GSK-3 INHIBITORS

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Provisional Patent Application USSN 61/900,465 filed November 6, 2013.

BACKGROUND OF THE INVENTION

[0002] The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds inhibit GSK-3 and may be useful for the treatment of various disorders of the central nervous system.

[0003] GSK-3 is a proline directed serine/threonine kinase that carries out the phosphorylation of multiple protein substrates. Many of these proteins are involved in the regulation of numerous diverse cellular functions, including metabolism, differentiation, proliferation and apoptosis. GSK-3 is constitutively active, with its base level of activity being positively modulated by phosphorylation on Tyr216/219, depending on isoform. GSK-3 has a unique substrate selectivity profile that is distinguished by the strong preference for the presence of a phosphorylated residue optimally located four amino acids C-terminal to the site of GSK-3 phosphorylation. Most commonly, GSK-3 activity is associated with inducing a loss of substrate function, such that GSK-3 inhibition will frequently result in increased downstream substrate activity.

[0004] GSK-3 exists in two isoforms, GSK-3α (51 kDa) and GSK-3β (47kDa), that share 84% overall identity and greater than 98% identity within their respective catalytic domains. Both primary isoforms are ubiquitously expressed, with high levels observed in the brain, particularly in the cortex and hippocampus. In most brain areas, GSK-3β is the predominant isoform. However, some studies suggest that GKS-3α and GSK-3β share very similar, if not entirely redundant functions in a number of cellular processes. The activity of GSK-3β is significantly reduced by phosphorylation at Ser9 in the N-terminal domain, most notably by protein kinase B (PKB or AKT). This inhibitory pathway has been proposed to result in neuroprotection, neurogenesis, and favorable outcomes following pharmacological treatment in various mood disorders.

[0005] Alzheimer's disease (AD) pathology is prominently associated with the formation of beta-amyloid (Aβ) plaques, soluble forms of Aβ such as Aβ1-42 that are associated with increased neuronal toxicity, and neurofibrillary tangles (NFTs). There is evidence to suggest that certain pathological mechanisms in AD, such as Aβ1-42, cause increases in GSK-3 activity in the brain. A principal consequence of this dysregulation is the hyperphosphorylation of the microtubule associated protein tau. This function of GSK-3 has been demonstrated both in cell culture, and in in vivo studies looking at tau and NFT formation. Hyper-phosphorylated tau disengages from microtubules resulting in structural destabilization of microtubules with concomitant negative effects on intracellular structures and transport mechanisms. In addition, the uncomplexed hyperphosphorylated tau assembles into paired helical filaments (PHFs) that aggregate to produce the stereotypic intracellular NFTs associated with AD. Other potential pathological consequences of over-activation of GSK-3 include neuroinflammation and neuronal apoptosis. In addition, GSK-3 has been demonstrated to be involved in mechanisms underlying memory and learning, and dysregulation of GSK-3 function may explain some of the early cognitive deficits observed in AD.

[0006] GSK-3 is also known to play a key role in glucose metabolism, and was first identified as the enzyme responsible for effecting the inhibitory phosphorylation of glycogen synthase, the result of which is to reduce the rate of conversion of glucose to glycogen, giving rise to elevated blood glucose levels. This function of GSK-3 is controlled by insulin. Binding of insulin to its receptor leads indirectly to the activation of AKT and subsequent inhibitory Ser9 phosphorylation of GSK-3.

[0007] These results and observations suggest that modulation of GSK-3 activity may be useful in the treatment of both the neuropathologic and symptomatic aspects of Alzheimer's disease, as well as other neurodegenerative diseases. These include, but are not limited to, tauopathies (for example, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease), Parkinson's disease, amyotrophic lateral schlerosis, stroke, Huntington's disease, peripheral neuropathies, traumatic brain injury, spinal cord trauma, and vascular dementias.

[0008] Compounds that inhibit GSK-3 may also have utility in the treatment of diabetes, inflammatory diseases such as rheumatoid arthritis and osteoarthritis, treatment-resistant depression, schizophrenia, bipolar disorder, manic depression, osteoporosis, cardioprotection, and various cancers such as gliomas, non-small cell lung cancer, pancreatic cancer, breast cancer, T- or B-cell leukemia, and multiple myeloma.

[0009] Recent reviews on the functions of GSK-3, potential therapeutic applications, and other compounds that inhibit the enzyme are listed below:

Kaidanovich-Beilin O and Woodgett JR (2011) GSK-3: functional insights from cell biology and animal models. Front. Mol. Neurosci. 4:40. doi: 10.3389/fnmol.2011.00040.

"Glycogen Synthase Kinase 3 (GSK-3) and Its Inhibitors", Martinez, Ana / Castro, Ana / Medina, Miguel (eds.), John Wiley and Sons (2006).

Gentles, RG, Hu, S. and Dubowchik, GM (2009) Recent Advances in the Discovery of GSK-3 Inhibitors and a Perspective on their Utility for the Treatment of Alzheimer's Disease. Annual Reports in Medicinal Chemistry 44, 3-26.

WO 2005/105780 A2 describes bicyclic heteroaryl derivatives as useful inhibitors of a range of protein kinases, such as GSK-3.

US 2002/119963 A1 describes imidazole derivatives, which are indicated to have activity inhibiting cdk5, cdk2, and GSK-3.

WO 2009/106209 A1 describes carboxamide-heteroaryl derivatives as activators of glucokinase which can be used for the prevention and/or treatment of diabetes type 1 and 2, obesity, neuropathy and/or nephropathy.

C. J. Helal et al. describe N-(5-isopropyl-thiazol-2-yl)isobutyramide as an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 in "Discovery and SAR of 2-aminothiazole inhibitors of cyclin-depndent kinase 5/p25 as a potential treatment for Alzheimer's deisease" (Bioorg. Med. Chem. Lett., 14(22), p. 5521-5525).

[0010] The invention provides technical advantages, for example, the compounds are novel inhibitors of GSK-3 and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

DESCRIPTION OF THE INVENTION

[0011] The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions, and their use in treating disorders associated with GSK-3.

[0012] One aspect of the invention is a compound of formula I

where:

R¹ is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;

R² is hydrogen, cyano, halo, alkyl, cyanoalkyl, haloalkyl, cycloalkyl, cyanocycloalkyl, (alkoxycarbonyl)alkenyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylsulfinyl, cycloalkylsulfinyl, phenylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, morpholinyl, SO₂N(R⁴)(R⁵);

R³ is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R² and R³ taken together is -CH=CH-CH=CH-;

R⁴ is hydrogen or alkyl;

R⁵ is hydrogen or alkyl;

or N(R⁴)(R⁵) taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and is substituted with 0-4 halo or alkyl substituents;

Ar¹ is 3-pyridinyl, 2-pyrazinyl, 4-pyridazinyl, 4-pyrimidinyl, 4-pyrazolyl, 4-isothiazolyl, or 3-imidazo[1,2-b]pyridazinyl, and is substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, (dicycloalkyl)hydroxyalkyl, (hydroxy)haloalkyl, alkoxyalkyl, (N(R⁴)(R⁵))alkyl, cycloalkyl, hydroxycycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, ((alkyl)cycloalkyl)alkoxy, alkylcarbonyl, cycloalkylcarbonyl, tetrahydrofuranyl, (alkyl)tetrahydrofuranyl, dioxolanyl, (alkyl)dioxolanyl, (cycloalkyl)dioxolanyl, (phenyl)dioxolanyl, (dialkyl)dioxolanyl, (haloalkyl)(alkyl)dioxolanyl, (trialkyl)dioxolanyl, dihydrpyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, N(R⁴)(R⁵), and Ar²; and is also substituted with 0-1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

Ar² is phenyl, pyridinyl, or pyrazolyl, and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

or a pharmaceutically acceptable salt thereof.

[0013] Another aspect of the invention is a compound of formula I where R¹ is hydrogen or halo.

[0014] Another aspect of the invention is a compound of formula I where R² is haloalkyl.

[0015] Another aspect of the invention is a compound of formula I where Ar¹ is 3-pyridinyl substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, (dicycloalkyl)hydroxyalkyl, (hydroxy)haloalkyl, alkoxyalkyl, (N(R⁴)(R⁵))alkyl, cycloalkyl, hydroxycycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, ((alkyl)cycloalkyl)alkoxy, alkylcarbonyl, cycloalkylcarbonyl, tetrahydrofuranyl, (alkyl)tetrahydrofuranyl, dioxolanyl, (alkyl)dioxolanyl, (cycloalkyl)dioxolanyl, (phenyl)dioxolanyl, (dialkyl)dioxolanyl, (haloalkyl)(alkyl)dioxolanyl, (trialkyl)dioxolanyl, dihydrpyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, N(R⁴)(R⁵), and Ar²; and is also substituted with 0-1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

[0016] Another aspect of the invention is a compound of formula I where Ar² is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

[0017] For a compound of formula I, the scope of any instance of a variable substituent, including R¹, R², R³, R⁴, R⁵, Ar¹, and Ar², can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects.

[0018] Unless specified otherwise, these terms have the following meanings. "Halo" includes fluoro, chloro, bromo, and iodo. "Alkyl" means a straight or branched alkyl group composed of 1 to 6 carbons. "Alkenyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. "Alkynyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. "Cycloalkyl" means a monocyclic ring system composed of 3 to 7 carbons. "Haloalkyl" and "haloalkoxy" include all halogenated isomers from monohalo to perhalo. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion. "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group. Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. "Heteroaryl" means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

[0019] The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0020] Some Formula I compounds contain at least one asymmetric carbon atom, an example of which is shown below. The invention includes all stereoisomeric forms of the compounds, both mixtures and separated isomers. Mixtures of stereoisomers can be separated into individual isomers by methods known in the art.

[0021] The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

Synthetic Methods

[0022] Compounds of Formula I may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention. The schemes encompass reasonable variations known in the art.

[0023] Compounds of Formula I can be synthesized through the following general scheme. Starting from either 2-chloro-isonicotinic acid or iosnicotinic acid dichloride, reaction with commercially available or prepared 3-amino heterocycles can afford 2-chloro-isonicotinamides of formula II. Reaction of Formula II compounds with substituted 2-amino pyridines can obtain Formula I compounds. Direct amination of 2-chloro-isonicotinic acid with substituted 2-amino pyridines can afford intermediate acids of Formula III, which after amide formation reaction with various 3-amino heterocycles can also lead to Formula I compounds.

[0024] The variously substituted 3-amino heterocycles could be prepared through different appraoches shown in General Scheme II.

Biological Methods

[0025] The kinase assay was performed in V-bottom 384-well plates. The final assay volume was 30 µl prepared from 15 µl additions of enzyme, substrates (fluoresceinated peptide FL-KRREILSRRP[ps]ERYR-NH2 and ATP) and test compounds in assay buffer (100 mM HEPES pH 7.4, 10 mM MgCl₂, 25mM Beta-Glycerolphosphate, 0.015% Brij35 and 0.25 mM DTT). The reaction was incubated at room temperature for 20 hours and terminated by adding 45µl of 35 mM EDTA to each sample. The reaction mixture was analyzed on the Caliper LabChip3000 (Caliper, Hopkinton, MA) by electrophoretic separation of the unphosphorylated substrate and phosphorylated product. Inhibition data were calculated by comparison of the no enzyme control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition. The final concentration of reagents in the assay were 250 pM GSK3α or GSK3β, 20 uM ATP, 1.5 uM FL-KRREILSRRP[ps]ERYR-NH2, and 1.6% DMSO. Dose response curves were generated to determine the concentration required to inhibit 50% of the kinase activity (IC₅₀). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at eleven concentrations. IC₅₀ values were derived by non-linear regression analysis.

Example	R1	R2	GSK3β/α (nM)	pTau (nM)
1	H	Ph	3.4/2.6	213
2	6-CF3	Ph	6.8/7.3	574
3	4-CF3	Ph	9.0/8.7	705
4	5-CF3	Ph
5	5-Me	Ph	0.77/4.8	183
6	4-Me	Ph	1.1/1.3	164
7	6-F	Ph	8.5/5.9	249
8	5-F	Ph	4.1/1.9	132
9	4-Me-5-F	Ph	4.1/2.5	110
10	5-CN	Ph	0.98/0.58	27
11	H	OEt	8.9/2.8	294
12	3,4-Benzo	OEt	5.9/35	5400
13	4-Me	OEt	1.4/2.3	154
14	5-Me	OEt	0.47/1.5	125
15	5-CF3	OEt	1.3/0.56	42
16	5-CN	OEt	1.1/0.62	12
17	5-CF3	OCH2tBu	1.6/0.89	43
18	5-CF3	OCH2CF3	0.71/0.42	13
19	5-CF3	OiPr	1.6/0.55	16
20	5-CF3	4-(3S-Me)-morpholinyl	0.10/0.09	0.66
21	5-CF3	4-(3R-Me)-morpholinyl	0.70/0.28	9.1
22	5-CF3	4-(2,2-Me2)-morpholinyl	0.48/0.31	18
23	5-CF3	1-piperidinyl	0.24/0.15	6.5
24	5-CF3	1-(4,4-F2)-piperidinyl	0.69/0.49	4.6
25	5-CN	OCH2tBu	4.3/2.0	30
26	5-CN	Me	14/8.2	670
27	5-CN	1-piperidinyl	0.42/0.18	5.2
28	5-CN	4-(2,2-Me2)-morpholinyl	0.55/0.37	16
29	5-CN	OCH2CF3	0.69/0.62	16
30	5-S(O)2NMe2	OCH2CF3	0.50/0.31	24
31	5-Cl	OCH2CF3	0.74/0.30	22
32	5-CF3		2.3/0.78	71
33	5-CF3		0.29/0.18	0.55
34	5-CF3		3.2/1.4	37
35	5-CF3		16/8.7	760
36	5-CF3		2.9/1.4	130
37	5-CF3		3.3/1.5	130
38	5-CF3		1.1/0.71	8.8
39	5-CF3		1.2/0.93	140
40	5-CF3		23/46	3300
41	5-CF3		13/-	120
42	5-CF3	OCH2CHF2	0.49/0.27	21
43	5-CF3	4-(2-Pyridine)	0.77/0.59	-
44	5-CF3		1.4/0.33	52
45	5-CF3		17/11	150
46	5-CF3		150/75	4300
47	5-CF3		18/5.6	420
48	6-Cl	4-(4-F-Ph)	2.9/1.9	270

Examples	R1	R2	GSK3β/α (nM)	pTau (nM)
49	CF3	2-F	0.65/0.32	53
50	CF3	4-F	2.1/0.86	54
51	CF3	4-Cl	9.9/6.9	266
52	CF3	2-F-4-CN	3.6/1.5	35
53	CF3	2-CF3-4-F	0.51/0.57	8.3
54	CF3	2-F-4-F	2.8/0.96	57
55	CF3	2-F-4-OMe	3.2/0.89	86
56	CN	4-F	2.4/0.98	36
57	CN	2-F-4-F	1.3/0.59	19
58	Cl	4-F	0.86/0.36	57
59	Cl	H	0.90/0.39	45
60	Cl	4-Cl	2.7/1.2	270
61		H	1.5/0.54	150
62		H	0.62/0.29	37
63	Br	H	9.3/3.4	150

Examples	R1	GSK3β/α (nM)	pTau (nM)
64	CF3	10/3.1	610
65	CN	8.5/3.2	420

Examples	R1	R2	X	GSK3β/α (nM)	pTau (nM)
66	CF3	Ph	Cl	61/29	5849
67	CF3	Ph	F	7.0/4.0	524
68	CF3	Ph	Me	12/5.7	1011
69	CF3	OCH2CF3	F	2.6/-	165
70	CF3		Cl	7.6/2.6	564
71	CF3		F	1.3/0.36	60
72	CF3		Me	3.5/0.76	120
73	CF3		F	1.0/0.6	43
74	CF3		Cl	3.4/2.5	180
75	CF3		F	5.1/2.4	830
76	CF3		Cl	0.32/0.20	13
77	CF3		Cl	0.63/0.35	31
78	CF3		Cl	4.5/3.2	170
79	CF3		Cl	0.31/0.17	33
80	CF3	OCH2CHF2	F	6.2/3.3	86
81	CF3		Cl	6.7/4.0	1900
82	CF3		F	7.1/1.9	230
83	CF3		Cl	1.1/0.55	57
84	CF3		O(CH2)2OH	9.2/5.0	350
85	CF3		Cl	64/35	5500
86	CF3		Cl	12/2.4	510
87	CF3		Cl	0.04/0.17	6.6
88	CF3		Cl	0.69/0.23	80
89	CF3		Cl	1.6/1.7	340
90	CF3		Cl	2.0/0.94	150
91	CF3		OMe	3.9/20	1200
92	CF3		Cl	8.8/4.0	1400
93	CF3		Cl	2.6/0.78	110
94	CF3		F	0.06/0.03	1.2
95	CF3		Cl	10/5.5	910
96	CF3		Cl	0.29/0.16	39
97	CF3		Cl	1.5/0.56	84
98	CF3		Cl	3.7/4.0	230
99	CF3		Cl	6.4/4.6	430
100	CF3		Cl	11/8.4	500
101	CF3		Cl	11/7.4	660
102	CF3		Cl	43/30	1200
103	CF3		Cl	6.7/3.9	540
104	CF3		Cl	18/9.9	280
105	CF3		Me	-/-	2.0
106	CF3		Me	0.25/0.49	22
107	CF3		Me	0.92/0.75	94
108	H		Cl	1.4/0.95	30
109	Me		Cl	1.8/1.2	45
110	Cl	OCH2CF3	F	3.8/0.51	170
111	Cl		Cl	2.6/1.4	530
112	Cl		F	5.0/3.0	850
113	F		Cl	1.7/0.04	14
114	F	OCH2CHF2	F	4.4/1.5	220

Examples	GSK3β/α (nM)	pTau (nM)
115	0.97/0.65	297

Examples	GSK3β/α (nM)	pTau (nM)
116	7.8/3.9	610

Examples	GSK3β/α (nM)	pTau (nM)
117	3.0/1.4	254

Examples	R1	R2	GSK3β/α (nM)	pTau (nM)
118	5-CF3		7.3/-	360
119	5-CF3
120	5-CF3		29/14	1500
121	5-CF3		25/12	1500
122	6-CF3		6.9/2.2	2000
123	6-CF3		7.4/3.2	520
124	6-CF3		9.4/3.5	3600
125	6-CF3		12/3.8	2200
126	6-CF3		9.7/4.8	3200

Examples	R1	R2	GSK3β/α (nM)	pTau (nM)
127	5-CF3	2-F	11/6.0	1753
128	5-CF3	2-Cl	12/16	2176
129	5-CF3	2,5-di-F	18/9.8	2100
130	5-CF3	2,3-di-F	42/20	2600
131	5-F	2-F	6.1/3.0	640
132	4-Me	2-F	9.0/6.2	1900
133	5-Me	2-F	7.3/3.4	1400
134	6-CF3	2-F	3.9/1.5	470
135	5-CN	2-F	3.0/1.7	670
136	6-F	2-F	11/2.7	1100
137	6-Me	2-F	7.1/5.6	2700
138	6-Et	2-F	3.5/2.2	4700
139	6-OMe	2-F	5.4/3.2	1300
140		2-F	6.7/10	980
141	5-OMe	2-F	3.5/1.8	680
142		2-F	23/5.6	2100
143	5,6-di-Me	2-F	8.7/6.0	2800
144	6-CF3	H	10/39	910
145	6-CF3	2-Cl	6.4/4.4	730
146	6-CF3	2,5-di-F	5.1/3.2	1400
147	6-CF3	2,3-di-F	2.3/44	380
148	6-Et, 5-CN	2-F	4.5/-	360
149	6-CO2Me	2-F	2.7/-	1700
150	6-Cl	2-F	3.5/-	1100
151	6,5-di-MeO	2-F	6.0/2.4	510
152	6-CN	2-F	1.6/0.87	260
153		2-F	1.5/0.45	200
154	6-NHC(O)tBu	2-F	9.2/2.2	1100
155	5-CN-6-Me	2-F	3.6/1.2	570
156	5-S(O)2NH2	2-F	3.0/1.6	5600
157	5-S(O)2NMe2	2-F	3.6/1.6	750
158	5-C(O)Me	2-F	6.0/3.0	690
159	5-S(O)2N(CH2)5	2-F	3.9/1.9	960
160	5-C(O)NH2	2-F	16/7.6	-
161	5-CH=CHCO2Me	2-F	23/8.0	-
162	6-CN	4-CN	3.5/2.4	-
163		2-F	3.2/1.1	610
164		2-F	4.9/2.4	3100
165	6-CN	3-F-4-CN	1.2/0.40	84
166	6-CN	2-CN-3-F	0.91/0.28	390

Examples	R	GSK3β/α (nM)	pTau (nM)
167	Ph	1.8/0.55	230
168	OCH2CF3	1.5/0.73	-

Examples	R	GSK3β/α (nM)	pTau (nM)
169	OCH2CF3	28/10	3898

Examples	R	X	GSK3β/α(nM)	pTau (nM)
170	n-Pr	H	0.75/0.21	49
171	CH2CF3	H	1.2/0.61	47
172	Ph	H	5.6/1.1	240
173	2-Pr	H	0.52/0.19	48
174	t-Bu	H	0.14/0.08	27
175	i-Bu	H	1.1/0.40	78
176	Cyclopropyl	Cl	11/7.0	1100

Examples	R	X	GSK3β/α(nM)	pTau (nM)
177	Ph	H	3.9/1.1	760
178	t-Bu	H	0.12/1.2	13
179	2-Pr	H	4.3/1.2	-
180	Cyclopropyl	Cl	15/7.6	790

Examples	R	X	GSK3β/α (nM)	pTau (nM)
181	Me	H	1.2/0.77	-
182	n-Pr	H	5.2/2.1	15
183	Ph	H	2.2/0.75	200
184	CH2CF3	H	120/4.8	130
185	i-Bu	H	0.51/4.8	49
186	2-Pr	H	1.2/0.04	2.0
187	t-Bu	H	0.40/0.07	1.1
188	Cyclopropyl	Cl	5.0/3.3	150

Examples	R	GSK3β/α (nM)	pTau (nM)
189	H	11/4.3	1030
190	2-F-Ph	68/29	10000

Examples	R1	R2	GSK3β/α (nM)	pTau (nM)
191	H	H	17/9	1600
192	Br	H	23/9.3	520
193	Ph	H	3.6/1.9	165
194	OCH2CF3	H	3.2/1.6	140
195		H	17/7.9	710

Examples	R	GSK3β/α (nM)	pTau (nM)
196	H	80/25	7400
197	Br	70/22	3500
198	Ph	6.7/2.9	180
199		8.7/-	470
200		0.62/0.39	3.2
201		0.19/0.40	28
202		2.9/1.1	-
203		1.2/0.94	10000

Examples		GSK3β/α (nM)	pTau (nM)
204		3.0/1.7	300

Examples	R1	R2	GSK3β/α (nM)	pTau (nM)
205	Ph	H	28/20	10000
206		Me	3.1/2.7	400
207		Me	0.09/0.10	1.4
208		Me	3.0/3.6	120
209		Me	0.30/0.21	21

Examples		GSK3β/α (nM)	pTau (nM)
210		33/11	2300

Pharmaceutical Compositions and Methods of Treatment

[0026] Compounds of formula I can be useful in treating neurological or psychiatric disorders. Therefore, another aspect of the invention is a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0027] Another aspect of the invention is a compound of formula I for use in a method for the treatment for modulation of GSK-3 activity may be useful in the treatment of both the neuropathologic and symptomatic aspects of Alzheimer's disease, as well as other neurodegenerative diseases. These include, but are not limited to, tauopathies (for example, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease), Parkinson's disease, amyotrophic lateral sclerosis, stroke, Huntington's disease, peripheral neuropathies, traumatic brain injury, spinal cord trauma, and vascular dementias, which comprises administering to a patient a therapeutically affective amount of a compound of formula I.

[0028] Another aspect of the invention is a compound of formula I for use in a method for the treatment for diabetes, inflammatory diseases such as rheumatoid arthritis and osteoarthritis, treatment-resistant depression, schizophrenia, bipolar disorder, manic depression, osteoporosis, cardioprotection, and various cancers such as gliomas, non-small cell lung cancer, pancreatic cancer, breast cancer, T- or B-cell leukemia, and multiple myeloma, which comprises administering to a patient a therapeutically affective amount of a compound of formula I.

[0029] Another aspect of the invention is a compound of formula I for use in a method for the treatment of Alzheimer's disease which comprises administering to a patient a therapeutically affective amount of a compound of formula I.

[0030] Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment of Alzheimer's disease.

[0031] "Patient" means a person suitable for therapy as understood by practitioners in the field of affective disorders and neurodegenerative disorders.

[0032] "Treatment," "therapy," and related terms are used as understood by practitioners in the field of neurological and psychiatric disorders.

[0033] The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985.

[0034] Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

[0035] Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.

[0036] The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

DESCRIPTION OF SPECIFIC EMBODIMENTS

[0037] Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: "NaHMDS" for sodium bis(trimethylsilyl)amide; "DMF" for N,N-dimethylformamide; "MeOH" for methanol; "NBS" for N-bromosuccinimide; "Ar" for aryl; "TFA" for trifluoroacetic acid; "LAH" for lithium aluminum hydride; "BOC" for t-butoxycarbonyl, "DMSO" for dimethylsulfoxide; "h" for hours; "rt" for room temperature or retention time (context will dictate); "min" for minutes; "EtOAc" for ethyl acetate; "THF" for tetrahydrofuran; "EDTA" for ethylenediaminetetraacetic acid; "Et₂O" for diethyl ether; "DMAP" for 4-dimethylaminopyridine; "DCE" for 1,2-dichloroethane; "ACN" for acetonitrile; "DME" for 1,2-dimethoxyethane; "HOBt" for 1-hydroxybenzotriazole hydrate; "DIEA" for diisopropylethylamine, "Nf" for CF₃(CF₂)₃SO₂-; and "TMOF" for trimethylorthoformate.

[0038] Abbreviations as used herein, are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for thrice, "°C" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "µL" for microliter or microliters, "N" for normal, "M" for molar, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrate, "sat" or "sat'd" for saturated, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry , "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "¹H" for proton, "δ" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

General Synthesis of Formula II

[0039] 

2-Chloro-N-(4-phenylpyridin-3-yl)isonicotinamide. In a 100 mL round-bottom flask was added 2-chloroisonicotinoyl chloride (556 mg, 3.16 mmol) and 4-phenylpyridin-3-amine dihydrochloride (384 mg, 1.58 mmol) in methylene chloride (14 mL) to give a tan suspension. DIEA (0.910 mL, 5.21 mmol) was added dropwise. The solids dissolved and the resulting greenish solution was stirred at rt for two days. To this was added 12 mL of 1.0 N NaOH (7.6 equiv.), and the mixture was stirred at rt for 5 h. LCMS showed complete conversion to the desired product. The mixture was partitioned between ethyl acetate and water. The layers were separated. The organic layer was washed with brine, dried, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 8% methanol/methylene chloride, to afford the desired product (470 mg, 96%) as a tan foam: ¹H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.69 - 8.36 (m, 2H), 8.22 (s, 1H), 7.55 (s, 4H), 7.43 (d, J = 6.3 Hz, 2H), 7.37 (d, J = 3.7 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H).

2-Chloro-N-(4-iodopyridin-3-yl)isonicotinamide. MS (ESI) (m/z): 360.0 (M+H)⁺.

2-Chloro-N-(4-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-yl)isonicotinamide. A mixture of PdCl2(dppf) (0.013 g, 0.018 mmol), sodium carbonate (0.296 mL, 0.591 mmol), (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid (0.123 g, 0.591 mmol) and 2-chloro-N-(4-iodopyridin-3-yl)isonicotinamide (0.1063 g, 0.296 mmol) was heated for 1 h at 80 °C. LCMS showed the desired product. The reaction was filtered through a celite cartridge and washed with methylene chloride. The filtrate was concentrated and the product purified by flash chromatography on silica gel, eluting with ethyl acetate in hexane from 0 to 50% to 100%, to afford the desired product (41 mg, 35%): MS (ESI) (m/z): 396.1 (M+H)⁺; ¹H NMR (500MHz, CHLOROFORM-d) δ 9.25 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.46 (dd, J=5.1, 0.7 Hz, 1H), 7.68 (br. s., 1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (dd, J=1.4, 0.7 Hz, 1H), 7.40 (dd, J=6.4, 1.5 Hz, 2H), 7.28 - 7.26 (m, 1H), 7.23 (d, J=4.9 Hz, 1H).

2-Chloro-N-(4-(4-cyano-2-fluorophenyl)pyridin-3-yl)isonicotinamide. MS (ESI) (m/z): 353.1 (M+H)⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 9.01 (s, 1H), 8.62 (d, J=5.0 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.31 (br. s., 1H), 7.64 - 7.59 (m, 2H), 7.57 - 7.49 (m, 2H), 7.46 (dd, J=5.1, 1.4 Hz, 1H), 7.33 (d, J=5.0 Hz, 1H); ¹⁹F NMR (376MHz, CHLOROFORM-d) δ -111.21 (s, 1F).

2-Chloro-N-(4-(4-methoxy-2-fluorophenyl)pyridin-3-yl)isonicotinamide. MS (ESI) (m/z): 358.1 (M+H)⁺.

2-Chloro-N-(4-(4-fluorophenyl)pyridin-3-yl)isonicotinamide. MS (ESI) (m/z): 328.1 (M+H)⁺.

2-Chloro-N-(4-(2,4-difluorophenyl)pyridin-3-yl)isonicotinamide. MS (ESI) (m/z): 346.1 (M+H)⁺.

2-Chloro-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)isonicotinamide. MS (ESI) (m/z) : 332 (M+H)⁺.

2-Chloro-N-(4-phenylpyridin-3-yl)isonicotinamide (alternative synthesis). To 4-phenylpyridin-3-amine (0.5 g, 2.94 mmol) and 2-chloroisonicotinic acid (0.486 g, 3.08 mmol) in EtOAc (10 mL) was added DIEA (2.57 mL, 14.69 mmol) followed by T3P, 50% in EtOAc (2 mL, 3.43 mmol). The reaction was stirred at rt overnight. It was diluted with EtOAc and washed with water, brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 120 g silica gel cartridge which was eluted with 0-15% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 2-chloro-N-(4-phenylpyridin-3-yl)isonicotinamide (0.75g, 2.421 mmol, 82 % yield). MS (ESI) (m/z): 310.0(M+H)⁺.

Example 1.

[0040] 

N-(4-Phenylpyridin-3-yl)-2-(pyridin-2-ylamino)isonicotinamide. In a 5 mL vial was added 2-chloro-N-(4-phenylpyridin-3-yl)isonicotinamide (31.7 mg, 0.102 mmol), pyridin-2-amine (11.6 mg, 0.123 mmol), and Cs₂CO₃ (50.0 mg, 0.154 mmol) in dioxane (0.6 mL) to give a tan suspension under nitrogen. PdOAc₂ (0.919 mg, 4.09 µmol) and XANTPHOS (3.55 mg, 6.14 µmol) were added under nitrogen. The vial was sealed under nitrogen, and the mixture was heated at 100°C overnight. After 18 h, LCMS showed ca 60% conversion to the desired product. The mixture was diluted with water and ethyl acetate. The layers were separated. The organic layer was dried and concentrated. The residue was dissolved in 1.5 ml DMF and purified by prep-HPLC (13.4 mg, 36%): MS (ESI) (m/z): 368.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.35 (s, 1H), 9.91 (s, 1H), 8.65 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.25 (dd, J = 4.9, 1.3 Hz, 1H), 8.13 (s, 1H), 7.69 (d, J = 2.9 Hz, 2H), 7.57 - 7.52 (m, 2H), 7.52 - 7.45 (m, 3H), 7.44 - 7.39 (m, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.95 - 6.88 (m, 1H).

Example 2:

[0041] 

N-(4-Phenylpyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 436.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 0.42 - 10.36 (m, 2H), 8.65 (s, 1H), 8.59 (d, J=4.9 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.54 (d, J=7.3 Hz, 2H), 7.52 - 7.45 (m, 3H), 7.44 - 7.39 (m, 1H), 7.27 (d, J=4.6 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H).

Example 3:

[0042] 

N-(4-Phenylpyridin-3-yl)-2-((4-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 436.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.42 (s, 1H), 10.39 (s, 1H), 8.62 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.12 (d, J=8.5 Hz, 1H), 8.03 (s, 1H), 7.96 (t, J=7.9 Hz, 1H), 7.54 (d, J=7.3 Hz, 2H), 7.50 (d, J=5.2 Hz, 1H), 7.46 (t, J=7.5 Hz, 2H), 7.42 - 7.37 (m, 2H), 7.25 (d, J=5.2 Hz, 1H).

Example 5:

[0043] 

2-((5-Methylpyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/Z): 382.2 (M+H)⁺.

Example 6:

[0044] 

2-((4-Methylpyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 382.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.81 (s, 1H), 8.65 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.16 - 8.08 (m, 2H), 7.57 - 7.36 (m, 7H), 7.16 (d, J=4.6 Hz, 1H), 6.77 (d, J=5.2 Hz, 1H), 2.29 (s, 3H).

Example 7:

[0045] 

2-((6-Fluoropyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 386.3 (M+H)⁺.

Example 8:

[0046] 

2-((5-Fluoropyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 386.2 (M+H)⁺.

Example 9:

[0047] 

2-((5-Fluoro-4-methylpyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 400.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.87 (s, 1H), 8.64 (s, 1H), 8.58 (d, J=5.2 Hz, 1H), 8.34 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.51 - 7.45 (m, 3H), 7.44 - 7.38 (m, 1H), 7.16 (d, J=4.9 Hz, 1H), 2.28 (s, 3H).

Example 10:

[0048] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 393.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.58 (br. s., 1H), 10.42 (br. s., 1H), 8.69 (d, J=2.4 Hz, 1H), 8.66 (s, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.14 - 8.06 (m, 2H), 7.87 (d, J=8.9 Hz, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.51 - 7.44 (m, 3H), 7.43 - 7.38 (m, 1H), 7.33 (d, J=4.9 Hz, 1H).

Example 115:

[0049] 

2-(Isoquinolin-3-ylamino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 418.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.36 (s, 1H), 10.05 (s, 1H), 9.11 (s, 1H), 8.65 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.47 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.57 - 7.53 (m, 2H), 7.53 - 7.38 (m, 5H), 7.17 (d, J=5.2 Hz, 1H).

Example 116:

[0050] 

N-(4-Phenylpyridin-3-yl)-2-(quinolin-2-ylamino)isonicotinamide: MS (ESI) (m/z): 418.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.46 (s, 1H), 10.31 (s, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.61 (d, J=5.2 Hz, 1H), 8.42 (d, J=4.9 Hz, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.68 - 7.63 (m, 1H), 7.59 (s, 2H), 7.56 (d, J=9.2 Hz, 1H), 7.52 (d, J=5.2 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.39 (dd, J=7.0, 2.1 Hz, 2H), 7.27 (d, J=4.6 Hz, 1H).

Example 11:

[0051] 

N-(4-Ethoxypyridin-3-yl)-2-(pyridin-2-ylamino)isonicotinamide: MS (ESI) (m/z): 336.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 9.94 (s, 1H), 9.86 (s, 1H), 8.67 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.35 (d, J=5.8 Hz, 1H), 8.29 - 8.25 (m, 1H), 8.23 (s, 1H), 7.76 - 7.66 (m, 2H), 7.34 (d, J=4.6 Hz, 1H), 7.18 (d, J=5.5 Hz, 1H), 6.92 (ddd, J=6.5, 5.0, 1.7 Hz, 1H), 4.21 (q, J=6.9 Hz, 2H), 1.37 (t, J=6.9 Hz, 3H).

Example 12:

[0052] 

N-(4-Ethoxypyridin-3-yl)-2-(isoquinolin-1-ylamino)isonicotinamide: MS (ESI) (m/z): 386.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.90 (br. s., 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.51 (d, J=4.9 Hz, 1H), 8.35 (d, J=5.5 Hz, 1H), 8.14 (d, J=5.8 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.77 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.3 Hz, 1H), 7.46 (br. s., 1H), 7.40 (d, J=5.8 Hz, 1H), 7.18 (d, J=5.8 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).

Example 13:

[0053] 

N-(4-Ethoxypyridin-3-yl)-2-((4-methylpyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 350.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 9.84 (d, J=6.7 Hz, 2H), 8.67 (s, 1H), 8.40 (d, J=4.9 Hz, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.24 (s, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J=4.3 Hz, 1H), 7.17 (d, J=5.5 Hz, 1H), 6.77 (d, J=4.9 Hz, 1H), 4.21 (q, J=6.9 Hz, 2H), 2.30 (s, 3H), 1.37 (t, J=6.9 Hz, 3H).

Example 14:

[0054] 

N-(4-Ethoxypyridin-3-yl)-2-((5-methylpyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 350.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 9.82 (s, 1H), 8.67 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.12 (d, J=19.2 Hz, 2H), 7.67 (d, J=8.5 Hz, 1H), 7.54 (dd, J=8.5, 2.1 Hz, 1H), 7.29 (d, J=4.3 Hz, 1H), 7.17 (d, J=5.8 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 2.24 (s, 3H), 1.37 (t, J=7.0 Hz, 3H).

Example 15:

[0055] 

N-(4-Ethoxypyridin-3-yl)-2-((5-trifluoromethylpyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 404.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.91 (s, 1H), 8.64 (d, J=15.9 Hz, 2H), 8.48 (d, J=5.2 Hz, 1H), 8.3 5 (d, J=5.8 Hz, 1H), 8.22 (s, 1H), 8.06 (dd, J=8.9, 2.4 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H), 7.18 (d, J=5.5 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 1.37 (t, J=6.9 Hz, 3H).

Example 16:

[0056] 

N-(4-Ethoxypyridin-3-yl)-2-((5-cyanopyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 361.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.62 (br. s., 1H), 9.95 (br. s., 1H), 8.71 (d, J=2.4 Hz, 1H), 8.65 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.35 (d, J=5.5 Hz, 1H), 8.21 (s, 1H), 8.11 (dd, J=8.9, 2.4 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.49 (d, J=4.6 Hz, 1H), 7.18 (d, J=5.8 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).

Example 30:

[0057] 

2-((5-(N,N-Dimethylsulfamoyl)pyridin-2-yl)amino)-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 497.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.63 (s, 1H), 10.17 (br. s., 1H), 8.61 (s, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.28 (s, 1H), 8.03 (dd, J=9.0, 2.6 Hz, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.45 (d, J=4.9 Hz, 1H), 7.33 (d, J=5.5 Hz, 1H), 4.98 (q, J=8.5 Hz, 2H), 2.65 (s, 6H).

Example 50:

[0058] 

N-(4-(4-Fluorophenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 454.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.43 (s, 2H), 8.64 (s, 1H), 8.57 (d, J=4.9 Hz, 2H), 8.42 (d, J=4.9 Hz, 1H), 8.08 (s, 1H), 8.03 (dd, J=9.0, 2.6 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.57 (dd, J=8.5, 5.5 Hz, 2H), 7.49 (d, J=4.9 Hz, 1H), 7.36 - 7.24 (m, 3H).

Example 52:

[0059] 

N-(4-(2-Fluoro-4-cyano-phenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 479.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (br. s., 1H), 10.46 (s, 1H), 8.77 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.60 (s, 1H), 8.43 (d, J=4.9 Hz, 1H), 8.07 - 7.95 (m, 3H), 7.89 (d, J=8.9 Hz, 1H), 7.80 (dd, J=7.9, 1.2 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.54 (d, J=5.2 Hz, 1H), 7.23 (d, J=4.9 Hz, 1H).

Example 53:

[0060] 

N-(4-(2-Trifluoromethyl-4-fluoro-phenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 522.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.44 (s, 1H), 10.21 (br. s., 1H), 8.77 (s, 1H), 8.57 (d, J=4.9 Hz, 2H), 8.39 (d, J=4.9 Hz, 1H), 8.04 (dd, J=9.2, 2.4 Hz, 1H), 7.99 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.77 (dd, J=9.3, 2.6 Hz, 1H), 7.63 (td, J=8.5, 2.6 Hz, 1H), 7.49 (dd, J=8.5, 5.5 Hz, 1H), 7.38 (d, J=4.9 Hz, 1H), 7.12 (dd, J=5.2, 1.2 Hz, 1H).

Example 54:

[0061] 

N-(4-(2,4-Difluoro-phenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 472.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.46 (s, 1H), 10.40 (br. s., 1H), 8.74 (s, 1H), 8.62 - 8.56 (m, 2H), 8.42 (d, J=5.2 Hz, 1H), 8.09 - 8.02 (m, 2H), 7.87 (d, J=8.9 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.44 - 7.34 (m, 1H), 7.27 - 7.16 (m, 2H).

Example 55:

[0062] 

N-(4-(2-Fluoro-4-methoxy-phenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 484.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.47 (s, 1H), 10.33 (br. s., 1H), 8.70 (s, 1H), 8.58 (s, 1H), 8.55 (d, J=4.9 Hz, 1H), 8.43 (d, J=4.9 Hz, 1H), 8.11 (s, 1H), 8.04 (dd, J=8.9, 2.4 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.45 (d, J=4.9 Hz, 1H), 7.37 (t, J=8.7 Hz, 1H), 7.27 (d, J=4.6 Hz, 1H), 6.95 (dd, J=12.4, 2.3 Hz, 1H), 6.88 (dd, J=8.5, 2.4 Hz, 1H), 3.78 (s, 3H).

Example 56:

[0063] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-(4-fluorophenyl)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 411.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.55 (s, 1H), 10.43 (br. s., 1H), 8.68 - 8.62 (m, 2H), 8.57 (d, J=5.2 Hz, 1H), 8.44 (d, J=4.9 Hz, 1H), 8.10 - 8.02 (m, 2H), 7.83 (d, J=9.5 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.49 (d, J=5.2 Hz, 1H), 7.35 - 7.26 (m, 3H).

Example 57:

[0064] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-(2,4-difluorophenyl)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 429.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.58 (s, 1H), 10.44 (br. s., 1H), 8.74 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.57 (d, J=5.2 Hz, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.09 (dd, J=8.9, 2.1 Hz, 1H), 8.06 (s, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.42 - 7.35 (m, 1H), 7.28 (d, J=5.2 Hz, 1H), 7.20 (td, J=8.5, 2.6 Hz, 1H).

Example 63:

[0065] 

2-((5-Bromopyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 448.2 (M+H)⁺; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.85 (s, 1 H) 8.52 (d, J=5.27 Hz, 1 H) 8.33 (d, J=5.77 Hz, 2 H) 7.81 - 7.92 (m, 2 H) 7.41 - 7.50 (m, 7 H) 7.37 (d, J=9.04 Hz, 1 H) 7.30 (br. s., 1 H).

General Synthesis of Formula III:

[0066] 

2-((5-(Trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid. To an oven-dried vial containing a stir bar, Brettphos precatalyst (0.101 g, 0.127 mmol), Brettphos (0.068 g, 0.127 mmol), 2-chloroisonicotinic acid (2.0 g, 13 mmol), 5-(trifluoromethyl)pyridin-2-amine (2.68 g, 16.5 mmol) and K₂CO₃ (2.63 g, 19.0 mmol) were added. The solid mixture was purged with N₂ (degassed and flushed) three times. Then tert-butanol (30 mL) was added. The vial was degassed and flushed with N₂ three times and the vessel was capped and placed in a preheated oil bath at 110 °C for 10 h. The sample was cooled to rt, diluted with ethyl acetate, and washed with water. The aqueous layer was acidified to pH 5-6 and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to give the desired product (1.35 g, 4.77 mmol, 38% yield). The solid was collected by filtration and dried under vacuo to give more of the desired product (1.9 g, 6.71 mmol, 53% yield). Total yield was 91%: MS (ESI) (m/z): 284.1(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.69 (br. s., 1 H) 10.48 (s, 1 H) 8.58 - 8.67 (m, 1 H) 8.44 (d, J=5.14 Hz, 1 H) 8.25 (s, 1 H) 8.04 (dd, J=9.05, 2.45 Hz, 1 H) 7.94 (d, J=9.05 Hz, 1 H) 7.38 (dd, J=5.14, 1.22 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -59.78 (s, 3 F).

2-((5-Chloropyridin-2-yl)amino)isonicotinic acid. The mixture of XANTPHOS (0.055 g, 0.095 mmol), cesium carbonate (0.414 g, 1.269 mmol), palladium acetate (0.014 g, 0.063 mmol), 2-chloroisonicotinic acid (0.1 g, 0.635 mmol) and 5-chloropyridin-2-amine (0.082 g, 0.635 mmol) in Dioxane (1.5 mL) was heat at 110 °C for over night under N2. The reaction was partitioned between ethyl acetate and water. The aqueous was separated and washed with ethyl acetate two more times. The ethyl acetate layer was discarded. The aqueous was adjust to PH ∼ 4 by adding 1N HCl. The aqueous was extract three more times with ethyl acetate. The ethyl acetate layer was combined, dried (Na2SO4), filtered and concentrated to give the crude as a yellow solid (116.5 mg, 74% yield). MS (ES+) m/e 250 [M+H]⁺.

2-((6-Chloropyridin-2-yl)amino)isonicotinic acid. MS[ES+] m/e 250 [M+H]⁺.

2-((5-Cyanopyridin-2-yl)amino)isonicotinic acid. MS[ES+] m/e 241 [M+H]⁺.

2-((6-Cyanopyridin-2-yl)amino)isonicotinic acid. MS[ES+] m/e 241 [M+H]⁺.

2-(6-Chloropyridin-3-yl)-2-methylpropanenitrile. To 2-(6-chloropyridin-3-yl)acetonitrile (1.0 g, 6.55 mmol) in NaOH, 10 M (19.66 ml, 197 mmol) was N-benzyl-N,N-diethylethanaminium chloride (0.373 g, 1.638 mmol)followed by iodomethane (0.943 ml, 15.07 mmol)). The reaction mixture was placed on an oil bath preheated to 60 °C and stirred for 3 hrs. Ethylacetate and 1N HCl was added. The layers were separated and the org layer was washed with brine and dried over sodium sulfate. The solvent was removed and the residue was dissolved in a small amount of dichloromethane and charged to a 120 g silica gel cartridge which was eluted with 0-60% ethyl acetate / hexanes over a period of 50 mins. The desired fractions were combined and dried under vacuo to give 2-(6-chloropyridin-3-yl)-2-methylpropanenitrile (0.7 g, 3.88 mmol, 59.1 % yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.54 (dd, J=2.81, 0.61 Hz, 1 H) 7.80 (dd, J=8.31, 2.69 Hz, 1 H) 7.40 (dd, J=8.44, 0.61 Hz, 1 H) 1.79 (s, 6 H). MS (ESI) (m/z): 181.0 (M+H)⁺.

1-(6-Chloropyridin-3-yl)cyclopropanecarbonitrile. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.36 (d, J=2.20 Hz, 1 H) 7.63 (dd, J=8.56, 2.69 Hz, 1 H) 7.36 (dd, J=8.44, 0.61 Hz, 1 H) 1.80 - 1.89 (m, 2 H) 1.42 - 1.50 (m, 2 H). MS (ESI) (m/z): 179.0 (M+H)⁺.

Methyl 2-((5-(2-cyanopropan-2-yl)pyridin-2-yl)amino)isonicotinate. To an oven dried vial with a stir bar, brettphos (5.83 mg, 0.011 mmol), brettphos precatalyst (8.84 mg, 0.011 mmol), 2-(6-chloropyridin-3-yl)-2-methylpropanenitrile (0.2 g, 1.107 mmol), methyl 2-aminoisonicotinate (0.168 g, 1.107 mmol)and K2CO3 (0.230 g, 1.661 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (5 mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 110 °C for 3 hrs. The reaction mixture was cooled, diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with brine and dried over sodium sulfate and evaporated. The residue was dried under vacuo to give methyl 2-((5-(2-cyanopropan-2-yl)pyridin-2-yl)amino)isonicotinate (0.32g, 1.080 mmol, 98 % yield). Taken to the next step without further purification. MS (ESI) (m/z): 297.5 (M+H)⁺.

2-((5-(2-Cyanopropan-2-yl)pyridin-2-yl)amino)isonicotinic acid. To methyl 2-((5-(2-cyanopropan-2-yl)pyridin-2-yl)amino)isonicotinate (0.3 g, 1.012 mmol) in THF (2 mL) and MeOH (0.5 mL) was added LiOH, 2N (3 ml, 6.00 mmol). The reaction was stirred at rt for 2 hr. The solvent was removed and the residue was redissolved in ethyl acetate. 1NHCl was added (til pH 5-6) and the org layer was collected and dried over sodium sulfate. The residue was dried under vacuo to give 2-((5-(2-cyanopropan-2-yl)pyridin-2-yl)amino)isonicotinic acid (0.15 g, 0.531 mmol, 52.5 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.49 (br. s., 1 H) 10.08 (s, 1 H) 8.35 - 8.42 (m, 2 H) 8.26 (s, 1 H) 7.82 - 7.89 (m, 1 H) 7.74 - 7.80 (m, 1 H) 7.29 (dd, J=5.14, 1.22 Hz, 1 H) 1.72 (s, 6 H). MS (ESI) (m/z): 283.5 (M+H)⁺.

1-(6-Aminopyridin-3-yl)cyclopropanecarbonitrile. A mixture of 1-(6-chloropyridin-3-yl)cyclopropanecarbonitrile (0.5 g, 2.80 mmol), BINAP (0.174 g, 0.280 mmol)and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (2.56 g, 2.80 mmol) in Toluene (15 mL) was degassed with N2 for 10 min. To this mixture was added diphenylmethanimine (0.515 mL, 3.08 mmol) and SODIUM TERT-BUTOXIDE (0.350 g, 3.64 mmol)). The mixture was heated at 90 °C for 4.0 h. LCMS showed desired M+H. The mixture was then diluted with EtOAc/water/brine (brine for better separation), filtered through a pad of wet celite to remove insoluble material. The organic layer was collected and washed with brine, dried over sodium sulfate and concentrated to give the crude imine. The crude imine was dissolved in THF (12 mL) and was treated with 6.0 N HCl for 30 min. The reaction was left stirring at rt overnight. The mixture was then diluted with EtOAc, the aqueous was collected (through a filter to remove insoluble material) and the organic was further extratcted with 4.0 N HCl (2X10 mL). The aqueous layers were combined and treated at 0 °C with 8.0 N NaOH to adjust the pH to 12-13, expecting precipitation of product. However, no precipitate formed. It was then extracted with THF/EtOAc (much better than CH₂Cl₂ for solubility reason), washed with brine and dried over sodium sulfate. After evaporation of solvent, 1-(6-aminopyridin-3-yl)cyclopropanecarbonitrile was obtained as a dark brown solid. MS (ESI) (m/z): 160.1 (M+H)⁺.

2-((5-(1-Cyanocyclopropyl)pyridin-2-yl)amino)isonicotinic acid. To an oven dried vial with a stir bar, brettphos precatalyst (10.14 mg, 0.013 mmol), brettphos (6.81 mg, 0.013 mmol), 2-chloroisonicotinic acid (0.2 g, 1.269 mmol), 1-(6-aminopyridin-3-yl)cyclopropanecarbonitrile (0.263 g, 1.650 mmol) and K2CO3 (0.263 g, 1.904 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (2mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 110 °C for 10 hrs. The sample was cooled to rm temp, diluted with ethyl acetate and washed with water. The aq layer was acidified to pH5-6 and extracted with ethyl acetate. The org extracts were combined and dried over sodium sulfate. The solid collected between layers were filtered and dried and combined with the dried org layer to give 2-((5-(1-cyanocyclopropyl)pyridin-2-yl)amino)isonicotinic acid (0.15 g, 0.535 mmol, 42.2 % yield). MS (ESI) (m/z): 281.1 (M+H)⁺.

Example 4:

[0067] 

N-(4-Phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To 3-amino-4-phenyl-pyridine (2.65 g, 15.6 mmol) and 2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid (4.2 g, 15 mmol) in ethyl acetate (50 mL) was added DIEA (12.9 mL, 74.2 mmol) followed by 1-propanephosphonic acid cyclic anhydride, 50% (by weight) in ethyl acetate (18.9 g, 29.7 mmol) dropwise. The reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and saturated sodium bicarbonate. A solid formed between the layers. This was filtered, collected and washed with dichloromethane. The solid was further triturated with dichloromethane, filtered and dried in vacuo to obtain the desired product (4.77 g, 73%) as a white solid: MS (ESI) (m/z): 436.2 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.48 (s, 1 H) 10.40 (s, 1 H) 8.65 (s, 1 H) 8.56 - 8.61 (m, 2 H) 8.42 (d, J=5.38 Hz, 1 H) 8.12 (s, 1 H) 8.04 (dd, J=9.05, 2.45 Hz, 1 H) 7.90 (d, J=8.80 Hz, 1 H) 7.36 - 7.56 (m, 6 H) 7.29 (d, J=4.89 Hz, 1 H) ; ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -59.80 (s, 3 F). For the following examples that were soluble in EtOAc, the products were generally purified by flash column chromotography.

Example 17:

[0068] 

N-(4-(Neopentyloxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 446.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.47 (s, 1H), 10.00 (s, 1H), 8.57 (s, 1H), 8.51 - 8.45 (m, 2H), 8.35 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.04 (dd, J=9.2, 2.4 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.40 (d, J=4.6 Hz, 1H), 7.16 (d, J=5.5 Hz, 1H), 3.76 (s, 2H), 0.95 (s, 9H).

Example 18:

[0069] 

N-(4-(Trifluoroethoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 458.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (s, 1H), 10.17 (br. s., 1H), 8.61 (s, 2H), 8.49 (d, J=5.2 Hz, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.06 (dd, J=8.9, 2.4 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.43 (d, J=4.9 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H), 4.98 (q, J=8.9 Hz, 2H).

Example 19:

[0070] 

N-(4-(Isopropoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 418.2 (M+H)⁺.

Example 20:

[0071] 

(S)-N-(4-(3-Methylmorpholino)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 459.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.95 (s, 1H), 8.76 (s, 1H), 8.62 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.07 (dd, J=8.9, 2.4 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.44 (d, J=4.6 Hz, 1H), 7.20 (d, J=5.5 Hz, 1H), 3.78 (dd, J=11.0, 2.7 Hz, 2H), 3.74 - 3.67 (m, 1H), 3.60 - 3.52 (m, 1H), 3.45 (dd, J=11.0, 5.5 Hz, 1H), 3.19 (ddd, J=12.2, 6.9, 2.9 Hz, 1H), 2.90 (br. s., 1H), 0.93 (d, J=6.1 Hz, 3H).

Example 21:

[0072] 

(R)-N-(4-(3-Methylmorpholino)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 459.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.55 (s, 1H), 9.95 (s, 1H), 8.76 (s, 1H), 8.62 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 8.07 (dd, J=8.9, 2.4 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.44 (d, J=4.6 Hz, 1H), 7.20 (d, J=5.5 Hz, 1H), 3.78 (dd, J=10.8, 2.9 Hz, 2H), 3.74 - 3.66 (m, 1H), 3.60 - 3.52 (m, 1H), 3.45 (dd, J=11.0, 5.5 Hz, 1H), 3.19 (ddd, J=12.1, 6.8, 3.1 Hz, 1H), 2.90 (d, J=7.9 Hz, 1H), 0.93 (d, J=6.4 Hz, 3H).

Example 22:

[0073] 

N-(4-(2,2-Dimethylmorpholino)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 473.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (s, 1H), 10.11 (s, 1H), 8.61 (s, 1H), 8.50 (d, J=4.9 Hz, 1H), 8.35 (s, 1H), 8.31 (d, J=5.8 Hz, 1H), 8.27 (s, 1H), 8.06 (dd, J=8.9, 2.4 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.49 (d, J=4.6 Hz, 1H), 7.05 (d, J=5.8 Hz, 1H), 3.74 - 3.69 (m, 2H), 3.10 (br. s., 2H), 2.95 (s, 2H), 1.15 (s, 6H).

Example 23:

[0074] 

N-(4-(Piperidin-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 443.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (s, 1H), 9.93 (s, 1H), 8.61 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.30 - 8.24 (m, 2H), 8.06 (dd, J=8.9, 2.4 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 7.48 (d, J=4.3 Hz, 1H), 7.02 (d, J=5.5 Hz, 1H), 3.10 - 3.04 (m, 4H), 1.63 (d, J=3.7 Hz, 4H), 1.55 (d, J=4.9 Hz, 2H).

Example 24:

[0075] 

N-(4-(4,4-Difluoropiperidin-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 479.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (s, 1H), 9.82 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 8.49 (d, J=4.9 Hz, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.22 (s, 1H), 8.06 (dd, J=8.9, 2.4 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.19 (d, J=5.8 Hz, 1H), 4.82 (dt, J=12.0, 6.1 Hz, 1H), 1.33 (d, J=5.8 Hz, 7H).

Example 25:

[0076] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-(neopentyloxy)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 403.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.63 (s, 1H), 10.03 (s, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.48 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 8.23 (s, 1H), 8.11 (dd, J=8.9, 2.4 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.46 (d, J=4.6 Hz, 1H), 7.17 (d, J=5.5 Hz, 1H), 3.78 (s, 2H), 0.97 (s, 9H).

Example 26:

[0077] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-methylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 331.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.63 (br. s., 1H), 10.39 (br. s., 1H), 8.72 (d, J=2.1 Hz, 1H), 8.56 - 8.48 (m, 2H), 8.36 (d, J=4.9 Hz, 1H), 8.26 (s, 1H), 8.11 (dd, J=9.0, 2.3 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.53 (d, J=4.9 Hz, 1H), 7.36 (d, J=4.9 Hz, 1H), 2.29 (s, 3H).

Example 27:

[0078] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-(piperidin-1-yl)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 400.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.65 (br. s., 1H), 10.00 (br. s., 1H), 8.70 (d, J=2.4 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.43 (s, 1H), 8.26 (d, J=5.5 Hz, 2H), 8.11 (dd, J=8.9, 2.4 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.52 (d, J=4.6 Hz, 1H), 7.02 (d, J=5.5 Hz, 1H), 3.07 (m, 4H), 1.64 - 1.51 (m, 6H).

Example 28:

[0079] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-(2,2-dimethylmorpholino)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 430.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.66 (s, 1H), 10.16 (br. s., 1H), 8.70 (d, J=2.4 Hz, 1H), 8.51 (d, J=4.9 Hz, 1H), 8.33 (s, 1H), 8.31 (d, J=5.5 Hz, 1H), 8.27 (s, 1H), 8.11 (dd, J=8.9, 2.1 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H), 7.02 (d, J=5.8 Hz, 1H), 3.72 - 3.68 (m, 2H), 3.09 - 3.04 (m, 2H), 2.91 (s, 2H), 1.14 (s, 6H).

Example 29:

[0080] 

2-((5-Cyanopyridin-2-yl)amino)-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 415.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.64 (br. s., 1H), 10.22 (br. s., 1H), 8.70 (d, J=2.1 Hz, 1H), 8.60 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.45 (d, J=5.8 Hz, 1H), 8.23 (s, 1H), 8.11 (dd, J=8.9, 2.1 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.33 (d, J=5.5 Hz, 1H), 4.98 (q, J=8.7 Hz, 2H).

Example 46:

[0081] 

N-(4-(2-(Pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 471 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.49 (s, 1H), 10.00 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 8.35 (d, J = 5.6 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 5.4 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 4.22 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.47 (d, J = 5.9 Hz, 4H), 1.57 (d, J = 5.5 Hz, 4H).

Example 47:

[0082] 

N-(4-(2-Morpholinoethoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 487 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.50 (s, 1H), 10.04 - 9.90 (m, 1H), 8.62 (s, 2H), 8.47 (d, J = 4.2 Hz, 1H), 8.40 - 8.30 (m, 1H), 8.23 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.95 - 7.82 (m, 1H), 7.50 - 7.37 (m, 1H), 7.21 (d, J = 5.4 Hz, 1H), 4.24 (s, 2H), 3.47 (d, J = 4.8 Hz, 4H), 2.71 (s, 2H), 2.43 (s, 4H).

Example 42:

[0083] 

N-(4-(2,2-Difluoroethoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 440.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.48 (br. s., 1 H) 10.04 (br. s., 1 H) 8.67 (br. s., 1 H) 8.61 (br. s., 1 H) 8.47 (br. s., 1 H) 8.39 (br. s., 1 H) 8.23 (br. s., 1 H) 8.05 (d, J=8.24 Hz, 1 H) 7.91 (d, J=8.24 Hz, 1 H) 7.42 (br. s., 1 H) 7.28 (br. s., 1 H) 6.25 - 6.54 (m, 1 H) 4.51 (t, J=13.28 Hz, 2 H) 2.51 (br. s., 4 H).

Example 43:

[0084] 

N-([2,4'-Bipyridin]-3'-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 437.5 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.22 (br. s., 1 H) 10.62 (s, 1 H) 9.69 (s, 1 H) 8.80 (d, J=3.97 Hz, 1 H) 8.52 - 8.58 (m, 3 H) 8.38 (s, 1 H) 8.24 (d, J=8.24 Hz, 1 H) 8.05 - 8.15 (m, 2 H) 8.01 (d, J=5.19 Hz, 1 H) 7.93 (d, J=8.85 Hz, 1 H) 7.56 (dd, J=7.02, 4.88 Hz, 1 H) 7.46 (dd, J=5.19, 1.22 Hz, 1 H).

Example 44:

[0085] 

N-(4-((1-Methylcyclopropyl)methoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 444.4 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.49 (br. s., 1 H) 9.94 (br. s., 1 H) 8.60 (br. s., 1 H) 8.54 (br. s., 1 H) 8.48 (d, J=4.27 Hz, 1 H) 8.34 (d, J=5.19 Hz, 1 H) 8.25 (br. s., 1 H) 8.04 (d, J=8.54 Hz, 1 H) 7.90 (d, J=8.85 Hz, 1 H) 7.42 (br. s., 1 H) 7.12 (d, J=5.49 Hz, 1 H) 3.92 (br. s., 2 H) 1.14 (s, 3 H) 0.54 (br. s., 2 H) 0.34 (br. s., 2 H).

Example 45:

[0086] 

N-(4-(3-Fluorooxetan-3-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide.: MS (ESI) (m/z): 433.9 (M+H)⁺.

Example 49:

[0087] 

N-(4-(2-Fluorophenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 454.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.45 (s, 1H), 10.39 (br. s., 1H), 8.73 (s, 1H), 8.58 (d, J=4.9 Hz, 2H), 8.41 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 8.04 (dd, J=8.9, 2.4 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.52 - 7.41 (m, 3H), 7.34 - 7.27 (m, 2H), 7.22 (d, J=4.9 Hz, 1H).

Example 51:

[0088] 

N-(4-(4-Cholorophenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 470.1 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.68 (s, 1H), 8.63 - 8.55 (m, 2H), 8.44 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 8.05 (dd, J=8.9, 2.4 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.62 - 7.52 (m, 4H), 7.50 (d, J=4.9 Hz, 1H), 7.32 (d, J=4.9 Hz, 1H).

Example 64:

[0089] 

N-(Isoquinolin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 410.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.81 (br. s., 1H), 10.56 (s, 1H), 9.29 (s, 1H), 8.69 - 8.62 (m, 2H), 8.54 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J=7.9 Hz, 1H), 8.11 - 7.99 (m, 3H), 7.90 - 7.83 (m, 1H), 7.80 - 7.74 (m, 1H), 7.62 (d, J=4.6 Hz, 1H).

Example 65:

[0090] 

2-((5-Cyanopyridin-2-yl)amino)-N-(isoquinolin-4-yl)isonicotinamide: MS (ESI) (m/z): 367.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.65 (br. s., 1H), 9.30 (s, 1H), 8.73 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=4.9 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 8.13 (dd, J=8.7, 2.3 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.95 (d, J=8.9 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.66 (br. s., 1H).

Example 66:

[0091] 

N-(6-Chloro-4-phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 470.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.49 (s, 1H), 10.45 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.12 (s, 1H), 8.05 (dd, J = 8.9, 2.4 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J = 7.3 Hz, 2H), 7.46 (dt, J = 23.5, 7.2 Hz, 3H), 7.28 (d, J = 4.9 Hz, 1H).

Example 67:

[0092] 

N-(6-Fluoro-4-phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 454.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.47 (s, 1H), 10.39 (s, 1H), 8.59 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 8.05 (dd, J = 8.9, 2.5 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.54 - 7.40 (m, 3H), 7.35 (d, J = 1.7 Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H).

Example 68:

[0093] 

N-(6-Methyl-4-phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 450.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.46 (s, 1H), 10.28 (s, 1H), 8.62 - 8.56 (m, 1H), 8.49 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.11 (s, 1H), 8.04 (dd, J = 8.9, 2.6 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 7.0 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.42 - 7.34 (m, 2H), 7.29 (dd, J = 5.2, 1.5 Hz, 1H), 2.57 (s, 3H).

Example 69:

[0094] 

N-(6-Fluoro-4-(2,2,2-trifluoroethoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 476.1 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ10.52 (s, 1H), 10.22 (br. s., 1H), 8.61 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.28 - 8.22 (m, 2H), 8.06 (dd, J=8.9, 2.4 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.42 (d, J=4.9 Hz, 1H), 7.19 (s, 1H), 5.03 (q, J=8.9 Hz, 2H).

Example 70:

[0095] 

N-(6-Chloro-4-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 514.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.53 (s, 1H), 10.15 (s, 1H), 8.61 (s, 1H), 8.50 (d, J = 5.1 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.06 (dd, J = 9.0, 2.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 4.7 Hz, 1H), 7.16 (s, 1H), 3.34 - 3.29 (m, 4H), 2.17 - 2.04 (m, 4H).

Example 71:

[0096] 

N-(6-Fluoro-4-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 497.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.53 (s, 1H), 10.15 (s, 1H), 8.61 (s, 1H), 8.49 (d, J= 5.0 Hz, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 8.06 (dd, J= 8.9, 2.2 Hz, 1H), 7.90 (d, J= 8.8 Hz, 1H), 7.47 (d, J= 4.7 Hz, 1H), 6.82 (s, 1H), 3.35 (obscured by solvent peak), 2.10 (dd, J = 16.4, 10.7 Hz, 4H).

Example 72:

[0097] 

N-(6-Methyl-4-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 493.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.52 (s, 1H), 9.97 (s, 1H), 8.62 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.06 (dd, J = 9.1, 2.6 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 6.98 (s, 1H), 3.22 (t, J = 5.6 Hz, 4H), 2.43 (s, 3H), 2.18 - 2.04 (m, 4H).

Example 73:

[0098] 

N-(6-Fluoro-4-morpholinopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 463.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.53 (s, 1H), 10.15 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 8.07 (dd, J = 8.9, 2.6 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.50 - 7.40 (m, 1H), 6.75 (s, 1H), 3.70 (t, J = 4.7 Hz, 4H), 3.22 (t, J = 4.6 Hz, 4H).

Example 58:

[0099] 

2-((5-Chloropyridin-2-yl)amino)-N-(4-(4-fluorophenyl)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 420 (M+H)⁺; ¹H NMR (500MHz, DMSO-d6) δ 10.38 (s, 1H), 10.12 (s, 1H), 8.65 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.38 (d, J=5.2 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 7.97 (s, 1H), 7.86 - 7.78 (m, 2H), 7.58 (dd, J=8.5, 5.5 Hz, 2H), 7.50 (d, J=5.2 Hz, 1H), 7.32 (t, J=9.0 Hz, 2H), 7.22 (d, J=4.6 Hz, 1H).

Example 59:

[0100] 

2-((5-Chloropyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 402 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.36 (s, 1H), 10.12 (s, 1H), 8.65 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.37 (d, J=4.9 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 7.99 (s, 1H), 7.85 - 7.77 (m, 2H), 7.57 - 7.38 (m, 6H), 7.21 (d, J=4.9 Hz, 1H).

Example 31:

[0101] 

2-((5-Chloropyridin-2-yl)amino)-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 424 (M+H)⁺; ¹H NMR (500MHz, DMSO-d6) S δ 10.16 (s, 1H), 10.11 (s, 1H), 8.60 (s, 1H), 8.44 (dd, J=9.2, 5.5 Hz, 2H), 8.28 (d, J=1.8 Hz, 1H), 8.10 (s, 1H), 7.87 - 7.79 (m, 2H), 7.37 - 7.31 (m, 2H), 4.98 (q, J=8.6 Hz, 2H).

Example 110:

[0102] 

2-((5-Chloropyridin-2-yl)amino)-N-(6-fluoro-4-(2,2,2-trifluoroethoxy)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 442 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.18 - 10.13 (m, 2H), 8.44 (d, J=5.2 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.87 - 7.79 (m, 2H), 7.34 (d, J=4.6 Hz, 1H), 7.20 (s, 1H), 5.03 (q, J=8.5 Hz, 2H).

Example 60:

[0103] 

N-(4-(4-Chlorophenyl)pyridin-3-yl)-2-((5-chloropyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 436 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.40 (br. s., 1H), 10.12 (s, 1H), 8.66 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.39 (d, J=4.9 Hz, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.83 - 7.78 (m, 2H), 7.58 - 7.49 (m, 5H), 7.23 (d, J=4.9 Hz, 1H).

Example 61:

[0104] 

2-((5-(2-Cyanopropan-2-yl)pyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 435 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.33 (s, 1 H) 10.06 (s, 1 H) 8.65 (s, 1 H) 8.59 (d, J=5.19 Hz, 1 H) 8.33 - 8.41 (m, 2 H) 8.11 (s, 1 H) 7.85 (dd, J=8.85, 2.75 Hz, 1 H) 7.74 (d, J=8.85 Hz, 1 H) 7.53 - 7.57 (m, 2 H) 7.45 - 7.52 (m, 3 H) 7.41 - 7.45 (m, 1 H) 7.20 (d, J=5.19 Hz, 1 H) 1.72 (s, 6 H).

Example 62:

[0105] 

2-((5-(1-Cyanocyclopropyl)pyridin-2-yl)amino)-N-(4-phenylpyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 433 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.34 (s, 1 H) 10.06 (s, 1 H) 8.65 (s, 1 H) 8.59 (d, J=4.88 Hz, 1 H) 8.36 (d, J=4.88 Hz, 1 H) 8.27 (d, J=2.44 Hz, 1 H) 8.07 (s, 1 H) 7.70 - 7.74 (m, 1 H) 7.64 - 7.68 (m, 1 H) 7.52 - 7.57 (m, 2 H) 7.39 - 7.51 (m, 4 H) 7.20 (d, J=4.58 Hz, 1 H) 1.70 - 1.76 (m, 2 H) 1.48 - 1.54 (m, 2 H).

Example 75:

[0106] 

N-(6-Fluoro-4-(neopentyloxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 464 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.51 (s, 1H), 10.04 (s, 1H), 8.60 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.08 - 8.04 (m, J=8.9, 2.4 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.42 (d, J=4.6 Hz, 1H), 6.98 (s, 1H), 3.82 (s, 2H), 0.96 (s, 9H).

Example 112:

[0107] 

2-((5-Chloropyridin-2-yl)amino)-N-(6-fluoro-4-(neopentyloxy)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 430 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.16 (s, 1H), 10.01 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.11 (s, 2H), 7.85 - 7.79 (m, 2H), 7.34 (d, J=5.2 Hz, 1H), 6.98 (s, 1H), 3.82 (s, 2H), 0.96 (s, 9H).

Example 117:

[0108] 

N-(5-Fluoro-4-phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 454.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 10.38 (s, 1H), 8.65 (s, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.09 - 8.02 (m, 2H), 7.88 (d, J = 9.1 Hz, 1H), 7.52 - 7.40 (m, 6H), 7.21 (s, 1H).

Example 111:

[0109] 

N-(6-Chloro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-((5-chloropyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 460 (M+H)⁺.

Example 48:

[0110] 

2-((6-Chloropyridin-2-yl)amino)-N-(4-(4-fluorophenyl)pyridin-3-yl)isonicotinamide: MS (ESI) (m/z): 420 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.42 (s, 1H), 10.29 (s, 1H), 8.63 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.40 (d, J=5.2 Hz, 1H), 7.92 - 7.84 (m, 2H), 7.76 (t, J=7.9 Hz, 1H), 7.59 (dd, J=8.7, 5.6 Hz, 2H), 7.50 (d, J=4.9 Hz, 1H), 7.31 (t, J=8.9 Hz, 2H), 7.24 (d, J=4.6 Hz, 1H), 7.00 (d, J=7.3 Hz, 1H).

Example 32:

[0111] 

N-(4-(3,6-Dihydro-2H-pyran-4-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 442 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (s, 1H), 10.33 (s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 8.48 (dd, J=9.2, 5.2 Hz, 2H), 8.22 (s, 1H), 8.06 (dd, J=9.0, 2.6 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.43 - 7.37 (m, 2H), 6.00 (br. s., 1H), 4.17 (d, J=2.7 Hz, 2H), 3.79 (t, J=5.3 Hz, 2H), 3.18 (d, J=5.2 Hz, 2H).

Example 35:

[0112] 

N-(4-(Tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 444 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.53 (s, 1H), 10.37 (s, 1H), 8.63 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.48 (d, J=2.4 Hz, 2H), 8.22 (s, 1H), 8.07 (dd, J=8.9, 2.4 Hz, 1H), 7.98 (d, J=8.9 Hz, 1H), 7.50 - 7.45 (m, 2H), 3.99 - 3.93 (m, 2H), 3.43 - 3.38 (m, 1H), 3.06 (t, J=11.1 Hz, 1H), 1.75 - 1.64 (m, 3H).

Example 36:

[0113] 

N-(4-(Cyclohex-1-en-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 440 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (s, 1H), 10.21 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.20 (s, 1H), 8.06 (dd, J=8.7, 2.6 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 7.39 (d, J=4.6 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 5.87 - 5.83 (m, 1H), 2.28 (br. s., 2H), 2.10 (d, J=3.7 Hz, 2H), 1.71 - 1.65 (m, 2H), 1.62 - 1.56 (m, 2H).

Example 37:

[0114] 

N-(4-Acetylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 402 (M+H)⁺.

Example 33:

[0115] 

N-(4-(2-Methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 446 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.60 (s, 1H), 10.09 (s, 1H), 9.16 (s, 1H), 8.63 (s, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.35 (s, 1H), 8.07 (dd, J=9.2, 2.4 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.50 (d, J=4.9 Hz, 1H), 7.42 (dd, J=5.2, 1.2 Hz, 1H), 4.13 - 4.08 (m, 2H), 3.85 - 3.80 (m, 2H), 1.64 (s, 3H).

Example 34:

[0116] 

N-(4-(1-Hydroxyethyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. Sodiumborohydride (2.357 mg, 0.062 mmol) was added to the MeOH (3 mL) solution of N-(4-acetylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (5 mg, 0.012 mmol) at rt. The reaction was stirred for 20 min. The solvent was removed via vacuum and the product was purified via SCP. MS(ES+) m/e 404 MS[M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.58 - 10.50 (m, 1H), 8.83 (s, 1H), 8.64 (s, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.45 (d, J=4.9 Hz, 1H), 8.34 (s, 1H), 8.07 (dd, J=9.0, 2.6 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.51 (d, J=5.2 Hz, 1H), 7.44 (d, J=4.0 Hz, 1H), 5.91 (br. s., 1H), 5.02 (q, J=6.4 Hz, 1H), 1.36 (d, J=6.4 Hz, 3H).

Example 74:

[0117] 

N-(6-Chloro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 494 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.34 (br. s., 1H), 10.63 (s, 1H), 9.30 (s, 1H), 8.70 (s, 1H), 8.58 - 8.54 (m, 2H), 8.07 (dd, J=8.9, 2.4 Hz, 1H), 7.76 (d, J=8.9 Hz, 1H), 7.54 (s, 1H), 7.39 (dd, J=5.2, 1.5 Hz, 1H), 6.83 (br. s., 1H), 3.86 - 3.71 (m, 4H), 2.12 (td, J=12.6, 5.0 Hz, 2H), 1.83 (d, J=13.1 Hz, 2H).

Example 76:

[0118] 

N-(6-Chloro-4-(2-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 480 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.59 (s, 1H), 10.10 (s, 1H), 9.00 (s, 1H), 8.61 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.06 (dd, J=8.9, 2.1 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.52 (s, 1H), 7.41 - 7.36 (m, 1H), 4.12 - 4.07 (m, 2H), 3.87 - 3.82 (m, 2H), 1.64 (s, 3H).

Example 38:

[0119] 

N-(4-(1-Hydroxycyclohexyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 458 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.62 (s, 1H), 10.59 (s, 1H), 9.51 (s, 1H), 8.70 (s, 1H), 8.64 (s, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.09 - 8.02 (m, J=8.9, 2.1 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.43 - 7.39 (m, J=4.0, 4.0 Hz, 2H), 6.45 (s, 1H), 1.98 - 1.91 (m, J=9.2 Hz, 2H), 1.81 - 1.72 (m, J=9.8 Hz, 4H), 1.67 - 1.59 (m, J=12.2 Hz, 1H), 1.58 - 1.49 (m, 2H), 1.30 - 1.19 (m, J=10.1 Hz, 1H).

Example 39:

[0120] 

N-(4-(3,4-Dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 442 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.53 - 10.44 (m, 1H), 10.20 (br. s., 1H), 8.84 - 8.74 (m, 1H), 8.63 - 8.54 (m, 1H), 8.52 - 8.45 (m, 1H), 8.44 - 8.35 (m, 1H), 8.25 - 8.15 (m, 1H), 8.02 (d, J=8.9 Hz, 1H), 7.97 - 7.86 (m, 1H), 7.49 - 7.33 (m, 2H), 5.46 - 5.36 (m, 1H), 4.14 - 4.01 (m, 2H), 2.13 (d, J=4.6 Hz, 2H), 1.87 - 1.73 (m, 2H).

Example 77:

[0121] 

N-(6-Chloro-4-(2-methyltetrahydrofuran-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 478 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.70 (br. s., 1H), 10.56 (s, 1H), 8.84 (s, 1H), 8.59 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.05 (dd, J=8.7, 2.0 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J=4.9 Hz, 1H), 4.00 (td, J=7.9, 4.9 Hz, 1H), 3.81 (q, J=7.5 Hz, 1H), 2.34 - 2.26 (m, 1H), 2.19 (ddd, J=12.7, 7.7, 5.5 Hz, 1H), 2.01 (dt, J=12.1, 7.7 Hz, 1H), 1.89 - 1.80 (m, 1H), 1.48 (s, 3H).

Example 41:

[0122] 

N-(4-(Tetrahydro-2H-pyran-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 444 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.49 (s, 1H), 10.36 (br. s., 1H), 8.67 (s, 1H), 8.60 (br. s., 1H), 8.50 (d, J=4.6 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 8.04 (d, J=7.0 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.47 (d, J=4.9 Hz, 1H), 7.41 (d, J=4.6 Hz, 1H), 4.59 (d, J=11.0 Hz, 1H), 4.07 (d, J=10.1 Hz, 1H), 1.87 - 1.79 (m, J=9.2 Hz, 2H), 1.54 (br. s., 3H), 1.38 (d, J=10.4 Hz, 1H).

Example 78:

[0123] 

N-(6-Chloro-4-(2,4,5-trimethyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 508 (M+H)⁺.

Example 80:

[0124] 

N-(4-(2,2-Difluoroethoxy)-6-fluoropyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 458 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.48 (s, 1H), 10.08 (s, 1H), 8.60 (br. s., 1H), 8.48 (d, J=4.9 Hz, 1H), 8.28 (s, 1H), 8.22 (br. s., 1H), 8.04 (d, J=9.2 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.41 (d, J=3.7 Hz, 1H), 7.13 (s, 1H), 6.53 - 6.27 (m, 1H), 4.56 (t, J=14.3 Hz, 2H).

Example 79:

[0125] 

N-(6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 458 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.59 (s, 1H), 10.11 (br. s., 1H), 9.03 (s, 1H), 8.61 (br. s., 1H), 8.53 (d, J=5.2 Hz, 1H), 8.35 (s, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.47 (s, 1H), 7.38 (d, J=4.0 Hz, 1H), 4.13 - 4.06 (m, 2H), 3.91 - 3.85 (m, 2H), 1.94 - 1.88 (m, 2H), 0.82 (t, J=7.3 Hz, 3H).

Example 81:

[0126] 

N-(6-Chloro-4-(2-ethyl-4,5-dimethyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 522 (M+H)⁺.

Example 83:

[0127] 

N-(6-Chloro-4-(2-isopropyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 508 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.60 (br. s., 1H), 10.16 (br. s., 1H), 9.08 (s, 1H), 8.65 - 8.49 (m, 2H), 8.36 (br. s., 1H), 8.06 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.41 - 7.34 (m, 1H), 4.14 - 4.03 (m, 2H), 3.96 - 3.82 (m, 2H), 2.24 - 2.13 (m, 1H), 0.85 (d, J=6.4 Hz, 6H).

Example 85:

[0128] 

N-(6-Chloro-4-((2R,4S)-2-ethyl-4-(trifluoromethyl)-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 562 (M+H)⁺.

Example 86:

[0129] 

N-(6-Chloro-4-((2R,4R)-2-ethyl-4-(trifluoromethyl)-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 562 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.56 (br. s., 1H), 8.83 (br. s., 1H), 8.59 (br. s., 1H), 8.51 (br. s., 1H), 8.41 (br. s., 1H), 8.05 (d, J=8.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.54 (br. s., 1H), 7.40 (br. s., 1H), 4.93 (br. s., 1H), 4.32 (d, J=10.1 Hz, 1H), 4.00 - 3.93 (m, 1H), 2.02 (d, J=6.4 Hz, 2H), 0.89 - 0.80 (m, 3H).

Example 87:

[0130] 

N-(6-Chloro-4-(2-cyclopropyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 506 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.62 - 10.58 (m, 1H), 10.16 (br. s., 1H), 9.12 - 9.06 (m, 1H), 8.61 (br. s., 1H), 8.55 - 8.51 (m, J=4.9 Hz, 1H), 8.39 (br. s., 1H), 8.09 - 8.03 (m, J=8.2 Hz, 1H), 7.89 - 7.83 (m, J=9.2 Hz, 1H), 7.46 - 7.39 (m, 2H), 4.10 - 4.03 (m, 2H), 3.92 - 3.83 (m, 2H), 1.52 - 1.41 (m, 1H), 0.53 - 0.41 (m, 4H).

Example 88:

[0131] 

N-(6-Chloro-4-(2-propyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 508 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.57 (s, 1H), 10.12 (br. s., 1H), 9.02 (s, 1H), 8.59 (br. s., 1H), 8.52 (d, J=5.2 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J=8.9 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J=4.9 Hz, 1H), 4.12 - 4.05 (m, 2H), 3.89 - 3.82 (m, 2H), 1.91 - 1.83 (m, 2H), 1.32 - 1.21 (m, 2H), 0.79 (t, J=7.3 Hz, 3H).

Example 89:

[0132] 

N-(6-Chloro-4-((2R,4S)-2-ethyl-4-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 508 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.62 (s, 1H), 10.10 (d, J=10.4 Hz, 1H), 9.09 (s, 1H), 8.60 (br. s., 1H), 8.54 (d, J=5.2 Hz, 1H), 8.35 (s, 1H), 8.06 (d, J=7.0 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J=5.2 Hz, 1H), 4.43 - 4.27 (m, 2H), 1.96 - 1.84 (m, 3H), 1.16 (d, J=5.8 Hz, 3H), 0.82 (t, J=7.3 Hz, 3H).

Example 90:

[0133] 

N-(6-Chloro-4-((2R,4R)-2-ethyl-4-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 508 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.59 (s, 1H), 10.07 (br. s., 1H), 9.04 (s, 1H), 8.61 (br. s., 1H), 8.53 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 8.09 - 8.01 (m, J=9.2 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.48 (s, 1H), 7.37 (d, J=5.2 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.02 (t, J=7.0 Hz, 1H), 3.57 (t, J=7.2 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.26 (d, J=5.8 Hz, 3H), 0.84 (t, J=7.3 Hz, 3H).

Example 92:

[0134] 

N-(6-Chloro-4-(cyclopropanecarbonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 462 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.27 (br. s., 1H), 10.56 (br. s., 1H), 9.01 (d, J=3.7 Hz, 1H), 8.63 (br. s., 1H), 8.54 - 8.49 (m, J=4.3 Hz, 1H), 8.35 (br. s., 1H), 8.08 - 8.02 (m, J=8.2 Hz, 1H), 7.99 - 7.95 (m, J=3.7 Hz, 1H), 7.89 - 7.84 (m, J=8.5 Hz, 1H), 7.45 - 7.40 (m, 1H), 2.77 - 2.70 (m, J=3.7 Hz, 1H), 1.17 - 1.08 (m, J=3.4 Hz, 4H).

Example 93:

[0135] 

N-(6-Chloro-4-(cyclopropyl(hydroxy)methyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 464 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.90 (s, 1H), 8.64 (s, 1H), 8.52 (d, J=4.6 Hz, 1H), 8.41 (s, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J=4.6 Hz, 1H), 4.40 (d, J=7.3 Hz, 1H), 1.17 (d, J=6.4 Hz, 1H), 0.52 - 0.32 (m, 4H).

Example 98:

[0136] 

N-(6-Chloro-4-(1-cyclopropyl-1-hydroxyethyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. Methylmagnesium bromide (0.1 mL, 0.300 mmol) was added to the THF (1 mL) solution of N-(6-chloro-4-(cyclopropanecarbonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (1.8 mg, 3.90 µmol) at room temperature. The reaction was stirred at rt for 1 hour before quenched with MeOH. The solvent was removed via vacuum and the crude was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. The product was submitted to SCP for further purification (obtained 1.3mg, 70% yield). MS(ES+) m/e 478 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.57 (br. s., 1H), 9.33 (s, 1H), 8.64 (s, 1H), 8.50 (d, J=4.9 Hz, 1H), 8.43 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.56 (s, 1H), 7.37 (d, J=5.2 Hz, 1H), 1.51 (s, 3H), 1.39 (d, J=5.8 Hz, 1H), 0.55 - 0.38 (m, 4H).

Example 99:

[0137] 

N-(6-Chloro-4-(dicyclopropyl(hydroxy)methyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 504 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.52 (br. s., 1H), 10.57 (s, 1H), 9.34 (s, 1H), 8.64 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 8.10 - 8.03 (m, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.67 (s, 1H), 7.36 (dd, J=5.2, 1.2 Hz, 1H), 6.35 (s, 1H), 1.42 - 1.32 (m, 2H), 0.67 - 0.58 (m, 2H), 0.49 (dt, J=7.5, 3.9 Hz, 2H), 0.44 - 0.33 (m, 4H).

Example 101:

[0138] 

N-(6-Chloro-4-(1-cyclopropyl-1-hydroxypropyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 492 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.30 (s, 1H), 9.07 (s, 1H), 8.38 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 7.81 (dd, J=8.9, 2.1 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 7.11 - 7.06 (m, 1H), 1.84 - 1.73 (m, 1H), 1.67 - 1.56 (m, 1H), 1.30 - 1.20 (m, 1H), 0.55 (t, J=7.3 Hz, 3H), 0.38 - 0.31 (m, 1H), 0.21 (dd, J=9.0, 5.3 Hz, 1H), 0.17 - 0.04 (m, 2H).

Example 102:

[0139] 

N-(6-Chloro-4-(1-cyclopropyl-1-hydroxy-2-methylpropyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 506 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.14 (s, 1H), 8.44 (s, 1H), 8.30 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 7.86 (dd, J=9.0, 2.3 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.39 (s, 1H), 7.17 (dd, J=5.2, 1.2 Hz, 1H), 2.13 - 2.05 (m, 1H), 1.37 (br. s., 1H), 0.71 (d, J=1.0 Hz, 3H), 0.70 (d, J=2.7 Hz, 3H), 0.56 (dd, J=9.3, 4.4 Hz, 1H), 0.34 (d, J=5.2 Hz, 1H), 0.20 - 0.12 (m, 1H), 0.01 (dd, J=9.2, 4.0 Hz, 1H).

Example 113:

[0140] 

N-(6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-fluoropyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 444 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.14 (s, 1H), 10.08 (br. s., 1H), 9.06 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.27 - 8.21 (m, 2H), 7.80 - 7.65 (m, 2H), 7.47 (s, 1H), 7.27 (d, J=4.9 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.94 - 3.85 (m, 2H), 1.91 (q, J=7.0 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H).

Example 114:

[0141] 

N-(4-(2,2-Difluoroethoxy)-6-fluoropyridin-3-yl)-2-((5-fluoropyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 408 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.02 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 8.06 (s, 1H), 7.84 (dd, J=9.2, 3.7 Hz, 1H), 7.68 (td, J=8.7, 3.1 Hz, 1H), 7.31 (d, J=4.3 Hz, 1H), 7.14 (s, 1H), 6.54 - 6.27 (m, 1H), 4.62 - 4.51 (m, 2H).

Example 95:

[0142] 

N-(6-Chloro-4-(2-phenyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 542 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.59 (s, 1H), 10.02 - 9.55 (m, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 8.49 (d, J=4.9 Hz, 1H), 8.23 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.78 (s, 1H), 7.43 - 7.36 (m, 2H), 7.32 - 7.20 (m, 4H), 4.26 - 4.09 (m, 4H).

Example 108:

[0143] 

N-(6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-(pyridin-2-ylamino)isonicotinamide: MS (ESI) (m/z) 426 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.05 (s, 1H), 9.09 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.43 (s, 1H), 8.28 (d, J=3.7 Hz, 1H), 7.73 - 7.67 (m, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.47 (s, 1H), 7.28 (d, J=5.2 Hz, 1H), 6.96 - 6.91 (m, 1H), 4.15 - 4.08 (m, 2H), 3.90 (br. s., 2H), 1.97 - 1.88 (m, 2H), 0.83 (t, J=7.3 Hz, 3H).

Example 109:

[0144] 

N-(6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-methylpyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 440 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.08 (br. s., 1H), 9.95 (s, 1H), 9.09 (s, 1H), 8.44 (d, J=4.9 Hz, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.62 - 7.52 (m, 2H), 7.48 (s, 1H), 7.24 (d, J=5.2 Hz, 1H), 4.16 - 4.05 (m, 2H), 3.90 (t, J=6.9 Hz, 2H), 2.25 (s, 3H), 1.93 (q, J=7.1 Hz, 2H), 0.84 (t, J=7.3 Hz, 3H).

Example 96:

[0145] 

N-(6-Chloro-4-((2R,4R)-2-cyclopropyl-4-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 520 (M+H)⁺.

Example 97:

[0146] 

N-(6-Chloro-4-((2R,4S)-2-cyclopropyl-4-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 520 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.62 (s, 1H), 10.21 (br. s., 1H), 9.11 (s, 1H), 8.64 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.47 (s, 1H), 8.07 (dd, J=8.9, 2.1 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.45 (s, 1H), 7.42 (dd, J=5.2, 1.5 Hz, 1H), 4.22 - 4.14 (m, 1H), 4.02 (t, J=7.2 Hz, 1H), 3.54 (t, J=7.3 Hz, 1H), 1.53 - 1.44 (m, 1H), 1.24 (d, J=6.1 Hz, 3H), 0.60 - 0.53 (m, 1H), 0.52 - 0.43 (m, 3H).

Intermediate for Example 100:

[0147] 

N-(4-Butyryl-6-chloropyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. Followed synthesis of Example 4. MS(ES+) m/e 464 [M+H]⁺.

Example 100:

[0148] 

N-(6-Chloro-4-(1-hydroxybutyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 466 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 8.06 (dd, J=9.0, 2.3 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.57 (s, 1H), 7.43 (d, J=4.9 Hz, 1H), 4.88 (dd, J=7.5, 5.0 Hz, 1H), 1.64 - 1.54 (m, 2H), 1.36 (td, J=15.3, 7.5 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H).

Intermediate for Example 103:

[0149] 

N-(6-Chloro-4-isobutyrylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. Followed synthesis of Example 4. MS(ES+) m/e 464 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 12.20 (s, 1H), 10.09 (s, 1H), 8.71 - 8.68 (m, 1H), 8.54 - 8.49 (m, 2H), 7.86 (dd, J=8.8, 2.3 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.59 - 7.52 (m, 2H), 3.67 (dt, J=13.6, 6.8 Hz, 1H), 1.34 (s, 3H), 1.32 (s, 3H).

Example 103:

[0150] 

N-(6-Chloro-4-(1-hydroxy-2-methylpropyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 466 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.80 (s, 1H), 8.63 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.05 (dd, J=9.2, 2.4 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J=5.2, 1.2 Hz, 1H), 4.71 (d, J=5.2 Hz, 1H), 1.90 (dd, J=12.2, 6.7 Hz, 1H), 0.85 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H).

Intermediate for Example 104:

[0151] 

N-(6-Chloro-4-(1-hydroxy-2,2-dimethylpropyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of Example 4. MS (ESI) (m/z) 478 (M+H)⁺.

Example 104:

[0152] 

N-(6-Chloro-4-(1-hydroxy-2,2-dimethylpropyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 480 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.54 (s, 1H), 8.97 (s, 1H), 8.63 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.04 (dd, J=8.9, 2.4 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.46 (s, 1H), 7.39 (dd, J=5.2, 1.2 Hz, 1H), 4.67 (s, 1H), 0.86 (s, 9H).

Example 105:

[0153] 

N-(4-(2-Cyclopropyl-1,3-dioxolan-2-yl)-6-methylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 486 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 10.07 (s, 1H), 9.61 (s, 1H), 8.59 (s, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.29 (s, 1H), 8.00 - 7.79 (m, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.44 (dd, J=5.1, 1.5 Hz, 1H), 7.23 (s, 1H), 4.28 - 4.03 (m, 2H), 4.00 - 3.76 (m, 2H), 2.59 (s, 3H), 1.44-1.38 (m, 1H), 0.66 - 0.40 (m, 4H).

Example 106:

[0154] 

N-(4-(Cyclopropyl(hydroxy)methyl)-6-methylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 444 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 10.55 (br. s., 2H), 8.88 (s, 1H), 8.65 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.40 (s, 1H), 8.06 (d, J=8.9 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.42 (d, J=4.6 Hz, 1H), 7.33 (s, 1H), 6.10 (br. s., 1H), 4.33 (d, J=7.0 Hz, 1H), 1.20 - 1.10 (m, 1H), 0.50 - 0.29 (m, 4H).

Example 107:

[0155] 

N-(4-(1-Cyclopropyl-1-hydroxyethyl)-6-methylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 458 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.36 (br. s., 1H), 10.55 (s, 1H), 9.33 (s, 1H), 8.64 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.43 (s, 1H), 8.05 (dd, J=8.7, 2.3 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.38 - 7.33 (m, 2H), 2.48 (s, 3H), 1.49 (s, 3H), 1.42 - 1.27 (m, 1H), 0.51 - 0.35 (m, 4H).

General synthesis of Amine A:

[0156] 

4-(Cyclopropylmethoxy)-3-nitropyridine. In a small round bottom flask was added 4-chloro-3-nitropyridine (191.4 mg, 1.21 mmol) and K₂CO₃ (334 mg, 2.41 mmol) in dimethylformamide (1.2 mL) to give a tan suspension. Cyclopropylmethanol (0.382 mL, 4.83 mmol) was added, and the mixture was stirred at 65°C. After 18 h, the mixture was diluted with water and ethyl acetate. The layers were separated. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated. Purification by flash column chromatography on silica gel using 60% ethyl acetate/hexane afforded the desired product (95.3 mg, 41%) as an off-white solid: ¹H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.56 (d, J = 5.9 Hz, 1H), 6.99 (d, J = 5.9 Hz, 1H), 4.05 (d, J = 6.9 Hz, 2H), 1.36 - 1.24 (m, 1H), 0.71 - 0.64 (m, 2H), 0.44 - 0.37 (m, 2H).

4-(Cyclopropylmethoxy)pyridin-3-amine. In a 100 mL round-bottom flask was dissolved 4-(cyclopropylmethoxy)-3-nitropyridine (95.3 mg, 0.491 mmol) in methanol (4 mL) to give a yellow solution. Pd/C (104 mg, 0.098 mmol) was carefully added, and the mixture was stirred under hydrogen (1 atm) for 3h. The mixture was filtered, washed, and concentrated to a give tan solid (78 mg, 97%): ¹H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.87 (d, J = 5.4 Hz, 1H), 6.58 (d, J = 5.4 Hz, 1H), 3.86 (s, 2H), 3.81 (d, J = 7.0 Hz, 2H), 1.32 - 1.17 (m, 1H), 0.64 - 0.55 (m, 2H), 0.35 - 0.27 (m, 2H).

4-Isopropoxy-3-nitropyridine. In a 100 mL round-bottom flask was dissolved 3-nitropyridin-4-ol (0.985 g, 7.03 mmol), Ph₃P (2.77 g, 10.5 mmol), and 2-propanol (0.81 mL, 10.5 mmol) in tetrahydrofuran (20 mL) to give a yellow solution. DIAD (2.05 mL, 10.5 mmol) was added dropwise at rt. The mixture was stirred at rt. After 5h, the mixture was concentrated to a tan oil and directly purified by flash column chromatography on silica, eluting with 8% methanol/methylene chloride. However the desired product could not be separated from triphenylphosphine oxide. The mixture was directly carried on to the next reaction.

4-Isopropoxypyridin-3-amine. In a 100 mL round-bottom flask was dissolved 4-isopropoxy-3-nitropyridine (crude product from previous step, ca. 7.03 mmol) in methanol (40 mL) to give a yellow solution. Pd/C (748 mg, 0.703 mmol) was carefully added, and the mixture was stirred under hydrogen (1 atm) overnight. The mixture was filtered, washed, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting 10% methanol/methylene chloride, to afford the desired product contaminated with triphenylphosphine oxide. The pure fractions were pooled and concentrated to a colorless oil (94 mg, 9%): ¹H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.86 (d, J = 5.5 Hz, 1H), 6.61 (d, J = 5.5 Hz, 1H), 4.58 (dt, J = 12.1, 6.1 Hz, 1H), 3.70 (s, 2H), 1.32 (d, J = 6.1 Hz, 6H). The impure fractions were pooled, concentrated, and dissolved in ether/methylene chloride. HCl in ether were slowly added to precipitate out the desired product. After standing for 3 days, the organic solution was decanted and the solid was washed with ether and dried as a white solid (1.08 g, 68%). The total yield for the two-step reaction was 77%.

3-Nitro-4-phenoxypyridine. LCMS: M+H=217.03; ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.55 (d, J = 5.9 Hz, 1H), 7.51 (dd, J = 10.7, 5.3 Hz, 2H), 7.36 (dd, J = 10.8, 4.2 Hz, 1H), 7.18 (dd, J = 5.4, 3.3 Hz, 2H), 6.79 (d, J = 5.9 Hz, 1H).

4-Phenoxypyridin-3-amine. ¹H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.42 (ddt, J = 9.8, 7.6, 2.2 Hz, 2H), 7.27 - 7.19 (m, 1H), 7.11 (q, J = 1.7 Hz, 1H), 7.09 (dd, J = 2.0, 0.9 Hz, 1H), 6.58 (d, J = 5.4 Hz, 1H), 3.93 (s, 2H).

4-(Neopentyloxy)-3-nitropyridine. ¹H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.61 (d, J = 5.8 Hz, 1H), 7.01 (d, J = 5.9 Hz, 1H), 3.82 (s, 2H), 1.10 (s, 9H).

4-(Neopentyloxy)pyridin-3-amine. ¹H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (d, J = 5.4 Hz, 1H), 6.59 (d, J = 5.4 Hz, 1H), 3.84 (s, 2H), 3.59 (s, 2H), 0.99 (s, 9H).

3-Nitro-4-(2-(pyrrolidin-1-yl)ethoxy)pyridine. MS (ESI) (m/z): 238 (M+H)⁺; ¹H NMR (400 MHz, Chloroform-d) δ 9.01 (s, 1H), 8.62 (d, J = 5.9 Hz, 1H), 7.04 (d, J = 5.9 Hz, 1H), 4.33 (t, J = 5.8 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H), 2.71 - 2.60 (m, 4H), 1.87 - 1.76 (m, 4H).

4-(2-(Pyrrolidin-1-yl)ethoxy)pyridin-3-amine. MS (ESI) (m/z): 208 (M+H)⁺.

4-(2-((3-Nitropyridin-4-yl)oxy)ethyl)morpholine. MS (ESI) (m/z): 254 (M+H)⁺; ¹H NMR (400 MHz, Chloroform-d) δ 8.93 (d, J = 1.5 Hz, 1H), 8.56 (dd, J = 5.9, 1.3 Hz, 1H), 7.00 (d, J = 5.9 Hz, 1H), 4.28 (t, J = 5.4 Hz, 2H), 3.73 - 3.58 (m, 4H), 2.83 (td, J = 5.5, 1.2 Hz, 2H), 2.61 - 2.49 (m, 4H).

4-(2-Morpholinoethoxy)pyridin-3-amine. MS (ESI) (m/z): 224 (M+H)⁺.

4-(2,2-Difluoroethoxy)pyridin-3-amine. A stirred suspension of 4-chloro-3-nitropyridine (1.5106 g, 9.53 mmol), potassium carbonate (2.63 g, 19.1 mmol) and 2,2-difluoroethanol (3.0 ml, 48 mmol) in 1,2,-dichloroethane (10 mL) was heated at reflux overnight. The mixture was diluted with ethyl acetate and washed with water (2 x) and brine, dried over magnesium sulfate and evaporated to give the nitropyridine ether a light-yellow oil. A solution of crude 4-(2,2-difluoroethoxy)-3-nitropyridine (1.84 g, 9.01 mmol) in ethanol (40 mL) was degassed for 10 minutes with nitrogen and then 10% palladium on carbon (0.16 g) was carefully added. The mixture was stirred under 1 atm. of hydrogen overnight. The mixture was then degassed with nitrogen, and carefully filtered through celite. The filtrated was concentrated in vacuo, and the light-brown oil flushed with methylene chloride. The crude amine was used without further purification. MS (ESI) (m/z): 175.1(M+H)⁺.

4-((1-Methylcyclopropyl)methoxy)-3-nitropyridine. To 4-chloro-3-nitropyridine (0.5 g, 3.15 mmol) and (1-methylcyclopropyl)methanol (0.543 g, 6.31 mmol) in THF (5 mL) at 0 °C was added NaH (0.139 g, 3.47 mmol). The reaction mixture was allowed to warm to rt overnight. LCMS did not show desired M+H, s/m was still present. DMF (2 mL) was added and the reaction was stirred at rt overnight. Ethyl acetate and water was added. The org layer was washed with water, brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 40 g silica gel cartridge which was eluted with 0-50% ethyl acetate / hexanes over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 4-((1-methylcyclopropyl)methoxy)-3-nitropyridine (0.36 g, 1.729 mmol, 54.8 % yield) as orange solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.03 (s, 1 H) 8.61 (d, J=5.62 Hz, 1 H) 6.96 (d, J=5.62 Hz, 1 H) 3.97 (s, 2 H) 1.29 (s, 3 H) 0.59 - 0.65 (m, 2 H) 0.49 - 0.56 (m, 2 H).

4-((1-Methylcyclopropyl)methoxy)pyridin-3-amine. To 4-((1-methylcyclopropyl)methoxy)-3-nitropyridine (0.36 g, 1.729 mmol) and Pd/C (0.1 g, 0.094 mmol) under N2 was added EtOH (20 mL). The reaction mixture was degassed and flushed with N2 (3x). Then H2 balloon (1.729 mmol) was introduced, mixture was degassed and flushed with H2 (3x). The reaction mixture was stirred under H2 overnight. The catalyst was carefully filtered over celite and washed with ethanol. The filtrate was concentrated and dried under vacuo to give 4-((1-methylcyclopropyl)methoxy)pyridin-3-amine (0.315 g, 1.767 mmol, 102 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.87 (s, 1 H) 7.69 (d, J=5.38 Hz, 1 H) 6.74 (d, J=5.38 Hz, 1 H) 4.73 (s, 2 H) 3.81 (s, 2 H) 1.21 (s, 3 H) 0.51 - 0.58 (m, 2 H) 0.37 - 0.43 (m, 2 H).

2-Fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)pyridine. A solution of 2,4-difluoro-5-nitropyridine (0.1523 g, 0.951 mmol) in tetrahydrofuran (2 mL) was cooled to 0 °C. 2,2,2-Trifluoroethanol (0.082 mL, 1.142 mmol) was added to the mixture. After 5 min, triethylamine (0.265 mL, 1.903 mmol) was added. The reaction was stirred at 0 °C for 1 h, and then allowed to warm to rt. The reaction was stirred at rt for 4.5 h. The solvent was removed in vacuo and the crude product carried on without further purification.

6-Fluoro-4-(2,2,2-trifluoroethoxy)pyridin-3-amine. A mixture of Pd/C (14.6 mg, 0.014 mmol) and 2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)pyridine (228 mg, 0.951 mmol) in ethanol (4 mL) was stirred under hydrogen (1 atm) at room tenperature overnight. The mixture was degassed before filtration through celite. The filtrate was concentrated and the product was purified by via flash chromatography on silica gel, eluting with methanol in methylene chloride from 0 to 10% to give the product as a tan solid (134 mg, 66%). ¹H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=1.5 Hz, 1H), 6.34 (d, J=1.5 Hz, 1H), 4.45 (q, J=7.8 Hz, 2H), 3.70 (br. s., 2H); ¹⁹F NMR (376MHz, CHLOROFORM-d) δ -72.90 - -73.97 (m, 3F), -75.77 (s, 1F).

4-(2,2-Difluoroethoxy)-6-fluoropyridin-3-amine. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.53 (d, J=1.3 Hz, 1H), 6.31 (d, J=1.5 Hz, 1H), 6.28 - 5.98 (m, 1H), 4.25 (td, J=12.9, 4.0 Hz, 2H), 3.69 (d, J=6.8 Hz, 2H); MS(ES+) m/e 193 [M+H]⁺.

6-Fluoro-4-(neopentyloxy)pyridin-3-amine. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.51 (d, J=1.3 Hz, 1H), 6.31 (d, J=1.0 Hz, 1H), 3.68 (s, 2H), 1.07 (s, 9H); MS(ES+) m/e 199 [M+H]⁺.

General synthesis of amine B:

[0157] 

3-Nitro-4-(piperidin-1-yl)pyridine. In a 15 mL vial was dissolved 4-chloro-3-nitropyridine (300 mg, 1.892 mmol) in tetrahydrofuran (5 mL) to give a tan solution. Piperidine (0.281 mL, 2.84 mmol) and Et₃N (0.791 mL, 5.68 mmol) were added. The cloudy yellow mixture was stirred at rt overnight. After 18 h, the mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatographyusing 80% ethyl acetate/hexane to afford the desired product (297.3 mg, 76%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J = 0.9 Hz, 1H), 8.32 (dd, J = 6.0, 0.8 Hz, 1H), 6.86 (d, J = 6.1 Hz, 1H), 3.21 (d, J = 5.3 Hz, 4H), 1.72 (d, J = 7.2 Hz, 6H).

4-(Piperidin-1-yl)pyridin-3-amine. In a 250 mL round-bottom flask was dissolved 3-nitro-4-(piperidin-1-yl)pyridine (297.3 mg, 1.435 mmol) in methanol (12 mL) to give a yellow solution. Pd/C (153 mg, 0.143 mmol) was added, and the mixture was stirred under hydrogen (1 atm) overnight. After 16 h, the mixture was filtered, washed, and concentrated to give an off-white solid (254 mg, 100%): ¹H NMR (500 MHz, MeOD) δ 7.90 (s, 1H), 7.81 (d, J = 5.4 Hz, 1H), 6.94 (d, J = 5.5 Hz, 1H), 3.03 (d, J = 4.1 Hz, 4H), 1.74 (d, J = 4.5 Hz, 4H), 1.65 (d, J = 3.9 Hz, 2H).

4-(4,4-Difluoropiperidin-1-yl)-3-nitropyridine. ¹H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H), 6.86 (d, J = 5.9 Hz, 1H), 3.37 - 3.19 (m, 4H), 2.10 (ddd, J = 19.4, 13.5, 5.8 Hz, 4H); ¹⁹F NMR (376 MHz, CDCl3) δ -98.19 (s).

4-(4,4-Difluoropiperidin-1-yl)pyridin-3-amine. ¹H NMR (500 MHz, MeOD) δ 7.94 (d, J = 4.2 Hz, 1H), 7.80 (s, 1H), 6.90 (s, 1H), 3.12 (s, 4H), 2.15 (s, 4H); ¹⁹F NMR (470 MHz, MeOD) δ -98.65 (s).

(R)-3-Methyl-4-(3-nitropyridin-4-yl)morpholine. ¹H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 6.82 (d, J = 6.0 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.81 - 3.74 (m, 1H), 3.69 - 3.58 (m, 2H), 3.58 - 3.50 (m, 1H), 3.46 (ddd, J = 12.8, 11.4, 3.5 Hz, 1H), 2.81 (d, J = 12.9 Hz, 1H), 1.28 - 1.19 (m, 3H).

(R)-4-(3-Methylmorpholino)pyridin-3-amine. ¹H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.94 (d, J = 5.3 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 4.42 (br, 2H), 3.84 (dt, J = 7.0, 5.7 Hz, 2H), 3.75 (ddd, J = 11.4, 9.0, 2.7 Hz, 1H), 3.45 - 3.29 (m, 2H), 3.08 (d, J = 12.1 Hz, 1H), 2.65 (ddd, J = 12.1, 8.9, 3.2 Hz, 1H), 0.85 (d, J = 6.0 Hz, 3H).

(S)-3-Methyl-4-(3-nitropyridin-4-yl)morpholine. ¹H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.37 (d, J = 6.0 Hz, 1H), 6.86 (d, J = 6.0 Hz, 1H), 3.94 - 3.87 (m, 1H), 3.87 - 3.80 (m, 1H), 3.68 (ddd, J = 13.4, 11.1, 1.9 Hz, 2H), 3.62 - 3.55 (m, 1H), 3.51 (ddd, J = 12.8, 11.4, 3.5 Hz, 1H), 2.86 (dd, J = 10.2, 2.7 Hz, 1H), 1.34 - 1.22 (m, 3H).

(S)-4-(3-Methylmorpholino)pyridin-3-amine. ¹H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.87 (d, J = 5.5 Hz, 1H), 6.85 (d, J = 5.5 Hz, 1H), 5.66 (br, 2H), 3.82 (d, J = 8.4 Hz, 1H), 3.80 - 3.68 (m, 2H), 3.46 - 3.31 (m, 2H), 3.16 - 3.06 (m, 1H), 2.68 - 2.56 (m, 1H), 0.83 (d, J = 6.0 Hz, 3H).

2,2-Dimethyl-4-(3-nitropyridin-4-yl)morpholine. ¹H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.20 (d, J = 6.0 Hz, 1H), 6.74 (d, J = 6.0 Hz, 1H), 3.80 - 3.60 (m, 2H), 3.01 - 2.95 (m, 2H), 2.92 (s, 2H), 1.14 (s, 6H).

4-(2,2-Dimethylmorpholino)pyridin-3-amine. ¹H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.00 (d, J = 5.3 Hz, 1H), 6.80 (d, J = 5.3 Hz, 1H), 3.96 - 3.89 (m, 2H), 3.50 (s, 2H), 2.98 (dd, J = 5.6, 4.0 Hz, 2H), 2.81 (s, 2H), 1.38 (s, 6H).

2,4-Difluoro-5-nitropyridine. In a 250 mL round-bottom flask was added 2,4-dichloro-5-nitropyridine (0.73 g, 3.8 mmol), potassium fluoride (0.659 g, 11.3 mmol), and 18-crown-6 (0.160 g, 0.605 mmol) in N-methylpyrrolidinone (3 mL) to give a tan suspension. The mixture was heated at 100°C under nitrogen for 3 h. The mixture was then partitioned between water and ether/hexane. The organic layer was washed with water, brine, dried and concentrated to give a tan solid (0.515 g, 85%): 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 9.7 Hz, 1H), 6.96 (dd, J = 9.5, 2.5 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -52.20 (d, J = 29.3 Hz), -98.13 (d, J = 28.9 Hz).

4-(2-Fluoro-5-nitropyridin-4-yl)morpholine. In a 50 mL round-bottom flask vial was dissolved 2,4-difluoro-5-nitropyridine (175.7 mg, 1.098 mmol) in tetrahydrofuran (5 mL) to give a tan solution. After cooling to -40°C, morpholine (0.080 mL, 0.918 mmol) was added, followed by Et₃N (0.256 mL, 1.83 mmol). The cloudy yellow mixture was stirred at-40 °C - 0°C for 3 h. The mixture was concentrated togive a yellow solid. The solid was purified by flash column chromatography on silica gel, eluting with 60% ethyl acetate/hexane, to afford the desired product (209 mg, 100%) as a yellow solid: ¹H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 6.42 (s, 1H), 3.96 - 3.81 (m, 4H), 3.33 - 3.18 (m, 4H); ¹⁹F NMR (376 MHz, Chloroform-d) δ -61.42.

6-Fluoro-4-morpholinopyridin-3-amine. In a 100 mL round-bottom flask was dissolved 4-(2-fluoro-5-nitropyridin-4-yl)morpholine (209 mg, 0.920 mmol) in methanol (6 mL) to give a yellow solution. Pd/C (98.0 mg, 0.092 mmol) was added, and the mixture was stirred under hydrogen (1 atm) for 17 h. The mixture was filtered and the filtrate evaporated to afford the desired product (171 mg, 94%) as a tan solid: ¹H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 1.1 Hz, 1H), 6.37 (d, J = 1.3 Hz, 1H), 3.90 - 3.74 (m, 4H), 3.66 (s, 2H), 3.06 - 2.90 (m, 4H); ¹⁹F NMR (376 MHz, Chloroform-d) δ -78.22.

4-(4,4-Difluoropiperidin-1-yl)-2-fluoro-5-nitropyridine. ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 6.46 (s, 1H), 3.40 - 3.30 (m, 4H), 2.22 (dd, J = 13.4, 6.0 Hz, 4H).

4-(4,4-Difluoropiperidin-1-yl)-6-fluoropyridin-3-amine. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (s, 1H), 7.55 (d, J = 0.9 Hz, 1H), 6.39 (d, J = 1.2 Hz, 1H), 3.15 - 3.04 (m, 4H), 2.16 - 2.10 (m, 4H).

2-Chloro-4-(4,4-difluoropiperidin-1-yl)-5-nitropyridine. In a 50 mL round-bottom flask vial was added 2,4-dichloro-5-nitropyridine (314 mg, 1.627 mmol) in tetrahydrofuran (8 mL) to give a tan solution. 4,4-Difluoropiperidine hydrochloride (256 mg, 1.63 mmol) was added in one portion, followed by Et₃N (0.454 mL, 3.25 mmol). The cloudy yellow mixture was stirred at rt for 18 h. The mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 80% ethyl acetate/hexane, to afford the desired product (430 mg, 95%) as a crystalline yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 6.93 (s, 1H), 3.45 - 3.29 (m, 4H), 2.21 (ddd, J = 19.3, 13.4, 5.9 Hz, 4H); ¹⁹F NMR (376 MHz, CDCl₃) δ -98.47 (s).

6-Chloro-4-(4,4-difluoropiperidin-1-yl)pyridin-3-amine. In a 20 mL round-bottom flask was dissolved 2-chloro-4-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (181 mg, 0.652 mmol) in ethanol (4 ml) to give a yellow solution. Tin (II) chloride (618 mg, 3.26 mmol) was added, and the mixture was heated at 70°C under nitrogen for 2 h. The reaction was cooled to rt and diluted with ethyl acetate. Aqueous NaHCO₃ was added to adjust pH to 7-8. The suspension was carefully filtered and washed with ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, and concentrated to give the desired product (158 mg, 98%) as an off white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 6.82 (s, 1H), 3.74 (s, 2H), 3.24 - 2.97 (m, 4H), 2.15 (ddd, J = 19.1, 13.2, 5.7 Hz, 4H); ¹⁹F NMR (376 MHz, CDCl₃) δ -98.04 (s).

4-(4,4-Difluoropiperidin-1-yl)-2-methyl-5-nitropyridine. In a 5 mL vial was dissolved 2-chloro-4-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (105 mg, 0.378 mmol), methylboronic acid (113 mg, 1.891 mmol), and potassium carbonate (105 mg, 0.756 mmol) in dioxane (1.6 mL) (degassed) and water (0.16 mL) to give a yellow solution under nitrogen. Pd(Ph₃P)₄ (21.85 mg, 0.019 mmol) was added, and the vial was sealed under nitrogen. The mixture was stirred at 120°C for 21 h. The mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 60% ethyl acetate/hexane, to afford the desired product (69 mg, 71 %) as a yellow solid: ¹H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 6.75 (s, 1H), 3.37 - 3.26 (m, 4H), 2.54 (s, 3H), 2.23 - 2.15 (m, 4H); ¹⁹F NMR (376 MHz, Chloroform-d) δ -98.28.

4-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-3-amine. In a 100 mL round-bottom flask was dissolved 4-(4,4-difluoropiperidin-1-yl)-2-methyl-5-nitropyridine (69 mg, 0.268 mmol) in methanol (2 mL) to give a yellow solution. Pd/C (28.5 mg, 0.027 mmol) was added, and the mixture was stirred under hydrogen (1 atm) for 16 h. The mixture was filtered and the filtrate concentrated to give the desired product (41 mg, 67%) as a tan solid: ¹H NMR (500 MHz, Chloroform-d) δ 8.01 (s, 1H), 6.69 (s, 1H), 3.84 (s, 2H), 3.12 (t, J = 5.7 Hz, 4H), 2.45 (s, 3H), 2.15 (dt, J = 13.6, 5.7 Hz, 4H); ¹⁹F NMR (470 MHz, Chloroform-d) δ -97.92.

General synthesis of amine C:

[0158] 

6-Chloro-4-phenylpyridin-3-amine. In a 15 mL vial was dissolved 6-chloro-4-iodopyridin-3-amine (186 mg, 0.731 mmol), phenylboronic acid (143 mg, 1.170 mmol), and Na₂CO₃ (1.096 mL, 2.193 mmol) in dioxane (4 mL) to give a slightly tan solution under nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene (30.1 mg, 0.037 mmol) was added under nitrogen. The vial was sealed and heated at 100°C (oil bath) for 1 h. The mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 60% ethyl acetate/hexane, to afford the desired product (145 mg, 97%) as a wax solid/oil: ¹H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.55 - 7.48 (m, 2H), 7.47 - 7.42 (m, 3H), 7.08 (s, 1H), 3.89 (s, 2H).

6-Methyl-4-phenylpyridin-3-amine. In a 2 mL vial was dissolved 6-chloro-4-phenylpyridin-3-amine (44.2 mg, 0.216 mmol), methylboronic acid (64.6 mg, 1.080 mmol), and potassium carbonate (59.7 mg, 0.432 mmol) in dioxane (1 mL) (degassed) and water (0.1 mL) to give a tan solution. Pd(Ph₃P)₄ (12.48 mg, 10.80 µmol) was added. The mixture was stirred at 120°C for 16 h. The mixture was diluted with ethyl acetate and water. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 10% methanol/methylene chloride, to afford the desired product as a tan oil (7.5 mg, 19%): ¹H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.53 - 7.45 (m, 4H), 7.45 - 7.39 (m, 1H), 6.94 (s, 1H), 3.68 (s, 2H), 2.49 (s, 3H).

In a 50 mL round-bottom flask was dissolved 6-fluoropyridin-3-amine (332 mg, 2.96 mmol) in acetic acid (6 mL) to give a tan solution. At 70°C, bromine (0.168 mL, 3.26 mmol) was added. After 30 min, the mixture was diluted with ethyl acetate and water. The layers were separated. The organic layer was washed with 1N NaOH, saturated NaHCO₃, and brine, dried and concentrated. The dark oil was purified by flash column chromatography on silica gel, eluting with 60% ethyl acetate/hexane, to afford several components. The first (M+H=270.9) was the dibrominated product (118 mg, 15%), which was used in the next step.

In a 50 mL flask was dissolved 2,4-dibromo-6-fluoropyridin-3-amine (118 mg, 0.437 mmol), phenylboronic acid (64.0 mg, 0.525 mmol), and Na₂CO₃ (0.656 mL, 1.31 mmol) in dioxane (3 mL) to give a slightly tan solution under nitrogen. 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene (18.0 mg, 0.022 mmol) was added under nitrogen. The vial was sealed and heated at 100°C for 1.5 h. The mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was directly carried on to next reaction without further purification and characterization.

In a 100 mL round-bottom flask was added the crude mixture from the previous step (117 mg, 0.437 mmol) in methanol (4 mL) to give a tan solution. Pd/C (93 mg, 0.087 mmol) was carefully added, and the mixture was stirred under hydrogen (1 atm) for 18 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, 70% ethyl acetate/hexane, to afford three components: the first was the bis-phenyl component; the second and the third were identified by ¹H NMR. 02 (4.8mg, 5.8%): ¹H NMR (400 MHz, CDCl₃) δ 7.73 (t, J = 1.7 Hz, 1H), 7.71 (q, J = 1.6 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.46 - 7.39 (m, 1H), 7.20 (dd, J= 8.5, 6.9 Hz, 1H), 6.76 (dd, J= 8.5, 3.7 Hz, 1H), 3.81 (s, 2H);¹⁹F NMR (376 MHz, CDCl3) δ -79.87 (s). 03 (7.5mg, 9.1%): ¹H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.3 Hz, 1H), 7.58 - 7.43 (m, 5H), 6.75 (d, J = 2.6 Hz, 1H), 3.71 (s, 2H); ¹⁹F NMR (376 MHz, CDCl3) δ -81.64 (s).

tert-Butyl [2,4'-bipyridin]-3'-ylcarbamate. To a pressure vessel was added tert-butyl (4-iodopyridin-3-yl)carbamate (0.25g, 0.781 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.176 g, 0.859 mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.032 g, 0.039 mmol). The reaction mixture was degassed and flushed with N2 (3x). Then Dioxane (5) was added and the system was degassed and flushed with N2(3x). SODIUM CARBONATE (0.781 ml, 1.562 mmol) was added and the system was degassed and flushed with N2(3x). The reaction mixture was heated to 85 °C for 3h. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to 110g silica gel cartridge which was eluted with 0-100% ethyl acetate / hexanes over a period of 60 mins. The desired fractions were combined and dried under vacuo to give tert-butyl [2,4'-bipyridin]-3'-ylcarbamate (0.02 g, 0.074 mmol, 9.44 % yield). MS (ESI) (m/z): 272.1(M+H)⁺.

2,4'-Bipyridin]-3'-amine. To tert-butyl [2,4'-bipyridin]-3'-ylcarbamate (0.02 g, 0.074 mmol) was added HCl, 4 M dioxane (0.5 ml, 2.000 mmol). The reaction mixture was stirred overnight at rt. The solvent was removed and the residue was neutralized with satd sodium bicarbonate and extracted with ethyl acetate (3x). The org extracts were combined and dried over sodium sulfate. The solvent was removed, dried under vacuo to give [2,4'-bipyridin]-3'-amine (15 mg, 0.088 mmol. MS (ESI) (m/z): 172.4(M+H)⁺.

General synthesis of amine D:

[0159] 

tert-Butyl (5-fluoropyridin-3-yl)carbamate. In a 250 mL round-bottom flask was added 3-bromo-5-fluoropyridine (2.84 g, 16.1 mmol), tert-butyl carbamate (2.080 g, 17.75 mmol), and Cs₂CO₃ (10.52 g, 32.3 mmol) in dioxane (40 mL) (degassed) to give a colorless suspension under nitrogen. Pd₂(dba)₃ (0.443 g, 0.484 mmol) and XANTPHOS (0.374 g, 0.646 mmol) were added. The flasked was heated at 100°C under nitrogen overnight for 20 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate/hexane, to afford the desired product (2.93 g, 86%) as an off-white solid: ¹H NMR (400 MHz, Chloroform-d) δ 8.22 - 8.18 (m, 1H), 8.16 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 10.8 Hz, 1H), 6.88 (s, 1H), 1.55 (s, 9H); ¹⁹F NMR (376 MHz, Chloroform-d) δ -125.88.

tert-Butyl (5-fluoro-4-iodopyridin-3-yl)carbamate. In a 500 mL round-bottom flask was dissolved tert-butyl (5-fluoropyridin-3-yl)carbamate (1.802 g, 8.49 mmol) and N,N,N',N'-tetramethylethylenediamine (3.84 mL, 25.5 mmol) in ethyl ether (40 mL) to give a light yellow solution. After cooling to -78°C, n-BuLi (9.69 mL, 25.5 mmol) was slowly added via syringe (to maintain the temperature below -60°C). Upon addition, the mixture was allowed to warm to -20°C and was stirred for 90 min. The mixture was cooled to -78°C and a solution of iodine in THF (12 mL) was added dropwise over 10 min. The reaction mixture was allowed to gradually warm to rt and stirred overnight. The mixture was poured onto 1M HCl (20 mL) and crushed ice. The aqueous phase was extracted twice with ether. The combined organic layers were washed with water, NaHCO₃ solution, sodium thiosulfate solution, and brine, dried and concentrated. Purification by flash column chromatography on silica gel, eluting with 30% ethyl acetate/hexane, afforded the desired product (1.79 g, 62%) as a light yellow solid: ¹H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 8.07 (d, J = 0.9 Hz, 1H), 6.77 (s, 1H), 1.58 (s, 9H); ¹⁹F NMR (376 MHz, Chloroform-d) δ - 105.13.

tert-Butyl (5-fluoro-4-phenylpyridin-3-yl)carbamate. In a 15 mL vial was dissolved tert-butyl (5-fluoro-4-iodopyridin-3-yl)carbamate (188.3 mg, 0.557 mmol), phenylboronic acid (109 mg, 0.891 mmol), and Na₂CO₃ (0.835 mL, 1.67 mmol) in dioxane (3 mL) to give a slightly yellow solution under nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) dichloride, toluene (22.91 mg, 0.028 mmol) was added under nitrogen. The vial was sealed and heated at 80°C for 20 h. The mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate/hexane, to afford the desired product (144 mg, 90%) as a white solid: ¹H NMR (400 MHz, Chloroform-d) δ 9.22 (s, 1H), 8.26 (s, 1H), 7.60 - 7.46 (m, 3H), 7.40 - 7.30 (m, 2H), 6.41 (s, 1H), 1.46 (s, 9H); ¹⁹F NMR (376 MHz, Chloroform-d) δ -130.69.

5-Fluoro-4-phenylpyridin-3-amine. In a 100 mL round-bottom flask was dissolved tert-butyl (5-fluoro-4-phenylpyridin-3-yl)carbamate (143.3 mg, 0.497 mmol) in methylene chloride (2 mL) to give a colorless solution. TFA (1.0 mL, 13 mmol) was added, and the mixture was stirred at rt for 1 h. The mixture was evaporated and the residue diluted with ethyl acetate. The solution was washed with 10 ml 1N NaOH, water, saturated NaHCO₃ solution, and brine, dried and concentrated to give the desired product (94 mg, 100%) as a white solid: ¹H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.94 (s, 1H), 7.55 - 7.47 (m, 2H), 7.47 - 7.36 (m, 3H), 3.96 (s, 2H); ¹⁹F NMR (376 MHz, Chloroform-d) δ -132.65.

General synthesis of amine E:

[0160] 

tert-Butyl (6-chloro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)carbamate. BuLi (2.166 mL, 5.70 mmol) was added to the diethyl ether (17 mL) solution of TMEDA (0.706 mL, 4.68 mmol) and tert-butyl (6-chloropyridin-3-yl)carbamate (0.4653 g, 2.035 mmol) at -78 °C. The reaction was stirred at this temperature for 1 hour. Dihydro-2H-pyran-4(3H)-one (0.230 mL, 2.442 mmol) was added to the reaction mixture (at this moment, the bath temperature was -75°C). The reaction was stirred for 2.5 hours before quenched with NH₄Cl (sat.). The reaction was diluted with ethyl acetate and washed with water three times. The organic layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product (0.3600g, 45% yield, 83% pure). MS(ES+) m/e 329 [M+H]+.

tert-Butyl (6-chloro-4-(2-methyltetrahydrofuran-2-yl)pyridin-3-yl)carbamate. BuLi (2.224 mL, 5.85 mmol) was added to the diethyl ether (20 mL) solution of TMEDA (0.802 mL, 5.32 mmol) and tert-butyl (6-chloropyridin-3-yl)carbamate (0.6079 g, 2.66 mmol) at -78 °C. The reaction was stirred at this temperature for 1 hour. 5-chloropentan-2-one (0.366 mL, 3.19 mmol) was added to the reaction mixture (at this moment, the bath temperature was -70°C). The reaction was stirred for 1 hour before it was quenched by adding water. The reaction was diluted with ethyl acetate and washed with water three times. The organic layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product(67.3 3mg, 7% yield). MS(ES+) m/e 313 [M+H]+.

tert-Butyl (6-chloro-4-(1-hydroxycyclohexyl)pyridin-3-yl)carbamate. BuLi (1.432 mL, 3.77 mmol) was added to the diethyl ether (10 mL) solution of TMEDA (0.467 mL, 3.09 mmol) and tert-butyl (6-chloropyridin-3-yl)carbamate (0.3075 g, 1.345 mmol) at -78 °C. The reaction was stirred at this temperature for 1 hour. cyclohexanone (0.167 mL, 1.614 mmol) was added to the reaction mixture (at this moment, the bath temperature was -78°C). The reaction was stirred for overnight while it was slowly warmed up to the room temperature. The reaction was diluted with ethyl acetate and washed with water three times. The organic layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product with contamination of the starting material.(0.312g, 24% yield, 34% pure). MS(ES+) m/e 327 [M+H]+.

tert-Butyl (6-chloro-4-(1-hydroxypropyl)pyridin-3-yl)carbamate. BuLi (2.90 mL, 4.65 mmol) was added to the diethyl ether (10 mL) solution of TMEDA (0.638 mL, 4.22 mmol) and tert-butyl (6-chloropyridin-3-yl)carbamate (0.483 g, 2.112 mmol) at -78 °C. The reaction was stirred at this temperature for 0.5 hour. propionaldehyde (0.349 mL, 4.65 mmol) was added to the reaction mixture (at this moment, the bath temperature was -78°C). The reaction was stirred for 1 hour before it was quenched by adding water. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 50% gave the desired product (obtained 306.6 mg, 40 % yield). MS(ES+) m/e 309 [M+Na]⁺.

tert-Butyl (6-chloro-4-(1-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate. React with isobutylaldehyde. 1H NMR (400MHz, CHLOROFORM-d) δ 8.86 (br. s., 1H), 8.29 (br. s., 1H), 6.95 (s, 1H), 4.58 (d, J=3.3 Hz, 1H), 4.34 (dd, J=7.8, 3.8 Hz, 1H), 1.49 (s, 9H), 1.04 (d, J=6.5 Hz, 3H), 0.78 (d, J=6.8 Hz, 3H).

tert-Butyl (6-chloro-4-(1-hydroxybutyl)pyridin-3-yl)carbamate. React with butylaldehyde. MS(ES+) m/e 301 [M+H]⁺.

tert-Butyl (6-chloro-4-(cyclopropyl(hydroxy)methyl)pyridin-3-yl)carbamate. React with cyclopropanecarbaldehyde. MS(ES+) m/e 299 [M+H]+ . ¹H NMR (400MHz, CHLOROFORM-d) δ 8.97 (br. s., 1H), 8.13 (br. s., 1H), 7.19 (s, 1H), 3.93 (dd, J=8.9, 3.1 Hz, 1H), 3.43 (d, J=3.3 Hz, 1H), 1.52 (s, 9H), 1.39 - 1.32 (m, 1H), 0.84 - 0.65 (m, 2H), 0.54 (dq, J=9.7, 4.9 Hz, 1H), 0.38 - 0.31 (m, 1H).

tert-butyl (6-chloro-4-(hydroxy(phenyl)methyl)pyridin-3-yl)carbamate. React with benzaldehyde. MS(ES+) m/e 335 [M+H]⁺ . ¹H NMR (400MHz, CHLOROFORM-d) δ 8.72 (s, 1H), 7.64 (br. s., 1H), 7.43 - 7.30 (m, 5H), 7.04 (s, 1H), 5.83 (d, J=3.5 Hz, 1H), 4.37 (d, J=3.0 Hz, 1H), 1.46 (s, 9H).

tert-Butyl (4-acetyl-6-chloropyridin-3-yl)carbamate. ¹H NMR (400MHz, CHLOROFORM-d) δ 10.19 (br. s., 1H), 9.57 (s, 1H), 7.63 (s, 1H), 2.67 (s, 3H), 1.53 (s, 9H).

4-(5-Amino-2-chloropyridin-4-yl)tetrahydro-2H-pyran-4-ol. The solution of tert-butyl (6-chloro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl)carbamate (0.1572 g, 0.478 mmol) in CH₂Cl₂ (3 mL) and TFA (2 mL) was stirred at room temperature for 30 min. LCMS showed completely conversion to the desired product. The solvent was removed via vaccum and the crude was partitioned between ethyl aeetate and NaOH (1N). The orgainc layer was separated and washed two more times by water before dried(Na₂SO₄), filtered and concentrated. The crude was purified by flash column eluted with ethyl acetate in hexane from 0 to 45% to 85% to give the product as a white solid (82.3mg. 75% yield). MS(ES+) m/e 229 [M+H]⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.76 (s, 1H), 7.00 (s, 1H), 4.67 (br. s., 2H), 4.00 - 3.86 (m, 5H), 2.14 - 2.06 (m, 3H), 2.04 - 2.01 (m, 1H).

1-(5-Amino-2-chloropyridin-4-yl)cyclohexanol. The mixture of TFA (2 mL, 26.0 mmol) and tert-butyl (6-chloro-4-(1-hydroxycyclohexyl)pyridin-3-yl)carbamate (0.312 g, 0.325 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for over night. The solvent was removed via vacuum and the crude was partitioned between etnyl acetate and NaOH(1N). The organic layer was separated and washed with water two more times before dried (Na2SO4), filtered and concentrated. Flash column eluted by ethyl acetate in hexane from 0 to 50% gave the desired product (26.4 mg, 36% yield). ¹H NMR (400MHz, CHLOROFORM-d) δ 7.63 (s, 1H), 6.98 (s, 1H), 4.73 (br. s., 2H), 2.11 (d, J=12.0 Hz, 2H), 1.81 - 1.61 (m, 7H), 1.30 - 1.21 (m, 2H). MS(ES+) m/e 227 [M+H]⁺.

1-(5-Amino-2-chloropyridin-4-yl)propan-1-ol. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.76 (s, 1H), 6.97 (s, 1H), 4.58 (t, J=6.9 Hz, 1H), 4.27 (br. s., 2H), 2.47 (br. s., 1H), 1.93 - 1.84 (m, 2H), 0.99 (t, J=7.4 Hz, 3H). MS(ES+) m/e 187 [M+H]⁺.

1-(3-Aminopyridin-4-yl)cyclohexanol. The mixture of Pd/C (15 mg, 0.014 mmol) and 1-(5-amino-2-chloropyridin-4-yl)cyclohexanol (26.4 mg, 0.116 mmol) in EtOH (4 mL) was hydrogenated via H2 balloon at room temperature for 5 hours. The reaction was filtered through celite cartridge and washed with DCM. The filtrate was concentrated to give the crude product (22 mg, 100% yield). MS(ES+) m/e 193 [M+H]⁺ . ¹H NMR (400MHz, METHANOL-d4) δ 7.98 (d, J=0.8 Hz, 1H), 7.88 (dd, J=5.9, 0.9 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 2.14 (d, J=11.5 Hz, 2H), 1.96 - 1.82 (m, 2H), 1.80 - 1.60 (m, 5H), 1.41 - 1.28 (m, 1H).

tert-Butyl (4-(3-hydroxyoxetan-3-yl)pyridin-3-yl)carbamate. To tert-butyl (4-iodopyridin-3-yl)carbamate (1.0 g, 3.12 mmol) in THF (8 ml) was added ISOPROPYLMAGNESIUM CHLORIDE, 2.9 M (3.23 ml, 9.37 mmol)dropwise at - 40°C. The reaction mixture was stirred at this temp for 1.5 h then cooled to -78 °C before being cannulated to a solution of oxetan-3-one (0.405 g, 5.62 mmol) in THF (8 ml) at -78 °C. After addition, the reaction mixture was stirred at -78 °C for 10 mins, then at 0 °C for 2 hrs and then at rt for 30 mins. Satd ammonium chloride was added then solvent was removed. Ethyl acetate and water was added to the residue. The layers were separated and the org layer was washed with brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 24 g silica gel cartridge which was eluted with 0-100% ethyl acetate / hexanes over a period of 50 mins. The desired fractions were combined and dried under vacuo to give the tert-butyl (4-(3-hydroxyoxetan-3-yl)pyridin-3-yl)carbamate (0.4 g, 1.502 mmol, 48.1 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.81 (s, 1 H) 8.37 (d, J=4.89 Hz, 1 H) 8.30 (br. s., 1 H) 7.47 (d, J=5.14 Hz, 1 H)) 6.93 (br. s., 1 H) 4.87 (d, J=7.58 Hz, 2 H) 4.73 (d, J=7.58 Hz, 2 H) 1.46 (s, 9 H). ¹H NMR (400 MHz, DMSO-d₆) ppm 8.81 (s, 1 H) 8.37 (d, J=5.14 Hz, 1 H) 8.29 (br. s., 1 H) 7.47 (d, J=4.89 Hz, 1 H) 6.91 (s, 1 H) 4.87 (d, J=7.09 Hz, 2 H) 4.73 (d, J=7.09 Hz, 2 H) 1.47 (s, 9 H).

tert-Butyl (4-(3-fluorooxetan-3-yl)pyridin-3-yl)carbamate. To tert-butyl (4-(3-hydroxyoxetan-3-yl)pyridin-3-yl)carbamate (0.11g, 0.413 mmol) in CH2Cl2 (2.5 mL) at -78 °C was added DAST (0.055 mL, 0.413 mmol). The reaction mixture was stirred for 1hr at -78 °C then quenched with water. The reaction mixture was warmed to rt then extracted with DCM. The org extracts were combined and dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in a small amount of dichloromethane and charged to a 24 g silica gel cartridge which was eluted with 0-80% ethyl acetate / hexanes over a period of 50 mins. The desired fractions were combined and dried under vacuo to give tert-butyl (4-(3-fluorooxetan-3-yl)pyridin-3-yl)carbamate (0.052 g, 0.194 mmol, 46.9 % yield). MS (ESI) (m/z): 269.0 (M+H)⁺.

4-(3-Fluorooxetan-3-yl)pyridin-3-amine. To tert-butyl (4-(3-fluorooxetan-3-yl)pyridin-3-yl)carbamate (0.052 g, 0.194 mmol) in CH2Cl2 (3 mL) at 0 °C was added TFA (0.03 ml, 0.389 mmol). The reaction mixture was stirred at rt for 24 hrs. The reaction was concentrated and dried under vacuo to give the desired prod. Taken as is to the next step. MS (ESI) (m/z): 169.0 (M+H)⁺.

4-(3,6-Dihydro-2H-pyran-4-yl)pyridin-3-amine. The mixture of 4-iodopyridin-3-amine (0.316 g, 1.437 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3019 g, 1.437 mmol), XPhos precatalyst (0.045 g, 0.057 mmol) and Phosphoric acid, potassium salt (0.5 M aq) (5.75 mL, 2.87 mmol) in dioxane (3.0 mL) was heat at 80 °C for 2.5 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water three times before dried (Na2SO4), filtered and concentrated. The product was purified by flash column eluted with ethyl acetate in hexane from 0 to 100% and eluted with 100% of ethyl acetate until the purple fraction (desired product) was eluted out (0.020g, 8% yield). ¹H NMR (400MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 8.00 (d, J=5.0 Hz, 1H), 6.90 (d, J=5.0 Hz, 1H), 5.97 (dt, J=3.0, 1.3 Hz, 1H), 4.32 (q, J=2.8 Hz, 2H), 3.95 (t, J=5.4 Hz, 2H), 3.83 (br. s., 2H), 2.45 - 2.38 (m, 2H). MS(ES+) m/e 177 [M+H]⁺.

4-(Cyclohex-1-en-1-yl)pyridin-3-amine. The mixture of 4-iodopyridin-3-amine (0.161 g, 0.734 mmol), cyclohex-1-en-1-ylboronic acid (0.0924 g, 0.734 mmol), XPhos precatalyst (0.023 g, 0.029 mmol), Phosphoric acid, potassium salt (2M aq) (0.550 mL, 1.100 mmol) in THF (3.0 mL) was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 100% gave the desired product (33 mg, 25% yield). MS(ES+) m/e 175 MS[M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 8.06 (s, 1H), 7.95 (d, J=5.0 Hz, 1H), 6.89 - 6.85 (m, 1H), 5.86 (dt, J=3.8, 1.9 Hz, 1H), 3.80 (br. s., 2H), 2.26 - 2.15 (m, 4H), 1.81 - 1.74 (m, 2H), 1.73 - 1.64 (m, 2H).

4-(3,4-Dihydro-2H-pyran-6-yl)pyridin-3-amine. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.02 (s, 1H), 7.91 (d, J=5.0 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H), 5.18 (t, J=4.0 Hz, 1H), 4.34 (br. s., 2H), 4.19 - 4.13 (m, 2H), 2.24 - 2.17 (m, J=6.3, 6.3, 4.1 Hz, 2H), 1.96 - 1.88 (m, 2H); MS(MS+) m/e 177 [M+H]⁺.

4-(3,6-Dihydro-2H-pyran-4-yl)pyridin-3-amine. ¹H NMR (400MHz, CDCl₃) δ 8.11 (s, 1H), 8.02 (d, J=4.8 Hz, 1H), 6.92 (d, J=4.8 Hz, 1H), 5.98 (tt, J=2.9, 1.5 Hz, 1H), 4.33 (q, J=2.8 Hz, 2H), 3.96 (t, J=5.5 Hz, 2H), 3.83 (br. s., 2H), 2.46 - 2.38 (m, 2H); MS(MS+) m/e 177 [M+H]⁺.

4-(Tetrahydro-2H-pyran-2-yl)pyridin-3-amine. The mixture of Pd/C (0.015 g, 0.014 mmol) and 4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-amine (0.080 g, 0.454 mmol) in MeOH (0.3 mL) and Ethyl acetate (0.3 mL) was hydrogenated by H₂ balloon overnight at room temperature. The reaction was filtered through celite plug and washed with ethyl acetate. The filtrate was concentrated and the crude was used as it is. MS(MS+) m/e 179 [M+H]⁺.

4-(Tetrahydro-2H-pyran-4-yl)pyridin-3-amine. MS(MS+) m/e 179 [M+H]⁺.

tert-Butyl (6-chloro-4-propionylpyridin-3-yl)carbamate. Dess-MartinPeriodinane (0.458 g, 1.080 mmol) was added to the CH2Cl2 (8 mL) solution of tert-butyl (6-chloro-4-(1-hydroxypropyl)pyridin-3-yl)carbamate (0.258 g, 0.900 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour and the reaction mixture was directly loaded onto the column, which was eluted with ethyl acetate in hexane from 0 to 25%. The product was obtained as a white solid (0.1319 g, 52% yield). ¹H NMR (400MHz, CHLOROFORM-d) δ 10.21 (br. s., 1H), 9.57 (s, 1H), 7.65 (s, 1H), 3.04 (q, J=7.1 Hz, 2H), 1.53 (s, 9H), 1.23 (t, J=7.2 Hz, 3H).

tert-Butyl (4-butyryl-6-chloropyridin-3-yl)carbamate. MS(ES+) m/e 299 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 10.21 (br. s., 1H), 9.58 (s, 1H), 7.65 (s, 1H), 2.98 (t, J=7.2 Hz, 2H), 1.83 - 1.72 (m, 2H), 1.54 (s, 9H), 1.03 (t, J=7.5 Hz, 3H).

tert-Butyl (6-chloro-4-isobutyrylpyridin-3-yl)carbamate. ¹H NMR (400MHz, CHLOROFORM-d) δ 10.17 (br. s., 1H), 9.60 (s, 1H), 7.66 (s, 1H), 3.55 (spt, J=6.8 Hz, 1H), 1.54 (s, 9H), 1.25 (d, J=6.8 Hz, 6H).

tert-Butyl (6-chloro-4-(cyclopropanecarbonyl)pyridin-3-yl)carbamate. MS(ES+) m/e 297 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 9.95 (s, 1H), 9.51 (s, 1H), 7.83 (s, 1H), 2.61 (tt, J=7.7, 4.5 Hz, 1H), 1.51 (s, 9H), 1.36 - 1.30 (m, 2H), 1.23 - 1.17 (m, 2H).

tert-Butyl (4-benzoyl-6-chloropyridin-3-yl)carbamate. ¹H NMR (400MHz, CHLOROFORM-d) δ 9.42 (s, 1H), 8.90 (s, 1H), 7.77 (dd, J=8.3, 1.3 Hz, 2H), 7.72 - 7.65 (m, 1H), 7.59 - 7.51 (m, 2H), 7.34 (d, J=0.5 Hz, 1H), 1.51 (s, 9H); MS(ES+) m/e 333 [M+H]⁺.

(5-Amino-2-chloropyridin-4-yl)(cyclopropyl)methanone. The mixture of TFA (0.5 mL, 6.49 mmol) and tert-butyl (6-chloro-4-(cyclopropanecarbonyl)pyridin-3-yl)carbamate (0.1912 g, 0.644 mmol) in DCM (4 mL) was stirred at room temperature for 6 hours. The solvent was removed via vacuum. The crude was diluted with ethyl acetate and washed with NaOH(1N). The ethyl acetate layer was separated, dried(Na₂SO₄), filtered and concentrated to give the crude product (0.118g, 93% yield) as a yellow solid: MS(ES+) m/e 197 [M+H]⁺.

1-(5-Amino-2-chloropyridin-4-yl)-2,2-dimethylpropan-1-one. MS(ES+) m/e 214 [M+H]⁺.

1-(5-Amino-2-chloropyridin-4-yl)butan-1-one. MS(ES+) m/e 199 [M+H]⁺.

1-(5-Amino-2-chloropyridin-4-yl)-2-methylpropan-1-one. MS(ES+) m/e 199 [M+H]⁺.

4-(2-Methyl-1,3-dioxolan-2-yl)pyridin-3-amine. The mixture of P-TOLUENESULFONIC ACID MONOHYDRATE (0.065 g, 0.340 mmol), ETHYLENE GLYCOL (0.379 mL, 6.80 mmol) and 1-(3-aminopyridin-4-yl)ethanone (0.4631 g, 3.40 mmol) in Toluene (5 mL) was heat to reflux for over night. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product (59.8 mg obtained, 8% yield) as a wax. MS(ES+) m/e 181 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 8.01 (s, 1H), 7.95 (d, J=5.0 Hz, 1H), 7.18 (d, J=4.8 Hz, 1H), 4.46 (br. s., 2H), 4.09 - 4.04 (m, 2H), 3.82 - 3.77 (m, 2H), 1.66 (s, 3H).

6-Chloro-4-(2,4,5-trimethyl-1,3-dioxolan-2-yl)pyridin-3-amine. The mixture of p-toluenesulfonic acid monhydrate (0.034 g, 0.179 mmol), butane-2,3-diol (0.5 mL, 0.060 mmol) and 1-(5-amino-2-chloropyridin-4-yl)ethanone (0.0102 g, 0.060 mmol) in Toluene (4 mL) was heat to reflux for 3 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product (15.6 mg obtained, 66% yield) as a wax. MS(ES+) m/e 243 [M+H]⁺.

[0161] The mixture of p-toluenesulfonic acid monhydrate (0.557 g, 2.93 mmol), butane-2,3-diol (0.5 mL, 0.975 mmol) and 1-(5-amino-2-chloropyridin-4-yl)ethanone (0.1664 g, 0.975 mmol) in Toluene (4 mL) was heat to reflux for 3 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product. 6-Chloro-4-((4S,5R)-2,4,5-trimethyl-1,3-dioxolan-2-yl)pyridin-3-amine. (0.0923g, 39%); 6-Chloro-4-((4R,5R)-2,4,5-trimethyl-1,3-dioxolan-2-yl)pyridin-3-amine. (0.0490g, 21%). MS(ES+) m/e 243 [M+H]⁺. (Structure assignment is arbitrary).

[0162] The mixture of p-toluenesulfonic acid monhydrate (0.035 g, 0.182 mmol), 3,3,3-trifluoropropane-1,2-diol (0.05 mL, 0.182 mmol) and tert-butyl (6-chloro-4-propionylpyridin-3-yl)carbamate (0.0517 g, 0.182 mmol) in Toluene (0.4 mL) was heated to reflux for 18 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 45% gave the desired product.

6-Chloro-4-((2R,4S)-2-ethyl-4-(trifluoromethyl)-1,3-dioxolan-2-yl)pyridin-3-amine.

[0163] (0.0104g, 19%): ¹H NMR (400MHz, CHLOROFORM-d) δ 7.81 (s, 1H), 7.18 (s, 1H), 4.58 - 4.48 (m, 1H), 4.41 (dd, J=8.9, 6.9 Hz, 1H), 4.37 - 4.27 (m, 2H), 3.96 (dd, J=9.0, 7.5 Hz, 1H), 2.06 - 1.95 (m, 2H), 0.92 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376MHz, CHLOROFORM-d) S δ -76.52 (s, 3F). MS(ES+) m/e 297 [M+H]⁺. (Structure assignment is arbitrary).

6-Chloro-4-((2R,4R)-2-ethyl-4-(trifluoromethyl)-1,3-dioxolan-2-yl)pyridin-3-amine.

[0164] (0.0132g, 24%). ¹H NMR (400MHz, CHLOROFORM-d) δ 7.82 (s, 1H), 7.19 (s, 1H), 4.45 - 4.34 (m, 3H), 4.28 (dd, J=9.5, 3.3 Hz, 1H), 3.94 (td, J=8.5, 0.8 Hz, 1H), 2.12 - 2.02 (m, 2H), 0.95 (t, J=7.5 Hz, 3H); ¹⁹F NMR (376MHz, CHLOROFORM-d) δ - 78.09 (s, 3F); MS(ES+) m/e 297 [M+H]⁺. (Structure assignment is arbitrary).

6-Chloro-4-(2-methyl-1,3-dioxolan-2-yl)pyridin-3-amine. The mixture of p-toluenesulfonic acid monhydrate (7.59 mg, 0.040 mmol), ethylene glycol (0.111 mL, 1.995 mmol) and tert-butyl (4-acetyl-6-chloropyridin-3-yl)carbamate (0.108 g, 0.399 mmol) in Toluene (5 mL) was heat to reflux for over night. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired product (43.3 mg obtained, 51% yield) as a wax. MS(ES+) m/e 215 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 7.78 (s, 1H), 7.24 (s, 1H), 4.46 (br. s., 2H), 4.12 - 4.06 (m, 2H), 3.85 - 3.79 (m, 2H), 1.66 (s, 3H).

6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridin-3-amine. The mixture of p-toluenesulfonic acid monhydrate (5.01 mg, 0.026 mmol), ethylene glycol (0.2 mL, 3.59 mmol) and tert-butyl (6-chloro-4-propionylpyridin-3-yl)carbamate (0.025 g, 0.088 mmol) in Toluene (2 mL) was heat to reflux for 2 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 45% gave the desired product (9.3 mg obtained, 46% yield) as a wax. MS(ES+) m/e 229 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 7.78 (s, 1H), 7.21 (s, 1H), 4.44 (br. s., 2H), 4.10 - 4.05 (m, 2H), 3.87 - 3.82 (m, 2H), 1.97 (q, J=7.4 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).

6-Chloro-4-(2-propyl-1,3-dioxolan-2-yl)pyridin-3-amine. MS(ES+) m/e 243 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 7.77 (s, 1H), 7.20 (s, 1H), 4.45 (br. s., 2H), 4.08 - 4.02 (m, 2H), 3.85 - 3.79 (m, 2H), 1.95 - 1.88 (m, 2H), 1.45 - 1.32 (m, 2H), 0.90 (t, J=7.4 Hz, 3H).

6-Chloro-4-(2-isopropyl-1,3-dioxolan-2-yl)pyridin-3-amine. MS(ES+) m/e 243 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 7.77 (s, 1H), 7.17 (s, 1H), 4.46 (br. s., 2H), 4.09 - 3.98 (m, 2H), 3.88 - 3.77 (m, 2H), 2.35 (dt, J=13.7, 6.8 Hz, 1H), 0.92 (d, J=6.8 Hz, 6H).

6-Chloro-4-(2-cyclopropyl-1,3-dioxolan-2-yl)pyridin-3-amine. MS(ES+) m/e 241 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 7.79 (s, 1H), 7.16 (s, 1H), 4.52 (br. s., 2H), 4.08 - 4.02 (m, 2H), 3.85 - 3.79 (m, 2H), 1.55 - 1.46 (m, 1H), 0.59 - 0.47 (m, 4H).

6-Chloro-4-(2-phenyl-1,3-dioxolan-2-yl)pyridin-3-amine. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.77 (s, 1H), 7.51 - 7.43 (m, 3H), 7.40 - 7.32 (m, 3H), 4.32 (br. s., 2H), 4.24 - 4.16 (m, 2H), 4.09 - 4.00 (m, 2H); MS(ES+) m/e 277 [M+H]⁺.

6-Chloro-4-(2-ethyl-4,5-dimethyl-1,3-dioxolan-2-yl)pyridin-3-amine. The mixture of p-toluenesulfonic acid monhydrate (3.95 mg, 0.021 mmol), butane-2,3-diol (0.2 mL, 0.069 mmol) and tert-butyl (6-chloro-4-propionylpyridin-3-yl)carbamate (0.0197 g, 0.069 mmol) in Toluene (1 mL) was heat to reflux for 2 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 45% gave the desired product (11.3 mg obtained, 59% yield) as a green wax. MS(ES+) m/e 257 [M+H]⁺.

6-Chloro-4-(2-ethyl-4-methyl-1,3-dioxolan-2-yl)pyridin-3-amine. The mixture of p-toluenesulfonic acid monhydrate (0.030 g, 0.158 mmol), propane-1,2-diol (0.05 mL, 0.158 mmol) and tert-butyl (6-chloro-4-propionylpyridin-3-yl)carbamate (0.045 g, 0.158 mmol) in Toluene (0.5 mL) was heated to reflux for 2 hours. The reaction was diluted with ethyl acetate and washed with NaOH (1N) one time and water two times. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 45% gave the desired product (33 mg obtained, 86% yield) as a wax. MS(ES+) m/e 243 [M+H]⁺; NMR showed that the product is a mixture with ratio about 2:1.

Methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate. To a solution of methyl 4-chloro-6-methylnicotinate (0.371 g, 2 mmol) in dioxane (3 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.762 g, 3.00 mmol), potassium acetate (0.589 g, 6.00 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (0.114 g, 0.140 mmol). The reaction mixture was flushed with Argon for 5 min and then heated to 90°C for ∼96 h. At the end, the mixture was filtered through celite and the filtrate was evaporated in vacuo. The residual crude product was used as is for the reaction with the cyclopropanecarbonyl chloride.

Methyl 4-(cyclopropanecarbonyl)-6-methylnicotinate. To a suspension of crude boronate ester (554 mg, 2 mmol) with bis(triphenylphosphine)palladium(II) dichloride (23.44 mg, 0.033 mmol), potassium phosphate tribasic (532 mg, 2.505 mmol) and water (0.068 mL, 3.76 mmol) in toluene (8.35 mL) was added cyclopropanecarbonyl chloride (0.156 mL, 1.67mmol). The reaction mixture was heated to 80 °C for ∼18h. Another portion of bis(triphenylphosphine)palladium(II) dichloride (23.44 mg, 0.033 mmol), potassium phosphate tribasic (426 mg, 2 mmol) and cyclopropanecarbonyl chloride (0.125 mL, 1.34 mmol) was added and continued heating for another ~18 h. At the end, the reaction mixture was diluted with toluene (20 mL), sat. NaHCO₃ (20 mL) and filtered through celite. From the filtrate layers were separated and the organic layer was dried (Na₂SO₄) and evaporated in vacuo. The residue was purified by silica gel chromatography Biotage (EtOAc : Hexane = 1:3) to give the required product (83 mg, 20%) as light yellow oil: MS (ESI) (m/z): 220 (M+H)⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 9.05 (s, 1H), 7.11 (s, 1H), 3.92 (d, J=0.7Hz, 3H), 2.65 (s, 3H), 2.22 - 2.07 (m, 1H), 1.38 - 1.29 (m, 2H), 1.19 - 1.08 (m, 2H).

4-(Cyclopropanecarbonyl)-6-methylnicotinic acid. To a solution of Methyl 4-(cyclopropanecarbonyl)-6-methylnicotinate (50 mg, 0.228 mmol) in mixed solvents THF/MeOH/Water (1 mL:0.5 mL:0.5 mL) was added lithium hydroxide (27.3 mg, 1.140 mmol). The reaction mixture was stirred at ambient temperature for ∼18h. At the end, all volatiles were evaporated in vacuo and the residue was dissolved in MeOH (2 mL) and purified by Prep-HPLC. The fractions with required product were combined and added Hunig's base (80 µL, 0.456 mmol, 2 equivalent). All volatiles were removed under vacuo and white Hunig's base salt was obtained (69 mg, 90%). The sample was directly used for next step. MS (ESI) (m/z): 206 (M+H)⁺.

5-Amino-2-methylpyridin-4-yl)(cyclopropyl)methanone. To a solution of 4-(cyclopropanecarbonyl)-6-methylnicotinic acid (69 mg, 0.206 mmol) in tert-butanol (1 mL) was added TEA (0.086 mL, 0.619 mmol) followed by Diphenylphosphoryl azide (0.133 mL, 0.619 mmol) under nitrogen. The reaction mixture was heated at 80°C for ∼18h. At the end volatiles were evapoarted in vacuo. The residue taken in EtOAc (100 mL) was washed with water, brine and dried (Na₂SO₄). The solution was filtered and evaporated and the residue was purified by silica gel chromatography (EtOAc:Hexane = 1:2) to give desired intermediate as white solid (23.4 mg, 40%): MS (ESI) (m/z): 277 (M+H)⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 9.88 (br. s., 1H), 9.59 (s, 1H), 7.65 (s, 1H), 2.71 - 2.63 (m, 1H), 2.61 (s, 3H), 1.53 (s, 9H), 1.33-1.29 (m, 2H), 1.20 - 1.01 (m, 2H). The intermediate (23.4 mg) obtained above was dissolved in TFA/Dichloromethane (10%, 2 mL) and stirred at ambient temperature for 4h. The TFA/Dichloromethane were evaporated and the residue was coevaporated with heptane twice and dried under vacuum. The crude was driectly used without further purification: MS (ESI) (m/z): 177 (M+H)⁺.

4-(2-Cyclopropyl-1,3-dioxolan-2-yl)-6-methylpyridin-3-amine. This compound was prepared according to a described procedure (Fieser, L.F. and Stevenson, R. in JACS 1954, 76, 1728-1733) except that dichloroethane was used as solvent instead of acetic acid (8.5 mg, purity >98%): MS (ESI) (m/z): 221 (M+H)⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 7.94 (s, 1H), 6.99 (s, 1H), 4.37 (br. s., 2H), 4.14 - 3.95 (m, 2H), 3.88 - 3.69 (m, 2H), 2.43 (s, 3H), 1.60 - 1.44 (m, 1H), 0.63 - 0.38 (m, 4H).

41-(5-Amino-2-methylpyridin-4-yl)-1-cyclopropylethanol. MS (ESI) (m/z): 193 (M+H)⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 7.87 (s, 1H), 7.05 (s, 1H), 4.49 (br. s., 2H), 2.43 (s, 3H), 1.44 (s, 3H), 1.55 - 1.34 (m, 1H), 0.72 - 0.42 (m, 4H).

General synthesis of Formula IV:

[0165] 

2-((5-(Trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. The mixture of XANTPHOS (0.087 g, 0.151 mmol), cesium carbonate (0.817 g, 2.509 mmol), palladium acetate (0.023 g, 0.100 mmol), 2-chloroisonicotinamide (0.3928 g, 2.509 mmol) and 5-(trifluoromethyl)pyridin-2-amine (0.488 g, 3.01 mmol) in Dioxane (15 mL) was heat at 110 °C for over night under N₂. The reaction was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with water two more times. The ethyl acetate layer was separated, dried(Na₂SO₄), filtered and concentrated to give the crude product as a yellow solid. The product was purified via flash column eluted with ethyl acetate in hexane from 0 to 100% and gave the desired product as a white solid (0.1937g, 27% yield). MS[ES+] m/e 283 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.90 (d, J=2.1 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.19 (br. s., 1H), 7.79 (d, J=8.5 Hz, 1H), 7.67 (br. s., 1H), 7.33 (s, 1H), 7.27 (d, J=5.5 Hz, 1H).

General synthesis of Formula V:

[0166] 

5-Bromo-4-(dibromomethyl)-2-fluoropyridine and 5-bromo-4-(bromomethyl)-2-fluoropyridine. BENZOYL PEROXIDE (0.434 g, 1.792 mmol) was added to the CCl₄ (25 mL) mixture of NBS (3.83 g, 21.51 mmol) and 5-bromo-2-fluoro-4-methylpyridine (3.4059 g, 17.92 mmol) at room temperature. The reaction was heated to reflux overnight. The solid was filtered off and the filtrate was passed through a silica plug, which was washed by DCM. The filtrate was concentrated. The product was purified by flash column eluted with ethyl acetate in hexane from 0 to 25%. The product obtained is the mixture of mono, bis bromides as well as the unreacted starting material. The crude was used as it is.

5-Bromo-2-fluoroisonicotinaldehyde. The suspension of 5-bromo-4-(bromomethyl)-2-fluoropyridine compound with 5-bromo-4-(dibromomethyl)-2-fluoropyridine (1:1) (5.6 g, 9.08 mmol) and Calcium carbonate (4.54 g, 45.4 mmol) in DMSO (12 mL) was stirred at 145 °C for 3 hours. The reaction was filtered and the solid was washed with ethyl acetate. The filtrate was diluted more with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. The product was purified via flash column eluted with ethyl acetate in hexane from 0 to 45% (0.843g, 45% yield). MS(ES+) m/e 208 MS[M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 10.31 (d, J=2.5 Hz, 1H), 8.53 - 8.50 (m, 1H), 7.37 (d, J=2.8 Hz, 1H).

1-(5-Bromo-2-fluoropyridin-4-yl)ethanol. methylmagnesium bromide (0.4058 g, 3.40 mmol) was added to the Tetrahydrofuran (5 mL) solution of 5-bromo-2-fluoroisonicotinaldehyde (1.134 mL, 3.40 mmol) at 0 °C. The reaction was stirred for 3 hours before quenched by water. The reaction was diluted with ethyl acetate and washed with water three times. The aqueous layer was eztract one time with ethyl acetate. The ethyl acetate was combined, dried (Na₂SO₄), filtered and concentrated. The product (0.2370g, 32% yield) was purified via flash column, which was eluted with ethyl acetate in hexane from 0 to 25% to 40%. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.26 (s, 1H), 7.25 (d, J=2.0 Hz, 1H), 5.15 (qd, J=6.4, 3.8 Hz, 1H), 2.09 (dd, J=3.6, 1.1 Hz, 1H), 1.51 (d, J=6.5 Hz, 3H). 19F NMR (376MHz, CHLOROFORM-d) Shift -69.60 (s, 1F).

(5-Bromo-2-fluoropyridin-4-yl)(cyclopropyl)methanol. Grignard reagnet: cyclopropylmagnesium bromide. MS(ES+) m/e 248 [M+2H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 8.28 (s, 1H), 7.21 (d, J=2.3 Hz, 1H), 4.67 (dd, J=6.9, 3.1 Hz, 1H), 2.28 (d, J=3.5 Hz, 1H), 1.31 - 1.19 (m, 1H), 0.72 - 0.46 (m, 4H); ¹⁹F NMR (376MHz, CHLOROFORM-d) Shift -70.09 (s, 1F).

1-(5-Bromo-2-fluoropyridin-4-yl)ethanone. Dess-Martin oxidation of corresponding alcohol as previously described for similar alcohols. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.42 (s, 1H), 6.98 (d, J=3.0 Hz, 1H), 2.65 (s, 3H); ¹⁹F NMR (470MHz, CHLOROFORM-d) δ -68.45 (br. s., 1F).

(5-Bromo-2-fluoropyridin-4-yl)(cyclopropyl)methanone. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.40 (d, J=0.5 Hz, 1H), 7.02 - 6.94 (m, 1H), 2.36 (tt, J=7.8, 4.5 Hz, 1H), 1.43 - 1.35 (m, 2H), 1.28 - 1.18 (m, 2H); ¹⁹F NMR (376MHz, CHLOROFORM-d) δ -68.81 (s, 1F).

5-Bromo-2-fluoro-4-(2-methyl-1,3-dioxolan-2-yl)pyridine. MS(ES+) m/e 262 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 8.34 (s, 1H), 7.24 (d, J=2.3 Hz, 1H), 4.16 - 4.05 (m, 2H), 3.85 - 3.75 (m, 2H), 1.78 (s, 3H); ¹⁹F NMR (376MHz, CHLOROFORM-d) δ -70.45 (s, 1F).

1-(5-Bromo-2-methoxypyridin-4-yl)ethanone. The mixture of 1-(5-bromo-2-fluoropyridin-4-yl)ethanone (0.1055 g, 0.484 mmol) and sodium methanolate (1.161 ml, 0.581 mmol) was heated at rt for 2 hours. LCMS showed the desired product. The solvent was removed via vacuum and the crude was purified via flash column eluted with ethyl acetate in hexane from 0 to 25% to give the desired product as a clear oil (obtained 67 mg,51 % yield). MS(ES+) m/e 232 [M+H]+.

5-Bromo-2-methoxy-4-(2-methyl-1,3-dioxolan-2-yl)pyridine. Starting material is 1-(5-bromo-2-methoxypyridin-4-yl)ethanone. MS(ES+) m/e 276 [M+H]⁺.

3-Bromo-4-(1,3-dioxolan-2-yl)pyridine. Starting material is 3-bromoisonicotinaldehyde. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.74 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 7.50 (d, J=5.0 Hz, 1H), 6.04 (s, 1H), 4.19 - 4.07 (m, 4H); MS (ES+) m/e 232 (M+H)⁺.

[0167] The mixture of p-toluenesulfonic acid monohydrate (0.168 g, 0.885 mmol), ethane-1,2-diol (0.110 g, 1.770 mmol) and (5-bromo-2-fluoropyridin-4-yl)(cyclopropyl)methanone (0.108 g, 0.443 mmol) in benzene (3 mL) was heat to reflux for 5 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na₂SO₄), filtered and concentrated. Flash column eluted with ethyl acetate in hexane from 0 to 25% to 50% gave the desired products.

[0168] 5-Bromo-4-(2-cyclopropyl-1,3-dioxolan-2-yl)-2-fluoropyridine. (21 % yield, 81 % pure). ¹H NMR (400MHz, CHLOROFORM-d) δ 8.35 (s, 1H), 7.13 (d, J=2.3 Hz, 1H), 4.08 - 4.02 (m, 2H), 3.84 - 3.77 (m, 2H), 1.77 (tt, J=8.3, 5.2 Hz, 1H), 0.66 - 0.60 (m, 2H), 0.55 - 0.48 (m, 2H); ¹⁹F NMR (376MHz, CHLOROFORM-d) Shift -68.78 (s, 1F), -70.83 (s, 1F)(main peak); MS(ES+) m/e 290 [M+2H]⁺.

[0169] 2-((5-Bromo-4-(2-methyl-1,3-dioxolan-2-yl)pyridin-2-yl)oxy)ethanol. (33% yield). MS(ES+) m/e 305 [M+H]⁺ ; ¹H NMR (400MHz, CHLOROFORM-d) δ 8.23 (s, 1H), 7.10 (s, 1H), 4.46 - 4.43 (m, 2H), 4.11 - 4.06 (m, 2H), 3.96 (m, 2H), 3.81 - 3.77 (m, 2H), 1.77 (s, 3H).

General synthesis of Formula I:

Example 91:

[0170] 

N-(6-Methoxy-4-(2-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. The mixture of XANTPHOS (5.09 mg, 8.80 µmol), cesium carbonate (0.048 g, 0.147 mmol), palladium acetate (1.317 mg, 5.87 µmol), 2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.041 g, 0.147 mmol) and 5-bromo-2-methoxy-4-(2-methyl-1,3-dioxolan-2-yl)pyridine (0.060 g, 0.147 mmol) in Dioxane (1.5 mL) was heated at 110 °C for 5 hours under N₂. The reaction was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed two more times with water. The ethyl acetate layer was dried(Na₂SO₄), filtered and concentrated. The crude was purified via flash column eluted with ethyl acetate in hexane from 0 to 45% to 80% (obtained 8.0 mg,11 % yield). MS(ES+) m/e 476 [M+H]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 9.67 (s, 1H), 9.13 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.47 (d, J=5.3 Hz, 1H), 8.36 (dd, J=8.5, 2.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.25 - 7.21 (m, 2H), 6.95 (s, 1H), 4.22 - 4.17 (m, 2H), 3.96 (s, 3H), 3.96 - 3.90 (m, 2H), 1.68 (s, 3H); ¹⁹F NMR (376MHz, CHLOROFORM-d) δ -67.06 (s, 3F).

Example 40:

[0171] 

N-(4-(1,3-Dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 432 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.39 (br. s., 1H), 10.08 (s, 1H), 8.94 (d, J=1.8 Hz, 1H), 8.71 (s, 1H), 8.58 - 8.51 (m, 2H), 8.46 (d, J=5.2 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.55 (d, J=4.9 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J=5.5 Hz, 1H), 6.05 (s, 1H), 4.05 - 3.93 (m, 4H).

Example 84:

[0172] 

N-(6-(2-Hydroxyethoxy)-4-(2-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 506 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.10 (br. s., 1H), 9.83 (br. s., 1H), 8.94 (br. s., 1H), 8.59 - 8.38 (m, 3H), 7.82 (d, J=8.5 Hz, 1H), 7.46 - 7.31 (m, 2H), 6.88 (br. s., 1H), 4.87 (br. s., 1H), 4.29 (br. s., 2H), 4.04 (br. s., 2H), 3.82 - 3.67 (m, 4H), 1.58 (br. s., 3H).

Example 82:

[0173] 

N-(6-Fluoro-4-(2-methyl-1,3-dioxolan-2-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 464 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.10 (br. s., 1H), 10.02 (br. s., 1H), 8.94 (br. s., 1H), 8.66 - 8.44 (m, 3H), 7.82 (d, J=8.2 Hz, 1H), 7.47 - 7.20 (m, 3H), 4.07 (br. s., 2H), 3.81 (br. s., 2H), 1.61 (br. s., 3H).

Example 94:

[0174] 

N-(4-(2-Cyclopropyl-1,3-dioxolan-2-yl)-6-fluoropyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z) 490 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.59 (s, 1H), 10.09 (br. s., 1H), 8.79 (s, 1H), 8.62 (br. s., 1H), 8.53 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.42 (d, J=4.9 Hz, 1H), 7.16 (s, 1H), 4.10 - 4.00 (m, 2H), 3.91 - 3.81 (m, 2H), 1.45 (d, J=5.2 Hz, 1H), 0.53 - 0.39 (m, 4H).

Synthesis of intermdiate bromide:

[0175] 

N-(5-Bromopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: To 5-bromopyridin-3-amine (0.096 g, 0.556 mmol) and 2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid (0.15 g, 0.530 mmol) in DMF (10 mL) was added DIEA (0.463 mL, 2.65 mmol) followed by 1-Propanephosphonic acid cyclic anhydride (1.546 mL, 2.65 mmol) dropwise. The reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and water. The org extracts was washed with brine and dried over sodium sulfate and evaporated. The crude product was dissolved in a small amount of dichloromethane and charged to a 80 g silica gel cartridge which was eluted with 0-80% ethyl acetate / hexanes over a period of 40 mins. The desired frns were combined, evaporated and dried to give N-(5-bromopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.21 g, 0.479 mmol, 90 % yield). MS (ESI) (m/z): 439.8 (M+H)⁺.

Example 118:

[0176] 

N-(5-(4-Cyano-1H-pyrazol-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To an oven dried vial with a stir bar, N-(5-bromopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.02 g, 0.046 mmol), RockPhos (0.428 mg, 0.913 µmol),Pd2(dba)3 (0.042 g, 0.046 mmol),1H-pyrazole-4-carbonitrile (4.25 mg, 0.046 mmol) and K3PO4 (9.69 mg, 0.046 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (1mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 120 °C for 5 hrs. The reaction mixture was diluted with ethyl acetate and washed with ammonium chloride. The org layer was dried over sodium sulfate, filtered and then concentrated. The residue was purified by prep LCMS to give desired prod. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.02 (br. s., 1 H) 10.55 (s, 1 H) 9.48 (s, 1 H) 8.98 (d, J=1.83 Hz, 1 H) 8.90 (d, J=2.14 Hz, 1 H) 8.84 (t, J=2.29 Hz, 1 H) 8.65 (s, 1 H) 8.52 (d, J=5.19 Hz, 1 H) 8.48 (s, 1 H) 8.28 (s, 1 H) 8.07 (dd, J=8.85, 2.44 Hz, 1 H) 7.90 - 7.98 (m, 1 H) 7.51 (dd, J=5.19, 1.22 Hz, 1 H). MS (ESI) (m/z): 451.1(M+H)⁺.

Example 119:

[0177] 

N-(5-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.87 (s, 1 H) 10.53 (s, 1 H) 8.85 (d, J=1.83 Hz, 1 H) 8.83 (d, J=2.44 Hz, 1 H) 8.74 (t, J=2.14 Hz, 1 H) 8.65 (s, 1 H) 8.52 (d, J=5.19 Hz, 1 H) 8.39 (s, 1 H) 8.27 (s, 1 H) 8.07 (dd, J=9.00, 2.59 Hz, 1 H) 7.93 (d, J=8.55 Hz, 1 H) 7.68 (s, 1 H) 7.50 (d, J=5.19 Hz, 1 H) 2.14 (s, 3 H). MS (ESI) (m/z): 440.3(M+H)⁺.

Example 120:

[0178] 

N-(5-(3-(Trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To an oven dried microwave vial was added N-(5-bromopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.02 g, 0.046 mmol), 3-(trifluoromethyl)-1H-pyrazole (7.45 mg, 0.055 mmol), POTASSIUM CARBONATE (0.013 g, 0.091 mmol) and COPPER(I) IODIDE (4.87 mg, 0.026 mmol). The vial was capped with a septum and the system was degassed and flushed with nitrogen (3x). Then 2,2,6,6-tetramethylheptane-3,5-dione (0.013 mL, 0.064 mmol) and DMF (1 mL) was added and then the reaction mixture was degassed and flushed with nitrogen (3x). The vial was sealed and place on a pre-heated oil bath at 110 °C. The reaction mixture was stirred at 110 °Cfor 20 hrs, then at rt for 48 hrs. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by prep LCMS to give desired prod. MS (ESI) (m/z): 494.2(M+H)⁺.

Example 121:

[0179] 

N-(5-Morpholinopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To an oven dried microwave vial was added N-(5-bromopyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.025 g, 0.057 mmol), XPhos (2.176 mg, 4.56 µmol) and Pd2(dba)3 (2.090 mg, 2.282 µmol). The solid mixture was degassed and flushed with N2 (3x). Then LiHMDS, 1 M THF (0.228 mL, 0.228 mmol), morpholine (0.00753 mL, 0.086 mmol) and THF (1 mL) was added and the reaction mixture was degassed and flushed with N2 (3x). The vial was capped, reaction placed on a preheated oil bath at 65 °C and stirred overnight. The reaction mixture was diluted with ethylacetate, washed with sat'd ammonium chloride, water and dried over sodium sulfate. The solvent was evaporated and the residue was purified by prep LCMS to give desired prod. MS (ESI) (m/z): 445.2(M+H)⁺.

Example 127:

[0180] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.86 (s, 1H), 10.54 (s, 1H), 9.00 (d, J = 2.3 Hz, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 8.06 (dd, J = 8.9, 2.5 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.65 (td, J = 7.9, 1.6 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.45 - 7.37 (m, 2H); MS (ESI) (m/z): 454 (M+H)⁺.

Example 128:

[0181] 

N-(5-(2-Chlorophenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.86 (s, 1H), 10.53 (s, 1H), 9.00 (d, J = 2.3 Hz, 1H), 8.64 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.35 (t, J = 2.1 Hz, 1H), 8.25 (s, 1H), 8.06 (dd, J = 8.9, 2.5 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 5.8, 3.3 Hz, 1H), 7.59 - 7.44 (m, 4H); MS (ESI) (m/z): 470 (M+H)⁺.

Example 129:

[0182] 

N-(5-(2,5-Difluorophenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.90 (br. s., 1 H) 10.56 (s, 1 H) 9.02 (s, 1 H) 8.65 (br. s., 1 H) 8.58 (s, 1 H) 8.52 (d, J=5.19 Hz, 1 H) 8.47 (br. s., 1 H) 8.28 (s, 1 H) 8.07 (d, J=8.54 Hz, 1 H) 7.94 (d, J=8.85 Hz, 1 H) 7.57 (br. s., 1 H) 7.44 - 7.52 (m, 2 H) 7.39 (d, J=8.24 Hz, 1 H). MS (ESI) (m/z): 472.3(M+H)⁺.

Example 130:

[0183] 

N-(5-(2,3-Difluorophenyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.87 (s, 1 H) 10.54 (s, 1 H) 9.02 (br. s., 1 H) 8.65 (s, 1 H) 8.59 (br. s., 1 H) 8.52 (d, J=5.19 Hz, 1 H) 8.47 (br. s., 1 H) 8.27 (s, 1 H) 8.07 (d, J=7.02 Hz, 1 H) 7.93 (d, J=8.85 Hz, 1 H) 7.53 - 7.61 (m, 1 H) 7.45 - 7.51 (m, 2 H) 7.36 - 7.43 (m, 1 H). MS (ESI) (m/z): 472.3 (M+H)⁺.

Synthesis of intermdiate bromide:

[0184] 

N-(5-Bromopyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To 5-bromopyridin-3-amine (0.128 g, 0.742 mmol) and 2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinic acid (0.2 g, 0.706 mmol) in DMF (2 mL) was added DIEA (0.617 mL, 3.53 mmol) followed by 1-Propanephosphonic acid cyclic anhydride (0.825 mL, 1.412 mmol) dropwise. The reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and water. The org extracts was washed with satd sodium bicarbonate brine, and dried over sodium sulfate and evaporated. The crude product triturated in dichloromethane, filtered to obtain white solid. The solid was collected and dried under vacuo to give N-(5-bromopyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.3 g, 0.685 mmol, 97 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.85 (s, 1 H) 10.48 (s, 1 H) 8.89 (d, J=1.96 Hz, 1 H) 8.53 (t, J=2.08 Hz, 1 H) 8.46 - 8.51 (m, 2 H) 8.17 (s, 1 H) 8.11 (d, J=8.56 Hz, 1 H) 7.97 (t, J=7.95 Hz, 1 H) 7.43 (dd, J=5.14, 1.47 Hz, 1 H) 7.39 (d, J=7.09 Hz, 1 H). ¹⁹F NMR (376 MHz, DMSO-d₆) d ppm -66.80 (s, 3 F). MS (ESI) (m/z): 440.0(M+H)⁺.

Example 122:

[0185] 

N-(5-(4-Cyano-1H-pyrazol-1-yl)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.05 (br. s., 1 H) 10.48 (s, 1 H) 9.48 (s, 1 H) 8.95 (d, J=1.83 Hz, 1 H) 8.88 (d, J=2.14 Hz, 1 H) 8.83 - 8.86 (m, 1 H) 8.49 (d, J=5.19 Hz, 1 H) 8.47 (s, 1 H) 8.20 (s, 1 H) 8.14 (d, J=8.54 Hz, 1 H) 7.95 - 8.01 (m, 1 H) 7.49 (d, J=5.19 Hz, 1 H) 7.40 (d, J=7.32 Hz, 1 H). MS(ESI) (m/z): 451.4(M+H)⁺.

Example 123:

[0186] 

N-(5-(2,2,2-Trifluoroethoxy)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To an oven dried vial with a stir bar, N-(5-bromopyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide -01 (0.02 g, 0.046 mmol), RockPhos (0.428 mg, 0.913 µmol),Pd2(dba)3 (0.418 mg, 0.456 µmol), 2,2,2-trifluoroethanol (4.57 mg, 0.046 mmol) and K3PO4 (0.015 g, 0.068 mmol)were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (1mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 120 °C for 5 hrs. The solvent was evaporated and the residue was purified with prep LCMS to give desired prod. ¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.58 (s, 1 H) 8.43 (d, J=5.19 Hz, 1 H) 8.30 (s, 1 H) 8.17 (d, J=2.14 Hz, 1 H) 8.12 (d, J=2.14 Hz, 1 H) 7.83 - 7.95 (m, 2 H) 7.33 - 7.39 (m, 1 H) 7.30 (d, J=7.02 Hz, 1 H) 4.72 (q, J=8.34 Hz, 2 H). MS(ESI) (m/z): 458.2(M+H)⁺.

Example 124:

[0187] 

N-(5-(Cyclopropylmethoxy)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To an oven dried vial with a stir bar, N-(5-bromopyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.04 g, 0.091 mmol), RockPhos (0.856 mg, 1.826 µmol),Pd2(dba)3 (0.836 mg, 0.913 µmol), cyclopropylmethanol (6.58 mg, 0.091 mmol) and K3PO4 (0.029 g, 0.137 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (1mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 120 °C for 5 hrs, then at rt for 48 hrs. The reaction mixture was diluted with ethyl acetate and washed with ammonium chloride. The org layer was dried over sodium sulfate, filtered and then concentrated. The residue was purified by prep LCMS to give desired prod. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.67 (s, 1 H) 10.47 (s, 1 H) 8.54 (d, J=1.53 Hz, 1 H) 8.48 (d, J=5.19 Hz, 1 H) 8.07 - 8.15 (m, 3 H) 7.98 (t, J=7.93 Hz, 1 H) 7.87 (s, 1 H) 7.34 - 7.46 (m, 2 H) 3.92 (d, J=7.02 Hz, 2 H) 1.22 -1.33 (m, 2 H) 0.54 - 0.67 (m, 2 H) 0.33 - 0.42 (m, 2 H). MS (ESI) (m/z): 430.5(M+H)⁺.

Example 125:

[0188] 

N-(5-((1-Methylcyclopropyl)methoxy)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.47 (d, J=1.83 Hz, 1 H) 8.43 (d, J=5.19 Hz, 1 H) 8.28 (s, 1 H) 8.05 (d, J=2.44 Hz, 1 H) 7.96 (t, J=2.29 Hz, 1 H) 7.83 - 7.94 (m, 2 H) 7.36 (dd, J=5.19, 1.53 Hz, 1 H) 7.30 (d, J=7.32 Hz, 1 H) 3.89 (s, 2 H) 1.27 (s, 3 H) 0.59 - 0.65 (m, 2 H) 0.44 - 0.50 (m, 2 H). MS(ESI) (m/z): 444.2(M+H)⁺.

Example 126:

[0189] 

N-(5-((2-Methylcyclopropyl)methoxy)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.47 (d, J=1.53 Hz, 1 H) 8.42 (d, J=5.19 Hz, 1 H) 8.29 (s, 1 H) 8.04 (d, J=2.44 Hz, 1 H) 7.95 (t, J=2.14 Hz, 1 H) 7.83 - 7.94 (m, 2 H) 7.35 (dd, J=5.19, 1.53 Hz, 1 H) 7.30 (d, J=7.32 Hz, 1 H) 3.89 - 4.03 (m, 2 H) 1.12 (d, J=6. 10 Hz, 3 H) 0.97 - 1.06 (m, 1 H) 0.79 - 0.87 (m, 1 H) 0.55 - 0.62 (m, 1 H) 0.37 - 0.45 (m, 1 H). MS(ESI) (m/z): 444.5(M+H)⁺.

Example 144:

[0190] 

N-(5-Phenylpyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. To a microwave vial was added N-(5-bromopyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.02 g, 0.046 mmol), phenylboronic acid (5.57 mg, 0.046 mmol) and PdCl2(dppf)-CH2Cl2Adduct (3.73 mg, 4.56 µmol). The reaction mixture was degassed and flushed with N2 (3x). Then DMF (1.0mL) was added and the system was degassed and flushed with N2(3x). SODIUM CARBONATE (0.046 mL, 0.091 mmol) was added and the system was degassed and flushed with N2(3x). The reaction mixture was heated to 85 °C for 3h. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified with prep LCMS to give desired prod. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.79 (s, 1 H) 10.49 (s, 1 H) 8.95 (d, J=2.14 Hz, 1 H) 8.69 (d, J=2.14 Hz, 1 H) 8.47 - 8.53 (m, 2 H) 8.18 (s, 1 H) 8.14 (d, J=8.54 Hz, 1 H) 7.98 (t, J=7.93 Hz, 1 H) 7.74 (d, J=7.32 Hz, 2 H) 7.56 (t, J=7.63 Hz, 2 H) 7.44 - 7.51 (m, 2 H) 7.40 (d, J=7.32 Hz, 1 H). MS (ESI) (m/z): 436.1 (M+H)⁺.

Example 145:

[0191] 

N-(5-(2-Chlorophenyl)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.83 (s, 1 H) 10.48 (s, 1 H) 8.99 (d, J=2.14 Hz, 1 H) 8.49 (d, J=5.19 Hz, 1 H) 8.43 (d, J=1.83 Hz, 1 H) 8.34 (s, 1 H) 8.17 (s, 1 H) 8.13 (d, J=8.54 Hz, 1 H) 7.98 (t, J=7.93 Hz, 1 H) 7.63 - 7.69 (m, 1 H) 7.48 - 7.56 (m, 3 H) 7.46 (d, J=4.88 Hz, 1 H) 7.40 (d, J=7.63 Hz, 1 H). MS (ESI) (m/z): 470.1 (M+H)⁺.

Example 146:

[0192] 

N-(5-(2,5-Difluorophenyl)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.84 (br. s., 1 H) 10.49 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.58 (s, 1 H) 8.50 (d, J=5.19 Hz, 1 H) 8.46 (s, 1 H) 8.18 (s, 1 H) 8.13 (d, J=8.54 Hz, 1 H) 7.98 (t, J=7.93 Hz, 1 H) 7.57 (ddd, J=9.00, 5.95, 3.36 Hz, 1 H) 7.43 - 7.52 (m, 2 H) 7.35 - 7.42 (m, 2 H). MS (ESI) (m/z): 472.2 (M+H)⁺.

Example 147:

[0193] 

N-(5-(2,3-Difluorophenyl)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. MS (ESI) (m/z): 472.2 (M+H)⁺.

Synthesis of amine F:

[0194] 

5-(2-Fluorophenyl)pyridin-3-amine. A mixture of Phosphoric acid, potassium salt (1.043 g, 4.91 mmol), PCy3 (0.019 g, 0.069 mmol), Pd2(dba)3 (0.026 g, 0.029 mmol), 5-bromopyridin-3-amine (0.5 g, 2.89 mmol) and (2-fluorophenyl)boronic acid (0.607 g, 4.33 mmol) in DMF (5 mL)and water (0.5 mL) was heated at 100 °C under N2 overnight. The reaction was filtered through a silica plug and washed with ethyl acetate. The filtrate was concentrated and the product was purified via flash column eluted with ethyl acetate in hexane from 0 to 100% to give 5-(2-fluorophenyl)pyridin-3-amine (0.5 g, 2.66 mmol, 92 % yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.22 (t, J=1.59 Hz, 1 H) 8.12 (d, J=2.69 Hz, 1 H) 7.45 (td, J=7.70, 1.71 Hz, 1 H) 7.34 - 7.41 (m, 1 H) 7.15 - 7.28 (m, 3 H) 3.78 (br. s., 2 H). MS (ESI) (mlz): 189.1(M+H)⁺.

Example 164:

[0195] 

2-((5-(2-Cyanopropan-2-yl)pyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. To 5-(2-fluorophenyl)pyridin-3-amine (0.035 g, 0.186 mmol) and 2-((5-(2-cyanopropan-2-yl)pyridin-2-yl)amino)isonicotinic acid (0.05 g, 0.177 mmol) in 2 was added DIEA (0.155 mL, 0.886 mmol) followed by 1-Propanephosphonic acid cyclic anhydride, 50% in EtOAc (0.207 mL, 0.354 mmol) dropwise. The reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and satd sodium bicarbonate and water and dried over sodium sulfate. The solvent was evaporated and the residue was purified with prep LCMS to give desired prod. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.80 (s, 1 H) 10.14 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.36 - 8.48 (m, 3 H) 8.23 (s, 1 H) 7.88 (dd, J=8.85, 2.75 Hz, 1 H) 7.79 (d, J=8.85 Hz, 1 H) 7.65 (td, J=7.78, 1.83 Hz, 1 H) 7.48 - 7.58 (m, 1 H) 7.35 - 7.45 (m, 3 H) 1.72 (s, 6 H). MS(ESI) (m/z): 453.5 (M+H)⁺.

Synthesis of intermediate chloride:

[0196] 

2-Chloro-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. To 5-(2-fluorophenyl)pyridin-3-amine (0.5 g, 2.66 mmol) and 2-chloroisonicotinic acid (0.440 g, 2.79 mmol) in DMF (10 mL) was added DIEA (2.320 mL, 13.28 mmol) followed by T3P, 50% in DMF (4.65 mL, 7.97 mmol). The reaction was stirred at rt overnight. It was diluted with EtOAc and washed with water, brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 120 g silica gel cartridge which was eluted with 0-15% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 2-chloro-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide (0.5 g, 1.526 mmol, 57.4 % yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.77 (s, 1 H) 10.00 (d, J=1.96 Hz, 1 H) 9.85 (s, 1 H) 8.69 (d, J=5.87 Hz, 1 H) 8.62 (s, 1 H) 8.28 (br. s., 1 H) 8.04 (s, 1 H) 7.56 - 7.65 (m, 2 H) 7.31 - 7.46 (m, 2 H). MS (ESI) (m/z): 328.0 (M+H)⁺. ¹⁹F NMR (376 MHz, CHLOROFORM-d) d ppm -116.96 (s, 1 F).

Example 131:

[0197] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((5-fluoropyridin-2-yl)amino)isonicotinamide. To an oven dried vial with a stir bar, brettphos precatalyst (0.731 mg, 0.915 µmol), brett phos (0.482 mg, 0.915 µmol), 5-fluoropyridin-2-amine (10.26 mg, 0.092 mmol), 2-chloro-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide (0.03 g, 0.092 mmol) and K2CO3 (0.019 g, 0.137 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (1mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 110 °C for 3 hrs. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was dissolved in methanol/DMF, filtered and purified by prep LCMS to give desired prod. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.80 (s, 1 H) 10.07 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.40 - 8.46 (m, 2 H) 8.28 (d, J=3.05 Hz, 1 H) 8.12 (s, 1 H) 7.85 (dd, J=9.16, 3.97 Hz, 1 H) 7.61 - 7.75 (m, 2 H) 7.47 - 7.57 (m, 1 H) 7.35 - 7.45 (m, 3 H). MS (ESI) (m/z): 404.1(M+H)⁺.

Example 132:

[0198] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((4-methylpyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.82 (br. s., 1 H) 9.89 (s, 1 H) 8.99 (d, J=2.44 Hz, 1 H) 8.55 (s, 1 H) 8.43 (d, J=5.49 Hz, 2 H) 8.28 (s, 1 H) 8.14 (d, J=4.88 Hz, 1 H) 7.65 (t, J=7.78 Hz, 1 H) 7.50 - 7.57 (m, 2 H) 7.35 - 7.46 (m, 3 H) 6.78 (d, J=4.88 Hz, 1 H) 2.30 (s, 3 H). MS (ESI) (m/z): 400.2 (M+H)⁺.

Example 133:

[0199] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((5-methylpyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.82 (br. s., 1 H) 9.86 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.55 (s, 1 H) 8.44 (br. s., 1 H) 8.41 (d, J=5.19 Hz, 1 H) 8.19 (s, 1 H) 8.11 (s, 1 H) 7.61 - 7.70 (m, 2 H) 7.50 - 7.57 (m, 2 H) 7.37 - 7.45 (m, 2 H) 7.34 (dd, J=5.19, 1.22 Hz, 1 H) 2.24 (s, 3 H). MS (ESI) (m/z): 400.1 (M+H)⁺.

Example 134:

[0200] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.83 (br. s., 1 H) 10.48 (s, 1 H) 8.98 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.50 (d, J=5.19 Hz, 1 H) 8.44 (s, 1 H) 8.18 (s, 1 H) 8.14 (d, J=8.54 Hz, 1 H) 7.98 (t, J=7.93 Hz, 1 H) 7.65 (td, J=7.86, 1.68 Hz, 1 H) 7.50 - 7.57 (m, 1 H) 7.47 (dd, J=5.19, 1.53 Hz, 1 H) 7.35 - 7.44 (m, 3 H). MS (ESI) (m/z): 454.1 (M+H)⁺.

Example 135:

[0201] 

2-((5-Cyanopyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.86 (br. s., 1 H) 10.66 (br. s., 1 H) 9.00 (d, J=2.44 Hz, 1 H) 8.73 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.53 (d, J=5.19 Hz, 1 H) 8.45 (s, 1 H) 8.27 (s, 1 H) 8.11 (dd, J=8.85, 2.14 Hz, 1 H) 7.88 (d, J=8.85 Hz, 1 H) 7.65 (t, J=7.78 Hz, 1 H) 7.48 - 7.57 (m, 2 H) 7.32 - 7.45 (m, 2 H). MS (ESI) (m/z): 411.1 (M+H)⁺.

Example 136:

[0202] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((6-fluoropyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.81 (s, 1 H) 10.26 (s, 1 H) 8.99 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.49 (d, J=5.19 Hz, 1 H) 8.44 (s, 1 H) 8.04 (s, 1 H) 7.88 (q, J=8.24 Hz, 1 H) 7.78 (dd, J=8.09, 2.29 Hz, 1 H) 7.61 - 7.69 (m, 1 H) 7.49 - 7.57 (m, 1 H) 7.43 - 7.46 (m, 1 H) 7.37 - 7.42 (m, 2 H) 6.64 (dd, J=7.93, 2.14 Hz, 1 H). MS (ESI) (m/z): 404.1 (M+H)⁺.

Example 137:

[0203] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((6-methylpyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.80 (s, 1 H) 9.93 (s, 1 H) 8.99 (d, J=2.44 Hz, 1 H) 8.55 (s, 1 H) 8.45 (d, J=1.22 Hz, 1 H) 8.42 (d, J=5.19 Hz, 1 H) 8.20 (s, 1 H) 7.57 - 7.68 (m, 3 H) 7.49 - 7.57 (m, 1 H) 7.37 - 7.45 (m, 2 H) 7.35 (dd, J=5.19, 1.53 Hz, 1 H) 6.80 (d, J=7.02 Hz, 1 H) 2.42 (s, 3 H). MS (ESI) (m/z): 400.1 (M+H)⁺.

Example 138:

[0204] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((6-ethylpyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.79 (s, 1 H) 9.92 (s, 1 H) 8.99 (d, J=2.44 Hz, 1 H) 8.55 (t, J=1.68 Hz, 1 H) 8.36 - 8.47 (m, 3 H) 7.58 - 7.70 (m, 2 H) 7.49 - 7.57 (m, 2 H) 7.37 - 7.44 (m, 2 H) 7.33 - 7.36 (m, 1 H) 6.80 (d, J=7.32 Hz, 1 H) 2.71 (q, J=7.63 Hz, 2 H) 1.28 (t, J=7.63 Hz, 3 H). MS (ESI) (m/z) : 414.2 (M+H)⁺.

Example 139:

[0205] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((6-methoxylpyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.81 (br. s., 1 H) 9.95 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.60 (s, 1 H) 8.55 (s, 1 H) 8.38 - 8.46 (m, 2 H) 7.58 - 7.69 (m, 2 H) 7.49 - 7.56 (m, 1 H) 7.33 - 7.45 (m, 3 H) 7.09 (d, J=7.63 Hz, 1 H) 6.33 (d, J=7.93 Hz, 1 H) 3.92 (s, 3 H). MS (ESI) (m/z): 416.1 (M+H)⁺.

Example 140:

[0206] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((5-morpholinopyridin-2-yl)amino)isonicotinamide. MS (ESI) (m/z): 471.2 (M+H)⁺.

Example 141:

[0207] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((5-methoxylpyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.80 (br. s., 1 H) 9.80 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.55 (s, 1 H) 8.44 (s, 1 H) 8.39 (d, J=5.19 Hz, 1 H) 8.10 (s, 1 H) 8.02 (d, J=3.05 Hz, 1 H) 7.75 (d, J=8.85 Hz, 1 H) 7.65 (td, J=7.78, 1.53 Hz, 1 H) 7.49 - 7.57 (m, 1 H) 7.35 - 7.45 (m, 3 H) 7.31 (dd, J=5.19, 1.22 Hz, 1 H) 3.81 (s, 3 H). MS (ESI) (m/z): 416.2 (M+H)⁺.

Example 142:

[0208] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-(quinolin-2-ylamino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.91 (br. s., 1 H) 10.38 (s, 1 H) 8.93 - 9.09 (m, 2 H) 8.54 - 8.60 (m, 1 H) 8.51 (d, J=5.19 Hz, 1 H) 8.49 (d, J=1.22 Hz, 1 H) 8.21 (d, J=9.16 Hz, 1 H) 7.82 (d, J=7.32 Hz, 1 H) 7.78 (d, J=8.54 Hz, 1 H) 7.66 (qd, J=7.58, 1.37 Hz, 2 H) 7.62 (d, J=8.85 Hz, 1 H) 7.51 - 7.58 (m, 1 H) 7.49 (dd, J=5.04, 1.37 Hz, 1 H) 7.35 - 7.45 (m, 3 H). MS (ESI) (m/z): 436.2 (M+H)⁺.

Example 143:

[0209] 

2-((5,6-Dimethylpyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.80 (s, 1 H) 9.80 (s, 1 H) 8.99 (d, J=2.44 Hz, 1 H) 8.55 (t, J=1.53 Hz, 1 H) 8.45 (d, J=1.53 Hz, 1 H) 8.40 (d, J=5.19 Hz, 1 H) 8.15 (s, 1 H) 7.59 - 7.69 (m, 2 H) 7.49 - 7.56 (m, 1 H) 7.36 - 7.47 (m, 3 H) 7.31 (dd, J=5.19, 1.53 Hz, 1 H) 2.39 (s, 3 H) 2.20 (s, 3 H). MS (ESI) (m/z): 414.2 (M+H)⁺.

Example 148:

[0210] 

2-((5-Cyano-6-ethylpyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.85 (br. s., 1 H) 10.61 (s, 1 H) 8.99 (d, J=2.14 Hz, 1 H) 8.38 - 8.61 (m, 4 H) 8.04 (d, J=8.54 Hz, 1 H) 7.59 - 7.67 (m, 2 H) 7.48 - 7.57 (m, 2 H) 7.33 - 7.45 (m, 2 H) 2.92 (q, J=7.43 Hz, 2 H) 1.34 (t, J=7.63 Hz, 3 H). MS (ESI) (m/z): 439.2 (M+H)⁺.

Example 149:

[0211] 

Methyl 6-((4-((5-(2-fluorophenyl)pyridin-3-yl)carbamoyl)pyridin-2-yl)amino)picolinate. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.85 (br. s., 1 H) 10.39 (s, 1 H) 9.02 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.43 - 8.49 (m, 2 H) 8.39 (s, 1 H) 8.08 (d, J=8.24 Hz, 1 H) 7.90 (t, J=7.78 Hz, 1 H) 7.60 - 7.70 (m, 2 H) 7.47 - 7.57 (m, 1 H) 7.34 - 7.44 (m, 3 H) 3.85 (s, 3 H). MS (ESI) (m/z): 444.2 (M+H)⁺.

Example 150:

[0212] 

2-((5-Cyano-6-ethylpyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.84 (br. s., 1 H) 10.35 (s, 1 H) 8.99 (d, J=2.44 Hz, 1 H) 8.56 (s, 1 H) 8.48 (d, J=5.19 Hz, 1 H) 8.44 (s, 1 H) 7.99 (s, 1 H) 7.93 (d, J=8.24 Hz, 1 H) 7.77 (t, J=7.93 Hz, 1 H) 7.65 (td, J=7.78, 1.83 Hz, 1 H) 7.49 - 7.57 (m, 1 H) 7.33 - 7.47 (m, 3 H) 7.01 (d, J=7.63 Hz, 1 H). MS (ESI) (m/z): 420.1 (M+H)⁺.

Example 151:

[0213] 

2-((5,6-Dimethoxypyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.77 (s, 1 H) 9.66 (s, 1 H) 8.99 (d, J=2.14 Hz, 1 H) 8.54 (s, 1 H) 8.42 (s, 1 H) 8.39 (d, J=5.19 Hz, 1 H) 8.35 (s, 1 H) 7.61 - 7.68 (m, 1 H) 7.49 - 7.57 (m, 1 H) 7.36 - 7.44 (m, 2 H) 7.34 (d, J=8.55 Hz, 1 H) 7.31 (d, J=5.19 Hz, 1 H) 7.14 (d, J=8.55 Hz, 1 H) 3.94 (s, 3 H) 3.75 (s, 3 H). MS (ESI) (m/z): 446.2 (M+H)⁺.

Example 152:

[0214] 

2-((6-Cyanopyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.84 (br. s., 1 H) 10.50 (s, 1 H) 8.99 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.50 (d, J=4.88 Hz, 1 H) 8.45 (s, 1 H) 8.15 (d, J=8.54 Hz, 1 H) 8.11 (s, 1 H) 7.94 (t, J=7.93 Hz, 1 H) 7.65 (t, J=7.93 Hz, 1 H) 7.47 - 7.58 (m, 3 H) 7.34 - 7.46 (m, 2 H). MS(ESI) (m/z): 411.0 (M+H)⁺.

Example 153:

[0215] 

2-((1,6-Naphthyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.92 (br. s., 1 H) 10.72 (s, 1 H) 9.10 (s, 1 H) 9.00 - 9.07 (m, 2 H) 8.57 (t, J=6.10 Hz, 3 H) 8.49 (s, 1 H) 8.35 (d, J=9.16 Hz, 1 H) 7.64 - 7.72 (m, 2 H) 7.62 (d, J=5.80 Hz, 1 H) 7.51 - 7.59 (m, 2 H) 7.36 - 7.45 (m, 2 H). MS(ESI) (m/z): 437.2 (M+H)⁺.

Example 154:

[0216] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((6-pivalamidopyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.92 (s, 1 H) 9.95 (s, 1 H) 9.17 (s, 1 H) 9.10 (d, J=2.14 Hz, 1 H) 8.69 (s, 1 H) 8.55 (s, 1 H) 8.38 - 8.48 (m, 2 H) 7.59 - 7.72 (m, 2 H) 7.48 - 7.57 (m, 2 H) 7.37 - 7.45 (m, 2 H) 7.35 (d, J=4.88 Hz, 1 H) 7.19 (d, J=8.24 Hz, 1 H) 1.14 (s, 9 H). MS(ESI) (m/z): 485.2 (M+H)⁺.

Example 155:

[0217] 

2-((5-Cyano-6-methylpyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.87 (br. s., 1 H) 10.63 (s, 1 H) 8.99 (d, J=2.14 Hz, 1 H) 8.56 (s, 1 H) 8.52 (d, J=5.19 Hz, 1 H) 8.45 (s, 1 H) 8.24 (s, 1 H) 8.05 (d, J=8.85 Hz, 1 H) 7.83 (d, J=8.85 Hz, 1 H) 7.60 - 7.68 (m, 1 H) 7.49 - 7.56 (m, 2 H) 7.35 - 7.46 (m, 2 H) 2.61 (s, 3 H); MS(ESI) (m/z): 425.1 (M+H)⁺.

Example 156:

[0218] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((5-sulfamoylpyridin-2-yl)amino)isonicotinamide. MS (ESI) (m/z): 465.0 (M+H)⁺.

Example 157:

[0219] 

2-((5-(N,N-Dimethylsulfamoyl)pyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.85 (s, 1 H) 10.66 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.60 (d, J=2.44 Hz, 1 H) 8.56 (s, 1 H) 8.53 (d, J=5.19 Hz, 1 H) 8.45 (s, 1 H) 8.28 (s, 1 H) 8.02 - 8.07 (m, 1 H) 7.96 (d, J=8.85 Hz, 1 H) 7.65 (t, J=7.93 Hz, 1 H) 7.52 (d, J=6.10 Hz, 2 H) 7.36 - 7.45 (m, 2 H) 2.65 (s, 6 H). MS(ESI) (m/z): 493.3(M+H)⁺.

Example 158:

[0220] 

2-((5-Acetylpyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.85 (s, 1 H) 10.56 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.93 (d, J=2.44 Hz, 1 H) 8.56 (s, 1 H) 8.52 (d, J=5.19 Hz, 1 H) 8.45 (s, 1 H) 8.36 (s, 1 H) 8.19 (dd, J=8.70, 2.29 Hz, 1 H) 7.81 (d, J=9.16 Hz, 1 H) 7.65 (t, J=7.78 Hz, 1 H) 7.46 - 7.56 (m, 2 H) 7.36 - 7.45 (m, 2 H) 2.56 (s, 3 H). MS(ESI) (m/z): 428.5 (M+H)⁺.

Example 159:

[0221] 

N-(5-(2-Fluorophenyl)pyridin-3-yl)-2-((5-(piperidin-1-ylsulfonyl)pyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.86 (s, 1 H) 10.67 (s, 1 H) 9.00 (d, J=2.14 Hz, 1 H) 8.55 - 8.59 (m, 1 H) 8.53 (d, J=5.19 Hz, 1 H) 8.45 (s, 1 H) 8.28 (s, 1 H) 7.99 - 8.04 (m, 1 H) 7.93 - 7.98 (m, 2 H) 7.65 (t, J=7.78 Hz, 1 H) 7.50 - 7.56 (m, 2 H) 7.37 - 7.46 (m, 2 H) 2.93 (t, J=5.19 Hz, 4 H) 1.54 - 1.60 (m, 4 H) 1.40 (d, J=4.58 Hz, 2 H). MS(ESI) (m/z): 533.3 (M+H)⁺.

Example 160:

[0222] 

6-((4-((5-(2-Fluorophenyl)pyridin-3-yl)carbamoyl)pyridin-2-yl)amino)nicotinamide. MS (ESI) (m/z): 429.5 (M+H)⁺.

Example 161:

[0223] 

(E)-Eethyl 3-(6-((4-((5-(2-fluorophenyl)pyridin-3-yl)carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)acrylate. MS (ESI) (m/z): 470.3 (M+H)⁺.

Synthesis of amine F:

[0224] 

4-(5-Aminopyridin-3-yl)benzonitrile. To a pressure vessel was added 5-bromopyridin-3-amine (0.3 g, 1.734 mmol), (4-cyanophenyl)boronic acid (0.255 g, 1.734 mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.283 g, 0.347 mmol). The reaction mixture was degassed and flushed with N2 (3x). Then DMF (5 mL) was added and the system was degassed and flushed with N2(3x). SODIUM CARBONATE (1.734 mL, 3.47 mmol) was added and the system was degassed and flushed with N2(3x). The reaction mixture was heated to 85 °C for 3h. LCMS showed desired prod. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 120 g silica gel cartridge which was eluted with 0-100% ethyl acetate / hexanes over a period of 60 mins. The desired fractions were combined and dried under vacuo to give 4-(5-aminopyridin-3-yl)benzonitrile (0.28 g, 1.434 mmol, 83 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.10 (d, J=1.96 Hz, 1 H) 8.01 (d, J=2.45 Hz, 1 H) 7.90 - 7.96 (m, 2 H) 7.78 - 7.84 (m, 2 H) 7.21 (t, J=2.20 Hz, 1 H) 5.46 (s, 2 H). MS (ESI) (m/z): 196.1(M+H)⁺.

Example 162:

[0225] 

N-(5-(4-Cyanophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide. To 2-((6-cyanopyridin-2-yl)amino)isonicotinic acid (0.05 g, 0.208 mmol) and 4-(5-aminopyridin-3-yl)benzonitrile (0.041 g, 0.208 mmol) in Ethyl acetate (2 mL) was added DIEA (0.182 mL, 1.041 mmol) followed by 1-Propanephosphonic acid cyclic anhydride, 50% in EtOAc (0.243 mL, 0.416 mmol) dropwise. The reaction was stirred at rt overnight. LCMS showed product. The reaction was diluted with ethyl acetate and satd sodium bicarbonate and water. Solid was formed between layers which was filtered, collected and washed with dichloromethane. The solid was triturated in dichloromethane, filtered and dried under vacuo to obtain white solid. Water and ethyl acetate was added and the org layer was dried over sodium sulfate. The crude material was purified by prep LCMS to give desired product. MS (ESI) (m/z): 418.3(M+H)⁺.

Synthesis of intermdiate:

[0226] 

2-Amino-N-(5-bromopyridin-3-yl)isonicotinamide. To 5-bromopyridin-3-amine (0.406 g, 2.348 mmol) and 2-(cyclopentanecarboxamido)isonicotinic acid (0.5 g, 2.134 mmol) in DMF (2 mL) was added DIEA (1.864 mL, 10.67 mmol) followed by HATU (1.623 g, 4.27 mmol). The reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and water. The org extracts was washed with brine and dried over sodium sulfate and evaporated. The crude product was dissolved in a small amount of dichloromethane and charged to a 24 g silica gel cartridge which was eluted with 0-80% ethyl acetate / hexanes over a period of 40 mins. The desired frns were combined, evaporated and dried to give 2-amino-N-(5-bromopyridin-3-yl)isonicotinamide (0.19 g, 0.648 mmol, 30.4 % yield) and N-(5-bromopyridin-3-yl)-2-(cyclopentanecarboxamido)isonicotinamide (0.03 g, 0.077 mmol, 3.61 % yield). MS (ESI) (m/z): 295.0(M+H)⁺.

N-(5-Bromopyridin-3-yl)-2-((5-(1-cyanocyclopropyl)pyridin-2-yl)amino)isonicotinamide. To an oven dried vial with a stir bar, brettphos precatalyst (2.73 mg, 3.41 µmol), brett phos (1.797 mg, 3.41 µmol), 1-(6-chloropyridin-3-yl)cyclopropanecarbonitrile (0.061 g, 0.341 mmol), 2-amino-N-(5-bromopyridin-3-yl)isonicotinamide (0.1 g, 0.341 mmol) and K2CO3 (0.071 g, 0.512 mmol) were added. The solid mixture was purged with N2 (degassed and flushed) (3x). Then tBuOH (1mL) was added. The vial was degassed and flushed with N2 (3x) and the vessel was capped and placed in a preheated oil bath at 110 °C for 3 hrs. LCMS- showed a bit of prod with both s/m still present. The reaction was heated for 10 more hrs at 110 °C. LCMS showed no improvement. The reaction mixture was cooled, diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 24 g silica gel cartridge which was eluted with 0-15% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give N-(5-bromopyridin-3-yl)-2-((5-(1-cyanocyclopropyl)pyridin-2-yl)amino)isonicotinamide (10 mg, 0.023 mmol, 6.73 % yield). MS (ESI) (m/z): 434.9(M+H)⁺.

Example 163:

[0227] 

2-((5-(1-Cyanocyclopropyl)pyridin-2-yl)amino)-N-(5-(2-fluorophenyl)pyridin-3-yl)isonicotinamide. To a pressure vessel was added N-(5-bromopyridin-3-yl)-2-((5-(1-cyanocyclopropyl)pyridin-2-yl)amino)isonicotinamide (10 mg, 0.023 mmol), (2-fluorophenyl)boronic acid (3.21 mg, 0.023 mmol) and PdCl2(dppf)-CH2Cl2Adduct (3.75 mg, 4.59 µmol). The reaction mixture was degassed and flushed with N2 (3x). Then DMF (1) was added and the system was degassed and flushed with N2(3x). SODIUM CARBONATE (0.02297 mL, 0.046 mmol) was added and the system was degassed and flushed with N2(3x). The reaction mixture was heated to 85 °C for 3h. LCMS showed desired product. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was dried over sodium sulfate. The crude material was purified by prep LCMS to give desired prod. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.80 (br. s., 1 H) 10.13 (s, 1 H) 8.99 (d, J=2.44 Hz, 1 H) 8.56 (s, 1 H) 8.40 - 8.48 (m, 2 H) 8.30 (d, J=2.44 Hz, 1 H) 8.20 (s, 1 H) 7.74 - 7.80 (m, 1 H) 7.70 (dd, J=8.70, 2.59 Hz, 1 H) 7.65 (td, J=7.78, 1.83 Hz, 1 H) 7.51 - 7.57 (m, 1 H) 7.36 - 7.45 (m, 3 H) 1.70 - 1.75 (m, 2 H) 1.49 - 1.54 (m, 2 H). MS (ESI) (m/z): 451.3 (M+H)⁺.

Synthesis of intermdiate bromide:

[0228] 

N-(5-Bromopyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide. To 2-((6-cyanopyridin-2-yl)amino)isonicotinic acid (0.1 g, 0.416 mmol) and 5-bromopyridin-3-amine (0.076 g, 0.437 mmol) in Ethyl acetate (2 mL) 2 was added DIEA (0.364 mL, 2.081 mmol) followed by 1-Propanephosphonic acid cyclic anhydride, 50% in EtOAc (0.486 mL, 0.833 mmol) dropwise. The reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and satd sodium bicarbonate and water and dried over sodium sulfate. The solvent was removed and the residue was dried under vacuo to give N-(5-bromopyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide (0.15 g, 0.380 mmol, 91 % yield). MS (ESI) (m/z): 396.8(M+H)⁺.

Example 165:

[0229] 

N-(5-(4-Cyano-3-fluorophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide. To a microwave vial was added N-(5-bromopyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide (0.03g, 0.076 mmol),(4-cyano-3-fluorophenyl)boronic acid (0.013 g, 0.076 mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.012 g, 0.015 mmol). The reaction mixture was degassed and flushed with N2 (3x). Then DMF (1 mL) was added and the system was degassed and flushed with N2(3x). SODIUM CARBONATE (0.076 mL, 0.152 mmol) was added and the system was degassed and flushed with N2(3x). The reaction mixture was heated to 85°C for 3 hrs. LCMS showed desired prod. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by prep LCMS to give N-(5-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.88 (s, 1 H) 10.52 (s, 1 H) 9.01 (d, J=2.14 Hz, 1 H) 8.81 (d, J=2.14 Hz, 1 H) 8.60 (t, J=2.14 Hz, 1 H) 8.52 (d, J=5.19 Hz, 1 H) 8.07 - 8.17 (m, 3 H) 8.00 (dd, J=10.68, 1.53 Hz, 1 H) 7.91 - 7.98 (m, 1 H) 7.82 (dd, J=7.93, 1.53 Hz, 1 H) 7.56 (d, J=7.02 Hz, 1 H) 7.50 (dd, J=5.19, 1.53 Hz, 1 H). MS (ESI) (m/z): 436.2(M+H)⁺.

Example 166:

[0230] 

N-(5-(2-Cyano-3-fluorophenyl)pyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide. To a microwave vial was added N-(5-bromopyridin-3-yl)-2-((6-cyanopyridin-2-yl)amino)isonicotinamide (0.03g, 0.076 mmol),(2-cyano-3-fluorophenyl)boronic acid (0.013 g, 0.076 mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.012 g, 0.015 mmol). The reaction mixture was degassed and flushed with N2 (3x). Then DMF (3 mL) was added and the system was degassed and flushed with N2(3x). SODIUM CARBONATE (0.076 mL, 0.152 mmol) was added and the system was degassed and flushed with N2(3x). The reaction mixture was heated to 85°C for 3 hrs. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by prep LCMS to give desired prod. MS (ESI) (m/z): 436.5(M+H)⁺.

Synthesis of intermdiate for example 166-167:

[0231] 

2-Chloro-5-fluoro-N-(4-phenylpyridin-3-yl)isonicotinamide. 2 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.61 mL, 2.71 mmol) was added to a solution of triethylamine (0.378 mL, 2.71 mmol), 4-phenylpyridin-3-amine (0.1539 g, 0.904 mmol) and 2-chloro-5-fluoroisonicotinic acid (0.159 g, 0.904 mmol) in DMF (2.5 mL) at rt. The mixture was stirred overnight at rt. The reaction was diluted with ethyl acetate and washed with water (3x). The organic layer was separated, dried (Na₂SO₄), filtered and concentrated to give the crude product as a tan solid (145 mg, 49%): LCMS: M+H = 328.0.

Example 167:

[0232] 

5-Fluoro-N-(4-phenylpyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide. A mixture of potassium carbonate (7.84 mg, 0.057 mmol), 2-chloro-5-fluoro-N-(4-phenylpyridin-3-yl)isonicotinamide (12.4 mg, 0.038 mmol), 5-(trifluoromethyl)pyridin-2-amine (12.27 mg, 0.076 mmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (0.203 mg, 0.378 µmol), Brettphos precatalyst (0.302 mg, 0.378 µmol) in t-butanol (0.7 mL) (degassed) was heated at 110 °C for 18 h. The reaction was filtered through a small silica pad and washed with methanol. The filtrate was purified by prep-HPLC (6.0 mg, 35%): ¹H NMR (500MHz, DMSO-d₆) δ 10.51 (s, 1H), 10.45 (br. s., 1H), 8.72 (s, 1H), 8.63 - 8.54 (m, 2H), 8.42 (s, 1H), 8.09 - 8.01 (m, 2H), 7.71 (d, J=8.9 Hz, 1H), 7.59 - 7.41 (m, 6H).

Example 168:

[0233] 

5-Fluoro-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (br. s., 1H), 8.83 (br. s., 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.37 (d, J=5.5 Hz, 1H), 8.22 (d, J=4.6 Hz, 1H), 8.04 (dd, J=9.0, 2.3 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.28 (d, J=5.5 Hz, 1H), 5.00 (q, J=8.9 Hz, 2H).

Example 169:

[0234] 

3-Fluoro-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: ¹H NMR (500MHz, DMSO-d₆) δ 10.22 (br. s., 1H), 10.08 (br. s., 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.30 (d, J=4.9 Hz, 1H), 8.09 (dd, J=8.9, 2.4 Hz, 1H), 7.98 (d, J=8.9 Hz, 1H), 7.37 - 7.26 (m, 2H), 4.99 (q, J=8.5 Hz, 2H).

General synthesis of amine G:

[0235] 

3-Nitro-4-(propylthio)pyridine. In a 20 mL vial was propane-1-thiol (150 mg, 1.968 mmol) in Tetrahydrofuran (3 mL) to give a colorless solution.4-chloro-3-nitropyridine (260 mg, 1.640 mmol) and Hunig'sBase (0.372 mL, 2.132 mmol) were added. The mixture was stirred at rt overnight. TLC (3/1 hexane/EtOAc) indicated a major more polar spot with a little SM left. Another equivalent of thiol was added and the mixture was stirred over the weekend. TLC showed complete conversion. It was concentrated to a tan solid. Purification by FCC up to 50% EtOAc/hexane afforded the desired product (280 mg, 86%) as a yellow solid: ¹H NMR (500 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 7.32 (d, J = 5.6 Hz, 1H), 2.98 (t, J = 7.4 Hz, 2H), 1.83 (h, J = 7.4 Hz, 2H), 1.14 (t, J = 7.4 Hz, 3H).

3-Nitro-4-((2,2,2-trifluoroethyl)thio)pyridine:¹H NMR (500 MHz, Chloroform-d) δ 9.37 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.40 (d, J = 5.6 Hz, 1H), 3.70 (q, J = 9.3 Hz, 2H).

3-Nitro-4-(phenylthio)pyridine: ¹H NMR (500 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.34 (d, J = 5.6 Hz, 1H), 7.63 - 7.50 (m, 5H), 6.69 (d, J = 5.6 Hz, 1H).

3-Nitro-4-(isobutylthio)pyridine: ¹H NMR (400 MHz, Chloroform-d) δ 9.34 (d, J = 1.3 Hz, 1H), 8.57 (dd, J = 5.6, 1.0 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 2.87 (d, J = 6.8 Hz, 2H), 2.15 - 2.00 (m, 1H), 1.16 (d, J = 6.6 Hz, 6H).

2-Chloro-4-(cyclopropylthio)-5-nitropyridine: ¹H NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 7.82 (s, 1H), 2.13 (tt, J = 7.4, 4.5 Hz, 1H), 1.39 - 1.29 (m, 2H), 0.96 - 0.82 (m, 2H).

4-(Propylthio)pyridin-3-amine. In a 100 mL round-bottomed flask was 3-nitro-4-(propylthio)pyridine (131 mg, 0.661 mmol) and Pd/C (141 mg, 0.132 mmol) in MeOH (3 mL) to give a black suspension. The mixture was stirred under hydrogen (balloon) for 24h. LCMS showed slow reaction to completion. It was filtered and wahsed with MeOH. The elute was concentrated to the desired product (101 mg, 91%) as a tan oil: ¹H NMR (400 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.90 (d, J = 5.1 Hz, 1H), 7.07 (d, J = 5.1 Hz, 1H), 4.12 (s, 2H), 2.89 - 2.85 (m, 2H), 1.71 - 1.64 (m, 2H), 1.03 - 0.99 (m, 3H).

4-((2,2,2-Trifluoroethyl)thio)pyridin-3-amine: MS (ESI) (m/z): 209 (M+H)⁺.

4-(Phenylthio)pyridin-3-amine: MS (ESI) (m/z): 203 (M+H)+.

3-Nitro-4-(isopropylthio)pyridine. In a 20 mL vial was 4-chloro-3-nitropyridine (323 mg, 2.037 mmol) in DMF (4 mL) to give a tan solution. Potassium carbonate (563 mg, 4.07 mmol) and propane-2-thiol (0.388 mL, 4.07 mmol) were added. The vial was tightly capped and the mixture was stirred at 100°C overnight for 18 h. TLC (3/1 hexane/EtOAc) showed good conversion. It was diluted with water and EtOAc. The layers were separated. The organic layer was washed with water, brine, dried and concentrated to a tan oil. FCC up to 50% EtOAc/hexane afforded the desired product (149 mg, 37%) as a tan solid: ¹H NMR (400 MHz, Chloroform-d) δ 9.33 (s, 1H), 8.59 (d, J = 5.7 Hz, 1H), 7.37 (d, J = 5.6 Hz, 1H), 3.63 (hept, J = 6.7 Hz, 1H), 1.49 (d, J = 6.5 Hz, 6H).

3-Nitro-4-(tert-butylthio)pyridine. ¹H NMR (400 MHz, Chloroform-d) δ 9.18 - 9.10 (m, 1H), 8.60 (dt, J = 5.4, 1.0 Hz, 1H), 7.66 (d, J = 5.5 Hz, 1H), 1.5 (s, 9H).

4-(Isobutylthio)pyridin-3-amine: In a 20 mL vial was 4-(isobutylthio)-3-nitropyridine (433 mg, 2.040 mmol) in EtOH (6 ml) to give a yellow solution. SnCl₂ (967 mg, 5.10 mmol) was added, and the mixture was heated at 70°C under nitrogen. 2h: LCMS indicated good conversion to the desired product along with likely hydroxylamine product (M+16) as major. The heating was continued for another 18h. LCMS showed mainly the desired products. Cooled to r.t. Aqueous NaHCO3 was added to adjust pH around 7-8 (till no solids were forming). Some celite and Na2SO4 were added and stirring continued for 30 min. The suspension was then carefully filtered (through a plug of celite) and washed with EtOAc. The filtrated solution was concentrated to remove EtOH. The remainder was partitioned between water and EtOAc. The layers were separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated to the desired product (150 mg, 40%) as a tan oil. MS (ESI) (m/z): 209 (M+H)⁺.

4-(Isoropylthio)pyridin-3-amine. MS (ESI) (m/z): 169 (M+H)⁺.

4-(tert-Butylthio)pyridin-3-amine. MS (ESI) (m/z): 183 (M+H)⁺.

6-Chloro-4-(cyclopropylthio)pyridin-3-amine. MS (ESI) (m/z): 201 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.30 (s, 1H), 3.66 (s, 2H), 2.15 (tt, J = 7.4, 4.4 Hz, 1H), 1.23 - 1.13 (m, 2H), 0.78 - 0.70 (m, 2H).

Example 170:

[0236] 

N-(4-(Propylthio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 434 (M+H)⁺; ¹H NMR (400 MHz, Methanol-d4) δ 8.58 (s, 1H), 8.52 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 7.94 - 7.84 (m, 1H), 7.80 - 7.70 (m, 1H), 7.42 (dd, J = 8.9, 5.3 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H), 1.79 (q, J = 7.3 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H).

Example 171:

[0237] 

N-(4-((2,2,2-Trifluoroethyl)thio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 474 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.51 (s, 1H), 8.61 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.47 - 8.40 (m, 2H), 8.28 (s, 1H), 8.05 (dd, J = 9.0, 2.6 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 5.4 Hz, 1H), 7.48 (d, J = 5.1 Hz, 1H), 4.23 (q, J = 10.1 Hz, 2H).

Example 172:

[0238] 

N-(4-(Phenylthio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 468 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.51 (s, 1H), 8.61 (s, 1H), 8.54 - 8.41 (m, 2H), 8.37 - 8.24 (m, 2H), 8.05 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.68 - 7.41 (m, 6H), 6.76 (d, J = 5.3 Hz, 1H).

Example 173:

[0239] 

N-(4-(Isopropylthio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 434 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.29 (s, 1H), 8.61 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.39 (d, J = 5.3 Hz, 1H), 8.26 (s, 1H), 8.05 (dd, J = 9.1, 2.6 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.56 - 7.40 (m, 2H), 3.75 (p, J = 6.7 Hz, 1H), 1.32 (d, J = 6.7 Hz, 6H).

Example 174:

[0240] 

N-(4-(tert-Butylthio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 448 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 10.23 (s, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 5.3 Hz, 1H), 1.32 (s, 9H).

Example 175:

[0241] 

N-(4-(Isobutylthio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 448 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 10.33 (s, 1H), 8.60 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 4.8 Hz, 2H), 8.26 (s, 1H), 8.12 - 8.00 (m, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.53 - 7.35 (m, 2H), 2.94 (d, J = 6.9 Hz, 2H), 1.86 (p, J = 6.7 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H).

Example 176:

[0242] 

N-(6-Chloro-4-(cyclopropylthio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 466 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.60 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 8.05 (dd, J = 9.1, 2.6 Hz, 1H), 7.94 (t, J = 9.8 Hz, 1H), 7.66 (s, 1H), 7.44 (d, J = 5.2 Hz, 1H), 2.37 (tt, J = 7.7, 4.5 Hz, 1H), 1.21 (td, J = 7.1, 4.9 Hz, 2H), 0.64 (q, J = 5.1, 3.8 Hz, 2H).

Examples 177 and 183:

[0243] 

[0244] In a 100 mL round-bottomed flask was N-(4-(phenylthio)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (108 mg, 0.231 mmol) in CH2Cl2 (3 mL) to give a white suspension. TFA (0.178 mL, 2.310 mmol) and mCPBA (88 mg, 0.393 mmol) were added. The mixture was stirred at rt for 1 h. LCMS showed the formation of the desired products. The products were purified by prep-HPLC.
N-(4-(Phenylsulfinyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (177): MS (ESI) (m/z): 484 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.54 (s, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 8.09 - 8.01 (m, 1H), 7.92 (dd, J = 10.4, 7.1 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.49 (q, J = 7.2, 5.9 Hz, 3H), 7.36 (d, J = 5.2 Hz, 1H).
N-(4-(Phenylsulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (183): MS (ESI) (m/z): 500 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.45 (s, 1H), 9.07 (s, 1H), 8.80 (d, J = 5.3 Hz, 1H), 8.60 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.88 (d, J = 9.1 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.43 (d, J = 5.2 Hz, 1H).

Example 178:

[0245] 

N-(4-(tert-Butylsulfinyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 464 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.12 (s, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.63 - 8.58 (m, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.06 (dd, J = 8.9, 2.5 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.67 (d, J = 5.0 Hz, 1H), 7.41 (d, J = 5.2 Hz, 1H), 1.16 (s, 9H).

Example 187:

[0246] 

N-(4-(tert-butylsulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 480 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.55 (s, 1H), 9.61 (s, 1H), 8.73 (d, J = 5.1 Hz, 1H), 8.62 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.47 (s, 1H), 8.06 (dd, J = 8.8, 2.3 Hz, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 1.29 (s, 9H).

Example 179:

[0247] 

N-(4-(isopropylsulfinyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 450 (M+H)⁺; ¹H NMR (400 MHz, Methanol-d4) δ 9.35 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 8.58 - 8.55 (m, 1H), 8.47 (d, J = 5.3 Hz, 1H), 8.44 - 8.40 (m, 1H), 7.92 (dd, J = 8.8, 2.7 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 5.1 Hz, 1H), 7.44 (dd, J = 5.2, 1.6 Hz, 1H), 3.31 - 3.24 (m, 1H), 1.35 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H).

Example 186:

[0248] 

N-(4-(Isopropylsulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 466 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.55 (s, 1H), 9.42 (s, 1H), 8.78 (d, J = 5.1 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.05 (dd, J = 9.0, 2.6 Hz, 1H), 7.89 (d, J = 5.1 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 5.3, 1.7 Hz, 1H), 3.68 (p, J = 6.7 Hz, 1H), 1.21 (d, J = 6.8 Hz, 6H).

Example 180:

[0249] 

N-(6-Chloro-4-(cyclopropylsulfinyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 482 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.55 (s, 1H), 8.76 (s, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 8.06 (dd, J = 8.9, 2.6 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.82 (s, 1H), 7.45 (dd, J = 5.2, 1.6 Hz, 1H), 2.77 (q, J = 6.0, 5.3 Hz, 1H), 1.11 (q, J = 6.9, 6.2 Hz, 1H), 1.04 - 0.95 (m, 1H), 0.92 - 0.84 (m, 2H).

Example 188:

[0250] 

N-(6-Chloro-4-(cyclopropylsulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 498 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 10.56 (s, 1H), 9.16 (s, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 8.06 (dd, J = 9.0, 2.5 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.44 (dd, J = 5.2, 1.6 Hz, 1H), 3.29 (dd, J = 8.1, 4.7 Hz, 1H), 1.27 (p, J = 4.8 Hz, 2H), 1.17 (dt, J = 7.7, 3.7 Hz, 2H).

Example 182:

[0251] 

N-(4-(Propylsulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 466 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.57 (d, J = 8.4 Hz, 2H), 9.34 (d, J = 2.2 Hz, 1H), 8.78 (d, J = 5.0 Hz, 1H), 8.62 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.39 (s, 1H), 8.06 (dd, J = 8.8, 2.6 Hz, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.50 - 7.37 (m, 1H), 3.63 - 3.49 (m, 2H), 1.61 (q, J = 7.7 Hz, 2H), 0.92 (td, J = 7.2, 2.2 Hz, 3H).

Example 184:

[0252] 

N-(4-((2,2,2-Trifluoroethyl)sulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 506 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.54 (s, 1H), 8.85 (d, J = 5.0 Hz, 1H), 8.77 (d, J = 2.9 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.29 (s, 1H), 8.14 - 8.01 (m, 2H), 7.89 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 4.38 (dd, J = 13.7, 9.8 Hz, 1H), 4.26 - 4.08 (m, 1H).

Example 185:

[0253] 

N-(4-(Isobutylsulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 480 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.57 (s, 1H), 9.28 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.61 (s, 1H), 8.53 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 5.5 Hz, 1H), 3.43 (d, J = 6.5 Hz, 2H), 2.21 - 2.01 (m, 1H), 1.13 - 0.89 (m, 6H).

Example 181:

[0254] 

N-(4-(Methylsulfonyl)pyridin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 438.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.60 (d, J = 4.2 Hz, 2H), 9.29 (s, 1H), 8.81 (d, J = 5.2 Hz, 1H), 8.67 - 8.61 (m, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.07 (dd, J = 8.9, 2.5 Hz, 1H), 7.96 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 5.0, 1.4 Hz, 1H), 3.45 (s, 3H).

Example 189:

[0255] 

N-(Pyrazin-2-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 361 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 11.40 (s, 1H), 10.51 (s, 1H), 9.44 (d, J = 1.4 Hz, 1H), 8.64 (s, 1H), 8.56 - 8.50 (m, 1H), 8.50 - 8.41 (m, 2H), 8.26 (s, 1H), 8.06 (dd, J = 8.9, 2.5 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 5.2, 1.4 Hz, 1H).

Synthesis of intermediate amine H:

[0256] 

6-(2-fluorophenyl)pyrazin-2-amine. In a 15 mL vial was 6-bromopyrazin-2-amine, (2-fluorophenyl)boronic acid (280 mg, 2.005 mmol), and Na2CO3 (1.879 mL, 3.76 mmol) in Dioxane (6 mL) to give a slightly tan solution under nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride,Toluene (51.5 mg, 0.063 mmol) was added under nitrogen. The vial was sealed and heated at 135°C for 2h. LCMS showed the desired product (M+H=190) as the major peak. The mixture was partitioned between water and EtOAc. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by FCC up to 60% EtOAc/hexane to afford the desired product (211 mg, 89%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J = 2.7 Hz, 1H), 7.93 (s, 1H), 7.88 (td, J = 7.8, 1.8 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.24 (td, J = 7.6, 1.0 Hz, 1H), 7.15 (ddd, J = 11.1, 8.3, 0.8 Hz, 1H), 4.99 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -114.88 (s).

Example 190:

[0257] 

N-(6-(2-Fluorophenyl)pyrazin-2-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 455 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.47 (s, 1H), 9.34 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.05 (dd, J = 9.0, 2.5 Hz, 1H), 8.00 (dd, J = 9.3, 3.5 Hz, 2H), 7.61 - 7.55 (m, 2H), 7.42 (dd, J = 13.6, 5.4 Hz, 2H).

Example 191:

[0258] 

N-(Pyrimidin-5-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 361 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.91 (s, 1H), 10.55 (s, 1H), 9.19 (s, 2H), 8.99 (s, 1H), 8.65 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), 8.07 (dd, J = 8.9, 2.4 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 5.2, 1.3 Hz, 1H).

Example 192:

[0259] 

N-(4-Bromopyrimidin-5-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 439 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.74 (s, 1H), 10.56 (s, 1H), 8.98 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 5.0 Hz, 1H).

General synthesis of amine I:

[0260] 

4-Phenylpyrimidin-5-amine. In a 50 mL flask was dissolved 4-bromopyrimidin-5-amine (279 mg, 1.60 mmol), phenylboronic acid (293 mg, 2.40 mmol), and Na₂CO₃ (2.4 mL, 4.8 mmol) in dioxane (5 mL) to give a tan solution under nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene (66.0 mg, 0.080 mmol) was added under nitrogen. The vial was sealed and heated in a microwave reactor at 100°C for 2 h. The mixture was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 80% ethyl acetate/hexane, to afford the desired product (47.6 mg, 17%) as a tan oil: ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.25 (s, 1H), 7.75 (s, 2H), 7.52 (s, 3H), 3.99 (s, 2H).

Example 193:

[0261] 

N-(4-Phenylpyrimidin-5-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 437 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.69 (s, 1H), 10.51 (s, 1H), 9.20 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.19 (s, 1H), 8.05 (dd, J = 8.9, 2.3 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.89 - 7.80 (m, 2H), 7.57 - 7.46 (m, 3H), 7.38 (d, J = 5.2 Hz, 1H).

Synthesis of amine J:

[0262] 

2-Chloro-5-nitro-4-(2,2,2-trifluoroethoxy)pyrimidine. MS (ESI) (m/z): 258 (M+H)⁺.

4-(2,2,2-Trifluoroethoxy)pyrimidin-5-amine. ¹H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 8.02 (s, 1H), 4.85 (q, J = 8.4 Hz, 2H), 3.89 (s, 2H); ¹⁹F NMR (376 MHz, Chloroform-d) δ -73.77.

Example 194:

[0263] 

N-(4-(2,2,2-Trifluoroethoxy)pyrimidin-5-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 459 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 10.41 (s, 1H), 8.89 (s, 1H), 8.79 (s, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.27 (s, 1H), 8.06 (dd, J = 9.0, 2.6 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.43 (dd, J = 5.0, 1.5 Hz, 1H), 5.19 (q, J = 8.9 Hz, 2H).

Synthesis of amine K:

[0264] 

4-(2-Chloro-5-nitropyrimidin-4-yl)morpholine. MS (ESI) (m/z): 245 (M+H)⁺.

4-Morpholinopyrimidin-5-amine. MS (ESI) (m/z): 181 (M+H)⁺; ¹H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 1H), 7.94 (s, 1H), 3.90 - 3.81 (m, 4H), 3.54 (s, 2H), 3.41 - 3.33 (m, 4H).

Example 195:

[0265] 

N-(4-Morpholinopyrimidin-5-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 446 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 10.38 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.55 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.07 (dd, J = 8.9, 2.6 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 5.2, 1.5 Hz, 1H), 3.66 (s, 8H).

Example 196:

[0266] 

N-(Pyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 361 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 10.57 (s, 1H), 9.53 (d, J = 2.0 Hz, 1H), 9.14 (d, J = 5.8 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 8.12 (dd, J = 5.9, 2.7 Hz, 1H), 8.07 (dd, J = 8.9, 2.5 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.48 (dd, J = 5.2, 1.4 Hz, 1H).

Synthesis of amine L:

[0267] 

5-Bromopyridazin-4-amine: To a solution of pyridazin-4-amine (1.18 g, 12.41 mmol) in Acetic Acid (2.5 mL) was added dibromine (0.638 mL, 12.41 mmol)dropwise at rt in a water bath. After 1 h, 10 N NaOH was added and then extracted with dichloromethane (3x). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in a small amount of dichloromethane and charged to a 40 g silica gel cartridge which was eluted with 0-15% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 3-bromopyridazin-4-amine (0.1 g, 0.575 mmol, 4.63 % yield)(first eluting) and 5-bromopyridazin-4-amine (0.12 g, 0.690 mmol, 5.56 % yield)(second eluting). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.75 (s, 1 H) 8.55 (s, 1 H) 6.72 - 6.79 (m, 2 H).

tert-Butyl (5-bromopyridazin-4-yl)carbamate. To 5-bromopyridazin-4-amine (0.1 g, 0.575 mmol) and TRIETHYLAMINE (0.104 mL, 0.747 mmol)in DCM (2 mL) at 0 °C. The solution was stirred at rt for 10 mins then BOC2O (0.147 mL, 0.632 mmol) was added. The reaction was stirred at rt for 1 hr. The reaction was diluted with DCM and washed with brine, and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 24 g silica gel cartridge which was eluted with 0-10% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give tert-butyl (5-bromopyridazin-4-yl)carbamate (0.12 g, 0.438 mmol, 76 % yield). MS (ESI) (m/z): 276 (M+H)⁺.

5-(4-(Allyloxy)phenyl)pyridazin-4-amine hydrochloride. A mixture of tert-butyl (5-bromopyridazin-4-yl)carbamate (0.05 g, 0.182 mmol), (4-(allyloxy)phenyl)boronic acid (0.032 g, 0.182 mmol), (PdCl2(dppf)-CH2Cl2Adduct (0.030 g, 0.036 mmol) in a microwave vial was flushed and degassed with N2. Na2CO3, 2M (0.182 ml, 0.365 mmol) followed by Dioxane (2 ml) was added and then microwave vial was flushed and degassed with N2. The resulting mixture was heated to 100°C at reflux for 4h.
Satd ammonium chloride and ethyl acetate was added. The org layer was separated and washed with water and brine and dried over sodium sulfate. The crude product was dissolved in a small amount of dichloromethane and charged to a 80 g silica gel cartridge which was eluted with 0-15% dichloromethane / methanol over a period of 50 mins. The desired fractions were combined and dried under vacuo to give desired prod intermediate. To the intermediate was added HCl, 4 M dioxane (1 ml, 4.00 mmol) and ethyl acetate (0.5 mL) and stirred overnight. After solvent was removed, the residue was dried under to give the desired prod. MS (ESI) (m/z): 228.1 (M+H)⁺.

Example 197:

[0268] 

N-(5-Bromopyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 441 (M+H)⁺; ¹H NMR (500 MHz, DMSO) δ 10.47 (s, 1 H) 9.56 (s, 1 H) 9.38 (s, 1 H) 8.61 (s, 1 H) 8.47 (d, J=5.19 Hz, 1 H) 8.28 (s, 1 H) 8.04 (d, J=8.54 Hz, 1 H) 7.93 (d, J=9.16 Hz, 1 H) 7.51 (d, J=5.49 Hz, 1 H).

Example 199:

[0269] 

N-(5-(4-(Allyloxy)phenyl)pyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 493.5 (M+H)⁺; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 9.86 (s, 1 H) 9.10 (s, 1 H) 8.40 - 8.44 (m, 2 H) 8.24 (s, 1 H) 7.86 (dd, J=9.03, 2.26 Hz, 1 H) 7.69 (s, 1 H) 7.52 - 7.62 (m, 4 H) 7.29 (dd, J=5.27, 1.51 Hz, 1 H) 7.02 - 7.15 (m, 2 H) 6.02 (ddt, J=17.32, 10.54, 5.27, 5.27 Hz, 1 H) 5.33 - 5.45 (m, 1 H) 5.26 (dq, J=10.54, 1.42 Hz, 1 H) 4.57 (dt, J=5.27, 1.51 Hz, 2 H).

Example 198:

[0270] 

N-(5-Phenylpyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: To N-(5-bromopyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (0.084 g, 0.191 mmol)and phenylboronic acid (0.026 g, 0.210 mmol) was added DMF (3mL). The reaction was stirred at rt until solids are dissolved then PdCl2(dppf)-CH2Cl2Adduct (0.016 g, 0.019 mmol)was added. The flask was degassed and flushed with nitrogen and then Na2CO3, 2M (0.143 mL, 0.287 mmol) was added dropwise. The flask was degassed and flushed with nitrogen and then reaction vessel was sealed and then heated at 100 °C for 2.5 hrs. The reaction was diluted with ethyl acetate and satd ammonium chloride. The org layer was washed with water, brine and dried over sodium sulfate. The crude residue purified by prep LCMS to give desired product. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.61 (br. s., 1 H) 10.48 (s, 1 H) 9.53 (s, 1 H) 9.25 (s, 1 H) 8.58 (br. s., 1 H) 8.45 (d, J=5.19 Hz, 1 H) 8.16 (s, 1 H) 8.04 (d, J=8.85 Hz, 1 H) 7.86 (d, J=8.85 Hz, 1 H) 7.65 (d, J=7.63 Hz, 2 H) 7.43 - 7.58 (m, 3 H) 7.32 (d, J=5.19 Hz, 1 H). MS (ESI) (m/z): 437.3 (M+H)⁺.

Synthesis of amine M:

[0271] 

N-(Pyridazin-4-yl)pivalamide: This compound was prepared as reported in literature (Haider, N. and Schuller, H. J. Heterocyclic Chemistry 1995, 32, 841) and showed the reported spectral characteristics.

N-(5-Acetylpyridazin-4-yl)pivalamide: To 10mL of anhydrous THF under argon at -40 °C (dry ice - MeCN bath) was added n-BuLi (1.6M, 3 mL). To this was added dropwise 2,2,6,6-Tetramethylpiperidine (0.682g, 4.83 mmol) via a syringe with stirring. After addition the pale yellow solution was warmed up to 0 °C in about 10 min and then allowed to stir at this temperature for another 25 min. At the end, the yellow solution was cooled down in a dry ice-2-propanol bath. N-(Pyridazin-4-yl)pivalamide (214 mg, 1.194 mmol) was dissolved in 7 mL anhydrous THF and the solution was added dropwise via syringe to the LiTMP generated during 5 min. The dark solution was stirred at -77 °C for 2h. At the end N-methoxy-N-methylacetamide (0.51 mL, 4.8 mmol) was added in a thin stream in 3 min to the reaction mixture and the reaction was continued at the same temperature. After 2h a mixture of 4.8 mL of 1N HCl and 4.8 mL of ethanol were added to the reaction mixture and the pale brown suspension was stirred for 10 min at -77 °C and then stored at -22 °C for ∼18h. The reaction mixture was brought up to ambient temperature. Volatiles were evaporated in vacuo. The residue taken in 60 mL EtOAC was washed with satd. aq. NaHCO3 (40 mL) and then with water (2 x 50 mL). Organic layer was dried (Na2SO4) and evaporated in vacuo to give the crude product (206 mg, 87% pure, 78% yield). The crude product thus obtained was purified by prep HPLC (Waters XTERRA 30 x 200 mm, A=90% H₂O/10% MeOH, B=90% MeOH/10% H₂O, Modifier 0.1% TFA, 0.00 min = 20% B, 15 min = 100% B, 20.0 min = 100% B, Flow rate = 40 mL/min.). Fractions corresponding to the peak with t_R = 9.5 min were combined and evaporated in vacuo to give the required product as the TFA salt (215 mg, 54%): MS (ESI) (m/z): 222 (M+H)⁺; ¹H NMR (400MHz, METHANOL-d₄) δ 10.59 (s, 1H), 9.73 (s, 1H), 2.82 (s, 3H), 1.39 (s, 9H).

N-(5-(Cyclopropanecarbonyl)pyridazin-4-yl)pivalamide: This compound was prepared in 31 % yield and isolated after purification as TFA salt from N-(Pyridazin-4-yl)pivalamide (214 mg, 1.194 mmol) following the same procedure used for the synthsis of N-(5-Acetylpyridazin-4-yl)pivalamide. LC-MS (Phenomenex C18 (3 um) 2 x 50 mm, A=90% H₂O/10% MeOH, B=90% MeOH/10% H₂O, Modifier 0.1% TFA, 0.00 min = 0% B, 4.0 min = 100% B, 5.0 min = 100% B, Flow rate = 0.8 mL/min) t_R = 3.2 min, MS (ESI) (m/z): 248 (M+H)⁺; ¹H NMR (400MHz, METHANOL-d₄) δ 10.59 (s, 1H), 9.97 (s, 1H), 3.08 - 2.90 (m, 1H), 1.40 - 1.31 (m, 13H).

1-(5-Aminopyridazin-4-yl)ethanone: An amber colored solution of pivalamide (215 mg, 0.56 mmol) in a mixture of EtOH (1.5 mL) and water (0.62 mL) was combined with hydrochloric acid (0.93 mL, 11.2 mmol) and was refluxed for ∼18h. At the end, the ethanol was evaporated in vacuo and the remaining aq. solution was carefully basified with conc. NH4OH and then evaporated in vacuo. The residue was triturated with MeOH : DCM (1 :9, 15 mL) and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography on a biotage 12 g silica gel cartridge using a linear gradient of dichloromethane to 10% MeOH in dichloromethane. Fractions were pooled and evaporated in vacuo to give 56 mg (73% yield) of the aminopyridazine derivative: MS (ESI) (m/z): 138 (M+H)⁺; ¹H NMR (400MHz, METHANOL-d₄) δ 9.00 (s, 1H), 8.72 (s, 1H), 2.62 (s, 3H).

(5-Aminopyridazin-4-yl)(cyclopropyl)methanone: tert-Butyl pyridazin-4-ylcarbamate (98 mg, 0.37mmol) was dissolved in 20% TFA in DCM (7 mL) and stored at ambient temperature overnight. After ∼19h volatiles were evaporated, the residue coevaporated with DCM (15 mL) and then dried in vacuo. The crude product thus obtained was dissolved in 15 mL ethanol and stirred with BioRad AG-X2 resin (100 - 200 mesh, 2- 2.5 mequiv /g) hydroxide form (2.4 g wet resin, ∼30% water). After stirring for 10 min, the suspension was filtered, washed with 30 mL more ethanol. The solution of the free base thus obtained was evaporated in vacuo to dryness to give the desired product (71.3 mg, 83% purity, 97% yield). LC-MS (Phenomenex C18 2 x 50 mm (3 um) A=95% H₂O/5% ACN, B=95% ACN/5% H₂O, Modifier 10 mM NH₄OAc, 0.00 min = 0% B, 4 min = 100 % B 5min = 100%B, Flow rate = 0.8 mL/min) t_R = 1.6 min, MS (ESI) (m/z): 164 (M+H)⁺.

5-(2-(3-Chloropropyl)-1,3-dioxolan-2-yl)pyridazin-4-amine: Hydrolysis of N-(5-(Cyclopropanecarbonyl)pyridazin-4-yl)pivalamide was carried out on 146 mg scale using conditions similar to the hydrolysis of N-(5-Acetylpyridazin-4-yl)pivalamide. The crude product was purified by silica gel chromatography on a biotage 12 g silica gel cartridge using a linear gradient of dichloromethane to 10% MeOH in dichloromethane. The major product isolated was: 1-(5-aminopyridazin-4-yl)-4-chlorobutan-1-one (85 mg, 87% pure, 41% yield). MS (ESI) (m/z): 200, 202 (Cl pattern) (M+H)⁺. ¹H NMR (400MHz, METHANOL-d₄) δ 9.04 (s, 1H), 8.73 (s, 1H), 3.70 (t, J=6.6 Hz, 2H), 3.23 (t, J=7.0 Hz, 2H), 2.19 (m, 2H). This product was ketalized with ethylene glycol using the literature procedure (Fieser, L.F. and Stevenson, R. JACS 1954, 76, 1728-1733) with the exception that dichloroethane was used as solvent intstead of acetic acid: MS (ESI) (m/z): 244 (M+H)⁺; ¹H NMR (400MHz, METHANOL-d₄) δ 8.53 (s, 1H), 8.51 (s, 1H), 4.19 - 4.08 (m, 2H), 3.89 - 3.84 (m, 2H), 3.60 (t, J=6.6 Hz, 2H), 2.11 - 2.05 (m, 2H), 1.94 - 1.85 (m, 2H).

5-(2-Methyl-1,3-dioxolan-2-yl)pyridazin-4-amine: This compound was prepared in 64% yield on a 16 mg scale following the BF₃ etherate method for ketalization that was described before. MS (ESI) (m/z): 182 (M+H)⁺; ¹H NMR (400MHz, METHANOL-d₄) δ 8.54 (s, 1H), 8.53 (s, 1H), 4.20 - 4.03 (m, 2H), 3.90 - 3.74 (m, 2H), 1.64 (s, 3H).

1-(5-Aminopyridazin-4-yl)-1-cyclopropylethanol. MS (ESI) (m/z): 180 (M+H)⁺; ¹H NMR (400MHz, METHANOL-d₄) δ 8.69 (s, 1H), 8.48 (s, 1H), 1.51 (s, 3H), 1.42 - 1.33 (m, 1H), 0.70 - 0.40 (m, 4H).

Example 200:

[0272] 

N-(5-(2-Methyl-1,3-dioxolan-2-yl)pyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 447 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.66 (s, 1H), 10.34 (s, 1H), 10.15 (s, 1H), 9.14 (s, 1H), 8.62 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.37 (d, J=5.2 Hz, 1H), 4.19 - 4.13 (m, 2H), 3.92 - 3.87(m, 2H), 1.72(s, 3H).

Example 201:

[0273] 

N-(5-(2-(3-Chloropropyl)-1,3-dioxolan-2-yl)pyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 509 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 10.67 (s, 1H), 10.28 (br. s., 1H), 10.17 (s, 1H), 9.11 (s, 1H), 8.63 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.42 (s, 1H), 8.08 (dd, J=8.8, 2.3 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.39 (dd, J=5.1, 1.5 Hz, 1H), 4.25 - 4.12 (m, 2H), 4.02 - 3.86 (m, 2H), 3.63 (t, J=6.6 Hz, 2H), 2.23 - 2.07 (m, 2H), 1.87 - 1.73 (m, 2H).

Example 202:

[0274] 

N-(5-(Cyclopropanecarbonyl)pyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. LC-MS (Phenomenex C18 (3 um) 2 x 50 mm, A=90% H₂O/10% MeOH, B=90% MeOH/10% H₂O, Modifier 0.1% TFA, 0.00 min = 0% B, 4.0 min = 100% B, 5.0 min = 100% B, Flow rate = 0.8 mL/min.) t_R = 3.3 min, MS (ESI) (m/z): 429 (M+H)⁺.

Example 203:

[0275] 

N-(5-(1-Cyclopropyl-1-hydroxyethyl)pyridazin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 445 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.73 (br. s., 1H), 10.60 (s, 1H), 10.24 (s, 1H), 9.25 (s, 1H), 8.64 (s, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 8.06 (dd, J=9.0, 2.3 Hz, 1H), 7.81 (d, J=9.2 Hz, 1H), 7.34 (dd, J=5.2, 1.2 Hz, 1H), 1.58 (s, 3H), 1.48 - 1.41 (m, 1H), 0.61 - 0.40 (m, 4H).

Synthesis of amine N:

[0276] 

4-Nitro-5-phenylisothiazole. In a 15 mL vial was 5-bromo-4-nitroisothiazole (220 mg, 1.053 mmol), phenylboronic acid (205 mg, 1.684 mmol), and Na2CO3 (1.579 mL, 3.16 mmol) in Dioxane (3 mL) to give a slightly yellow solution under nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride,Toluene (43.3 mg, 0.053 mmol) was added under nitrogen. The vial was sealed and heated at 130°C (microwave) for 2h. LCMS showed a major new peak but no parent ion. TLC (3/1hexane/EtOAc) showed the same spot as SM. The mixture was partitioned between water and EtOAc. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified by FCC up to 30% EtOAc/hexane to afford the desired product (147 mg, 68%) as a light yellow solid: ¹H NMR (400 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.64 - 7.46 (m, 5H); ¹³C NMR (101 MHz, Chloroform-d) δ 166.95, 154.54, 141.23, 130.69, 128.83, 128.56, 126.10.

5-Phenylisothiazol-4-amine. In a 100 mL round-bottomed flask was 4-nitro-5-phenylisothiazole (147 mg, 0.713 mmol) (94149-042) in MeOH (4 mL) to give a light yellow solution. Pd/C (76 mg, 0.071 mmol) was added, and the mixture was stirred overnight under 1 atom hydrogen (balloon) (2:30pm). After 18h, LCMS showed complete conversion to the desired product (119mg, 95%) as a tan solid: ¹H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.60 - 7.44 (m, 4H), 7.41 - 7.32 (m, 1H), 3.85 (s, 2H); ¹³C NMR (101 MHz, Chloroform-d) δ 150.87, 139.30, 138.42, 130.39, 129.01, 127.89, 127.13.

Example 204:

[0277] 

N-(5-Phenylisothiazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 442 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.51 (s, 1H), 8.78 (s, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.24 (s, 1H), 8.06 (dd, J = 9.0, 2.6 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.59 - 7.52 (m, 2H), 7.52 - 7.46 (m, 1H), 7.44 (dd, J = 5.2, 1.5 Hz, 1H).

Example 205:

[0278] 

N-(5-Phenyl-1H-pyrazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 425.3 (M+H)⁺.

Synthesis of amine P:

[0279] 

1-(4-Amino-1-methyl-1H-pyrazol-5-yl)ethanone. In a 250 mL round-bottomed flask was 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)ethanone (77.8 mg, 0.460 mmol) and Pd/C (49.0 mg, 0.046 mmol) in MeOH (4 mL) to give a black suspension. The mixture was stirred under 1 atm hydrogen (balloon) for 1 h. LCMS showed good conversion to the desired product (M + H = 140.1). It was filtered, washed with MeOH and concentrated to the desired product (63.1 mg, 99%) as a a gray solid.

1-Methyl-5-(2-methyl-1,3-dioxolan-2-yl)-4-nitro-1H-pyrazole. In a 100 mL round-bottomed flask was 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)ethanone (340 mg, 2.010 mmol), Ts-OH (191 mg, 1.005 mmol), and Glycol (500 µl, 8.97 mmol) in Toluene (10 mL) to give a colorless suspension. The mixture was heated at 110°C for 2h. TLC (1/1 EtOAc/hexane) showed around 1/3 conversion to a slightly more polar spot. The reaction continued for another 18 h. TLC showed a little SM left. It was concentrated in vacuo and the residue was purified by FCC up to 70% EtOAc/hexane to afford the desired product (339 mg, 79%) as a white solid: ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 4.16 - 4.10 (m, 2H), 4.06 (s, 3H), 3.84 - 3.78 (m, 2H), 1.92 (s, 3H). 55 mg (16%) starting material was also recovered.

1-Methyl-5-(2-methyl-1,3-dioxolan-2-yl)-1H-pyrazol-4-amine. In a 250 mL round-bottomed flask was 1-methyl-5-(2-methyl-1,3-dioxolan-2-yl)-4-nitro-1H-pyrazole (226 mg, 1.060 mmol) and Pd/C (113 mg, 0.106 mmol) in MeOH (6 mL) to give a black suspension. The mixture was stirred under 1 atm hydrogen (balloon) for 2 h. LCMS showed complete conversion. It was filtered, washed with MeOH and concentrated to the desired product (194 mg, 100%) as a tan solid: ¹H NMR (400 MHz, Chloroform-d) δ 6.92 (s, 1H), 4.01 (tt, J = 5.9, 2.6 Hz, 2H), 3.80 (dd, J = 5.8, 2.1 Hz, 2H), 3.77 (s, 3H), 3.37 (s, 2H), 1.62 (s, 3H).

Example 206:

[0280] 

N-(5-Acetyl-1-methyl-1H-pyrazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. MS (ESI) (m/z): 405 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.48 (s, 1H), 8.63 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.32 (s, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 4.08 (s, 3H), 2.58 (s, 3H).

Example 207:

[0281] 

N-(1-Methyl-5-(2-methyl-1,3-dioxolan-2-yl)-1H-pyrazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: MS (ESI) (m/z): 449 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.52 (s, 1H), 8.64 - 8.56 (m, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.23 (s, 1H), 8.04 (dd, J = 8.9, 2.6 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.78 (s, 1H), 7.33 (dd, J = 5.2, 1.6 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.88 (s, 3H), 3.85 - 3.78 (m, 2H), 1.73 (s, 3H).

Example 208:

[0282] 

N-(5-(1-Hydroxyethyl)-1-methyl-1H-pyrazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: In a 5 mL vial was N-(5-acetyl-1-methyl-1H-pyrazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (21.6 mg, 0.053 mmol) in MeOH (0.5 mL) to give a yellow suspension. NaBH4 (8.08 mg, 0.214 mmol) was added. The vial was sealed and the mixture was stirred at rt for 110 min. LCMS showed good conversion to the desired product. The suspension was dissolved in DMF and purified by prep-HPLC (10 mg, 45%): MS (ESI) (m/z): 407 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.89 (s, 1H), 8.63 (s, 1H), 8.46 (t, J = 5.1 Hz, 1H), 8.24 (d, J = 4.5 Hz, 1H), 8.10 - 8.02 (m, 1H), 7.96 - 7.86 (m, 1H), 7.64 (d, J = 4.7 Hz, 1H), 7.37 (d, J = 5.6 Hz, 1H), 5.72 (t, J = 4.4 Hz, 1H), 5.07 (dd, J = 7.4, 4.2 Hz, 1H), 3.87 (s, 3H), 1.46 (d, J = 6.2 Hz, 3H).

Example 209:

[0283] 

N-(5-(1-Cyclopropyl-1-hydroxyethyl)-1-methyl-1H-pyrazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: In a 5 mL vial was N-(5-acetyl-1-methyl-1H-pyrazol-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide (28.4 mg, 0.070 mmol) in Tetrahydrofuran (0.3 mL) to give a yellow suspension. Cyclopropylmagnesium bromide (0.421 mL, 0.211 mmol) was added. The vial was sealed and the resulted red solution was stirred at rt. After 30 min, LCMS showed 30∼40% conversion to the desired product (M+H = 447.0). Another 1 equiv. of cyclopropylmagnesium bromide was added and the reaction continued. After 3 h, LCMS showed very little improvement. The reaction mixture was diluted with EtOAc and quenched with 3 ml 0.5 N HCl. The layers were separated. The organic layer was washed with water, brine, dried and concentrated to a tan oil, which was dissolved in DMF/MeOH and purified by prep-HPLC: (7.1 mg, 22%, 8.3 mg SM recovered: 51% bosm): MS (ESI) (m/z): 447 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 10.07 (s, 1H), 8.68 - 8.57 (m, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), 8.06 (dd, J = 9.1, 2.7 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.31 (d, J = 5.2 Hz, 1H), 5.68 (s, 1H), 3.97 (s, 3H), 1.57 (s, 3H), 1.42 (dd, J = 9.7, 4.3 Hz, 1H), 0.52 (ddq, J = 13.0, 8.9, 4.1 Hz, 2H), 0.43 (dd, J = 8.9, 4.3 Hz, 1H), 0.39-0.32 (m, 1H).

Example 210:

[0284] 

N-(Imidazo[1,2-b]pyridazin-3-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)isonicotinamide: Followed synthesis of example 4. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.90 (br. s., 1 H) 10.50 (s, 1 H) 8.62 (s, 1 H) 8.58 - 8.60 (m, 1 H) 8.51 (d, J=5.19 Hz, 1 H) 8.27 (s, 1 H) 8.17 (d, J=9.46 Hz, 1 H) 8.03 - 8.08 (m, 1 H) 7.94 (d, J=8.85 Hz, 1 H) 7.92 (s, 1 H) 7.53 (d, J=5.19 Hz, 1 H) 7.28 (dd, J=9.16, 4.27 Hz, 1 H). MS (ESI) (m/z): 400.2 (M+H)⁺.

Claims

1. A compound of formula I

where:

R¹ is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;

R² is hydrogen, cyano, halo, alkyl, cyanoalkyl, haloalkyl, cycloalkyl, cyanocycloalkyl, (alkoxycarbonyl)alkenyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylsulfinyl, cycloalkylsulfinyl, phenylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, morpholinyl, SO₂N(R⁴)(R⁵);

R³ is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R² and R³ taken together is -CH=CH-CH=CH-;

R⁴ is hydrogen or alkyl;

R⁵ is hydrogen or alkyl;

or N(R⁴)(R⁵) taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and is substituted with 0-4 halo or alkyl substituents;

Ar¹ is 3-pyridinyl, 2-pyrazinyl, 4-pyridazinyl, 4-pyrimidinyl, 4-pyrazolyl, 4-isothiazolyl, or 3-imidazo[1,2-b]pyridazinyl, and is substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, (dicycloalkyl)hydroxyalkyl, (hydroxy)haloalkyl, alkoxyalkyl, (N(R⁴)(R⁵))alkyl, cycloalkyl, hydroxycycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, ((alkyl)cycloalkyl)alkoxy, alkylcarbonyl, cycloalkylcarbonyl, tetrahydrofuranyl, (alkyl)tetrahydrofuranyl, dioxolanyl, (alkyl)dioxolanyl, (cycloalkyl)dioxolanyl, (phenyl)dioxolanyl, (dialkyl)dioxolanyl, (haloalkyl)(alkyl)dioxolanyl, (trialkyl)dioxolanyl, dihydrpyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, N(R⁴)(R⁵), and Ar²; and is also substituted with 0-1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

Ar² is phenyl, pyridinyl, or pyrazolyl, and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 where R¹ is hydrogen or halo.

3. A compound of claim 1 or 2 where R² is haloalkyl.

4. A compound of any one of claims 1 to 3 where Ar¹ is 3-pyridinyl substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, (dicycloalkyl)hydroxyalkyl, (hydroxy)haloalkyl, alkoxyalkyl, (N(R⁴)(R⁵))alkyl, cycloalkyl, hydroxycycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, ((alkyl)cycloalkyl)alkoxy, alkylcarbonyl, cycloalkylcarbonyl, tetrahydrofuranyl, (alkyl)tetrahydrofuranyl, dioxolanyl, (alkyl)dioxolanyl, (cycloalkyl)dioxolanyl, (phenyl)dioxolanyl, (dialkyl)dioxolanyl, (haloalkyl)(alkyl)dioxolanyl, (trialkyl)dioxolanyl, dihydrpyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, N(R⁴)(R⁵), and Ar²; and is also substituted with 0-1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

5. A compound of any one of claims 1 to 4 where Ar² is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

6. A pharmaceutical composition comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

7. A compound of any one of claims 1 to 5 for use in a method for the treatment of a condition selected from the group consisting of Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, Huntington's disease, peripheral neuropathy, traumatic brain injury, spinal cord trauma, and vascular dementia.

8. The compound for the use of claim 7, wherein the condition is Alzheimer's disease.

Ansprüche

1. Verbindung der Formel I

wobei:

R¹ Wasserstoff, Cyano, Halo, Alkyl, Haloalkyl, Alkoxy oder Haloalkoxy ist;

R² Wasserstoff, Cyano, Halo, Alkyl, Cyanoalkyl, Haloalkyl, Cycloalkyl, Cyanocycloalkyl, (Alkoxycarbonyl)alkenyl, Alkoxy, Haloalkoxy, Alkylthio, Haloalkylthio, Cycloalkylthio, Alkylcarbonyl, Alkoxycarbonyl, Aminocarbonyl, Alkylsulfinyl, Cycloalkylsulfinyl, Phenylsulfinyl, Alkylsulfonyl, Haloalkylsulfonyl, Cycloalkylsulfonyl, Alkylcarbonylamino, Morpholinyl, SO₂N(R⁴)(R⁵) ist;

R³ Wasserstoff, Cyano, Halo, Alkyl, Haloalkyl, Alkoxy oder Haloalkoxy ist;

oder R² und R³ zusammen genommen -CH=CH-CH=CH- sind;

R⁴ Wasserstoff oder Alkyl ist;

R⁵ Wasserstoff oder Alkyl ist;

oder N(R⁴)(R⁵) zusammen genommen Azetidinyl, Pyrrolidinyl, Piperidinyl, Piperazinyl, Morpholinyl ist und mit 0-4 Halo- oder Alkylsubstituenten substituiert ist;

Ar¹ 3-Pyridinyl, 2-Pyrazinyl, 4-Pyridazinyl, 4-Pyrimidinyl, 4-Pyrazolyl, 4-Isothiazolyl oder 3-Imidazo[1,2-b]pyridazinyl ist und mit 1 Substituent substituiert ist, ausgewählt aus Wasserstoff, Cyano, Halo, Alkyl, Haloalkyl, Hydroxyalkyl, (Cycloalkyl)hydroxyalkyl, (Dicycloalkyl)hydroxyalkyl, (Hydroxy)haloalkyl, Alkoxyalkyl, (N(R⁴)(R⁵))Alkyl, Cycloalkyl, Hydroxycycloalkyl, Cycloalkenyl, Alkoxy, Haloalkoxy, (Cycloalkyl)alkoxy, ((Alkyl)cycloalkyl)alkoxy, Alkylcarbonyl, Cycloalkylcarbonyl, Tetrahydrofuranyl, (Alkyl)tetrahydrofuranyl, Dioxolanyl, (Alkyl)dioxolanyl, (Cycloalkyl)dioxolanyl, (Phenyl)dioxolanyl, (Dialkyl)dioxolanyl, (Haloalkyl)(alkyl)dioxolanyl, (Trialkyl)dioxolanyl, Dihydropyranyl, Tetrahydropyranyl, Hydroxytetrahydropyranyl, N(R⁴)(R⁵) und Ar²; und außerdem mit 0-1 Substituent substituiert ist, ausgewählt aus Wasserstoff, Cyano, Halo, Alkyl, Haloalkyl, Alkoxy und Haloalkoxy;

Ar² Phenyl, Pyridinyl oder Pyrazolyl ist und mit 0-3 Substituenten substituiert ist, ausgewählt aus Cyano, Halo, Alkyl, Haloalkyl, Alkoxy und Haloalkoxy;

oder ein pharmazeutisch verträgliches Salz davon.

2. Verbindung nach Anspruch 1, wobei R¹ Wasserstoff oder Halo ist.

3. Verbindung nach Anspruch 1 oder 2, wobei R² Haloalkyl ist.

4. Verbindung nach einem der Ansprüche 1 bis 3, wobei Ar¹ 3-Pyridinyl ist, substituiert mit 1 Substituenten, ausgewählt aus Wasserstoff, Cyano, Halo, Alkyl, Haloalkyl, Hydroxyalkyl, (Cycloalkyl)hydroxyalkyl, (Dicycloalkyl)hydroxyalkyl, (Hydroxy)haloalkyl, Alkoxyalkyl, (N(R⁴)(R⁵))Alkyl, Cycloalkyl, Hydroxycycloalkyl, Cycloalkenyl, Alkoxy, Haloalkoxy, (Cycloalkyl)alkoxy, ((Alkyl)cycloalkyl)alkoxy, Alkylcarbonyl, Cycloalkylcarbonyl, Tetrahydrofuranyl, (Alkyl)tetrahydrofuranyl, Dioxolanyl, (Alkyl)dioxolanyl, (Cycloalkyl)dioxolanyl, (Phenyl)dioxolanyl, (Dialkyl)dioxolanyl, (Haloalkyl)(alkyl)dioxolanyl, (Trialkyl)dioxolanyl, Dihydropyranyl, Tetrahydropyranyl, Hydroxytetrahydropyranyl, N(R⁴)(R⁵) und Ar²; und außerdem mit 0-1 Substituenten substituiert ist, ausgewählt aus Wasserstoff, Cyano, Halo, Alkyl, Haloalkyl, Alkoxy und Haloalkoxy.

5. Verbindung nach einem der Ansprüche 1 bis 4, wobei Ar² Phenyl ist, substituiert mit 0-3 Substituenten, ausgewählt aus Cyano, Halo, Alkyl, Haloalkyl, Alkoxy und Haloalkoxy.

6. Pharmazeutische Zusammensetzung, umfassend eine Verbindung nach einem der Ansprüche 1 bis 5 oder ein pharmazeutisch verträgliches Salz davon und einen pharmazeutisch verträglichen Träger.

7. Verbindung nach einem der Ansprüche 1 bis 5, zur Verwendung in einem Verfahren zur Behandlung eines Zustands, ausgewählt aus Alzheimer-Krankheit, frontotemporaler Demenz, progressiver supranukleärer Lähmung, argyrophiler Kornerkrankung, kortikobasaler Degeneration, Pick'scher Erkrankung, Parkinson-Krankheit, amyotropher Lateralsklerose, Schlaganfall, Huntington-Erkrankung, peripherer Neuropathie, traumatischer Hirnverletzung, Rückenmarktrauma und vaskulärer Demenz.

8. Verbindung zur Verwendung nach Anspruch 7, wobei der Zustand Alzheimer-Krankheit ist.

Revendications

1. Composé de formule I

dans laquelle:

R¹ est hydrogène, cyano, halogéno, alkyle, halogénoalkyle, alcoxy ou halogénoalcoxy;

R² est hydrogène, cyano, halogéno, alkyle, cyanoalkyle, halogénoalkyle, cycloalkyle, cyanocycloalkyle, (alcoxycarbonyl)alcényle, alcoxy, halogénoalcoxy, alkylthio, halogénoalkylthio, cycloalkylthio, alkylcarbonyle, alcoxycarbonyle, aminocarbonyle, alkylsulfinyle, cycloalkylsulfinyle, phénylsulfinyle, alkylsulfonyle, halogénoalkylsulfonyle, cycloalkylsulfonyle, alkylcarbonylamino, morpholinyle, SO₂N(R⁴)(R⁵);

R³ est hydrogène, cyano, halogéno, alkyle, halogénoalkyle, alcoxy ou halogénoalcoxy;

ou R² et R³ pris ensemble sont -CH=CH-CH=CH-;

R⁴ est hydrogène ou alkyle;

R⁵ est hydrogène ou alkyle;

ou N(R⁴)(R⁵) pris ensemble est azétidinyle, pyrrolidinyle, pipéridinyle, pipérazinyle, morpholinyle, et est substitué par 0 à 4 substituants halogéno ou alkyle;

Ar¹ est 3-pyridinyle, 2-pyrazinyle, 4-pyridazinyle, 4-pyrimidinyle, 4-pyrazolyle, 4-isothiazolyle ou 3-imido[1,2-b]pyridazinyle, et est substitué par 1 substituant choisi parmi hydrogène, cyano, halogéno, alkyle, halogénoalkyle, hydroxyalkyle, (cycloalkyl)hydroxyalkyle, (dicycloalkyl)hydroxyalkyle, (hydroxy)halogénoalkyle, alcoxyalkyle, (N(R⁴)(R⁵))alkyle, cycloalkyle, hydroxycycloalkyle, cycloalcényle, alcoxy, halogénoalcoxy, (cycloalkyl)alcoxy, ((alkyl)cycloalkyl)alcoxy, alkylcarbonyle, cycloalkylcarbonyle, tétrahydrofuranyle, (alkyl)tétrahydrofuranyle, dioxolanyle, (alkyl)dioxolanyle, (cycloalkyl)dioxolanyle, (phényl)dioxolanyle, (dialkyl)dioxolanyle, (halogénoalkyl)(alkyl)dioxolanyle, (trialkyl)dioxolanyle, dihydropyranyle, tétrahydropyranyle, hydroxytétrahydropyranyle, N(R⁴)(R⁵) et Ar²; et est aussi substitué par 0 à 1 substituant choisi parmi hydrogène, cyano, halogéno, alkyle, halogénoalkyle, alcoxy et halogénoalcoxy;

Ar² est phényle, pyridinyle ou pyrazolyle, et est substitué par 0 à 3 substituants choisis dans le groupe constitué par cyano, halogéno, alkyle, halogénoalkyle, alcoxy et halogénoalcoxy;

ou sel pharmaceutiquement acceptable de celui-ci.

2. Composé selon la revendication 1, dans lequel R¹ est hydrogène ou halogéno.

3. Composé selon la revendication 1 ou 2, dans lequel R² est halogénoalkyle.

4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel Ar¹ est 3-pyridinyle substitué par 1 substituant choisi parmi hydrogène, cyano, halogéno, alkyle, halogénoalkyle, hydroxyalkyle, (cycloalkyl)hydroxyalkyle, (dicycloalkyl)hydroxyalkyle, (hydroxy)halogénoalkyle, alcoxyalkyle, (N(R⁴)(R⁵))alkyle, cycloalkyle, hydroxycycloalkyle, cycloalcényle, alcoxy, halogénoalcoxy, (cycloalkyl)alcoxy, ((alkyl)cycloalkyl)alcoxy, alkylcarbonyle, cycloalkylcarbonyle, tétrahydrofuranyle, (alkyl)tétrahydrofuranyle, dioxolanyle, (alkyl)dioxolanyle, (cycloalkyl)dioxolanyle, (phényl)dioxolanyle, (dialkyl)dioxolanyle, (halogénoalkyl)(alkyl)dioxolanyle, (trialkyl)dioxolanyle, dihydropyranyle, tétrahydropyranyle, hydroxytétrahydropyranyle, N(R⁴)(R⁵) et Ar²; et est aussi substitué par 0 à 1 substituant choisi parmi hydrogène, cyano, halogéno, alkyle, halogénoalkyle, alcoxy et halogénoalcoxy.

5. Composé selon l'une quelconque des revendications 1 à 4, dans lequel Ar² est phényle substitué par 0 à 3 substituants choisis dans le groupe constitué par cyano, halogéno, alkyle, halogénoalkyle, alcoxy et halogénoalcoxy.

6. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 5 ou un sel pharmaceutiquement acceptable de celui-ci et un véhicule pharmaceutiquement acceptable.

7. Composé selon l'une quelconque des revendications 1 à 5 pour l'utilisation dans un procédé pour le traitement d'une affection choisie dans le groupe constitué par une maladie d'Alzheimer, une démence frontotemporale, une paralysie supranucléaire progressive, une maladie des grains argyrophiles, une dégénérescence corticobasale, une maladie de Pick, une maladie de Parkinson, une sclérose latérale amyotrophique, une attaque, une maladie de Huntington, une neuropathie périphérique, une lésion cérébrale traumatique, un traumatisme de la moelle épinière et une démence vasculaire.

8. Composé pour l'utilisation selon la revendication 7, dans lequel l'affection est une maladie d'Alzheimer.