369	Ex84	ESI+: 477
370	Ex146	ESI+: 605
371	Ex84	ESI+: 538
372	Ex84	ESI+: 560
373	Ex84	ESI+: 631
374	Ex84	ESI+: 456
375	Ex84	ESI+: 455
376	Ex84	ESI+: 552
377	Ex84	ESI+: 468
378	Ex84	ESI+: 551
379	Ex84	ESI+: 464
380	Ex84	ESI+: 442
381	Ex381	ESI+: 469
382	Ex84	ESI+: 569
383	Ex84	ESI+: 484
384	Ex84	ESI+: 522
385	Ex84	ESI+: 617
386	Ex84	ESI+: 644
387	Ex84	ESI+: 453
388	Ex343	ESI+: 619
389	Ex343	ESI+: 646
390	Ex84	ESI-: 488
391	Ex84	ESI+: 482
392	Ex84	ESI+: 565
393	Ex84	ESI+: 540
394	Ex381	ESI+: 440
395	Ex302	ESI+: 522
396	Ex302	ESI+: 524

[Table 171]

Ex	Syn	Data
397	Ex84	ESI+: 543
398	Ex84	ESI-: 479
399	Ex84	ESI+: 562
400	Ex84	ESI+: 434, 436
401	Ex84	ESI+: 484
402	Ex84	ESI+: 536
403	Ex84	ESI+: 537
404	Ex84	ESI+: 522
405	Ex405	ESI+: 481
406	Ex84	ESI+: 536
407	Ex84	ESI+: 536
408	Ex84	ESI+: 536
409	Ex84	ESI+: 550
410	Ex84	ESI+: 484
411	Ex84	ESI+: 441
412	Ex84	ESI+: 456
413	Ex84	ESI+: 468
414	Ex84	ESI+: 482
415	Ex31	ESI+: 518
416	Ex302	ESI+: 482
417	Ex302	ESI+: 540
418	Ex84	ESI+: 607
419	Ex381	ESI+: 508
420	Ex84	ESI+: 554
421	Ex381	ESI+: 454
422	Ex146	ESI+: 535
423	Ex302	ESI+: 590
424	Ex302	ESI+: 536
425	Ex302	ESI+: 550
426	Ex302	ESI+: 496
427	Ex84	ESI+: 496
428	Ex84	ESI+: 555
429	Ex84	ESI+: 576
430	Ex84	ESI+: 518
431	Ex302	ESI+: 521
432	Ex84	ESI+: 553
433	Ex381	ESI+: 453
434	Ex31	ESI+: 531
435	Ex84	ESI+: 564
436	Ex436	ESI+: 550
437	Ex436	ESI+: 550
438	Ex438	ESI+: 655
439	Ex438	ESI+: 655
440	Ex84	ESI+: 453
441	Ex84	ESI+: 483
442	Ex84	ESI+: 4488
443	Ex84	ESI+: 483
444	Ex84	ESI+: 566
445	Ex84	ESI+: 544
446	Ex84	ESI+: 597
447	Ex302	ESI+: 602
448	Ex84	ESI+: 550
449	Ex302	ESI+: 642
450	Ex302	ESI-: 636
451	Ex302	ESI+: 467
452	Ex84	ESI+: 482
453	Ex84	ESI+: 609
454	Ex84	ESI+: 482
455	Ex84	ESI+: 607
456	Ex84	ESI+: 536
457	Ex84	ESI+: 566
458	Ex84	APCI/ESI+: 511
459	Ex84	ESI+: 581
460	Ex534	ESI+: 507
461	Ex84	ESI+: 522
462	Ex405	ESI+: 549

[Table 172]

Ex	Syn	Data
463	Ex405	ESI+: 641
464	Ex302	ESI+: 644
465	Ex84	ESI+: 561
466	Ex84	ESI+: 565
467	Ex84	ESI+: 570
468	Ex381	ESI+: 470
469	Ex302	ESI+: 495
1470	Ex302	ESI+: 535
471	Ex302	ESI+: 449
472	Ex84	ESI+: 449
473	Ex84	ESI+: 607
474	Ex381	ESI+: 507
475	Ex84	ESI+: 482
476	Ex84	ESI+: 471
477	Ex84	ESI+: 469
478	Ex84	ESI+: 567
479	Ex84	ESI+: 554
480	Ex84	ESI+: 469
481	Ex84	ESI+: 499
482	Ex159	ESI+: 533
483	Ex84	ESI+: 565
484	Ex84	ESI+: 511
485	Ex84	ESI+: 547
486	Ex84	ESI+: 530
487	Ex84	ESI+: 525
488	Ex302	ESI+: 512
489	Ex302	ESI+: 552
490	Ex84	ESI+: 579
491	Ex84	ESI+: 579
492	Ex302	ESI+: 608
493	Ex84	ESI+: 593
494	Ex84	ESI+: 593
495	Ex495	ESI+: 489
496	Ex84	FAB+. 553
497	Ex84	ESI+: 553
498	Ex84	ESI+: 540
499	Ex499	ESI+: 573
500	Ex84	FAB+: 540
501	Ex84	ESI+: 485
502	Ex84	ESI+: 499
503	Ex84	ESI+: 512
504	Ex84	ESI+: 498
505	Ex84	ESI+: 567
506	Ex84	ESI+: 551
507	Ex84	APCI/ESI+: 626
508	Ex508	APCI/ESI+: 446
509	Ex84	ESI+: 539
510	Ex84	ESI+: 567
511	Ex84	ESI+: 554
512	Ex84	ESI+: 537
513	Ex84	ESI+: 611
514	Ex302	ESI+: 521
515	Ex84	ESI+: 532
516	Ex84	ESI+: 568
517	Ex146	ESI+: 651
518	Ex381	ESI+: 551
519	Ex84	ESI+: 572
520	Ex84	ESI+: 663
521	Ex84	ESI+: 594
522	Ex84	ESI+: 608
523	Ex84	ESI+: 494
524	Ex84	ESI+: 514
525	Ex84	ESI+: 561
526	Ex84	ESI+: 511
527	Ex84	ESI+: 644
528	Ex84	ESI+: 547

[Table 173]

Ex	Syn	Data
529	Ex84	ESI+: 525
530	Ex84	ESI+: 483
531	Ex84	ESI+: 499
532	Ex159	ESI+: 517
533	Ex159	ESI+: 533
534	Ex534	ESI+: 536
535	Ex84	ESI+: 564
536	Ex495	ESI+: 473
537	Ex495	ESI+: 489
538	Ex499	ESI+: 557
539	Ex499	ESI+: 573
540	Ex84	ESI+: 573
541	Ex84	ESI+: 559
542	Ex84	APCI/ESI+: 613
543	Ex84	ESI+: 613
544	Ex84	ESI+: 550
545	Ex84	ESI+: 440
546	Ex84	ESI+: 523
547	Ex84	ESI+: 553
548	Ex84	ESI+: 470
549	Ex343	ESI+: 537
550	Ex84	ESI+: 458
551	Ex302	ESI+: 553
552	Ex302	ESI+: 523
553	Ex84	ESI+: 484
554	Ex84	ESI+: 454
555	Ex84	ESI+: 472
556	Ex84	ESI+: 567
557	Ex84	ESI+: 541
558	Ex84	ESI+: 537
559	Ex84	ESI+: 555
560	Ex84	APCI/ESI+: 535
561	Ex84	ESI+: 556
562	Ex381	ESI+: 456
563	Ex84	ESI+: 524
564	Ex381	ESI+: 426
565	Ex84	ESI+: 454
566	Ex84	ESI+: 537
567	Ex343	ESI+: 468
568	Ex146	ESI+: 605
569	Ex84	ESI+: 551
570	Ex343	ESI+: 619
571	Ex84	ESI+: 565
572	Ex302	ESI+: 496
573	Ex84	ESI+: 565
574	Ex84	ESI+: 537
575	Ex499	ESI+: 557
576	Ex84	ESI+: 523
577	Ex84	ESI+: 553
578	Ex343	ESI+: 537
579	Ex84	ESI+: 441
580	Ex84	ESI+: 484
581	Ex84	ESI+: 454
582	Ex84	ESI+: 537

[Table 174]

Ex	Data
86	1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.8 Hz), 1.33-1.50 (4H, m), 1.79-1.95 (4H, m), 2.60 (2H, q, J = 7.8 Hz), 3.21 (3H, s), 3.37-3.49 (1H, m), 3.89-4.01 (1H, m), 4.54 (1H, d, J = 4.4 Hz), 6.76 (1H, d, J = 7.9 Hz), 7.33-7.42 (1H, m), 7.44-7.57 (2H, m), 7.58-7.65 (1H, m), 7.96-8.03 (1H, m), 8.15-8.21 (1H, m), 11.59 (1H, s).
110	1H-NMR (DMSO-d6): 1.13-1.25 (6H, m), 1.46-1.64 (6H, m), 1.79-1.91 (2H, m), 2.61 (2H, q, J = 7.4 Hz), 3.21 (3H, s), 3.94-4.09 (1H, m), 4.26 (1H, s), 6.72 (1H, d, J = 7.9 Hz), 7.33-7.42 (1H, m), 7.44-7.58 (2H, m), 7.59-7.66 (1H, m), 7.98-8.04 (1H, m), 8.16-8.20 (1H, m), 11.58 (1H, s).
284	1H-NMR (CDCl3): 1.26-1.36 (5H, m), 1.48-1.56 (2H, m), 1.68-1.76 (2H, m), 1.95 (2H, d, J = 11.6 Hz), 2.08 (2H, d, J = 10.4 Hz), 2.26 (2H, d, J = 11.6 Hz), 2.30 (3H, s), 2.30-2.73 (13H, m), 3.64-3.74 (4H, m), 3.93-3.97 (4H, m), 4.52 (1H, d, J = 7.2 Hz), 5.13 (1H, br-s), 6.50 (1 H, dd, J = 2.4 Hz, 9.2 Hz), 6.58 (1 H, d, J = 2.4 Hz), 7.46 (1 H, br-s), 8.39 (1H, d, J = 8.8 Hz), 10.98 (1H, s).
325	1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz), 1.22-1.48 (4H, m), 1.84-2.00 (4H, m), 2.25 (3H, s), 2.44-2.59 (6H, m), 3.00-3.12 (4H, m), 3.43 (1H, m), 3.80 (1H, m), 4.56 (1H, d, J = 4.7 Hz), 6.63 (1H, d, J = 8.0 Hz), 6.87 (2H, d, J = 9.2 Hz), 7.13 (1H, br), 7.47 (1H, br), 7.51 (2H, d, J = 9.2 Hz), 10.9 (1H, s).
328	1H-NMR (CDCl3): 1.25-1.67 (7H, m), 2.04 (2H, m), 2.17-2.22 (2H, m), 2.48-2.55 (2H, m), 3.72 (1H, m), 4.03 (3H, s), 4.05 (1H, m), 4.60 (1H, m), 5.19 (1H, m), 7.44 (1H, m), 7.51 (1H, m), 7.62 (1H, m), 7.78 (1H, s), 7.88 (1H, s), 11.14 (1H, br-s).
340	1H-NMR (CDCl3): 1.22-1.54 (7H, m), 1.74-1.94 (4H, m), 2.01-2.10 (2H, m), 2.16-2.26 (2H, m), 2.30 (3H, s), 2.32-2.74 (13H, m), 3.50 (2H, d, J = 11.4 Hz), 3.65-3.76 (1H, m), 3.87 (3H, s), 3.92-4.03 (1H, m), 4.52 (1H, d, J = 7.3 Hz), 5.12 (1H, br-s), 6.71 (1H, s), 6.84-6.90 (2H, m), 7.45-7.55 (2H, m), 10.74 (1H, s).

[Table 175]

Ex	Data
341	1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz), 1.21-1.60 (6H, m), 1.75-2.00 (6H, m), 2.14 (3H, s), 2.20-2.72 (13H, m), 3.43 (1H, m), 3.58 (2H, m), 3.80 (1H, m), 4.57 (1H, d, J = 4.4 Hz), 6.63 (1H, d, J = 7.3 Hz), 6.86 (2H, d, J = 8.7 Hz), 7.13 (1H, br-s), 7.40-7.60 (3H, m), 10.92 (1H, s).
343	1H-NMR (DMSO-d6): 1.14 (6H, d, J =6.6 Hz), 1.21-1.48 (4H, m), 1.85-1.98 (4H, m), 2.22 (3H, s), 2.41-2.48 (4H, m), 2.99-3.18 (5H, m), 3.37-3.48 (1H, m), 3.74-3.87 (1H, m), 4.56 (1H, d, J = 4.7 Hz), 6.67 (1H, d, J = 7.6 Hz), 6.86 (2H, d, J = 9.0 Hz), 7.11-7.18 (1H, m), 7.40-7.47 (1H, m), 7.50 (2H, d, J = 9.0 Hz), 10.91 (1H, s)
347	1H-NMR (DMSO-d6): 1.10-1.49 (7H, m), 1.80-1.96 (4H, m), 2.22 (3H, s), 2.40-2.61 (6H, m), 3.06-3.18 (4H, m), 3.43 (1H, m), 3.86 (1H, m), 4.56 (1H, d, J = 4.3 Hz), 6.57 (1H, m), 6.63 (1H, d, J = 7.6 Hz), 6.91 (1H, m), 7.10 (1H, m), 7.18 (1H, br), 7.29 (1H, m), 7.51 (1H, br-s), 11.09 (1H, s).
354	1H-NMR (DMSO-d6): 1.12-1.32 (5H, m), 1.36-1.50 (2H, m), 1.78-1.96 (4H, m), 2.22 (3H, s), 2.35-2.63 (6H, m), 2.78-2.88 (4H, m), 3.41 (1H, m), 3.87 (1H, m), 4.55 (1H, d, J = 3.9 Hz), 6.68 (1H, d, J = 7.9 Hz), 7.27 (1H, br-s), 7.46 (1H, d, J = 8.7 Hz), 7.56 (1H, br-s), 7.61 (1H, m), 8.18 (1H, m), 11.37 (1H, s)
355	1H-NMR (DMSO-d6): 1.10-1.32 (5H, m), 1.32-1.50 (2H, m), 1.82-1.96 (4H, m), 2.21 (3H, s), 2.35-2.60 (6H, m), 2.84-2.99 (4H, m), 3.42 (1H, m), 3.81 (3H, s), 3.87 (1H, m), 4.56 (1H, d, J = 4.6 Hz), 6.61 (1H, d, J = 7.8 Hz), 6.79 (1H, d, J = 8.6 Hz), 7.09 (1H, d, J = 2.2 Hz), 7.16 (1 H, br-s), 7.24 (1H, dd, J = 8.6, 2.2 Hz), 7.49 (1H, br-s), 11.03 (1 H, s)
357	1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz), 1.21-1.48 (4H, m), 1.84-2.00 (4H, m), 2.55 (2H, q, J = 7.4 Hz), 3.00-3.06 (4H, m), 3.42 (1H, m), 3.69-3.86 (5H, m), 4.58 (1H, d, J = 4.8 Hz), 6.65 (1H, d, J = 7.4 Hz), 6.84-6.90 (2H, m), 7.16 (1H, m), 7.44-7.56 (3H, m), 10.95 (1H, s)

[Table 176]

Ex	Data
370	1H-NMR (DMSO-d6): 1.10-1.32 (5H, m), 1.36-1.58 (4H, m), 1.75-1.93 (6H, m), 2.14 (3H, s), 2.22-2.38 (4H, m), 2.40-2.62 (5H, m), 2.65-2.78 (2H, m), 2.87-2.97 (2H, m), 3.20-3.48 (3H, m), 3.87 (1H, m), 4.56 (1H, d, J = 3.9 Hz), 6.67 (1H, d, J = 7.9 Hz), 7.27 (1H, br-s), 7.42 (1H, d, J = 8.7 Hz), 7.55 (1H, br-s), 7.62 (1H, m), 8.15 (1H, m), 11.37 (1H, s)
377	1H-NMR (CDCl3): 1.24-1.35 (5H, m), 1.43-1.50 (2H, m), 2.04-2.07 (2H, m), 2.17-2.24 (2H, m), 2.32 (3H, s), 2.36 (3H, s), 2.47 (2H, q, J = 7.1 Hz), 2.58 (4H, br-s), 2.92-2.94 (4H, m), 3.70 (1H, m), 3.95-3.99 (1H, m), 4.51 (1H, d, J = 7.1 Hz), 5.11 (1H, br-s), 6.98 (1H, d, J = 8.3 Hz), 7.48-7.52 (3H, m), 10.70 (1H, br-s).
378	1H-NMR (CDCl3): 1.23-1.32 (5H, m), 1.45-1.72 (4H, m), 1.92-2.08 (4H, m), 2.17-2.30 (8H, m), 2.45-2.67 (13H, m), 3.15 (2H, m), 3.71-3.73 (1H, m), 3.98 (1H, m), 4.51 (1H, d, J = 7.1 Hz), 5.11 (1H, m), 6.93 (1H, d, J = 8.5 Hz), 7.46-7.52 (3H, m), 10.70 (1H, br-s).
383	1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz), 1.20-1.32 (2H, m), 1.35-1.48 (2H, m), 1.81-1.93 (4H, m), 2.22 (3H, s), 2.40-2.60 (6H, m), 2.94-3.04 (4H, m), 3.36-3.47 (1H, m), 3.76 (3H, s), 3.80-3.93 (1H, m), 4.53 (1H, d, J = 4.3 Hz), 6.58 (1H, d, J = 7.7 Hz), 6.82 (1H, d, J = 8.6 Hz), 6.86 (1H, d, J = 2.0 Hz), 7.10-7.17 (1H, m), 7.37 (1H, dd, J = 2.0, 8.6 Hz), 7.44-7.51 (1H, m), 10.93 (1H, s)
387	1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.3 Hz), 1.22-1.52 (4H, m), 1.54-1.78 (4H, m), 1.85-2.03 (6H, m), 2.18 (3H, s), 2.40 (1H, m), 2.56 (2H, q, J = 7.3 Hz), 2.80-2.90 (2H, m), 3.43 (1H, m), 3.82 (1H, m), 4.58 (1H, d, J = 4.7 Hz), 6.70 (1H, d, J = 7.3 H), 7.13 (2H, d, J = 8.5 Hz), 7.19 (1H, br), 7.50 (1H, br), 7.59 (2H, d, J = 8.5 Hz), 11.11 (1H, s)

[Table 177]

Ex	Data
388	1H-NMR (DMSO-d6): 1.15 (6H, d, J = 6.7 Hz), 1,18-1.33 (2H, m), 1.36-1.59 (4H, m), 1.75-1.91 (6H, m), 2.14 (3H, s), 2.21-2.56 (9H, m), 2.64-2.79 (2H, m), 2.87-2.98 (2H, m), 3.09-3.21 (1H, m), 3.36-3.48 (1H, m), 3.79-3.96 (1H, m), 4.56 (1H, d, J = 3.9 Hz), 6.72 (1H, d, J = 7.3 Hz), 7.22-7.33 (1H, m), 7.42 (1H, d, J = 9.0 Hz), 7.48-7.56 (1H, m), 7.58-7.66 (1H, m), 8.14 (1H, d, J = 2.3 Hz), 11.35 (1H, s).
391	1H-NMR (CDCl3): 1.26-1.30 (6H, m), 1.49-1.76 (6H, m), 1.97-2.01 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 2.48 (2H, q, J = 7.3 Hz), 2.59 (4H, br-s), 2.91-2.94 (4H, m), 3.73-3.97 (1H, m), 4.61 (1H, d, J = 7.5 Hz), 5.10 (1H, br-s), 6.96 (1H, d, J = 8.5 Hz), 7.48-7.53 (3H, m), 10.69 (1H, br-s).
392	1H-NMR (CDCl3): 1.26-1.32 (6H, m), 1.54-1.76 (8H, m), 1.92-2.00 (4H, m), 2.28 (3H, s), 2.30 (3H, s), 2.47 (2H, q, J = 7.3 Hz), 2.60-2.66 (11H, m), 3.12-3.15 (2H, m), 3.94-3.97 (1H, m), 4.60 (1H, d, J = 7.3 Hz), 5.10 (1H, br-s), 6.91 (1H, d, J = 8.5 Hz), 7.41-7.71 (3H, m), 10.69 (1H, br-s).
399	1H-NMR (CDCl3): 0.13-0.16 (2H, m), 0.52-0.57 (2H, m), 0.92 (1H, m), 1.24-1.58 (7H, m), 2.03 (2H, m), 2.18 (2H, m), 2.33 (2H, m), 2.49 (2H, q, J = 7.6 Hz), 2.68 (4H, br-s), 2.98 (4H, m), 3.66 (1H, m), 4.00 (1H, m), 4.56 (1H, d, J = 7.6 Hz), 5.16 (1H, m), 7.34 (1H, d, J = 8.8 Hz), 7.51 (1H, m), 7.62 (1H, dd, J = 8.8, 2.4 Hz), 8.18 (1H, d, J = 2.4 Hz), 10.96 (1H, br-s).
406	1H-NMR (CDCl3): 1.29 (3H, t, J = 7.3 Hz), 1.43-1.52 (4H, m), 1.85-1.90 (1H, m), 2.01-2.04 (2H, m), 2.12-2.18 (3H, m), 2.29 (6H, s), 2.46 (2H, q, J = 7.3 Hz), 2.86-2.90 (1H, m), 3.16-3.37 (4H, m), 3.66 (1H, m), 3.97-4.00 (1H, m), 4.53 (1H, d, J = 7.6 Hz), 5.15 (1H, br-s), 7.11 (1H, d, J = 8.8 Hz), 7.48-7.55 (2H, m), 8.15 (1H, d, J = 2.4 Hz), 10.84 (1H, br-s).

[Table 178]

Ex	Data
426	1H-NMR (CDCl3): 1.11 (6H, d, J = 6.3 Hz), 1.24-1.32 (5H, m), 1.39-1.52 (2H, m), 2.05-2.07 (2H, m), 2.20-2.23 (2H, m), 2.32 (3H, s), 2.47 (2H, q, J = 7.3 Hz), 2.70-2.78 (5H, m), 2.94-2.96 (5H, m), 3.66-3.71 (1 H, m), 3.93-3.98 (1H, m), 4.54 (1H, d, J = 7.1 Hz), 5.19 (1H, br-s), 6.99 (1H, d, J = 8.5 Hz), 7.44-7.55 (3H, m), 10.68 (1H, br-s).
459	1H-NMR (CDCl3):1.20-1.54 (10H, m), 1.70-2.09 (6H, m), 2.21 (2H, d, J = 11.4 Hz), 2.29 (3H, s), 2.32-2.73 (13H, m), 3.54 (2H, d, J = 11.6 Hz), 3.63-3.75 (1H, m), 3.92-4.40 (1H, m), 4.07 (2H, q, J = 6.9 Hz), 4.52 (1H, d, J = 7.3 Hz), 5.12 (1H, br-s), 6.84 (1H, d, J = 8.7 Hz), 6.93 (1H, d, J = 2.1 Hz), 7.26 (1H, s), 7.47 (2H, dd, J = 8.5, 2,2 Hz), 10.72 (1H, s).
466	1H-NMR (CDCl3): 1.26-2.74 (38H, m), 3.12-3.15 (2H, m), 4.08 (1H, m), 4.63 (1H, d, J = 6.8 Hz), 5.14 (1H, br-s), 6.93 (1H, d, J = 8.1 Hz), 7.49-7.54 (3H, m), 10.71 (1H, br-s).
490	1H-NMR (CDCl3): 0.96 (3H, t, J = 7.6 Hz), 1.25-2.71 (36H, m), 3.11 - 3.15 (2H, m), 3.95-3.97 (1H, m), 4.61 (1H, d, J = 7.3 Hz), 5.09 (1H, br-s), 6.91 (1H, d, J = 8.8 Hz), 7.40-7.56 (3H, m), 10.68 (1H, br-s).
491	1 H-NMR (CDCl3): 0.92 (3H, t, J = 7.3 Hz), 1.26-2.71 (36H, m), 3.12-3.15 (2H, m), 4.11-4.17 (1H, m), 4.64 (1H, d, J = 6.8 Hz), 5.13 (1H, br-s), 6.93 (1H, d, J = 8.1 Hz), 7.49-7.54 (3H, m), 10.71 (1H, br-s).
493	1H-NMR (CDCl3): 0.96 (6H, d, J = 7.1 Hz), 1.26-1.30 (5H, m), 1.56-2.69 (30H, m), 3.13 (2H, d, J = 10.5 Hz), 3.94 (1H, m), 4.61 (1H, d, J = 7.8 Hz), 5.09 (1H, br-s), 6.91 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 6.6 Hz), 7.48 (1H, br-s), 7.56 (1H, d, J = 2.7 Hz), 10.67 (1H, br-s).
494	1 H-NMR (CDCl3): 0.95 (6H, d, J = 6.8 Hz), 1.25-3.18 (37H, m), 3.64-3.67 (1H, m), 4.72 (1H, d, J = 7.1 Hz), 5.12 (1H, br-s), 6.92 (1H, d, J = 8.5 Hz), 7.48-7.54 (3H, m), 10.73 (1H, br-s).

[Table 179]

Ex	Data
512	1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.4 Hz), 1.46-1.72 (4H, m), 1.77-1.93 (4H, m), 2.15 (3H, s), 2.20-2.40 (8H, m), 2.44-2.63 (8H, m), 2.97-3.08 (2H, m), 3,34-3.46 (2H, m), 3.88-4.00 (2H, m), 4.11 (1H, m), 6.76 (1H, d, J = 7.5 Hz), 6.94 (1H, d, J = 8.6 Hz), 7.18 (1H, br-s), 7.34 (1H, m), 7.46 (1H, m), 7.51 (1H, br-s), 11.00 (1H, s).
534	1H-NMR (DMSO-d6): 1.18(3H, t, J = 7.4Hz), 1.39-1.61 (4H, m), 1.78-1.88 (4H, m), 2.14 (3H, s), 2.20-2.39 (8H, m), 2.44-2.62 (10H, m), 2.95-3.06 (4H, m), 3.95 (1H, m), 6.70 (1H, d, J = 7.6 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.15 (1H, br-s), 7.36 (1H, m), 7.43-7.54 (2H, m), 11.01 (1H, s).
544	1H-NMR (DMSO-d6): 1.18 (3H, t, J = 7.4 Hz), 1,48-1.72 (4H, m), 1.77-1.90 (4H, m), 1.90-2.01 (2H, m), 2.14 (3H, s), 2.18 (3H, s), 2.21-2.62 (16H, m), 2.77-2.87 (2H, m), 2.97-3.07 (2H, m), 3.87 (1H, m), 6.72 (1H, m), 6.92 (1H, m), 7.19 (1H, m), 7.28 (1H, m), 7.46-7.56 (2H, m), 11.02 (1H, s)
545	1H-NMR (DMSO-d6): 1.18 (3H, t, J = 7.4 Hz), 1.55-1.69 (2H, m), 1.83-1.92 (2H, m), 2.22 (3H, s), 2.40-2.50 (4H, m), 2.57 (2H, q, J = 7.4 Hz), 2.98-3.14 (4H, m), 3.36-4.48 (2H, m), 3.88-3.98 (2H, m), 4.06 (1H, m), 6.78 (1H, m), 6.84-6.94 (2H, m), 7.18 (1H, m), 7.40-7.54 (3H, m), 10.91 (1H, s)
546	1H-NMR (DMSO-d6): 1.18 (3H, t, J = 7,4 Hz), 1.42-1.68 (4H, m), 1.78-1.92 (4H, m), 2.13 (3H, s), 2.20-2.64 (13H, m), 3.26-3.46 (2H, m), 3.57-3.67 (2H, m), 3.89-3.97 (2H, m), 4.05 (1H, m), 6.78 (1H, m), 6.85-6.93 (2H, m), 7.17 (1H, m), 7.42-7.53 (3H, m), 10.89 (1H, s)
547	1 H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.4 Hz), 1.44-1.72 (4H, m), 1.74-1.90 (4H, m), 2.14 (3H, s), 2.18-2.64 (13H, m), 3.18-3.44 (4H, m), 3.81 (3H, s), 3.86-3.96 (2H, m), 4.10 (1H, m), 6.77 (1H, m), 6.82 (1H, m), 7.03 (1H, m), 7.20 (1H, m), 7.25 (1H, m), 7.52 (1H, m), 11.01 (1H, m)

[Table 180]

Ex	Data
565	1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.2 Hz), 1.22-1.48 (4H, m), 1.86-1.98 (4H, m), 2.26 (3H, s), 2.47-2.58 (6H, m), 3.01-3.14 (4H, m), 3.14-3.60 (1H, m), 3.82-3.87 (1H, m), 4.59 (1H, br-s), 6.60 (1H, s), 6.65 (1H, d, J = 7.6 Hz), 6.83-6.90 (2H, m), 7.12-7.19 (1H, m), 7.44-7.54 (3H, m), 10.95 (1H, s)
	XRD: 12.6, 17.6, 22.2, 23.5, 24.2
566	1H-NMR (DMSO-d6): 1.17(3H,t,J=7.6Hz), 1.22-1.62(6H,m), 1.78-2.02 (6H, m), 2.20 (3H, s), 2.24-2.76 (14H, m), 3.10-3.88 (4H, m), 6.55 (1H, s), 6.66 (1H, d, J = 6.0 Hz), 6.83-6.90 (2H, m), 7.12-7.19 (1H, m), 7.44-7.54 (3H, m), 10.93 (1 H, s)
	XRD: 5.7, 18.0, 18.9, 20.1, 20.2
567	1H-NMR (DMSO-d6): 1.13 (6H, d, J = 6.8 Hz), 1.21-1.48 (4H, m), 1.84-1.98 (4H, m), 2.26 (3H, s), 2.48-2.56 (4H, m), 3.03-3.18 (5H, m), 3.37-3.47 (1H, m), 3.75-3.86 (1H, m), 4.58 (1H, br-s), 6.59 (1H, s), 6.70 (1H, d, J = 7.6 Hz), 6.84-6.90 (2H, m), 7.15-7.20 (1H, m), 7.42-7.47 (1H, m), 7.48-7.54 (2H, m), 10.92 (1H, s)
	XRD: 11.0, 11.2, 17.3, 17.5, 22.5
568	1H-NMR (DMSO-d6): 1.14-1.34 (5H, m), 1.36-1,61 (4H, m), 1.78-1.94 (6H, m), 2.22 (3H, s), 2.28-2.65 (12H, m), 2.68-2.80 (2H, m), 2.89-3.01 (2H, m), 3.36-3.47 (1H, m), 3.81-3.94 (1H, m), 6.55 (1H, s), 6.70 (1H, d, J = 7.6 Hz), 7.28-7.32 (1H, m), 7.43 (1H, d, J = 8.8 Hz), 7.54-7.64 (2H, m), 8.17 (1H, d, J = 2.4 Hz), 11.39 (1H, s)
	XRD: 8.4, 8.5, 20.2, 20.3, 20.4
569	1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.6 Hz), 1.21-1.35 (2H, m), 1.36-1.49 (2H, m), 1.50-1.63 (2H, m), 1.80-1.98 (6H, m), 2.24 (3H, s), 2.25 (3H, s), 2.30-2.70 (14H, m), 2.98-3.10 (2H, m), 3.37-3.48 (1H, m), 3.80-3.92 (1H, m), 6.57 (1H, s), 6.65 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.14-7.22 (1H, m), 7.37 (1H, dd, J = 2.4, 8,8 Hz), 7.46-7.53 (2H, m), 11.03 (1H, s)
	XRD: 9.5, 18.4, 19.0, 19.4, 23.9

[Table 181]

Ex	Data
570	1H-NMR (DMSO-d6): 1.15 (6H, d, J = 6.4 Hz), 1.18-1.32 (2H, m), 1.37-1.58 (4H, m), 1.78-1.91 (6H, m), 2.21 (3H, s), 2.28-2.80 (12H, m), 2.89-2.98 (2H, m), 3.10-3.60 (2H, m), 3.82-3.94 (1H, m), 6.55 (1H, s), 6.75 (1H, d, J = 8.0 Hz), 7.28-7.35 (1H, m), 7.43 (1H, d, J = 8.4 Hz), 7.50-7.57 (1H, m), 7.59-7.65 (1 H, m), 8.15 (1H, d, J = 2.8 Hz), 11.36 (1H, s)
	XRD: 17.9, 18.3, 18.4, 18.9, 19.0
571	1H-NMR (DMSO-d6): 1.12-1.20 (6H, m), 1.33-1.45 (2H, m), 1,59-1,89 (10H, m), 2.23 (3H, s), 2.26 (3H, s), 2.30-2.73 (13H, m), 2.97-3.07 (2H, m), 3.79-3.91 (1H, m), 4.03-4.14 (1H, m), 6.57 (1H, s), 6.72 (1H, d, J = 7.6 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.14-7.19 (1H, m), 7.28 (1H, dd, J = 2.4, 8.4 Hz), 7.46-7.51 (1H, m), 7.56 (1H, d, J = 2.4 Hz), 11.01 (1H, s)
	XRD: 7.9, 15.1, 19.4, 19.9, 20.3
572	1H-NMR (DMSO-d6): 1.04 (6H, d, J = 6.8 Hz), 1.17 (3H, t, J = 7.2 Hz), 1.21-1.35 (2H, m), 1.36-1.50 (2H, m), 1.84-1.97 (4H, m), 2.27 (3H, s), 2.55 (2H, q, J = 7.2 Hz), 2.62-2.70 (4H, m), 2.72-2.86 (5H, m), 3.20-3.55 (2H, m), 3.80-3.91 (1H, m), 6.57 (1H, s), 6.66 (1H, d, J = 7.6 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.15-7.21 (1H, m), 7.39 (1H, dd, J = 2.4, 8.4 Hz), 7.46-7.52 (2H, m), 11.02 (1H, s)
	XRD: 10.1, 14.5, 17.9, 22.1, 23.0
573	1H-NMR (DMSO-d6): 1.14-1.22 (6H, m), 1.43-1.65 (8H, m), 1.79-1.90 (4H, m), 2.25 (3H, s), 2.27 (3H, s), 2.30-2.70 (14H, m), 2.99-3.09 (2H, m), 3.86-3.98 (1H, m), 6.57 (2H, s), 6.62 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.15-7.21 (1H, m), 7.36 (1H, dd, J = 2.0, 8.4 Hz), 7.47-7.52 (2H, m), 11.03 (1H, s)
	XRD: 6.3, 13.7, 16.7, 17.7, 18.4

[Table 182]

Ex	Data
574	1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz), 1.50-1.72 (4H, m), 1.80-1.93 (4H, m), 2.21 (3H, s), 2.24 (3H, s), 2.48-2.65 (13H, m), 2.99-3.08 (2H, m), 3.30-3.50 (2H, m), 3.90-4.00 (2H, m), 4.05-4.18 (1H, m), 6.56 (1H, s), 6.78 (1H, d, J = 7.6 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.17-7.24 (1H, m), 7.34 (1H, dd, J = 2.4, 8.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.49-7.55 (1H, m), 11.01 (1H, s)
	XRD: 11.5, 17.7, 19.1, 21.4, 22.3
575	1H-NMR (DMSO-d6): 1.17-1.33 (2H, m), 1.43-1.63 (4H, m), 1.79-1.94 (6H, m), 2.25 (3H, s), 2.26 (3H, s), 2.30-2.69 (11H, m), 2.99-3.89 (5H, m), 5.75 (2H, s), 6.95 (1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.31-7.35 (2H, m), 7.47-7.49 (1H, m), 7.54 (1H, s), 11.19 (1H, s)
	XRD: 5,6, 8.0, 17.8, 18.6, 24.0
576	1H-NMR (DMSO-d6): 1.18 (3H, t, J = 7.2 Hz), 1.44-1.72 (4H, m), 1.80-1.97 (4H, m), 2.21 (3H, s), 2.25-2.72 (13H, m), 3.30-3.70 (4H, m), 3.90-3.98 (2H, m), 3.99-4.11 (1H, m), 6.55 (1H, s), 6.78 (1H, d, J = 7.6 Hz), 6.85-6.93 (2H, m), 7.14-7.21 (1H, m), 7.43-7.52 (3H, m), 10.89 (1H, s)
	XRD: 8.9, 16.6, 13.1, 20.1, 22.4
577	1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz), 1.49-1.70 (4H, m), 1.77-1.91 (4H, m), 2.21 (3H, s), 2.26-2.70 (13H, m), 3.29-3.43 (4H, m), 3.81 (3H, s), 3.88-3.97 (2H, m), 4.06-4.18 (1H, m), 6.55 (1H, s), 6.77 (1H, d, J = 7.6 Hz), 6.82 (1H, d, J = 8.4 Hz), 7.03 (1H, d, J = 2.0 Hz), 7.18-7.29 (2H, m), 7.49-7.55 (1H, m), 11.01 (1H, s)
	XRD: 11.6, 17.7, 19.2, 21.5, 22.4
578	1H-NMR (DMSO-d6): 1.15 (6H, d, J = 6.8 Hz), 1.42-1.70 (4H, m), 1.78-1.92 (4H, m), 2.21 (3H, s), 2.26-2.72 (11H, m), 3.08-3.21 (1H, m), 3.34-3.48 (2H, m), 3.56-3.69 (2H, m), 3.87-3.98 (2H, m), 4.00-4.13 (1H, m), 6.55 (1H, s), 6.83 (1H, d, J = 7.6 Hz), 6.85-6.93 (2H, m), 7.15-7.22 (1H, m), 7.41-7.51 (3H, m), 10.87 (1H, s)
	XRD: 10.3, 16.9, 19.3, 19.9, 21.1

[Table 183]

Ex	Data
579	1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz), 1.58-1.72 (2H, m), 1.84-1.94 (2H, m), 2.26 (3H, s), 2.45-2.64 (6H, m), 2.91-3.02 (4H, m), 3.33-3.49 (2H, m), 3.91-3.99 (2H, m), 4.02-4.14 (1H, m), 6.59 (1H, s), 6.86-6.92 (1H, m), 6.93-7.04 (2H, m), 7.24-7.30 (1H, m), 7.52-7.59 (1H, m), 7.88 (1H, dd, J = 2.4, 16 Hz), 11.18 (1H, s)
	XRD: 5.7, 11.5, 18.2, 23.6, 23.9
580	1H-NMR (DMSO-d6): 1.16 (6H, d, J = 6,8 Hz), 1.57-1.70 (2H, m), 1.80-1.89 (2H, m), 2.29 (3H, s), 2.48-2.60 (4H, m), 2.89-3.00 (4H, m), 3.10-3.22 (1H, m), 3.30-3.42 (2H, m), 3.81 (3H, s), 3.87-3.96 (2H, m), 4.06-4.19 (1H, m), 6.58 (1H, s), 6.78-6.86 (2H, m), 7.04 (1H, d, J = 2.0 Hz), 7.19-7.30 (2H, m), 7.46-7.53 (1H, m), 11.00 (1H, s)
	XRD: 8.2, 11.8, 15.9, 18.0, 21.3
581	1H-NMR (DMSO-d6): 1.15 (6H, d, J = 6.4 Hz), 1.55-1.70 (2H, m), 1.81-1.91 (2H, m), 2.27 (3H, s), 2.47-2.55 (4H, m), 3.01-3.22 (5H, m), 3.34-3.50 (2H, m), 3.88-3.98 (2H, m), 4.00-4.13 (1H, m), 6.59 (1H, s), 6.83 (1H, d, J = 7.2 Hz), 6.86-6.92 (2H, m), 7.16-7.23 (1H, m), 7.43-7.51 (3H, m), 10.89 (1H, s)
	XRD: 11.1, 17.2, 19.5, 20.1, 20.5
582	1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.2 Hz), 1.43-1.57 (2H, m), 1.58-1.71 (2H, m), 1.74-1.91 (4H, m), 2.03-2.16 (2H, m), 2.20-2.30 (8H, m), 2.53-2.69 (5H, m), 2.74-2.84 (4H, m), 2.87-2.98 (2H, m), 3.34-3.45 (2H, m), 3.89-3.99 (2H, m), 4.04-4.17 (1H, m), 6.52 (1H, s), 6.79 (1H, d, J = 7.6 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.18-7.23 (1H, m), 7.36 (1H, dd, J = 2.4, 8.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.49-7.54 (1H, m), 11.01 (1H, s)
	XRD: 8.1, 13.1, 15.1, 17.5, 23.8

[0227] Tables 184 to 201 show the structures of other compounds of the present invention. These compounds were synthesized, or can be synthesized, using the above preparation processes, processes described in the Examples, processes obvious to those skilled in the art, or modified processes thereof.

[0228] The meanings of the symbols in the tables are as follows.
No: Compound No.
-R¹¹ and -R¹²: substituents in the general formulas.
cBu: cyclobutyl, 2Py: 2-pyridyl, 3Py: 3-pyridyl, 4Py: 4-pyridyl.

[Table 184]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
A1#	-H	-H		A31#	-H	-Me		A61	-H	-Et
A2#	-Me	-H		A32#	-Me	-Me		A62	-Me	-Et
A3#	-Et	-H		A33#	-Et	-Me		A63	-Et	-Et
A4#	-nPr	-H		A34#	-nPr	-Me		A64	-nPr	-Et
A5#	-iPr	-H		A35#	-iPr	-Me		A65	-iPr	-Et
A6#	-cPr	-H		A36#	-cPr	-Me		A66#	-cPr	-Et
A7#	-cBu	-H		A37#	-cBu	-Me		A67#	-cBu	-Et
A8#		-H		A38#		-Me		A68#		-Et
A9#		-H		A39#		-Me		A69#		-Et
A10#		-H		A40#		-Me		A70#		-Et
All#	-CF3	-H		A41#	-CF3	-Me		A71	-CF3	-Et
A12#	-CN	-H		A42#	-CN	-Me		A72#	-CN	-Et
A13#	-Ph	-H		A43#	-Ph	-Me		A73#	-Ph	-Et
A14#	-OMe	-H		A44#	-OMe	-Me		A74	-OMe	-Et
A15#	-OEt	-H		A45#	-OEt	-Me		A75	-OEt	-Et
A16#	-OnPr	-H		A46#	-OnPr	-Me		A76	-OnPr	-Et
A17#	-OiPr	-H		A47#	-OiPr	-Me		A77	-OiPr	-Et
A18#	-OcPr	-H		A48#	-OcPr	-Me		A78#	-OcPr	-Et
A19#	-OCH2cPr	-H		A49#	-OCH2cPr	-Me		A79#	-OCH2cPr	-Et
A20#	-OCHCF2	-H		A50#	-OCHCF2	-Me		A80	-OCHCF2	-Et
A21#	-OCF3	-H		A51#	-OCF3	-Me		A81	-OCF3	-Et
A22#	-OCH2CF3	-H		A52#	-OCH2CF3	-Me		A82	-OCH2CF3	-Et
A23#	-OCH2CH2F	-H		A53#	-OCH2CH2F	-Me		A83	-OCH2CH2F	-Et
A24#	-OCH2CH2OMe	-H		A54#	-OCH2CH2OMe	-Me		A84#	-OCH2CH2OMe	-Et
A25#	-OCH2CH2NMe2	-H		A55#	-OCH2CH2NMe2	-Me		A85#	-OCH2CH2NMe2	-Et
A26#	-F	-H		A56#	-F	-Me		A86	-F	-Et
A27#	-Cl	-H		A57#	-Cl	-Me		A87	-Cl	-Et
A28#	-Br	-H		A58#	-Br	-Me		A88	-Br	-Et
A29#	-I	-H		A59#	-I	-Me		A89	-I	-Et
A30a#	-2Py	-H		A60a#	-2Py	-Me		A90a#	-2Py	-Et
A30b#	-3Py	-H		A60b#	-3Py	-Me		A90b#	-3Py	-Et
A30c#	-4Py	-H		A60c#	-4Py	-Me		A90c#	-4Py	-Et

(# not part of the invention)

[Table 185]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
B1#	-H	-nPr		B31	-H	-iPr		B61#	-H	-cPr
B2#	-Me	-nPr		B32	-Me	-iPr		B62#	-Me	-cPr
B3#	-Et	-nPr		B33	-Et	-iPr		B63#	-Et	-cPr
B4#	-nPr	-nPr		B34	-nPr	-iPr		B64#	-nPr	-cPr
B5#	-iPr	-nPr		B35	-iPr	-iPr		B65#	-iPr	-cPr
B6#	-cPr	-nPr		B36#	-cPr	-iPr		B66#	-cPr	-cPr
B7#	-cBu	-nPr		B37#	-cBu	-iPr		B67#	-cBu	-cPr
B8#		-nPr		B38#		-iPr		B68#		-cPr
B9#		-nPr		B39#		-iPr		B69#		-cPr
B10#		-nPr		B40#		-iPr		B70#		-cPr
B11#	-CF3	-nPr		B41	-CF3	-iPr		B71#	-CF3	-cPr
B12#	-CN	-nPr		B42#	-CN	-iPr		B72#	-CN	-cPr
B13#	-Ph	-nPr		B43#	-Ph	-iPr		B73#	-Ph	-cPr
B14#	-OMe	-nPr		B44	-OMe	-iPr		B74#	-OMe	-cPr
B15#	-OEt	-nPr		B45	-OEt	-iPr		B75#	-OEt	-cPr
B16#	-OnPr	-nPr		B46	-OnPr	-iPr		B76#	-OnPr	-cPr
B17#	-OiPr	-nPr		B47	-OiPr	-iPr		B77#	-OiPr	-cPr
B18#	-OcPr	-nPr		B48#	-OcPr	-iPr		B78#	-OcPr	-cPr
B19#	-OCH2cPr	-nPr		B49#	-OCH2cPr	-iPr		B79#	-OCH2cPr	-cPr
B20#	-OCHCF2	-nPr		B50	-OCHCF2	-iPr		B80#	-OCHCF2	-cPr
B21#	-OCF3	-nPr		B51	-OCF3	-iPr		B81#	-OCF3	-cPr
B22#	-OCH2CF3	-nPr		B52	-OCH2CF3	-iPr		B82#	-OCH2CF3	-cPr
B23#	-OCH2CH2F	-nPr		B53	-OCH2CH2F	-iPr		B83#	-OCH2CH2F	-cPr
B24#	-OCH2CH2OMe	-nPr		B54#	-OCH2CH2OMe	-iPr		B84#	-OCH2CH2OMe	-cPr
B25#	-OCH2CH2NMe2	-nPr		B55#	-OCH2CH2NMe2	-iPr		B85#	-OCH2CH2NMe2	-cPr
B26#	-F	-nPr		B56	-F	-iPr		B86#	-F	-cPr
B27#	-Cl	-nPr		B57	-Cl	-iPr		B87#	-Cl	-cPr
B28#	-Br	-nPr		B58	-Br	-iPr		B88#	-Br	-cPr
B29#	-I	-nPr		B59	-I	-iPr		B89#	-I	-cPr
B30a#	-2Py	-nPr		B60a#	-2Py	-iPr		B90a#	-2Py	-cPr
B30b#	-3Py	-nPr		B60b#	-3Py	-iPr		B90b#	-3Py	-cPr
B30c#	-4Py	-nPr		B60c#	-4Py	-iPr		B90c#	-4Py	-cPr

(# not part of the invention)

[Table 186]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
C1	-H	-Cl		C31#	-H	-Br		C61#	-H	-I
C2	-Me	-Cl		C32#	-Me	-Br		C62#	-Me	-I
C3	-Et	-Cl		C33#	-Et	-Br		C63#	-Et	-I
C4	-nPr	-Cl		C34#	-nPr	-Br		C64#	-nPr	-I
C5	-iPr	-Cl		C35#	-iPr	-Br		C65#	-iPr	-I
C6#	-cPr	-Cl		C36#	-cPr	-Br		C66#	-cPr	-I
C7#	-cBu	-Cl		C37#	-cBu	-Br		C67#	-cBu	-I
C8#		-Cl		C38#		-Br		C68#		-I
C9#		-Cl		C39#		-Br		C69#		-I
C10#		-Cl		C40#		-Br		C70#		-I
C11	-CF3	-Cl		C41#	-CF3	-Br		C71#	-CF3	-I
C12#	-CN	-Cl		C42#	-CN	-Br		C72#	-CN	-I
C13#	-Ph	-Cl		C43#	-Ph	-Br		C73#	-Ph	-I
C14	-OMe	-Cl		C44#	-OMe	-Br		C74#	-OMe	-I
C15	-OEt	-Cl		C45#	-OEt	-Br		C75#	-OEt	-I
C16	-OnPr	-Cl		C46#	-OnPr	-Br		C76#	-OnPr	-I
C17	-OiPr	-Cl		C47#	-OiPr	-Br		C77#	-OiPr	-I
C18#	-OcPr	-Cl		C48#	-OcPr	-Br		C78#	-OcPr	-I
C19#	-OCH2cPr	-Cl		C49#	-OCH2cPr	-Br		C79#	-OCH2cPr	-I
C20	-OCHCF2	-Cl		C50#	-OCHCF2	-Br		C80#	-OCHCF2	-I
C21	-OCF3	-Cl		C51#	-OCF3	-Br		C81#	-OCF3	-I
C22	-OCH2CF3	-Cl		C52#	-OCH2CF3	-Br		C82#	-OCH2CF3	-I
C23	-OCH2CH2F	-Cl		C53#	-OCH2CH2F	-Br		C83#	-OCH2CH2F	-I
C24#	-OCH2CH2OMe	-Cl		C54#	-OCH2CH2OMe	-Br		C84#	-OCH2CH2OMe	-I
C25#	-OCH2CH2NMe2	-Cl		C55#	-OCH2CH2NMe2	-Br		C85#	-OCH2CH2NMe2	-I
C26	-F	-Cl		C56#	-F	-Br		C86#	-F	-I
C27	-Cl	-Cl		C57#	-Cl	-Br		C87#	-Cl	-I
C28	-Br	-Cl		C58#	-Br	-Br		C88#	-Br	-I
C29	-I	-Cl		C59#	-I	-Br		C89#	-I	-I
C30a#	-2Py	-Cl		C60a#	-2Py	-Br		C90a#	-2Py	-I
C30b#	-3Py	-Cl		C60b#	-3Py	-Br		C90b#	-3Py	-I
C30c#	-4Py	-Cl		C60c#	-4Py	-Br		C90c#	-4Py	-I

(# not part of the invention)

[Table 187]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
D1#	-H	-H		D31#	-H	-Me		D61	-H	-Et
D2#	-Me	-H		D32#	-Me	-Me		D62	-Me	-Et
D3#	-Et	-H		D33#	-Et	-Me		D63	-Et	-Et
D4#	-nPr	-H		D34#	-nPr	-Me		D64	-nPr	-Et
D5#	-iPr	-H		D35#	-iPr	-Me		D65	-iPr	-Et
D6#	-cPr	-H		D36#	-cPr	-Me		D66#	-cPr	-Et
D7#	-cBu	-H		D37#	-cBu	-Me		D67#	-cBu	-Et
D8#		-H		D38#		-Me		D68#		-Et
D9#		-H		D39#		-Me		D69#		-Et
D10#		-H		D40#		-Me		D70#		-Et
D11#	-CF3	-H		D41#	-CF3	-Me		D71	-CF3	-Et
D12#	-CN	-H		D42#	-CN	-Me		D72#	-CN	-Et
D13#	-Ph	-H		D43#	-Ph	-Me		D73#	-Ph	-Et
D14#	-OMe	-H		D44#	-OMe	-Me		D74	-OMe	-Et
D15#	-OEt	-H		D45#	-OEt	-Me		D75	-OEt	-Et
D16#	-OnPr	-H		D46#	-OnPr	-Me		D76	-OnPr	-Et
D17#	-OiPr	-H		D47#	-OiPr	-Me		D77	-OiPr	-Et
D18#	-OcPr	-H		D48#	-OcPr	-Me		D78#	-OcPr	-Et
D19#	-OCH2cPr	-H		D49#	-OCH2cPr	-Me		D79#	-OCH2cPr	-Et
D20#	-OCHCF2	-H		D50#	-OCHCF2	-Me		D80	-OCHCF2	-Et
D21#	-OCF3	-H		D51#	-OCF3	-Me		D81	-OCF3	-Et
D22#	-OCH2CF3	-H		D52#	-OCH2CF3	-Me		D82	-OCH2CF3	-Et
D23#	-OCH2CH2F	-H		D53#	-OCH2CH2F	-Me		D83	-OCH2CH2F	-Et
D24#	-OCH2CH2OMe	-H		D54#	-OCH2CH2OMe	-Me		D84#	-OCH2CH2OMe	-Et
D25#	-OCH2CH2NMe2	-H		D55#	-OCH2CH2NMe2	-Me		D85#	-OCH2CH2NMe2	-Et
D26#	-F	-H		D56#	-F	-Me		D86	-F	-Et
D27#	-Cl	-H		D57#	-Cl	-Me		D87	-Cl	-Et
D28#	-Br	-H		D58#	-Br	-Me		D88	-Br	-Et
D29#	-I	-H		D59#	-I	-Me		D89	-I	-Et
D30a#	-2Py	-H		D60a#	-2Py	-Me		D90a#	-2Py	-Et
D30b#	-3Py	-H		D60b#	-3Py	-Me		D90b#	-3Py	-Et
D30c#	-4Py	-H		D60c#	-4Py	-Me		D90c#	-4Py	-Et

(# not part of the invention)

[Table 188]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
E1#	-H	-nPr		E31	-H	-iPr		E61#	-H	-cPr
E2#	-Me	-nPr		E32	-Me	-iPr		E62#	-Me	-cPr
E3#	-Et	-nPr		E33	-Et	-iPr		E63#	-Et	-cPr
E4#	-nPr	-nPr		E34	-nPr	-iPr		E64#	-nPr	-cPr
E5#	-iPr	-nPr		E35	-iPr	-iPr		E65#	-iPr	-cPr
E6#	-cPr	-nPr		E36#	-cPr	-iPr		E66#	-cPr	-cPr
E7#	-cBu	-nPr		E37#	-cBu	-iPr		E67#	-cBu	-cPr
E8#		-nPr		E38#		-iPr		E68#		-cPr
E9#		-nPr		E39#		-iPr		E69#		-cPr
E10#		-nPr		E40#		-iPr		E70#		-cPr
E11#	-CF3	-nPr		E41	-CF3	-iPr		E71#	-CF3	-cPr
E12#	-CN	-nPr		E42#	-CN	-iPr		E72#	-CN	-cPr
E13#	-Ph	-nPr		E43#	-Ph	-iPr		E73#	-Ph	-cPr
E14#	-OMe	-nPr		E44	-OMe	-iPr		E74#	-OMe	-cPr
E15#	-OEt	-nPr		E45	-OEt	-iPr		E75#	-OEt	-cPr
E16#	-OnPr	-nPr		E46	-OnPr	-iPr		E76#	-OnPr	-cPr
E17#	-OiPr	-nPr		E47	-OiPr	-iPr		E77#	-OiPr	-cPr
E18#	-OcPr	-nPr		E48#	-OcPr	-iPr		E78#	-OcPr	-cPr
E19#	-OCH2cPr	-nPr		E49#	-OCH2cPr	-iPr		E79#	-OCH2cPr	-cPr
E20#	-OCHCF2	-nPr		E50	-OCHCF2	-iPr		E80#	-OCHCF2	-cPr
E21#	-OCF3	-nPr		E51	-OCF3	-iPr		E81#	-OCF3	-cPr
E22#	-OCH2CF3	-nPr		E52	-OCH2CF3	-iPr		E82#	-OCH2CF3	-cPr
E23#	-OCH2CH2F	-nPr		E53	-OCH2CH2F	-iPr		E83#	-OCH2CH2F	-cPr
E24#	-OCH2CH2OMe	-nPr		E54#	-OCH2CH2OMe	-iPr		E84#	-OCH2CH2OMe	-cPr
E25#	-OCH2CH2NMe2	-nPr		E55#	-OCH2CH2NMe2	-iPr		E85#	-OCH2CH2NMe2	-cPr
E26#	-F	-nPr		E56	-F	-iPr		E86#	-F	-cPr
E27#	-Cl	-nPr		E57	-Cl	-iPr		E87#	-Cl	-cPr
E28#	-Br	-nPr		E58	-Br	-iPr		E88#	-Br	-cPr
E29#	-I	-nPr		E59	-I	-iPr		E89#	-I	-cPr
E30a#	-2Py	-nPr		E60a#	-2Py	-iPr		E90a#	-2Py	-cPr
E30b#	-3Py	-nPr		E60b#	-3Py	-iPr		E90b#	-3Py	-cPr
E30c#	-4Py	-nPr		E60c#	-4Py	-iPr		E90c#	-4Py	-cPr

(# not part of the invention)

[Table 189]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
F1	-H	-Cl		F31#	-H	-Br		F61#	-H	-I
F2	-Me	-Cl		F32#	-Me	-Br		F62#	-Me	-I
F3	-Et	-Cl		F33#	-Et	-Br		F63#	-Et	-I
F4	-nPr	-Cl		F34#	-nPr	-Br		F64#	-nPr	-I
F5	-iPr	-Cl		F35#	-iPr	-Br		F65#	-iPr	-I
F6#	-cPr	-Cl		F36#	-cPr	-Br		F66#	-cPr	-I
F7#	-cBu	-Cl		F37#	-cBu	-Br		F67#	-cBu	-I
F8#		-Cl		F38#		-Br		F68#		-I
F9#		-Cl		F39#		-Br		F69#		-I
F10#		-Cl		F40#		-Br		F70#		-I
F11	-CF3	-Cl		F41#	-CF3	-Br		F71#	-CF3	-I
F12#	-CN	-Cl		F42#	-CN	-Br		F72#	-CN	-I
F13#	-Ph	-Cl		F43#	-Ph	-Br		F73#	-Ph	-I
F14	-OMe	-Cl		F44#	-OMe	-Br		F74#	-OMe	-I
F15	-OEt	-Cl		F45#	-OEt	-Br		F75#	-OEt	-I
F16	-OnPr	-Cl		F46#	-OnPr	-Br		F76#	-OnPr	-I
F17	-OiPr	-Cl		F47#	-OiPr	-Br		F77#	-OiPr	-I
F18#	-OcPr	-Cl		F48#	-OcPr	-Br		F78#	-OcPr	-I
F19#	-OCH2cPr	-Cl		F49#	-OCH2cPr	-Br		F79#	-OCH2cPr	-I
F20	-OCHCF2	-Cl		F50#	-OCHCF2	-Br		F80#	-OCHCF2	-I
F21	-OCF3	-Cl		F51#	-OCF3	-Br		F81#	-OCF3	-I
F22	-OCH2CF3	-Cl		F52#	-OCH2CF3	-Br		F82#	-OCH2CF3	-I
F23	-OCH2CH2F	-Cl		F53#	-OCH2CH2F	-Br		F83#	-OCH2CH2F	-I
F24#	-OCH2CH2OMe	-Cl		F54#	-OCH2CH2OMe	-Br		F84#	-OCH2CH2OMe	-I
F25#	-OCH2CH2NMe2	-Cl		F55#	-OCH2CH2NMe2	-Br		F85#	-OCH2CH2NMe2	-I
F26	-F	-Cl		F56#	-F	-Br		F86#	-F	-I
F27	-Cl	-Cl		F57#	-Cl	-Br		F87#	-Cl	-I
F28	-Br	-Cl		F58#	-Br	-Br		F88#	-Br	-I
F29	-I	-Cl		F59#	-I	-Br		F89#	-I	-I
F30a#	-2Py	-Cl		F60a#	-2Py	-Br		F90a#	-2Py	-I
F30b#	-3Py	-Cl		F60b#	-3Py	-Br		F90b#	-3Py	-I
F30c#	-4Py	-Cl		F60c#	-4Py	-Br		F90c#	-4Py	-I

(# not part of the invention)

[Table 190]

No	R11	-R12		No	-R11	-R12		No	-R11	-R12
G1#	-H	-H		G31#	-H	-Me		G61	-H	-Et
G2#	-Me	-H		G32#	-Me	-Me		G62	-Me	-Et
G3#	-Et	-H		G33#	-Et	-Me		G63	-Et	-Et
G4#	-nPr	-H		G34#	-nPr	-Me		G64	-nPr	-Et
G5#	-iPr	-H		G35#	-iPr	-Me		G65	-iPr	-Et
G6#	-cPr	-H		G36#	-cPr	-Me		G66#	-cPr	-Et
G7#	-cBu	-H		G37#	-cBu	-Me		G67#	-cBu	-Et
G8#		-H		G38#		-Me		G68#		-Et
G9#		-H		G39#		-Me		G69#		-Et
G10#		-H		G40#		-Me		G70#		-Et
G11#	-CF3	-H		G41#	-CF3	-Me		G71	-CF3	-Et
G12#	-CN	-H		G42#	-CN	-Me		G72#	-CN	-Et
G13#	-Ph	-H		G43#	-Ph	-Me		G73#	-Ph	-Et
G14#	-OMe	-H		G44#	-OMe	-Me		G74	-OMe	-Et
G15#	-OEt	-H		G45#	-OEt	-Me		G75	-OEt	-Et
G16#	-OnPr	-H		G46#	-OnPr	-Me		G76	-OnPr	-Et
G17#	-OiPr	-H		G47#	-OiPr	-Me		G77	-OiPr	-Et
G18#	-OcPr	-H		G48#	-OcPr	-Me		G78#	-OcPr	-Et
G19#	-OCH2cPr	-H		G49#	-OCH2cPr	-Me		G79#	-OCH2cPr	-Et
G20#	-OCHCF2	-H		G50#	-OCHCF2	-Me		G80	-OCHCF2	-Et
G21#	-OCF3	-H		G51#	-OCF3	-Me		G81	-OCF3	-Et
G22#	-OCH2CF3	-H		G52#	-OCH2CF3	-Me		G82	-OCH2CF3	-Et
G23#	-OCH2CH2F	-H		G53#	-OCH2CH2F	-Me		G83	-OCH2CH2F	-Et
G24#	-OCH2CH2OMe	-H		G54#	-OCH2CH2OMe	-Me		G84#	-OCH2CH2OMe	-Et
G25#	-OCH2CH2NMe2	-H		G55#	-OCH2CH2NMe2	-Me		G85#	-OCH2CH2NMe2	-Et
G26#	-F	-H		G56#	-F	-Me		G86	-F	-Et
G27#	-Cl	-H		G57#	-Cl	-Me		G87	-Cl	-Et
G28#	-Br	-H		G58#	-Br	-Me		G88	-Br	-Et
G29#	-I	-H		G59#	-I	-Me		G89	-I	-Et
G30a#	-2Py	-H		G60a#	-2Py	-Me		G90a#	-2Py	-Et
G30b#	-3Py	-H		G60b#	-3Py	-Me		G90b#	-3Py	-Et
G30c#	-4Py	-H		G60c#	-4Py	-Me		G90c#	-4Py	-Et

(# not part of the invention)

[Table 191]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
H1#	-H	-nPr		H31	-H	-iPr		H61#	-H	-cPr
H2#	-Me	-nPr		H32	-Me	-iPr		H62#	-Me	-cPr
H3#	-Et	-nPr		H33	-Et	-iPr		H63#	-Et	-cPr
H4#	-nPr	-nPr		H34	-nPr	-iPr		H64#	-nPr	-cPr
H5#	-iPr	-nPr		H35	-iPr	-iPr		H65#	-iPr	-cPr
H6#	-cPr	-nPr		H36#	-cPr	-iPr		H66#	-cPr	-cPr
H7#	-cBu	-nPr		H37#	-cBu	-iPr		H67#	-cBu	-cPr
H8#		-nPr		H38#		-iPr		H68#		-cPr
H9#		-nPr		H39#		-iPr		H69#		-cPr
H10#		-nPr		H40#		-iPr		H70#		-cPr
H11#	-CF3	-nPr		H41	-CF3	-iPr		H71#	-CF3	-cPr
H12#	-CN	-nPr		H42#	-CN	-iPr		H72#	-CN	-cPr
H13#	-Ph	-nPr		H43#	-Ph	-iPr		H73#	-Ph	-cPr
H14#	-OMe	-nPr		H44	-OMe	-iPr		H74#	-OMe	-cPr
H15#	-OEt	-nPr		H45	-OEt	-iPr		H75#	-OEt	-cPr
H16#	-OnPr	-nPr		H46	-OnPr	-iPr		H76#	-OnPr	-cPr
H17#	-OiPr	-nPr		H47	-OiPr	-iPr		H77#	-OiPr	-cPr
H18#	-OcPr	-nPr		H48#	-OcPr	-iPr		H78#	-OcPr	-cPr
H19#	-OCH2cPr	-nPr		H49#	-OCH2cPr	-iPr		H79#	-OCH2cPr	-cPr
H20#	-OCHCF2	-nPr		H50	-OCHCF2	-iPr		H80#	-OCHCF2	-cPr
H21#	-OCF3	-nPr		H51	-OCF3	-iPr		H81#	-OCF3	-cPr
H22#	-OCH2CF3	-nPr		H52	-OCH2CF3	-iPr		H82#	-OCH2CF3	-cPr
H23#	-OCH2CH2F	-nPr		H53	-OCH2CH2F	-iPr		H83#	-OCH2CH2F	-cPr
H24#	-OCH2CH2OMe	-nPr		H54#	-OCH2CH2OMe	-iPr		H84#	-OCH2CH2OMe	-cPr
H25#	-OCH2CH2NMe2	-nPr		H55#	-OCH2CH2NMe2	-iPr		H85#	-OCH2CH2NMe2	-cPr
H26#	-F	-nPr		H56	-F	-iPr		H86#	-F	-cPr
H27#	-Cl	-nPr		H57	-Cl	-iPr		H87#	-Cl	-cPr
H28#	-Br	-nPr		H58	-Br	-iPr		H88#	-Br	-cPr
H29#	-I	-nPr		H59	-I	-iPr		H89#	-I	-cPr
H30a#	-2Py	-nPr		H60a#	-2Py	-iPr		H90a#	-2Py	-cPr
H30b#	-3Py	-nPr		H60b#	-3Py	-iPr		H90b#	-3Py	-cPr
H30c#	-4Py	-nPr		H60c#	-4Py	-iPr		H90c#	-4Py	-cPr

(# not part of the invention)

[Table 192]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
I1	-H	-Cl		I31#	-H	-Br		I61#	-H	-I
I2	-Me	-Cl		I32#	-Me	-Br		I62#	-Me	-I
I3	-Et	-Cl		I33#	-Et	-Br		I63#	-Et	-I
I4	-nPr	-Cl		I34#	-nPr	-Br		I64#	-nPr	-I
I5	-iPr	-Cl		I35#	-iPr	-Br		I65#	-iPr	-I
I6#	-cPr	-Cl		I36#	-cPr	-Br		I66#	-cPr	-I
I7#	-cBu	-Cl		I37#	-cBu	-Br		I67#	-cBu	-I
I8#		-Cl		I38#		-Br		I68#		-I
I9#		-Cl		I39#		-Br		I69#		-I
I10#		-Cl		140#		-Br		I70#		-I
I11	-CF3	-Cl		I41#	-CF3	-Br		I71#	-CF3	-I
I12#	-CN	-Cl		I42#	-CN	-Br		I72#	-CN	-I
I13#	-Ph	-Cl		I43#	-Ph	-Br		I73#	-Ph	-I
I14	-OMe	-Cl		I44#	-OMe	-Br		I74#	-OMe	-I
I15	-OEt	-Cl		I45#	-OEt	-Br		I75#	-OEt	-I
I16	-OnPr	-Cl		I46#	-OnPr	-Br		I76#	-OnPr	-I
I17	-OiPr	-Cl		I47#	-OiPr	-Br		I77#	-OiPr	-I
I18#	-OcPr	-Cl		I48#	-OcPr	-Br		I78#	-OcPr	-I
I19#	-OCH2cPr	-Cl		I49#	-OCH2cPr	-Br		I79#	-OCH2cPr	-I
I20	-OCHCF2	-Cl		I50#	-OCHCF2	-Br		I80#	-OCHCF2	-I
I21	-OCF3	-Cl		I51#	-OCF3	-Br		I81#	-OCF3	-I
I22	-OCH2CF3	-Cl		I52#	-OCH2CF3	-Br		I82#	-OCH2CF3	-I
I23	-OCH2CH2F	-Cl		I53#	-OCH2CH2F	-Br		I83#	-OCH2CH2F	-I
I24#	-OCH2CH2OMe	-Cl		I54#	-OCH2CH2OMe	-Br		I84#	-OCH2CH2OMe	-I
I25#	-OCH2CH2NMe2	-Cl		I55#	-OCH2CH2NMe2	-Br		I85#	-OCH2CH2NMe2	-I
I26	-F	-Cl		I56#	-F	-Br		I86#	-F	-I
I27	-Cl	-Cl		I57#	-Cl	-Br		I87#	-Cl	-I
I28	-Br	-Cl		I58#	-Br	-Br		I88#	-Br	-I
I29	-I	-Cl		I59#	-I	-Br		I89#	-I	-I
I30a#	-2Py	-Cl		I60a#	-2Py	-Br		I90a#	-2Py	-I
I30b#	-3Py	-Cl		I60b#	-3Py	-Br		I90b#	-3Py	-I
I30c#	-4Py	-Cl		I60c#	-4Py	-Br		I90c#	-4Py	-I

(# not part of the invention)

[Table 193]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
J1#	-H	-H		J31#	-H	-Me		J61	-H	-Et
J2#	-Me	-H		J32#	-Me	-Me		J62	-Me	-Et
J3#	-Et	-H		J33#	-Et	-Me		J63	-Et	-Et
J4#	-nPr	-H		J34#	-nPr	-Me		J64	-nPr	-Et
J5#	-iPr	-H		J35#	-iPr	-Me		J65	-iPr	-Et
J6#	-cPr	-H		J36#	-cPr	-Me		J66#	-cPr	-Et
J7#	-cBu	-H		J37#	-cBu	-Me		J67#	-cBu	-Et
J8#		-H		J38#		-Me		J68#		-Et
J9#		-H		J39#		-Me		J69#		-Et
J10#		-H		J40#		-Me		J70#		-Et
J11#	-CF3	-H		J41#	-CF3	-Me		J71	-CF3	-Et
J12#	-CN	-H		J42#	-CN	-Me		J72#	-CN	-Et
J13#	-Ph	-H		J43#	-Ph	-Me		J73#	-Ph	-Et
J14#	-OMe	-H		J44#	-OMe	-Me		J74	-OMe	-Et
J15#	-OEt	-H		J45#	-OEt	-Me		J75	-OEt	-Et
J16#	-OnPr	-H		J46#	-OnPr	-Me		J76	-OnPr	-Et
J17#	-OiPr	-H		J47#	-OiPr	-Me		J77	-OiPr	-Et
J18#	-OcPr	-H		J48#	-OcPr	-Me		J78#	-OcPr	-Et
J19#	-OCH2cPr	-H		J49#	-OCH2cPr	-Me		J79#	-OCH2cPr	-Et
J20#	-OCHCF2	-H		J50#	-OCHCF2	-Me		J80	-OCHCF2	-Et
J21#	-OCF3	-H		J51#	-OCF3	-Me		J81	-OCF3	-Et
J22#	-OCH2CF3	-H		J52#	-OCH2CF3	-Me		J82	-OCH2CF3	-Et
J23#	-OCH2CH2F	-H		J53#	-OCH2CH2F	-Me		J83	-OCH2CH2F	-Et
J24#	-OCH2CH2OMe	-H		J54#	-OCH2CH2OMe	-Me		J84#	-OCH2CH2OMe	-Et
J25#	-OCH2CH2NMe2	-H		J55#	-OCH2CH2NMe2	-Me		J85#	-OCH2CH2NMe2	-Et
J26#	-F	-H		J56#	-F	-Me		J86	-F	-Et
J27#	-Cl	-H		J57#	-Cl	-Me		J87	-Cl	-Et
J28#	-Br	-H		J58#	-Br	-Me		J88	-Br	-Et
J29#	-I	-H		J59#	-I	-Me		J89	-I	-Et
J30a#	-2Py	-H		J60a#	-2Py	-Me		J90a#	-2Py	-Et
J30b#	-3Py	-H		J60b#	-3Py	-Me		J90b#	-3Py	-Et
J30c#	-4Py	-H		J60c#	-4Py	-Me		J90c#	-4Py	-Et

(# not part of the invention)

[Table 194]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
K1#	-H	-nPr		K31	-H	-iPr		K61#	-H	-cPr
K2#	-Me	-nPr		K32	-Me	-iPr		K62#	-Me	-cPr
K3#	-Et	-nPr		K33	-Et	-iPr		K63#	-Et	-cPr
K4#	-nPr	-nPr		K34	-nPr	-iPr		K64#	-nPr	-cPr
K5#	-iPr	-nPr		K35	-iPr	-iPr		K65#	-iPr	-cPr
K6#	-cPr	-nPr		K36#	-cPr	-iPr		K66#	-cPr	-cPr
K7#	-cBu	-nPr		K37#	-cBu	-iPr		K67#	-cBu	-cPr
K8#		-nPr		K38#		-iPr		K68#		-cPr
K9#		-nPr		K39#		-iPr		K69#		-cPr
K10#		-nPr		K40#		-iPr		K70#		-cPr
K11#	-CF3	-nPr		K41	-CF3	-iPr		K71#	-CF3	-cPr
K12#	-CN	-nPr		K42#	-CN	-iPr		K72#	-CN	-cPr
K13#	-Ph	-nPr		K43#	-Ph	-iPr		K73#	-Ph	-cPr
K14#	-OMe	-nPr		K44	-OMe	-iPr		K74#	-OMe	-cPr
K15#	-OEt	-nPr		K45	-OEt	-iPr		K75#	-OEt	-cPr
K16#	-OnPr	-nPr		K46	-OnPr	-iPr		K76#	-OnPr	-cPr
K17#	-OiPr	-nPr		K47	-OiPr	-iPr		K77#	-OiPr	-cPr
K18#	-OcPr	-nPr		K48#	-OcPr	-iPr		K78#	-OcPr	-cPr
K19#	-OCH2cPr	-nPr		K49#	-OCH2cPr	-iPr		K79#	-OCH2cPr	-cPr
K20#	-OCHCF2	-nPr		K50	-OCHCF2	-iPr		K80#	-OCHCF2	-cPr
K21#	-OCF3	-nPr		K51	-OCF3	-iPr		K81#	-OCF3	-cPr
K22#	-OCH2CF3	-nPr		K52	-OCH2CF3	-iPr		K82#	-OCH2CF3	-cPr
K23#	-OCH2CH2F	-nPr		K53	-OCH2CH2F	-iPr		K83#	-OCH2CH2F	-cPr
K24#	-OCH2CH2OMe	-nPr		K54#	-OCH2CH2OMe	-iPr		K84#	-OCH2CH2OMe	-cPr
K25#	-OCH2CH2NMe2	-nPr		K55#	-OCH2CH2NMe2	-iPr		K85#	-OCH2CH2NMe2	-cPr
K26#	-F	-nPr		K56	-F	-iPr		K86#	-F	-cPr
K27#	-Cl	-nPr		K57	-Cl	-iPr		K87#	-Cl	-cPr
K28#	-Br	-nPr		K58	-Br	-iPr		K88#	-Br	-cPr
K29#	-I	-nPr		K59	-I	-iPr		K89#	-I	-cPr
K30a#	-2Py	-nPr		K60a#	-2Py	-iPr		K90a#	-2Py	-cPr
K30b#	-3Py	-nPr		K60b#	-3Py	-iPr		K90b#	-3Py	-cPr
K30c#	-4Py	-nPr		K60c#	-4Py	-iPr		K90c#	-4Py	-cPr

(# not part of the invention)

[Table 195]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
L1	-H	-Cl		L31#	-H	-Br		L61#	-H	-I
L2	-Me	-Cl		L32#	-Me	-Br		L62#	-Me	-I
L3	-Et	-Cl		L33#	-Et	-Br		L63#	-Et	-I
L4	-nPr	-Cl		L34#	-nPr	-Br		L64#	-nPr	-I
L5	-iPr	-Cl		L35#	-iPr	-Br		L65#	-iPr	-I
L6#	-cPr	-Cl		L36#	-cPr	-Br		L66#	-cPr	-I
L7#	-cBu	-Cl		L37#	-cBu	-Br		L67#	-cBu	-I
L8#		-Cl		L38#		-Br		L68#		-I
L9#		-Cl		L39#		-Br		L69#		-I
L10#		-Cl		L40#		-Br		L70#		-I
L11	-CF3	-Cl		L41#	-CF3	-Br		L71#	-CF3	-I
L12#	-CN	-Cl		L42#	-CN	-Br		L72#	-CN	-I
L13#	-Ph	-Cl		L43#	-Ph	-Br		L73#	-Ph	-I
L14	-OMe	-Cl		L44#	-OMe	-Br		L74#	-OMe	-I
L15	-OEt	-Cl		L45#	-OEt	-Br		L75#	-OEt	-I
L16	-OnPr	-Cl		L46#	-OnPr	-Br		L76#	-OnPr	-I
L17	-OiPr	-Cl		L47#	-OiPr	-Br		L77#	-OiPr	-I
L18#	-OcPr	-Cl		L48#	-OcPr	-Br		L78#	-OcPr	-I
L19#	-OCH2cPr	-Cl		L49#	-OCH2cPr	-Br		L79#	-OCH2cPr	-I
L20	-OCHCF2	-Cl		L50#	-OCHCF2	-Br		L80#	-OCHCF2	-I
L21	-OCF3	-Cl		L51#	-OCF3	-Br		L81#	-OCF3	-I
L22	-OCH2CF3	-Cl		L52#	-OCH2CF3	-Br		L82#	-OCH2CF3	-I
L23	-OCH2CH2F	-Cl		L53#	-OCH2CH2F	-Br		L83#	-OCH2CH2F	-I
L24#	-OCH2CH2OMe	-Cl		L54#	-OCH2CH2OMe	-Br		L84#	-OCH2CH2OMe	-I
L25#	-OCH2CH2NMe2	-Cl		L55#	-OCH2CH2NMe2	-Br		L85#	-OCH2CH2NMe2	-I
L26	-F	-Cl		L56#	-F	-Br		L86#	-F	-I
L27	-Cl	-Cl		L57#	-Cl	-Br		L87#	-Cl	-I
L28	-Br	-Cl		L58#	-Br	-Br		L88#	-Br	-I
L29	-I	-Cl		L59#	-I	-Br		L89#	-I	-I
L30a#	-2Py	-Cl		L60a#	-2Py	-Br		L90a#	-2Py	-I
L30b#	-3Py	-Cl		L60b#	-3Py	-Br		L90b#	-3Py	-I
L30c#	-4Py	-Cl		L60c#	-4Py	-Br		L90c#	-4Py	-I

(# not part of the invention)

[Table 196]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
M1#	-H	-H		M31#	-H	-Me		M61	-H	-Et
M2#	-Me	-H		M32#	-Me	-Me		M62	-Me	-Et
M3#	-Et	-H		M33#	-Et	-Me		M63	-Et	-Et
M4#	-nPr	-H		M34#	-nPr	-Me		M64	-nPr	-Et
M5#	-iPr	-H		M35#	-iPr	-Me		M65	-iPr	-Et
M6#	-cPr	-H		M36#	-cPr	-Me		M66	-cPr	-Et
M7#	-cBu	-H		M37#	-cBu	-Me		M67	-cBu	-Et
M8#		-H		M38#		-Me		M68		-Et
M9#		-H		M39#		-Me		M69		-Et
M10#		-H		M40#		-Me		M70		-Et
M11#	-CF3	-H		M41#	-CF3	-Me		M71	-CF3	-Et
M12#	-CN	-H		M42#	-CN	-Me		M72	-CN	-Et
M13#	-Ph	-H		M43#	-Ph	-Me		M73	-Ph	-Et
M14#	-OMe	-H		M44#	-OMe	-Me		M74	-OMe	-Et
M15#	-OEt	-H		M45#	-OEt	-Me		M75	-OEt	-Et
M16#	-OnPr	-H		M46#	-OnPr	-Me		M76	-OnPr	-Et
M17#	-OiPr	-H		M47#	-OiPr	-Me		M77	-OiPr	-Et
M18#	-OcPr	-H		M48#	-OcPr	-Me		M78	-OcPr	-Et
M19#	-OCH2cPr	-H		M49#	-OCH2cPr	-Me		M79	-OCH2cPr	-Et
M20#	-OCHCF2	-H		M50#	-OCHCF2	-Me		M80	-OCHCF2	-Et
M21#	-OCF3	-H		M51#	-OCF3	-Me		M81	-OCF3	-Et
M22#	-OCH2CF3	-H		M52#	-OCH2CF3	-Me		M82	-OCH2CF3	-Et
M23#	-OCH2CH2F	-H		M53#	-OCH2CH2F	-Me		M83	-OCH2CH2F	-Et
M24#	-OCH2CH2OMe	-H		M54#	-OCH2CH2OMe	-Me		M84	-OCH2CH2OMe	-Et
M25#	-OCH2CH2NMe2	-H		M55#	-OCH2CH2NMe2	-Me		M85	-OCH2CH2NMe2	-Et
M26#	-F	-H		M56#	-F	-Me		M86	-F	-Et
M27#	-Cl	-H		M57#	-Cl	-Me		M87	-Cl	-Et
M28#	-Br	-H		M58#	-Br	-Me		M88	-Br	-Et
M29#	-I	-H		M59#	-I	-Me		M89	-I	-Et
M30a#	-2Py	-H		M60a#	-2Py	-Me		M90a	-2Py	-Et
M30b#	-3Py	-H		M60b#	-3Py	-Me		M90b	-3Py	-Et
M30c#	-4Py	-H		M60c#	-4Py	-Me		M90c	-4Py	-Et

(# not part of the invention)

[Table 197]

No	-R1l	-R12		No	-R11	-R12		No	-R11	-R12
N1#	-H	-nPr		N31	-H	-iPr		N61#	-H	-cPr
N2#	-Me	-nPr		N32	-Me	-iPr		N62#	-Me	-cPr
N3#	-Et	-nPr		N33	-Et	-iPr		N63#	-Et	-cPr
N4#	-nPr	-nPr		N34	-nPr	-iPr		N64#	-nPr	-cPr
N5#	-iPr	-nPr		N35	-iPr	-iPr		N65#	-iPr	-cPr
N6#	-cPr	-nPr		N36#	-cPr	-iPr		N66#	-cPr	-cPr
N7#	-cBu	-nPr		N37#	-cBu	-iPr		N67#	-cBu	-cPr
N8#		-nPr		N38#		-iPr		N68#		-cPr
N9#		-nPr		N39#		-iPr		N69#		-cPr
N10#		-nPr		N40#		-iPr		N70#		-cPr
N11#	-CF3	-nPr		N41	-CF3	-iPr		N71#	-CF3	-cPr
N12#	-CN	-nPr		N42#	-CN	-iPr		N72#	-CN	-cPr
N13#	-Ph	-nPr		N43#	-Ph	-iPr		N73#	-Ph	-cPr
N14#	-OMe	-nPr		N44	-OMe	-iPr		N74#	-OMe	-cPr
N15#	-OEt	-nPr		N45	-OEt	-iPr		N75#	-OEt	-cPr
N16#	-OnPr	-nPr		N46	-OnPr	-iPr		N76#	-OnPr	-cPr
N17#	-OiPr	-nPr		N47	-OiPr	-iPr		N77#	-OiPr	-cPr
N18#	-OcPr	-nPr		N48#	-OcPr	-iPr		N78#	-OcPr	-cPr
N19#	-OCH2cPr	-nPr		N49#	-OCH2cPr	-iPr		N79#	-OCH2cPr	-cPr
N20#	-OCHCF2	-nPr		N50	-OCHCF2	-iPr		N80#	-OCHCF2	-cPr
N21#	-OCF3	-nPr		N51	-OCF3	-iPr		N81#	-OCF3	-cPr
N22#	-OCH2CF3	-nPr		N52	-OCH2CF3	-iPr		N82#	-OCH2CF3	-cPr
N23#	-OCH2CH2F	-nPr		N53	-OCH2CH2F	-iPr		N83#	-OCH2CH2F	-cPr
N24#	-OCH2CH2OMe	-nPr		N54#	-OCH2CH2OMe	-iPr		N84#	-OCH2CH2OMe	-cPr
N25#	-OCH2CH2NMe2	-nPr		N55#	-OCH2CH2NMe2	-iPr		N85#	-OCH2CH2NMe2	-cPr
N26#	-F	-nPr		N56	-F	-iPr		N86#	-F	-cPr
N27#	-Cl	-nPr		N57	-Cl	-iPr		N87#	-Cl	-cPr
N28#	-Br	-nPr		N58	-Br	-iPr		N88#	-Br	-cPr
N29#	-I	-nPr		N59	-I	-iPr		N89#	-I	-cPr
N30a#	-2Py	-nPr		N60a#	-2Py	-iPr		N90a#	-2Py	-cPr
N30b#	-3Py	-nPr		N60b#	-3Py	-iPr		N90b#	-3Py	-cPr
N30c#	-4Py	-nPr		N60c#	-4Py	-iPr		N90c#	-4Py	-cPr

(# not part of the invention)

[Table 198]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
O1	-H	-Cl		O31#	-H	-Br		O61#	-H	-I
O2	-Me	-Cl		O32#	-Me	-Br		O62#	-Me	-I
O3	-Et	-Cl		O33#	-Et	-Br		O63#	-Et	-I
O4	-nPr	-Cl		O34#	-nPr	-Br		O64#	-nPr	-I
O5	-iPr	-Cl		O35#	-iPr	-Br		O65#	-iPr	-I
O6#	-cPr	-Cl		O36#	-cPr	-Br		O66#	-cPr	-I
O7#	-cBu	-Cl		O37#	-cBu	-Br		O67#	-cBu	-I
O8#		-Cl		O38#		-Br		O68#		-I
O9#		-Cl		O39#		-Br		O69#		-I
O10#		-Cl		O40#		-Br		O70#		-I
O11	-CF3	-Cl		O41#	-CF3	-Br		O71#	-CF3	-I
O12#	-CN	-Cl		O42#	-CN	-Br		O72#	-CN	-I
O13#	-Ph	-Cl		O43#	-Ph	-Br		O73#	-Ph	-I
O14	-OMe	-Cl		O44#	-OMe	-Br		O74#	-OMe	-I
O15	-OEt	-Cl		O45#	-OEt	-Br		O75#	-OEt	-I
O16	-OnPr	-Cl		O46#	-OnPr	-Br		O76#	-OnPr	-I
O17	-OiPr	-Cl		O47#	-OiPr	-Br		O77#	-OiPr	-I
O18#	-OcPr	-Cl		O48#	-OcPr	-Br		O78#	-OcPr	-I
O19#	-OCH2cPr	-Cl		O49#	-OCH2cPr	-Br		O79#	-OCH2cPr	-I
O20	-OCHCF2	-Cl		O50#	-OCHCF2	-Br		O80#	-OCHCF2	-I
O21	-OCF3	-Cl		O51#	-OCF3	-Br		O81#	-OCF3	-I
O22	-OCH2CF3	-Cl		O52#	-OCH2CF3	-Br		O82#	-OCH2CF3	-I
O23	-OCH2CH2F	-Cl		O53#	-OCH2CH2F	-Br		O83#	-OCH2CH2F	-I
O24#	-OCH2CH2OMe	-Cl		O54#	-OCH2CH2OMe	-Br		O84#	-OCH2CH2OMe	-I
O25#	-OCH2CH2NMe2	-Cl		O55#	-OCH2CH2NMe2	-Br		O85#	-OCH2CH2NMe2	-I
O26	-F	-Cl		O56#	-F	-Br		O86#	-F	-I
O27	-Cl	-Cl		O57#	-Cl	-Br		O87#	-Cl	-I
O28	-Br	-Cl		O58#	-Br	-Br		O88#	-Br	-I
O29	-I	-Cl		O59#	-I	-Br		O89#	-I	-I
O30a#	-2Py	-Cl		O60a#	-2Py	-Br		O90a#	-2Py	-I
O30b#	-3Py	-Cl		O60b#	-3Py	-Br		O90b#	-3Py	-I
O30c#	-4Py	-Cl		O60c#	-4Py	-Br		O90c#	-4Py	-I

(# not part of the invention)

[Table 199]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
P1#	-H	-H		P31#	-H	-Me		P61	-H	-Et
P2#	-Me	-H		P32#	-Me	-Me		P62	-Me	-Et
P3#	-Et	-H		P33#	-Et	-Me		P63	-Et	-Et
P4#	-nPr	-H		P34#	-nPr	-Me		P64	-nPr	-Et
P5#	-iPr	-H		P35#	-iPr	-Me		P65	-iPr	-Et
P6#	-cPr	-H		P36#	-cPr	-Me		P66#	-cPr	-Et
P7#	-cBu	-H		P37#	-cBu	-Me		P67#	-cBu	-Et
P8#		-H		P38#		-Me		P68#		-Et
P9#		-H		P39#		-Me		P69#		-Et
P10#		-H		P40#		-Me		P70#		-Et
P11#	-CF3	-H		P41#	-CF3	-Me		P71	-CF3	-Et
P12#	-CN	-H		P42#	-CN	-Me		P72#	-CN	-Et
P13#	-Ph	-H		P43#	-Ph	-Me		P73#	-Ph	-Et
P14#	-OMe	-H		P44#	-OMe	-Me		P74	-OMe	-Et
P15#	-OEt	-H		P45#	-OEt	-Me		P75	-OEt	-Et
P16#	-OnPr	-H		P46#	-OnPr	-Me		P76	-OnPr	-Et
P17#	-OiPr	-H		P47#	-OiPr	-Me		P77	-OiPr	-Et
P18#	-OcPr	-H		P48#	-OcPr	-Me		P78#	-OcPr	-Et
P19#	-OCH2cPr	-H		P49#	-OCH2cPr	-Me		P79#	-OCH2cPr	-Et
P20#	-OCHCF2	-H		P50#	-OCHCF2	-Me		P80	-OCHCF2	-Et
P21#	-OCF3	-H		P51#	-OCF3	-Me		P81	-OCF3	-Et
P22#	-OCH2CF3	-H		P52#	-OCH2CF3	-Me		P82	-OCH2CF3	-Et
P23#	-OCH2CH2F	-H		P53#	-OCH2CH2F	-Me		P83	-OCH2CH2F	-Et
P24#	-OCH2CH2OMe	-H		P54#	-OCH2CH2OMe	-Me		P84#	-OCH2CH2OMe	-Et
P25#	-OCH2CH2NMe2	-H		P55#	-OCH2CH2NMe2	-Me		P85#	-OCH2CH2NMe2	-Et
P26#	-F	-H		P56#	-F	-Me		P86	-F	-Et
P27#	-Cl	-H		P57#	-Cl	-Me		P87	-Cl	-Et
P28#	-Br	-H		P58#	-Br	-Me		P88	-Br	-Et
P29#	-I	-H		P59#	-I	-Me		P89	-I	-Et
P30a#	-2Py	-H		P60a#	-2Py	-Me		P90a#	-2Py	-Et
P30b#	-3Py	-H		P60b#	-3Py	-Me		P90b#	-3Py	-Et
P30c#	-4Py	-H		P60c#	-4Py	-Me		P90c#	-4Py	-Et

(# not part of the invention)

[Table 200]

No	-R11	-R12		No	-R11	-R12		No	-R11	-R12
Q1#	-H	-nPr		Q31	-H	-iPr		Q61#	-H	-cPr
Q2#	-Me	-nPr		Q32	-Me	-iPr		Q62#	-Me	-cPr
Q3#	-Et	-nPr		Q33	-Et	-iPr		Q63#	-Et	-cPr
Q4#	-nPr	-nPr		Q34	-nPr	-iPr		Q64#	-nPr	-cPr
Q5#	-iPr	-nPr		Q35	-iPr	-iPr		Q65#	-iPr	-cPr
Q6#	-cPr	-nPr		Q36#	-cPr	-iPr		Q66#	-cPr	-cPr
Q7#	-cBu	-nPr		Q37#	-cBu	-iPr		Q67#	-cBu	-cPr
Q8#		-nPr		Q38#		-iPr		Q68#		-cPr
Q9#		-nPr		Q39#		-iPr		Q69#		-cPr
Q10#		-nPr		Q40#		-iPr		Q70#		-cPr
Q11#	-CF3	-nPr		Q41	-CF3	-iPr		Q71#	-CF3	-cPr
Q12#	-CN	-nPr		Q42#	-CN	-iPr		Q72#	-CN	-cPr
Q13#	-Ph	-nPr		Q43#	-Ph	-iPr		Q73#	-Ph	-cPr
Q14#	-OMe	-nPr		Q44	-OMe	-iPr		Q74#	-OMe	-cPr
Q15#	-OEt	-nPr		Q45	-OEt	-iPr		Q75#	-OEt	-cPr
Q16#	-OnPr	-nPr		Q46	-OnPr	-iPr		Q76#	-OnPr	-cPr
Q17#	-OiPr	-nPr		Q47	-OiPr	-iPr		Q77#	-OiPr	-cPr
Q18#	-OcPr	-nPr		Q48#	-OcPr	-iPr		Q78#	-OcPr	-cPr
Q19#	-OCH2cPr	-nPr		Q49#	-OCH2cPr	-iPr		Q79#	-OCH2cPr	-cPr
Q20#	-OCHCF2	-nPr		Q50	-OCHCF2	-iPr		Q80#	-OCHCF2	-cPr
Q21#	-OCF3	-nPr		Q51	-OCF3	-iPr		Q81#	-OCF3	-cPr
Q22#	-OCH2CF3	-nPr		Q52	-OCH2CF3	-iPr		Q82#	-OCH2CF3	-cPr
Q23#	-OCH2CH2F	-nPr		Q53	-OCH2CH2F	-iPr		Q83#	-OCH2CH2F	-cPr
Q24#	-OCH2CH2OMe	-nPr		Q54#	-OCH2CH2OMe	-iPr		Q84#	-OCH2CH2OMe	-cPr
Q25#	-OCH2CH2NMe2	-nPr		Q55#	-OCH2CH2NMe2	-iPr		Q85#	-OCH2CH2NMe2	-cPr
Q26#	-F	-nPr		Q56	-F	-iPr		Q86#	-F	-cPr
Q27#	-Cl	-nPr		Q57	-Cl	-iPr		Q87#	-Cl	-cPr
Q28#	-Br	-nPr		Q58	-Br	-iPr		Q88#	-Br	-cPr
Q29#	-I	-nPr		Q59	-I	-iPr		Q89#	-I	-cPr
Q30a#	-2Py	-nPr		Q60a#	-2Py	-iPr		Q90a#	-2Py	-cPr
Q30b#	-3Py	-nPr		Q60b#	-3Py	-iPr		Q90b#	-3Py	-cPr
Q30c#	-4Py	-nPr		Q60c#	-4Py	-iPr		Q90c#	-4Py	-cPr

(# not part of the invention)

[Table 201]

No	-R11	-R12		No	-R11	R12		No	-R11	-R12
R1	-H	-Cl		R31#	-H	-Br		R61#	-H	-I
R2	-Me	-Cl		R32#	-Me	-Br		R62#	-Me	-I
R3	-Et	-Cl		R33#	-Et	-Br		R63#	-Et	-I
R4	-nPr	-Cl		R34#	-nPr	-Br		R64#	-nPr	-I
R5	-iPr	-Cl		R35#	-iPr	-Br		R65#	-iPr	-I
R6#	-cPr	-Cl		R36#	-cPr	-Br		R66#	-cPr	-I
R7#	-cBu	-Cl		R37#	-cBu	-Br		R67#	-cBu	-I
R8#		-Cl		R38#		-Br		R68#		-I
R9#		-Cl		R39#		-Br		R69#		-I
R10#		-Cl		R40#		-Br		R70#		-I
R11	-CF3	-Cl		R41#	-CF3	-Br		R71#	-CF3	-I
R12#	-CN	-Cl		R42#	-CN	-Br		R72#	-CN	-I
R13#	-Ph	-Cl		R43#	-Ph	-Br		R73#	-Ph	-I
R14	-OMe	-Cl		R44#	-OMe	-Br		R74#	-OMe	-I
R15	-OEt	-Cl		R45#	-OEt	-Br		R75#	-OEt	-I
R16	-OnPr	-Cl		R46#	-OnPr	-Br		R76#	-OnPr	-I
R17	-OiPr	-Cl		R47#	-OiPr	-Br		R77#	-OiPr	-I
R18#	-OcPr	-Cl		R48#	-OcPr	-Br		R78#	-OcPr	-I
R19#	-OCH2cPr	-Cl		R49#	-OCH2cPr	-Br		R79#	-OCH2cPr	-I
R20	-OCHCF2	-Cl		R50#	-OCHCF2	-Br		R80#	-OCHCF2	-I
R21	-OCF3	-Cl		R51#	-OCF3	-Br		R81#	-OCF3	-I
R22	-OCH2CF3	-Cl		R52#	-OCH2CF3	-Br		R82#	-OCH2CF3	-I
R23	-OCH2CH2F	-Cl		R53#	-OCH2CH2F	-Br		R83#	-OCH2CH2F	-I
R24#	-OCH2CH2OMe	-Cl		R54#	-OCH2CH2OMe	-Br		R84#	-OCH2CH2OMe	-I
R25#	-OCH2CH2NMe2	-Cl		R55#	-OCH2CH2NMe2	-Br		R85#	-OCH2CH2NMe2	-I
R26	-F	-Cl		R56#	-F	-Br		R86#	-F	-I
R27	-Cl	-Cl		R57#	-Cl	-Br		R87#	-Cl	-I
R28	-Br	-Cl		R58#	-Br	-Br		R88#	-Br	-I
R29	-I	-Cl		R59#	-I	-Br		R89#	-I	-I
R30a#	-2Py	-Cl		R60a#	-2Py	-Br		R90a#	-2Py	-I
R30b#	-3Py	-Cl		R60b#	-3Py	-Br		R90b#	-3Py	-I
R30c#	-4Py	-Cl		R60c#	-4Py	-Br		R90c#	-4Py	-I

(# not part of the invention)

INDUSTRIAL APPLICABILITY

[0229] The compound of formula (I) or a salt thereof has inhibitory activity against the kinase activity of EML4-ALK fusion protein, as well as growth inhibitory activity against EML4-ALK fusion protein-dependent cells, and can be used as an active ingredient in pharmaceutical compositions for preventing and/or treating cancer, such as lung cancer in one embodiment, non-small cell lung cancer or small cell lung cancer in another embodiment, ALK fusion polynucleotide-positive cancer in yet another embodiment, ALK fusion polynucleotide-positive lung cancer in yet another embodiment, ALK fusion polynucleotide-positive non-small cell lung cancer in yet another embodiment, ALK fusion protein-positive cancer in yet another embodiment, ALK fusion protein-positive lung cancer in yet another embodiment, ALK fusion protein-positive non-small cell lung cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive lung cancer in yet another embodiment, EML4-ALK fusion polynucleotide-positive non-small cell lung cancer in yet another embodiment, EML4-ALK fusion protein-positive cancer in yet another embodiment, EML4-ALK fusion protein-positive lung cancer in yet another embodiment, or EML4-ALK fusion protein-positive non-small cell lung cancer in yet another embodiment.

Claims

1. A compound of formula (I) or a salt thereof:

(wherein the symbols are as defined below:

-X-: a group of formula (II);

A: chloro, ethyl or isopropyl;

R¹:

(1) phenyl in which the carbon at the 4-position is substituted with -W-Y-Z and the carbon at the 3-position may be substituted with a group selected from the group consisting of halogen, R⁰⁰ and -O-R⁰⁰;
Z: a non-aromatic heterocyclic ring which may be substituted with one or more R⁰⁰;
R⁰⁰: linear or branched C_1-6 alkyl which may be substituted with one or more halogens;
-W-: a bond, piperidine-1,4-diyl, or piperazine-1,4-diyl;
-Y-: a bond;;
R²:

(i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of N(C_1-6 linear or branched alkyl)₂, C_1-6 linear or branched alkyl, -COO-C_1-6 linear or branched alkyl, -OH, -COOH, -CONH-R^ZB and morpholinyl, or,

(ii) a non-aromatic heterocyclic ring which may be substituted with one or more groups selected from the group consisting of C_1-6 linear or branched alkyl, -CO- C_1-6 linear or branched alkyl, oxo, -CO-R^ZB and benzyl;

R^ZB: phenyl which may be substituted with a group selected from the group consisting of halogen and -O-linear or branched C_1-6 alkyl;
R³: -H.

2. The compound according to Claim 1 or a salt thereof, wherein R¹ is phenyl in which the carbon at the 4-position is substituted with a group selected from the group consisting of 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-(1-methylpiperidin-4-yl)piperazin-1-yl, 4-methylpiperazin-1-yl, and 4-isopropylpiperazin-1-yl, and the carbon at the 3-position may be substituted with a group selected from the group consisting of fluoro, methyl, trifluoromethyl, and methoxy.

3. The compound according to Claim 2 or a salt thereof, wherein R² is 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl, or tetrahydropyran-4-yl.

4. The compound according to Claim 1 or a salt thereof, wherein said compound is:

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3- {[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide,

6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,

6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, or

6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.

5. A pharmaceutical composition, which comprises the compound according to Claim 1 or a salt thereof and a pharmaceutically acceptable excipient.

6. Compound according to claim 1 or a salt thereof for use in a method for inhibiting the kinase activity of EML4-ALK fusion protein.

7. A pharmaceutical composition for use in a method for preventing or treating cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, EML4-ALK fusion polynucleotide-positive cancer, EML4-ALK fusion polynucleotide-positive lung cancer, or EML4-ALK fusion polynucleotide-positive non-small cell lung cancer, which comprises the compound according to Claim 1 or a salt thereof.

8. Compound according to Claim 1 or a salt thereof for use in a method for preventing or treating of cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, EML4-ALK fusion polynucleotide-positive cancer, EML4-ALK fusion polynucleotide-positive lung cancer, or EML4-ALK fusion polynucleotide-positive non-small cell lung cancer.

Ansprüche

1. Verbindung der Formel (I) oder ein Salz davon:

worin die Symbole wie nachstehend definiert sind:

- X-: eine Gruppe der Formel (II);

A: Chlor, Ethyl oder Isopropyl;
R¹: (1) Phenyl, in dem der Kohlenstoff an der 4-Position mit -W-Y-Z substituiert ist und der Kohlenstoff an der 3-Position mit einer Gruppe, ausgewählt aus der Gruppe bestehend aus Halogen, R⁰⁰ und -O-R⁰⁰, substituiert sein kann;
Z: ein nicht-aromatischer heterocyclischer Ring, der mit einem oder mehreren R⁰⁰ substituiert sein kann;
R⁰⁰: geradkettiges oder verzweigtes C_1-6-Alkyl, das mit einer oder mehreren Halogenverbindung(en) substituiert sein kann;
-W-: eine Bindung, Piperidin-1,4-diyl oder Piperazin-1,4-diyl;
-Y-: eine Bindung;
R²:

(i) Cycloalkyl, das mit einer oder mehreren Gruppe(n), ausgewählt aus der Gruppe bestehend aus -N(geradkettigem oder verzweigtem C_1-6-Alkyl)₂, geradkettigem oder verzweigtem C_1-6-Alkyl, -COOgeradkettigem oder verzweigtem C_1-6-Alkyl, -OH, -COOH, -CONH-R^ZB und Morpholinyl, substituiert sein kann oder,

(ii) ein nicht-aromatischer heterocyclischer Ring, der mit einer oder mehreren Gruppe(n), ausgewählt aus der Gruppe bestehend aus geradkettigem oder verzweigtem C_1-6-Alkyl, -CO-geradkettigem oder verzweigtem C_1-6-Alkyl, Oxo, -CO-R^ZB und Benzyl, substituiert sein kann;

R^ZB: Phenyl, das mit einer Gruppe, ausgewählt aus der Gruppe bestehend aus Halogen und -O-geradkettigem oder verzweigtem C_1-6-Alkyl, substituiert sein kann;
R³: -H.

2. Verbindung gemäss Anspruch 1 oder ein Salz davon, worin R¹ Phenyl ist, in dem der Kohlenstoff an der 4-Position mit einer Gruppe, ausgewählt aus der Gruppe bestehend aus 4-(4-Methylpiperazin-1-yl)piperidin-1-yl, 4-(1-Methylpiperidin-4-yl)piperazin-1-yl, 4-Methylpiperazin-1-yl und 4-Isopropylpiperazin-1-yl, substituiert ist und der Kohlenstoff an der 3-Position mit einer Gruppe, ausgewählt aus der Gruppe bestehend aus Fluor, Methyl, Trifluormethyl und Methoxy, substituiert sein kann.

3. Verbindung gemäss Anspruch 2 oder ein Salz davon, worin R² 4-Hydroxycyclohexyl, 4-Hydroxy-4-methylcyclohexyl oder Tetrahydropyran-4-yl ist.

4. Verbindung gemäss Anspruch 1 oder ein Salz davon, worin die Verbindung ist:

6-Ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamid,

6-Ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-pyrazin-2-carboxamid,

5-[(trans-4-Hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamid,

6-Ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluormethyl)phenyl}amino)pyrazin-2-carboxamid,

6-Ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-phenyl}amino)pyrazin-2-carboxamid,

5-[(trans-4-Hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluormethyl)phenyl}amino)pyrazin-2-carboxamid,

6-Ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-phenyl}amino)pyrazin-2-carboxamid,

6-Ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}pyrazin-2-carboxamid,

6-Ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-phenyl}amino)pyrazin-2-carboxamid,

6-Ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)-piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-carboxamid,

6-Chlor-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-phenyl}amino)pyrazin-2-carboxamid,

6-Ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)-pyrazin-2-carboxamid,

6-Ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)-piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-carboxamid,

6-Isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)-pyrazin-2-carboxamid,

6-Ethyl-3-{[3-fluor-4-(4-methylpiperazin-1-yl)phenyl]-amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-carboxamid,

6-Isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)-phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-carboxamid,

6-Isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-carboxamid oder

6-Ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)-piperazin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-carboxamid.

5. Pharmazeutische Zusammensetzung, die eine Verbindung gemäss Anspruch 1 oder ein Salz davon und einen pharmazeutisch annehmbaren Hilfsstoff umfasst.

6. Verbindung gemäss Anspruch 1 oder ein Salz davon zur Verwendung in einem Verfahren zur Inhibierung der Kinaseaktivität eines EML4-ALK-Fusionsproteins.

7. Pharmazeutische Zusammensetzung zur Verwendung in einem Verfahren zur Prävention oder Behandlung von Krebs, Lungenkrebs, nicht-kleinzelligem Lungenkrebs, kleinzelligem Lungenkrebs, EML4-ALK-Fusions-Polynukleotid-positivem Krebs, EML4-ALK-Fusions-Polynukleotid-positivem Lungenkrebs oder EML4-ALK-Fusions-Polynukleotid-positivem nicht-kleinzelligem Lungenkrebs, die eine Verbindung gemäss Anspruch 1 oder ein Salz davon umfasst.

8. Verbindung gemäss Anspruch 1 oder ein Salz davon zur Verwendung in einem Verfahren zur Prävention oder Behandlung von Krebs, Lungenkrebs, nicht-kleinzelligem Lungenkrebs, kleinzelligem Lungenkrebs, EML4-ALK-Fusions-Polynukleotid-positivem Krebs, EML4-ALK-Fusions-Polynukleotid-positivem Lungenkrebs oder EML4-ALK-Fusions-Polynukleotid-positivem nicht-kleinzelligem Lungenkrebs.

Revendications

1. Composé de formule (I) ou sel de celui-ci :

(dans laquelle les symboles sont tels que définis ci-dessous :

-X- : un groupe de formule (II) ;

A : chloro, éthyle ou isopropyle ;

R¹ :

(1) un phényle dans lequel le carbone en position 4 est substitué par -W-Y-Z et le carbone en position 3 peut être substitué par un groupe choisi dans le groupe constitué par un halogène, R⁰⁰ et -O-R⁰⁰ ;
Z : un noyau hétérocyclique non aromatique qui peut être substitué par un ou plusieurs R⁰⁰ ;
R⁰⁰ : un alkyle linéaire ou ramifié en C_1-6 qui peut être substitué par un ou plusieurs halogènes ;
-W- : une liaison, un pipéridine-1,4-diyle, ou un pipérazine-1,4-diyle ;
-Y- : une liaison ;

R² :

(i) un cycloalkyle qui peut être substitué par un ou plusieurs groupes choisis dans le groupe constitué par un - N(alkyle linéaire ou ramifié en C_1-6)₂, alkyle linéaire ou ramifié en C_1-6, -COO-alkyle linéaire ou ramifié en C_1-6, - OH, -COOH, -CONH-R^ZB et morpholinyle, ou,

(ii) un noyau hétérocyclique non aromatique qui peut être substitué par un ou plusieurs groupes choisis dans le groupe constitué par un alkyle linéaire ou ramifié en C_1-6, -CO-alkyle linéaire ou ramifié en C_1-6, oxo, -CO-R^ZB et benzyle ;

R^ZB : un phényle qui peut être substitué par un groupe choisi dans le groupe constitué par un halogène et -O-alkyle linéaire ou ramifié en C_1-6 ;
R³ : -H.

2. Composé selon la revendication 1 ou sel de celui-ci, dans lequel R¹ est un phényle dans lequel le carbone en position 4 est substitué par un groupe choisi dans le groupe constitué par un 4-(4-méthylpipérazin-1-yl)pipéridin-1-yle, 4-(1-méthylpipéridin-4-yl)pipérazin-1-yle, 4-méthylpipérazin-1-yle, et 4-isopropylpipérazin-1-yle, et le carbone en position 3 peut être substitué par un groupe choisi dans le groupe constitué par un fluoro, méthyle, trifluorométhyle et méthoxy.

3. Composé selon la revendication 2 ou sel de celui-ci, dans lequel R² est un 4-hydroxycyclohexyle, 4-hydroxy-4-méthylcyclohexyle, ou tétrahydropyran-4-yle.

4. Composé selon la revendication 1 ou sel de celui-ci, dans lequel ledit composé est :

le 6-éthyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-méthylpipérazin-1-yl)phényl]amino}pyrazine-2-carboxamide,

le 6-éthyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)pyrazine-2-carboxamide,

le 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-méthylpipérazin-1-yl)phényl]amino}pyrazine-2-carboxamide,

le 6-éthyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]-3-(trifluorométhyl)phényl}amino)pyrazine-2-carboxamide,

le 6-éthyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-méthyl-4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)pyrazine-2-carboxamide,

le 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]-3-(trifluorométhyl)phényl}amino)pyrazine-2-carboxamide,

le 6-éthyl-5-[(cis-4-hydroxy-4-méthylcyclohexyl)amino]-3-({3-méthyl-4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)pyrazine-2-carboxamide,

le 6-éthyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpipérazin-1-yl)-3-méthylphényl]amino}pyrazine-2-carboxamide,

le 6-éthyl-5-[(trans-4-hydroxy-4-méthylcyclohexyl)amino]-3-({3-méthyl4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)pyrazine-2-carboxamide,

le 6-éthyl-3-({3-méthyl-4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

le 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-méthyl-4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)pyrazine-2-carboxamide,

le 6-éthyl-3-({4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

le 6-éthyl-3-({3-méthoxy-4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl]phényl}amino)-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

le 6-isopropyl-3-({4-[4-(4-méthylpipérazin-1-yl)pipéridin-1-yl)phényl}amino)-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

le 6-éthyl-3-{[3-fluoro-4-(4-méthylpipérazin-1-yl)phényl]amino}-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

le 6-isopropyl-3-{[3-méthoxy-4-(4-méthylpipérazin-1-yl)phényl]amino}-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,

le 6-isopropyl-3-{[4-(4-méthylpipérazin-1-yl)phényl]amino}-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, ou

le 6-éthyl-3-({3-méthyl-4-[4-(1-méthylpipéridin-4-yl)pipérazin-1-yl]phényl}amino)-5-(tétrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.

5. Composition pharmaceutique, qui comprend le composé selon la revendication 1, ou un sel de celui-ci et un excipient pharmaceutiquement acceptable.

6. Composé selon la revendication 1, ou un sel de celui-ci destiné à être utilisé dans un procédé pour inhiber l'activité kinase de la protéine de fusion EML4-ALK.

7. Composition pharmaceutique destinée à être utilisée dans un procédé pour prévenir ou traiter un cancer, un cancer du poumon, un cancer du poumon non à petites cellules, un cancer du poumon à petites cellules, un cancer positif pour un polynucléotide de fusion EML4-ALK, un cancer du poumon positif pour un polynucléotide de fusion EML4-ALK ou un cancer du poumon non à petites cellules positif pour un polynucléotide de fusion EML4-ALK, qui comprend le composé selon la revendication 1 ou un sel de celui-ci.

8. Composé selon la revendication 1 ou sel de celui-ci destiné à être utilisé dans un procédé pour prévenir ou traiter un cancer, un cancer du poumon, un cancer du poumon non à petites cellules, un cancer du poumon à petites cellules, un cancer positif pour un polynucléotide de fusion EML4-ALK, un cancer du poumon positif pour un polynucléotide de fusion EML4-ALK ou un cancer du poumon non à petites cellules positif pour un polynucléotide de fusion EML4-ALK.