CD38 inhibitors

Abstract

One embodiment of the present invention is a compound of formula I: or a pharmaceutically acceptable salt thereof. The variables in formula I are defined herein. The compound of formula I is a CD38 inhibitor, which can be used to treat diseases that benefit from NAD + Increased disease or condition in a subject, or for treating a mitochondrial disorder in a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Indian Patent Application No. 202041015255 filed on April 7, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application relates to CD38 inhibitors and methods of use thereof, such as controlling the activity of CD38 in a subject. Background Art

[0004] Nicotinamide adenine dinucleotide (NAD + ) is a biochemical found in all cells that was first characterized more than 100 years ago for its role in oxidoreductase reactions. + and its related pyridine nucleotides NADH, NADP + and NADPH are recognized as the major redox carriers in all organisms. These pyridine dinucleotides regulate the cytosolic and mitochondrial redox states and are key players in monitoring the metabolic state of the cell. This is because NAD + and NADH act as hydride accepting and donating cofactors for metabolic enzymes involved in glycolysis, the TCA cycle, and the respiratory chain, and thereby redistribute reducing equivalents generated by these catabolic processes to the de novo synthesis of new biomolecules. (Houtkooper et al., Endo Reviews (2010) 31:194-223; Koch-Nolte et al., Science Signaling (2009) 2:mr1; Houtkooper and Auwerx, J. Cell Biol (2012) 199:205-209; Berger et al., Trends in Bioch Sci (2004) 29:111-18)

[0005] In addition to its long-recognized role as a cofactor for oxidoreductases, recent studies have shown that NAD + It is also a substrate for various enzymes, including NAD + It is consumed in the process of donating its ADP-ribose to the acceptor molecule. + The enzymes that are the main consumers of Ca are ADP-ribosyltransferases (i.e., PARP and ART enzyme families), sirtuins (Sirt1-7), and ADP-ribosylcyclase / hydrolase (CD38 / CD157). These enzymes are involved in regulating Ca ++signal transduction, gene transcription, DNA repair, cell survival, energy metabolism, and oxidative stress pathways. + and its phosphorylation counterparts NADP and NAADP (both of which are derived from NAD + ) also acts as a signal transduction molecule. NAD + It is also a key component of the diurnal cycle with daily oscillations that link cellular metabolism with chromatin remodeling and gene transcription. Exercise and caloric restriction are known to increase NAD + Aging and obesity reduce cellular NAD + Because cells strive to maintain their energy status during stress, recovery consumes large amounts of NAD + NAD in Disease States + The content will likely have medical benefits. (Tevy et al., Trends in Endo and Metab [Endocrine and Metabolism Trends] (2013) 24:229-237; Pugh et al., Aging Cell [Aging Cell] (2013) 12:672-681; Massudi et al., PLoS ONE [Public Library of Science One] (2012) 7:e42357; Xu and Sauve (2010) Mech of Ageing and Development [Aging and Development Mechanism] 131:287-298).

[0006] Cellular NAD + It is produced by a de novo synthesis pathway from tryptophan or by a recycling synthesis pathway from precursors such as nicotinic acid and nicotinamide (both obtained from dietary sources). A third way to regulate cellular NAD+ levels is to prevent NAD+ consumption by inhibiting enzymes that consume NAD+.

[0007] CD38 is a consumer of NAD+. CD38, also known as ADP ribosyl cyclase, is a type II membrane-anchored enzyme. It efficiently catalyzes the decomposition of NAD+ into nicotinamide and ADPR, and hydrolyzes NAADP into ADPRP. CD38 can also act as a cyclase that converts NAD+ into cADPR, although it is 100 times less efficient as a cyclase than as a hydrolase. CD38 was first characterized as a surface antigen on immune cells and is widely distributed in most tissues in the body. It is present on cell membranes and on the membranes of intracellular organelles such as the nucleus and mitochondria. As predicted by its function as an NAD+ glycerol hydrolase, CD38 KO mice have elevated NAD+ levels relative to wild-type controls. Similarly, inhibitors of CD38 enzymatic activity also regulate NAD+ tissue content and will be useful in treating various diseases in which CD38 is overexpressed or in which cellular NAD+ content is reduced or asynchronous. (Malavasi et al., (2008) 88: 841-886)

[0008] Compounds that inhibit CD38 and thereby increase NAD+ levels are useful for treating diseases or conditions that are indicated to benefit from NAD+, including mitochondrial-related diseases or disorders. Diseases that can be treated by increasing NAD+ levels are disclosed in WO 2016 / 087975 and WO 2017 / 079195. Summary of the invention

[0009] The present invention provides a method for inhibiting CD38 and thereby increasing NAD in cells + For example, the IC of CD38 inhibition provided in Example 66 is 50 The values ​​confirm that these compounds are potent inhibitors of CD38. It is also disclosed that the compounds and compositions of the present invention can be used to treat diseases that can benefit from NAD in cells. + Methods for treating diseases or disorders associated with increased mitochondrial content and diseases.

[0010] In one embodiment, provided herein is a compound represented by formula (I).

[0011]

[0012] or a pharmaceutically acceptable salt thereof.

[0013] In a first aspect, the variables shown in formula (I) are defined as follows:

[0014] X1 and X2 are independently CH or N, provided that X1 and X2 are not both CH;

[0015] Cy is optionally substituted with an oxo group or one or two R x C 3-7 Cycloalkyl, where Rx For halogenated, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -NHSO2C1-C4alkyl, or -SO2C1-C4alkyl;

[0016] R 1 -H, -NR a R b , halo, -CN, -C(=O)NH2, -COOH, C1-C4 alkyl, C1-C4 haloalkyl), C1-C4 hydroxyalkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 alkoxyalkyl, C1-C4 alkylthio, C1-C4 alkylsulfone, C1-C4 alkoxyalkylthio, C1-C4 haloalkylthio, C1-C4 haloalkoxy, C3-C4 cycloalkyl, or 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by one, two or three C 1-4 Alkyl substitution;

[0017] R 2 is optionally ionized with one, two or three deuterium or C 1-4 Alkyl-substituted 5-membered heteroaryl;

[0018] R d H, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, or optionally C 1-4 Alkoxy substituted C 1-4 alkyl;

[0019] R a and R b are independently -H or C1-C4 alkyl; and

[0020] n is 0 or 1.

[0021] In a second aspect, the variables shown in formula (I) are defined as follows:

[0022] X1 and X2 are independently CH or N, provided that X1 and X2 are not both CH;

[0023] Cy is optionally substituted with an oxo group or one or two R x C 3-7 Cycloalkyl, where R x For halogenated, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or SO2Me;

[0024] R 1 -H, -NR a R b, halo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkoxyalkyl, C1-C4 alkylthio, C1-C4 alkoxyalkylthio, C1-C4 haloalkylthio, C1-C4 haloalkoxy or 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by one, two or three C 1-4 Alkyl substitution;

[0025] R 2 is optionally treated with one, two or three C 1-4 Alkyl-substituted 5-membered heteroaryl;

[0026] R d is H or optionally C 1-4 Alkoxy substituted C 1-4 alkyl;

[0027] R a and R b are independently -H or C1-C4 alkyl; and

[0028] n is 0 or 1.

[0029] Another embodiment of the present invention is a pharmaceutical composition comprising an acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0030] Another embodiment of the present invention is to treat patients who benefit from NAD + A method for increasing a disease or condition in a subject (or treating a mitochondrial disorder), the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound(s).

[0031] Another embodiment of the present invention is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s) for the preparation of a method for treating a disease that benefits from NAD + A pharmaceutical product for increasing the disease or condition of a subject (or treating a mitochondrial disorder).

[0032] Another embodiment of the present invention is a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s) for use in treating a disease that benefits from NAD + Increased disease or condition in a subject (or treatment of a mitochondrial disorder). BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1This is an X-ray powder diffraction (XRPD) pattern of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide polymorph Form A.

[0034] Figure 2 Combined graph of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide polymorph Form A.

[0035] Figure 3 This is the X-ray powder diffraction (XRPD) pattern of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide polymorph Form B.

[0036] Figure 4 Combined thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide polymorph Form B. DETAILED DESCRIPTION

[0037] The compounds of the present invention are CD38 inhibitors and can be used to treat diseases that benefit from NAD + The invention relates to a method for treating a disease or disorder of a subject with increased NAD or for treating a mitochondrial disorder. Such diseases or disorders include muscle structure disorders, neuronal activation disorders, muscle fatigue disorders, muscle mass disorders, metabolic diseases, cancer, vascular diseases, ocular vascular diseases, muscular eye diseases, or kidney diseases. More specifically, NAD + Diseases or conditions (or mitochondrial disorders) for which therapeutic benefits may be achieved include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia / reperfusion injury (IRI), Duchenne & Becker muscular dystrophy, diabetes (type I or II), obesity, and sarcopenia. In another embodiment, "NAD +The "disease or condition for which therapeutic benefit is achieved" or "mitochondrial-related disease or disorder" is selected from the group consisting of Alpers' Disease, CPEO-Chronic Progressive External Ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrial Myopathy, Brain Myopathy, Lactic Acidosis, Stroke-like Seizures, MERRF-Myoclonic Epilepsy and Ragged-red Fiber Disease, NARP-Neurogenic Muscular Weakness, Ataxia, Retinitis Pigmentosa, Pearson Syndrome, Platinum-based Chemotherapy-Induced Ototoxicity, Cockayne Syndrome, Xeroderma Pigmentosa A, Wallerian Degeneration, and HIV-Induced Lipodystrophy.

[0038] In a first embodiment, the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof. The variables in formula I are described above as the first aspect of formula I and the second aspect of formula I.

[0039] In a second embodiment, the present invention is a compound of formula IIa, IIb or IIc:

[0040]

[0041] or a pharmaceutically acceptable salt thereof. The variables in Formulae IIa, IIb and IIc are as described above with respect to Formula I (first and second aspects).

[0042] In a third embodiment, the present invention is a compound of formula IIIa, IIIb or IIIc:

[0043]

[0044] or a pharmaceutically acceptable salt thereof. The variables in Formula IIIa, IIIb or IIIc are as described above with respect to Formula I (first and second aspects).

[0045] In a fourth embodiment, the present invention is a compound of formula IVa, IVb or IVc:

[0046]

[0047] or a pharmaceutically acceptable salt thereof. The variables in Formula IVa, IVb or IVc are as described above with respect to Formula I (first and second aspects).

[0048] In a fifth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc, or a pharmaceutically acceptable salt thereof, wherein n is 1. The remaining variables in Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects).

[0049] In a sixth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R d For optionally 1-4 Alkoxy substituted C 1-4 The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above with respect to Formula I (first and second aspects) or in the fifth embodiment.

[0050] In a seventh embodiment, the present invention is a compound of I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R d For C 1-4 Alkoxy substituted C 1-4 Alternatively, R d The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above with respect to Formula I (first and second aspects) or in the fifth embodiment.

[0051] In an eighth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, and when n is 1, then R d The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects).

[0052] In a ninth embodiment, the present invention is a compound of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally treated with one, two or three C 1-4 The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects) or the fifth, sixth, seventh or eighth embodiment.

[0053] In a tenth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 1 is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole or oxadiazole, which is optionally substituted by one, two or three C 1-4 The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects) or the fifth, sixth, seventh or eighth embodiment.

[0054] In an eleventh embodiment, the present invention is a compound of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: Each optionally through one, two or three C 1-4 Alternatively, R 1 for The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects) or the fifth, sixth, seventh or eighth embodiment.

[0055] In a twelfth embodiment, the present invention is a compound of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 1 -H, -NR a R bThe remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects) or the fifth, sixth, seventh or eighth embodiment.

[0056] In the thirteenth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 1 is -H, -NH2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy or C1-C4 alkylthio. 1 is -H, -CH3, -CF3, -OCH3, -SCH3, -F, -Cl, -Br or -NH2. Alternatively, R 1 The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above with respect to Formula I (first and second aspects) or the fifth, sixth, seventh or eighth embodiment.

[0057] In the fourteenth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 2 is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole or oxadiazole, which is optionally substituted by one, two or three C 1-4 The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects) or the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0058] In the fifteenth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: Each optionally through one, two or three C 1-4 Alternatively, R 2 for Alternatively, R 2 for The remaining variables in Formulas I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb and IVc are as described above for Formula I (first and second aspects) or the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0059] In the sixteenth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(=O)NH2, -COOH, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkenyl, -CN, C1-C4 alkylsulfone, or C3-C4 cycloalkyl. The remaining variables are as described above for Formula I (first aspect) or the fifth, sixth, seventh, eighth, fourteenth or fifteenth embodiment.

[0060] In the seventeenth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(=O)NH2, -COOH, -CHF2, -CH2F, -CH(OH)CH3, -C(OH)(CH3)2, -CH2OH, -CH=CH2, -SO2Me, or cyclopropyl. The remaining variables are as described above for Formula I (first aspect) or the fifth, sixth, seventh, eighth, fourteenth, fifteenth or sixteenth embodiment.

[0061] In the eighteenth embodiment, the present invention is a compound of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5-membered heteroaryl (eg, imidazole) substituted with one, two, or three deuteriums. The remaining variables are as described above for Formula I (first aspect) or the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth embodiment.

[0062] In the nineteenth embodiment, the present invention is a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R d C 1-4 Haloalkyl or C 1-4The remaining variables are as described above for Formula I (first aspect) or the fifth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth or eighteenth embodiment.

[0063] In the twentieth embodiment, the present invention is a compound of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, wherein R d is -CHF2 or -CH2CH2OH. The remaining variables are as described above for Formula I (first aspect) or the fifth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth or nineteenth embodiment.

[0064] In the twenty-first embodiment, the present invention is a compound of formula I, IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, wherein Cy is cyclohexyl substituted with -NHSO2(C1-C4 alkyl)(-NHSO2Et). The remaining variables are as described above for Formula I (first aspect) or the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0065] The present invention also includes the compounds described in Table 3 and the compounds prepared in the Examples. Both pharmaceutically acceptable salts and neutral forms of these compounds are included. In another embodiment, the present invention relates to a hydrate or solvate and / or crystalline polymorph of a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to an anhydrous form (i.e., not a solvate or hydrate) of a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc or a pharmaceutically acceptable salt thereof, which is enriched at one or more positions with a radioactive or non-radioactive isotope. In another embodiment, the present invention relates to a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc, or a pharmaceutically acceptable salt thereof, which is enriched with deuterium at one or more positions.

[0066] The present invention teaches that the compounds disclosed herein are pharmaceutically acceptable salts. The compounds of the present invention teachings having a base can form pharmaceutically acceptable salts together with one or more pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid). The compounds of the present invention teachings having an acid group can form pharmaceutically acceptable salts together with one or more pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0067] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response and commensurate with a reasonable benefit / risk ratio within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66: 1-19.

[0068] The term "alkyl", used alone or as part of a larger moiety (such as "alkoxy", "haloalkyl", "haloalkoxy", "hydroxyalkyl", "alkoxyalkyl", "alkylthio", "alkoxyalkylthio", "haloalkylthio" and the like), means a saturated aliphatic straight or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., C1-C4 alkyl. As used herein, "C1-C4 alkyl" means a group having 1 to 4 carbon atoms in a straight or branched arrangement, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.

[0069] "Alkoxy" means an alkyl group attached via an oxygen linking atom, which is represented by -O-alkyl. For example, C1-C4 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and isopropoxy.

[0070] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy group that is optionally substituted with one or more halogen atoms. In some embodiments, "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy group that is optionally substituted with one or more fluorine atoms.

[0071] The term "halogen" or "halo" refers to fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br) or iodine or iodo (I).

[0072] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. For example, "C1-C4 hydroxyalkyl" includes, but is not limited to, hydroxyethyl and hydroxypropyl.

[0073] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0074] The term "alkylthio" refers to an alkyl group attached through a sulfur linking atom, which is represented by -S-alkyl.

[0075] The term "alkoxyalkylthio" refers to an alkylthio group substituted with an alkoxy group.

[0076] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen atoms, such as one or more fluorine atoms.

[0077] "Cycloalkyl" means a saturated aliphatic monocyclic hydrocarbon group. Unless otherwise specified, a cycloalkyl group has 3 to 7 ring carbon atoms, alternatively, 3 to 6 ring carbon atoms. For example, "C3-C6 cycloalkyl" means a group having 3 to 6 carbon atoms arranged in a single ring. C3-C6 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] The term "5-membered heteroaryl" refers to a monocyclic aromatic ring radical having five ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatom (eg, oxygen, nitrogen or sulfur).

[0079] Examples of 5-membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl).

[0080] If a group is described as "substituted," a non-hydrogen substituent replaces a hydrogen substituent on a carbon, sulfur, or nitrogen of the group. Thus, for example, a substituted alkyl is an alkyl group in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl group. For example, a monofluoroalkyl group is an alkyl group substituted with a fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be recognized that if more than one substitution is present on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise stated).

[0081] If a group is described as "optionally substituted," the substituent may be (1) unsubstituted, or (2) substituted.

[0082] If a group is described as being optionally substituted with up to a specified number of non-hydrogen substituents, then the group may be (1) unsubstituted; or (2) substituted with up to the specified number of non-hydrogen substituents or up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl group optionally substituted with up to 3 non-hydrogen substituents, then any cycloalkyl group having less than 3 substitutable positions would be optionally substituted with up to as many non-hydrogen substituents as the cycloalkyl group has substitutable positions.

[0083] Compounds with one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms and racemates and mixtures thereof. "Geometric isomers" refer to isomers in which the substituents are oriented differently with respect to the cycloalkyl ring, i.e., cis or trans isomers. "Cis" refers to substituents oriented on the same side of the ring, while trans refers to substituents oriented on opposite sides of the ring.

[0084] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses one of the possible stereoisomers or geometric isomers and not the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0085] When a geometric isomer or stereoisomer is depicted by name or structure, it is understood that the named or depicted isomer is present to a greater extent than its corresponding isomer, that is, the geometric purity of the named or depicted geometric isomer is greater than 50% purity by weight, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% purity by weight. The geometric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0086] A racemic mixture means 50% one enantiomer and 50% its corresponding enantiomer. When a compound having one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., both enantiomerically pure, enantiomerically enriched, or racemic). When a compound having two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers, such as racemic mixtures).

[0087] Enantiomeric mixtures can be resolved into their component enantiomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex or crystallization of the compound in a chiral solvent. Enantiomers can also be obtained from enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0088] When a compound is represented by a name or structure indicating a single enantiomer, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure") unless otherwise indicated. The optical purity is the weight of the mixture of the named or depicted enantiomers divided by the total weight of the mixture of the two enantiomers.

[0089] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0090] Disclosed herein are methods of treating a mitochondrial-related disease or disorder in a subject. Also disclosed herein are methods of treating a mitochondrial-related disease or disorder in a subject. + The content of NAD in vivo (e.g., intracellular NAD + NAD levels in tissues or plasma + The content and / or total NAD in the organism + Treatment with increased NAD + The method may include administering to a subject an effective amount of one or more compounds or compositions provided herein.

[0091] Diseases and disorders treatable by the compounds and pharmaceutical compositions of the present invention include those associated with aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood coagulation disorders, inflammation, cancer, and / or facial flushing, among others.

[0092] In one embodiment, the diseases or disorders include, but are not limited to, Alpers disease, CPEO-chronic progressive external ophthalmoplegia, Kearns-Sakella syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS-mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes, MERRF-myoclonic epilepsy with ragged red fibers, NARP-neurotropic muscle weakness, ataxia, retinitis pigmentosa, Pearson's syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne's syndrome, xeroderma pigmentosum A, Wallerian degeneration, and HIV-induced lipodystrophy.

[0093] In one embodiment, mitochondrial-related diseases or disorders may benefit from increased NAD + The disease or disorder of the content is a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a metabolic disease, cancer, a vascular disease, an ocular vascular disease, a muscular eye disease or a kidney disease.

[0094] The muscle structural disorder is selected from Bethlem myopathy, centralcore disease, congenital asymmetric muscle fiber type, distal muscular dystrophy (MD), Duchenne and Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline myopathy, limb-girdle MD, muscle sodium channel disorder, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nematode disease, oculopharyngeal MD, and stress urinary incontinence.

[0095] The neuronal activation disorder is selected from the group consisting of amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, focal neuropathy, peripheral neuropathy, spinal muscular atrophy, tardive ulnar nerve palsy, and toxic myoneural disorder.

[0096] The muscle fatigue disorder is selected from the group consisting of chronic fatigue syndrome, diabetes (type I or II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, and thyrotoxic myopathy; the muscle mass disorder is selected from the group consisting of cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, myopathy gravis, inclusion body myositis, muscular dystrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus.

[0097] The beta oxidation disease is selected from systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium chain acyl-CoA dehydrogenase (MCAD) deficiency, short chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin responsive disorder of beta oxidation (RR-MADD).

[0098] Metabolic diseases are selected from the group consisting of: hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and / or HLD noncholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, arteriosclerotic diseases, cardiovascular system diseases, cerebrovascular diseases, peripheral circulatory diseases, metabolic syndrome, syndrome X, obesity, diabetes (type I or II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperpancreatitis, Insulinaemia, complications of diabetes, heart failure, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Alzheimer's disease, neurodegenerative diseases, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, hair diseases, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis.

[0099] The vascular disease is selected from the group consisting of peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral artery disease (PAD), peripheral artery occlusive disease (PAOD), and peripheral occlusive arterial disease.

[0100] The ocular vascular disease is selected from the group consisting of age-related macular degeneration (AMD), Stargardt disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma.

[0101] The muscular eye disease is selected from the group consisting of strabismus, progressive extraocular muscle palsy, esotropia, exotropia, refractive and accommodative abnormalities, hyperopia, myopia, astigmatism, anisotropia, presbyopia, accommodative disorders, and internal ophthalmoplegia.

[0102] The kidney disease is selected from glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute renal failure (also known as acute kidney injury), chronic renal failure, diabetic nephropathy, and Bartter's syndrome.

[0103] In another embodiment, mitochondrial-related diseases or disorders may benefit from increased NAD + The disease or disorder of the present invention is selected from the group consisting of inherited lipodystrophy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia / reperfusion injury (IRI), cardiac ischemia / reperfusion injury, Duchenne and Becker muscular dystrophy, diabetes (type I or type II), obesity, and sarcopenia.

[0104] In another embodiment, the compounds of the present invention and their pharmaceutical compositions can be used to treat cells useful for transplantation or cell therapy, including, for example, solid tissue transplants, organ transplants, cell suspensions, stem cells, bone marrow cells, etc. The cell or tissue may be a self-transplant, an allogeneic transplant, a syngeneic transplant, or a xenograft. The compounds of the present invention and their pharmaceutical compositions can be used to treat cells or tissues before administration / implantation into a subject, at the same time as administration / implantation into a subject, and / or after administration / implantation into a subject. Cells or tissues can be treated before removing cells from a donor individual, after removing cells or tissues from a donor individual in vitro, or after implantation into a recipient. For example, a donor or recipient individual can be systemically treated with a CD38 inhibitor preparation or a pharmaceutical composition of the present invention, or may have a subset of cells / tissues that are locally treated with the compounds of the present invention and their pharmaceutical compositions. In certain embodiments, cells or tissues (or donor / recipient individuals) may be additionally treated with another therapeutic agent useful for extending the survival of a transplant, such as, for example, an immunosuppressant, a cytokine, an angiogenic factor, etc.

[0105] In yet other embodiments, the compounds of the present invention and / or its pharmaceutical composition can be used to treat skin disorders. Exemplary skin disorders that can be treated according to the methods described herein include disorders or diseases associated with inflammation, sunburn or natural aging or caused by it. For example, the composition is used to treat contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), photokeratosis, keratinization disorders (including eczema), bullous epidermolysis (including pemphigus), exfoliative dermatitis, seborrheic dermatitis, erythema (including erythema multiforme and erythema nodosum), scleroderma, damage caused by sunlight or other light sources, discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer and the effects of natural aging. In another embodiment, the compounds of the present invention and its pharmaceutical composition can be used to treat trauma and / or burns to promote recovery, including, for example, first-degree, second-degree or third-degree burns and / or thermal, chemical or electrical burns.

[0106] The compounds of the invention and pharmaceutical compositions thereof may also be administered to a subject for the treatment of diseases associated with cell death (e.g., chronic diseases) in order to protect cells from cell death. Exemplary diseases include those associated with: neuronal cell death, neuronal dysfunction, or muscle cell death or dysfunction, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and muscular dystrophy; AIDS; fulminant hepatitis; diseases associated with brain degeneration, such as Creutzfeld-Jakob disease, retinitis pigmentosa, and cerebellar degeneration; myelodysplasia, such as aplastic anemia; ischemic diseases, such as myocardial infarction and stroke; liver diseases, such as alcoholic hepatitis, hepatitis B and hepatitis C; joint diseases, such as osteoarthritis; atherosclerosis; alopecia; skin damage caused by UV light; lichen planus; skin atrophy; cataracts; and transplant rejection. Cell death may also be caused by surgery, drug therapy, chemical exposure, or radiation exposure.

[0107] The compounds of the present invention and their pharmaceutical compositions can also be administered to subjects suffering from acute diseases (e.g., organ or tissue damage), such as subjects suffering from stroke or myocardial infarction or subjects suffering from spinal cord injury. The compounds of the present invention and their pharmaceutical compositions can also be used to repair alcoholic liver.

[0108] In another embodiment, the present invention provides a method for treating cardiovascular disease by administering one or more of the compounds of the present invention and / or its pharmaceutical compositions to a subject in need. Cardiovascular diseases that can be treated using the compounds of the present invention and its pharmaceutical compositions include cardiomyopathy or myocarditis, such as idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, complications associated with percutaneous coronary intervention, and hypertensive cardiomyopathy. The compositions and methods described herein can also be used to treat atherosclerotic disorders (large vessel disease) of major blood vessels, such as the aorta, coronary arteries, carotid arteries, cerebrovascular arteries, renal arteries, crotch arteries, femoral arteries, and popliteal arteries. Other vascular diseases that can be treated include those associated with the following: platelet aggregation, retinal arterioles, glomerular arterioles, neural vasa nervorum, cardiac arterioles, and capillary beds associated with the eye, kidney, heart, and central and peripheral nervous systems. The compounds of the present invention and its pharmaceutical compositions can also be used to increase the HDL content in the plasma of an individual.

[0109] The compounds of the present invention and their pharmaceutical compositions can be administered to subjects who have recently received or are likely to receive a dose of radiation or toxins. In one embodiment, the dose of radiation or toxins is received as part of a work-related or medical procedure, such as working in a nuclear power plant, flying an aircraft, X-rays, CAT scans, or administering radioactive dyes for medical imaging; in this embodiment, the compound is administered as a preventive measure. In another embodiment, radiation or toxin exposure is unintentionally received, such as due to industrial accidents, living in natural radiation sites, acts of terrorism, or acts of war involving radioactive or toxic materials. In this case, the compounds of the present invention and their pharmaceutical compositions are preferably administered as soon as possible after the exposure dose to inhibit cell death and the subsequent progression of acute radiation syndrome.

[0110] In another embodiment, the compounds of the present invention and pharmaceutical compositions thereof may be useful for treating age-related disorders, such as cancer.

[0111] Exemplary cancers that can be treated using the compounds of the present invention and their pharmaceutical compositions include those of the brain and kidneys; hormone-dependent cancers, including breast cancer, prostate cancer, colon cancer, colorectal cancer, skin cancer, lung cancer, testicular cancer, pancreatic cancer, and ovarian cancer; lymphomas and leukemias. Other diseases that can be treated include autoimmune diseases, such as systemic lupus erythematosus, systemic scleroderma, and arthritis, in which autoimmune cells should be removed. Viral infections such as herpes, HIV, adenovirus, coronavirus, influenza, and HTLV-1-related malignant and benign disorders can also be treated by administering one or more of the compounds of the present invention and their pharmaceutical compositions.

[0112] In another embodiment, the compounds of the invention and pharmaceutical compositions thereof may be useful for accelerated aging disorders such as Hutchinson-Gilford progeria syndrome, Werner syndrome, telomere deficiency syndrome or telomere disorders and dyskeratosis. Additional diseases that may be treated include those associated with stress-induced premature aging, which may include extrapulmonary complications of COPD, such as cardiovascular disease, osteoporosis and dementia, and diseases in which "inflammatory" or secretory factors from senescent cells alter the balance of NAD synthesis and consumption.

[0113] In certain aspects, the compounds of the present invention and pharmaceutical compositions thereof can be used to treat patients suffering from neurodegenerative diseases and trauma or mechanical damage to the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis, primary lateral sclerosis, eye diseases (optic neuritis), chemotherapy-induced neuropathy (e.g., by vincristine, paclitaxel, bortezomib), diabetes-induced neuropathy, and Friedreich's ataxia. The compounds of the present invention and pharmaceutical compositions thereof can be used to treat these disorders and other disorders as described below.

[0114] In an exemplary embodiment, the compounds of the present invention and pharmaceutical compositions thereof can be used to treat multiple sclerosis (MS), including relapsing MS and monosymptomatic MS; and other demyelinating disorders, such as chromic inflammatory demyelinating polyneuropathy (CIDP) or symptoms associated therewith.

[0115] In yet another embodiment, the compounds of the invention and pharmaceutical compositions thereof can be used to treat neurotrauma, including trauma due to disease, injury (including surgical intervention), or environmental trauma (eg, neurotoxins, alcohol intoxication, etc.).

[0116] The compounds of the present invention and their pharmaceutical compositions may also be useful for treating and alleviating the symptoms of various peripheral nervous system (PNS) disorders. PNS disorders include a wide range of disorders in which nerves outside the brain and surrounding nerves of the spinal cord have been damaged. Peripheral neuropathy may also be referred to as peripheral neuritis, or if many nerves are involved, the terms polyneuropathy or polyneuritis may be used. PNS disorders may be the result of, for example, leprosy, diabetes, Guillain-Barré syndrome, and other conditions.

[0117] Other PNS diseases that can be treated with the compounds of the present invention and their pharmaceutical compositions include brachial plexus neuropathies (diseases of the peripheral nerve components of the cervical and first thoracic roots, nerve trunks, spinal cord, and brachial plexuses). Clinical manifestations include local pain, paresthesias; muscle weakness and decreased sensation in the upper limbs. These disorders can be associated with trauma, including birth trauma; thoracic outlet syndrome; tumors, neuritis, radiation therapy; and other conditions. (See Adams et al., Principles of Neurology, 6th ed., pp. 1351-2). Also included are diabetic neuropathy (peripheral, autonomic, and cranial nerve disorders associated with diabetes). These conditions are usually caused by diabetic microvascular damage involving the small blood vessels that supply the nerves (vasa nervorum). Relatively common conditions that may be associated with diabetic neuropathy include third nerve palsy; mononeuropathy; multiple mononeuropathy; diabetic amyotrophy; painful polyneuropathy; autonomic neuropathy; and thoracic and abdominal tissue neuropathy (see Adams et al., Principles of Neurology, 6th ed., p. 1325). PNS diseases also include mononeuropathy (disease or trauma involving a single peripheral nerve alone or out of proportion to evidence of diffuse peripheral nerve dysfunction). Multiple mononeuropathy refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathy can be caused by a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue disease; cumulative trauma disorder; and other conditions. Also included are neuralgia (intense pain or aching that occurs along the direction or distribution of a peripheral or cranial nerve); peripheral nervous system tumors (tumors arising from peripheral nerve tissue, which include neurofibromas; schwannomas; granular cell tumors; and malignant peripheral nerve sheath tumors, see DeVita Jr et al., Cancer: Principles and Practice of Oncology, 5th ed., pp1 750-1); and nerve compression syndromes (mechanical compression of a nerve or nerve root from internal or external causes, which can result in blockade of nerve impulse conduction, due to, for example, myelin dysfunction or axonal loss; damage to the nerve and nerve sheath can be caused by ischemia, inflammation, or direct mechanical action); and neuritis (a general term indicating inflammation of a peripheral or cranial nerve). Clinical manifestations may include pain; paresthesias; paresthesias; or hyperesthesias; polyneuropathy (disease of multiple peripheral nerves). The various forms are classified by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve damage (e.g., distal vs. proximal), by the neural components affected first (e.g., demyelinating vs. axonal), by etiology, or by inheritance pattern.

[0118] The compounds of the present invention and their pharmaceutical compositions can also be used to treat blood coagulation disorders (or hemostatic disorders). As used interchangeably herein, the terms "hemostasis", "blood coagulation" and "blood clotting" refer to the physiological properties of controlling bleeding, including vasoconstriction and coagulation.

[0119] The present invention also provides anticoagulant and antithrombotic therapies directed to inhibiting blood clot formation in order to treat blood coagulation disorders such as myocardial infarction, stroke, limb loss due to peripheral arterial disease or pulmonary embolism.

[0120] As used interchangeably herein, "modulating" or "modulation of hemostasis" and "regulating" or "regulation of hemostasis" include both inducing (eg, stimulating or increasing) hemostasis and inhibiting (eg, decreasing or reducing) hemostasis.

[0121] In one aspect, the present invention provides a method for reducing or inhibiting hemostasis in a subject by administering the compounds of the present invention and pharmaceutical compositions thereof. The compositions and methods disclosed herein are useful for treating thrombotic disorders. As used herein, the term "thrombotic disorder" includes any disorder or condition characterized by excessive or unwanted coagulation or hemostatic activity or an overly coagulated state. Examples of thrombotic disorders include, but are not limited to, thromboembolism; deep vein thrombosis; pulmonary embolism; stroke; myocardial infarction; miscarriage; thrombophilias associated with antithrombin III deficiency, protein C deficiency, protein S deficiency, resistance to activated protein C; dysfibrinogenemia; fibrinolytic disorders; homocystinuria; pregnancy; inflammatory disorders; myeloproliferative disorders; arteriosclerosis; angina, such as unstable angina; disseminated intravascular coagulation; thrombotic thrombocytopenic purpura; cancer metastasis; sickle cell disease; glomerulonephritis; and drug-induced thrombocytopenia (including, for example, heparin-induced thrombocytopenia).

[0122] Additionally, the compounds of the invention and pharmaceutical compositions thereof may be administered to reduce thrombotic events or to reduce re-embolism during or after therapeutic clot lysis or procedures such as angioplasty or surgery.

[0123] The compounds of the present invention and their pharmaceutical compositions can also be used to treat or reduce the weight gain or obesity of a subject. For example, the compounds of the present invention and their pharmaceutical compositions can be used to treat genetic obesity, dietary obesity, hormone-related obesity, obesity associated with drug administration, to reduce the weight of a subject or reduce the weight gain of a subject. Subjects in need of such treatment may be obese, likely to become obese, overweight, or likely to become overweight. Subjects who are likely to become obese or overweight can be identified, for example, based on family history, heredity, diet, active content, drug intake, or various combinations thereof.

[0124] In yet other embodiments, the compounds of the present invention and pharmaceutical compositions thereof may be administered to subjects suffering from a variety of other diseases and conditions that can be treated by promoting weight loss in the subject. Such diseases include, for example, high blood pressure, hypertension, high blood cholesterol, dyslipidemia, type 2 diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina, congestive heart failure, stroke, gallstones, cholecystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and breathing problems, some types of cancer (such as endometrial cancer, breast cancer, prostate cancer and colon cancer), complications of pregnancy, poor female reproductive health (such as irregular menstruation, infertility, irregular ovulation), bladder control problems (such as stress incontinence), uric acid kidney stones, mental disorders (such as depression, eating disorders, distorted body image and low self-esteem). Stunkard AJ, Wadden TA. (Eds.) Obesity: theory and therapy, 2nd ed. New York: Raven Press, 1993. Ultimately, patients with AIDS may develop lipid dystrophy or insulin resistance in response to combination therapy for AIDS. In another embodiment, the compounds of the invention and pharmaceutical compositions thereof may be used to inhibit adipogenesis or adipocyte differentiation, either in vitro or in vivo. Specifically, high circulating amounts of insulin and / or insulin-like growth factor (IGF) 1 will be prevented from recruiting preadipocytes to differentiate into adipocytes. Such methods may be used to treat obesity.

[0125] In other embodiments, the compounds of the present invention and pharmaceutical compositions thereof can be used to reduce appetite and / or increase satiety, thereby causing weight loss or avoiding weight gain. Subjects in need of such treatment may be overweight, obese subjects or subjects who are likely to become overweight or obese. The method may comprise administering a dose to the subject daily or every other day or once a week, for example in the form of a pill. The dose may be a "dose that reduces appetite".

[0126] In other embodiments, the compounds of the present invention and their pharmaceutical compositions can be used to treat subjects suffering from cachexia or who may suffer from cachexia. The method may further include monitoring the state of the disease in the subject. For example, the method for promoting appetite and / or weight gain may include, for example, identifying the subject in advance as needing to reduce fat or lipid metabolism by weighing the subject, measuring the subject's hungry BMI. The method may also include, for example, monitoring the subject during and / or after the administration of the compounds of the present invention and their pharmaceutical compositions. Administration may include, for example, one or more doses delivered in a pill or continuously. Monitoring may include evaluating hormones or metabolites. Exemplary hormones include leptin, adiponectin, resistin, and insulin. Exemplary metabolites include triglycerides, cholesterol, and fatty acids.

[0127] In another embodiment, the compounds of the present invention and pharmaceutical compositions thereof can be administered to reduce drug-induced weight gain. For example, the compounds of the present invention and pharmaceutical compositions thereof can be administered as combination therapy with drugs that can stimulate appetite or cause weight gain (specifically, weight gain caused by factors other than water retention).

[0128] Examples of drugs that may cause weight gain include, for example, diabetes therapeutic agents, including, for example, sulfonylureas (such as glipizide and glyburide), thiazolidinediones (such as pioglitazone and rosiglitazone), meglitinide, nateglinide, repaglinide, sulfonylurea drugs, and insulin; antidepressants, including, for example, tricyclic antidepressants (such as amitriptyline and imipramine), irreversible monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and insulin. reuptake inhibitor; SSRI), bupropion, paroxetine and mirtazapine; steroids, such as, for example, prednisone; hormone therapy; lithium carbonate; valproic acid; carbamazepine; chlorpromazine; thiothixene; beta blockers (such as propranolol); alpha blockers (such as clonidine, prazosin and terazosin); and contraceptives, including oral contraceptives (birth control pills) or other contraceptives containing estrogen and / or progesterone (Depo-Provera, Norplant, Ortho), testosterone or megestrol. In another exemplary embodiment, the compounds of the present invention and pharmaceutical compositions thereof can be administered as part of a smoking cessation program to reduce weight gain or reduce weight that has already been gained.

[0129] In another aspect, the compounds of the present invention and pharmaceutical compositions thereof can be used to treat metabolic disorders, such as insulin resistance, prediabetic conditions, type II diabetes and / or complications thereof.

[0130] Administration of the compounds of the invention and pharmaceutical compositions thereof can increase insulin sensitivity and / or reduce insulin levels in a subject. Subjects in need of such treatment may be subjects with insulin resistance or other prodromal symptoms of type II diabetes, with type II diabetes, or with the possibility of any of these conditions. For example, a subject may be a subject with insulin resistance, such as a subject with high circulating amounts of insulin and / or related conditions, such as hyperlipidemia, dyslipidogenesis, hypercholesterolemia, impaired glucose tolerance, high blood sugar levels, other manifestations of syndrome X, hypertension, atherosclerosis, and lipid dystrophy.

[0131] The compounds of the invention and pharmaceutical compositions thereof may also be used to treat diseases or disorders associated with inflammation. Exemplary inflammatory conditions include, for example, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin-dependent diabetes or juvenile-onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, , pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatitis (acute or chronic), multiple organ injury syndrome (e.g., secondary to sepsis or trauma), myocardial infarction, atherosclerosis, stroke, reperfusion injury (e.g., due to cardiopulmonary bypass or renal dialysis), acute glomerulonephritis, vasculitis, thermal injury (i.e., sunburn), necrotizing enterocolitis, granulocyte transfusion-associated syndrome, and / or Sjogren's syndrome. Exemplary inflammatory disorders of the skin include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriasis, and skin diseases with an acute inflammatory component.

[0132] In another embodiment, the compounds of the present invention and their pharmaceutical compositions can be used to treat allergic and respiratory diseases, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome and any chronic obstructive pulmonary disease (COPD). These compounds can be used to treat chronic hepatitis infections, including hepatitis B and hepatitis C.

[0133] In addition, the compounds of the present invention and their pharmaceutical compositions can be used to treat autoimmune diseases and / or inflammation associated with autoimmune diseases, such as organ tissue autoimmune diseases (e.g., Raynaud's syndrome), scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosus, Addison's disease, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome) and Graves' disease.

[0134] The compounds of the present invention and their pharmaceutical compositions can also be used to reduce the occurrence or severity of flushing and / or hot flashes as symptoms of the disorder. In one embodiment, the compounds of the present invention and their pharmaceutical compositions can be used to reduce the flushing side effects of vasodilators or anti-lipidemic agents (including anti-cholesterol agents and anti-fatty liver agents).

[0135] In another representative embodiment, the method involves using the compounds of the present invention and their pharmaceutical compositions to reduce the flushing side effect of antidepressants or antipsychotic agents. For example, the compounds of the present invention and their pharmaceutical compositions can be used in combination with the following (administered alone or together): serotonin reuptake inhibitors, 5HT2 receptor antagonists, anticonvulsants, norepinephrine reuptake inhibitors, α adrenergic receptor antagonists, NK-3 antagonists, NK-1 receptor antagonists, PDE4 inhibitors, neuropeptide Y5 receptor antagonists, D4 receptor antagonists, 5HT1 A receptor antagonists, 5HT1D receptor antagonists, CRF antagonists, monoamine oxidase inhibitors or sedative hypnotic drugs.

[0136] In certain embodiments, the compounds of the present invention and pharmaceutical compositions thereof can be used as part of a treatment to reduce flushing using a serotonin reuptake inhibitor (SRI). In certain preferred embodiments, the SRI is a selective serotonin reuptake inhibitor (SSRI), such as a fluoxetinoid (fluoxetine, norfluoxetine) or a nefazodonoid (nefazodone, hydroxynefazodone, oxonefazodone). Other exemplary SSRIs include duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine, paroxetine, and sertraline. The compounds of the present invention and their pharmaceutical compositions can also be used as part of a treatment using a sedative hypnotic drug, such as selected from the group consisting of: benzodiazepines (such as alprazolam, chlordiazepoxide, clonazepam, chlorazepate, clobazam, diazepam, halazepam, lorazepam, oxazepam and prazepam), zolpidem and barbiturates. In yet other embodiments, the compounds of the present invention and their pharmaceutical compositions can be used as part of a treatment using a 5-HT1 A receptor partial agonist, such as selected from the group consisting of: buspirone, flesinoxan, gepirone and ipsapirone. The compounds of the invention and pharmaceutical compositions thereof may also be used as part of a treatment using a norepinephrine reuptake inhibitor, such as selected from the group consisting of tertiary amine tricyclic compounds and secondary amine tricyclic compounds. Exemplary tertiary amine tricyclic compounds include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine.Exemplary secondary amine tricyclic compounds include amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline. In certain embodiments, the compounds of the invention and pharmaceutical compositions thereof can be used as part of a treatment using a monoamine oxidase inhibitor, such as selected from the group consisting of isocarboxazid, phenelzine, tranylcypromine, selegiline, and moclobemide.

[0137] In yet another representative embodiment, the compounds of the present invention and pharmaceutical compositions thereof can be used to reduce the flushing side effects of chemotherapeutic agents such as cyclophosphamide and tamoxifen. Similarly, the compounds can be used to reduce the cardiotoxicity associated with anti-tumor drugs (including anthracyclines, taxanes, and therapies targeting hEGFR2 / HER2, such as trastuzumab).

[0138] In another embodiment, the compounds of the present invention and pharmaceutical compositions thereof can be used to reduce the flushing side effect of calcium channel blockers such as amlodipine.

[0139] In another embodiment, the compounds of the present invention and their pharmaceutical compositions can be used to reduce the flushing side effect of antibiotics. For example, the compounds of the present invention and their pharmaceutical compositions can be used in combination with levofloxacin. Levofloxacin is used to treat infections of the sinuses, skin, lungs, ears, respiratory tract, bones and joints caused by susceptible bacteria.

[0140] When administered with another therapeutic agent, the compounds of the invention may be administered simultaneously in the same pharmaceutical formulation or in separate pharmaceutical formulations. Alternatively, when administered with another therapeutic agent, the compounds of the invention may be administered at different times, depending on the dosage requirements of the second therapeutic agent.

[0141] Pharmaceutical compositions are disclosed, which include one or more compounds provided herein (such as compounds of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb or IVc) and optionally at least one additional substance selected, such as excipients, known therapeutic agents other than those of the present invention, and combinations thereof. In some embodiments, the compounds of the present invention may be used in combination with other agents known to have the beneficial activity targeting diseases or disorders listed above. For example, the disclosed compounds may be administered alone or in combination with one or more compounds selected from the group consisting of: PPARδ agonists, AMPK activators, PARP inhibitors, SIRT-activating compounds, nicotinamide N-methyl transferase (NNMT) inhibitors, nicotinic acid, nicotinamide or nicotinamide riboside and derivatives thereof and acetyl-CoA carboxylase inhibitors, and pharmaceutically acceptable salts of these compounds.

[0142] As used herein, the terms "administer / administering / administration" and the like refer to methods by which delivery of a composition to a desired site of biological action can be achieved. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be employed with the agents and methods described herein are found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pennsylvania.

[0143] A "subject" is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0144] The exact amount of compound administered to provide an "effective amount" to a subject depends on the mode of administration, the type and severity of the disease or condition, and the characteristics of the subject, such as general health, age, sex, weight, and drug resistance. Those skilled in the art will be able to determine the appropriate dose depending on these and other factors. When administered in combination with other therapeutic agents, such as when administered in combination with anticancer agents, the "effective amount" of any one or more additional therapeutic agents will depend on the type of drug used. Suitable doses of approved therapeutic agents are known and can be adjusted by those skilled in the art according to the subject's condition, the type of condition being treated, and the amount of the compound of the invention used, following, for example, the doses reported in the literature and recommended in the Physician's Desk Reference (57th edition, 2003).

[0145] The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, such as inhibition, suppression or alleviation of the symptoms of the treated disorder in the subject as compared to a control. For example, a therapeutically effective amount can be given in a unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively, 1 mg to about 5 grams per day; and in another, alternatively, 10 mg to 1 gram per day).

[0146] The attending clinician will select a particular mode of administration and dosing regimen, taking into account the details of the case (e.g., the subject, the disease, the disease state involved, the specific treatment, and whether the treatment is prophylactic). Treatment may involve dosing daily or multiple days or less than daily (such as weekly or monthly, etc.) over a period of days to months or even years. However, considering the dosage of approved compositions for treating diseases using the disclosed compounds as a guide, the generally skilled artisan will immediately understand appropriate and / or equivalent dosages.

[0147] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. In one embodiment, the composition is formulated according to conventional procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0148] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that facilitate formulation and / or administration of an active agent and / or absorption by a subject and that can be included in the compositions of the invention without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard saline solution, lactated Ringer's, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose), amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants and the like. Such preparations can be sterilized and optionally mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants and / or aromatic substances and the like, which do not react harmfully with the compounds provided herein or interfere with the activity of the compounds provided herein. Those with ordinary knowledge in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0149] Example

[0150] abbreviation

[0151] Ac Acetyl

[0152] ACN Acetonitrile

[0153] aq aqueous solution

[0154] Boc tert-Butyloxycarbonyl

[0155] Boc-anhydride di-tert-butyl dicarbonate

[0156] Bn Benzyl

[0157] CuI Copper iodide

[0158] DCM Dichloromethane

[0159] DIPEA Diisopropylethylamine

[0160] DMF N,N-Dimethylformamide

[0161] DMSO Dimethyl sulfoxide

[0162] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[0163] EDC 3-(3-dimethylaminopropyl)-l-ethylcarbodiimide

[0164] Et Ethyl

[0165] EtOAc Ethyl acetate

[0166] FWHM Full Width Half Maximum

[0167] h hour

[0168] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0169] HOBt 1-Hydroxybenzotriazole

[0170] HPLC High Performance Liquid Chromatography

[0171] K2CO3 Potassium carbonate

[0172] LCMS Liquid chromatography mass spectrometry

[0173] M is the concentration expressed in mol / L

[0174] Me Methyl

[0175] MeOH Methanol

[0176] MEK Methyl Ethyl Ketone

[0177] MIBK Methyl Isobutyl Ketone

[0178] MTBE Methyl tert-butyl ether

[0179] Na2SO4 Sodium sulfate

[0180] NaOH Sodium hydroxide

[0181] Ph Phenyl

[0182] Prep.HPLC Preparative High Performance Liquid Chromatography

[0183] Rel.Int. Relative Intensity

[0184] RT Room temperature

[0185] TFA Trifluoroacetic acid

[0186] THF Tetrahydrofuran

[0187] TLC Thin layer chromatography

[0188] 1 H NMR (DMSO-d6)DMSO-d6 1δ of H NMR peak (ppm)

[0189] s Singlet peak (spectrum)

[0190] d Doublet (spectrum)

[0191] t triplet (spectrum) q quartet (spectrum)

[0192] dd Doublet of doublets (spectrum)

[0193] br broad peak (spectrum)

[0194] m Multiple peaks (spectrum)

[0195] mg milligram

[0196] mM millimolar

[0197] nM nanomole

[0198] °2Th 2θ angle or the angle between the transmitted and reflected columns

[0199] General information:

[0200] LCMS analysis conditions:

[0201] Instrument name: Agilent Technologies 1290 infinity 11.

[0202] Method A: Method: A-0.1% TFA / H2O, B-0.1% TFA / ACN; flow rate: 2.0 mL / min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0203] Method B: Method: A-10 mM NH4HCO3 / H2O, B-ACN; flow rate: 1.0 mL / min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0204] Method C: Method: A-0.1% HCOOH / H2O, B-0.1% FA / ACN; flow rate: 1.5 mL / min; column: ZORBAXXDBC-18 (50×4.6 mm, 3.5 μm).

[0205] Method D: Method: A-10 mM ammonium acetate / H2O, B-ACN; flow rate: 1.0 mL / min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0206] HPLC analysis conditions:

[0207] Instrument name: Agilent 1260Infinity II.

[0208] Method A: Method: A-0.1% TFA / H2O, B-0.1% TFA / ACN; flow rate: 2.0 mL / min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0209] Method B: Method: A-10 mM NH4HCO3 / H2O, B-ACN; flow rate: 1.0 mL / min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0210] Preparation HPLC purification conditions:

[0211] Method A: A-0.1% TFA / H2O, B-MeOH or ACN; Column: Sunfire C8 (19×250 mm, 5 μm) or Sunfire C18 (30×250 mm, 10 μm).

[0212] Method B: A-10 mM NH4HCO3 / H2O, B-MeOH or ACN, column: Sunfire C8 (19×250 mm, 5 μm) or Sunfire C18 (30×250 mm, 10 μm).

[0213] Method C: A-0.1% formic acid / H2O, B-MeOH or ACN; column: Sunfire C8 (19×250 mm, 5 μm) or Sunfire C18 (30×250 mm, 10 μm).

[0214] X-ray powder diffraction (XRPD)

[0215] X-ray powder diffraction data were collected on a Bruker D2 PHASER diffractometer with a 300 W low-power X-ray generator under ambient conditions. Powder patterns were collected on a zero-background sample holder, 0.15 sec / step, 1837 total steps, 0.02° 2θ per step, at 30 kV and 10 mA. A Cu (Kα) X-ray tube was used with a Kα2 / Kα1 intensity ratio of 0.50

[0216] Thermogravimetric analysis (TGA)

[0217] Thermogravimetric data were collected using a TA Discovery Series TGA. Several milligrams of material were heated from room temperature to 300°C at a heating rate of 10°C / min under nitrogen.

[0218] Differential Scanning Calorimetry (DSC)

[0219] Differential Scanning Calorimetry was performed with a TA Discovery series DSC using approximately several milligrams of material in a Tzero aluminum pan sealed with a Tzero sealing lid. The samples were analyzed under a 25 ml / min nitrogen flow using a heating rate of 10°C / min.

[0220] 7.2.4 Polarized Light Microscopy (PLM)

[0221] Micrographs were taken at room temperature using an Olympus BX53M polarizing microscope.

[0222] Example 1: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(1H-imidazol-1-yl)isonicotinamide

[0223]

[0224]

[0225] Step 1: 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0226]

[0227] To a stirred solution of 2,6-dichloroisonicotinic acid (0.5 g, 2.61 mmol) in DMF (5 mL) was added HATU (1.69 g, 4.45 mmol) and DIPEA (1.07 mL, 7.85 mmol) at RT. After stirring for 5 min at RT, (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (589 mg, 3.40 mmol) was added at RT, and the reaction mixture was stirred overnight at RT. Upon completion, the reaction mixture was diluted with water (50 mL) and the resulting solid was filtered and dried to give the title compound. Yield: 44% (400 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 7.6 Hz, 1H), 7.88 (s, 2H), 3.75-3.67 (m, 1H), 3.54-3.51 (m, 2H), 3.43-3.40 (m, 2H), 3.31-3.21 (m, 4H), 2.02-1.99 (m, 2H), 1.88-1.85 (m, 2H), 1.37-1.21 (m, 4H). LCMS: (Method A) 347.1 [M+H], Rt. 2.34 min.

[0228] Step 2: 2-Chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0229]

[0230] A stirred solution of 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (320 mg, 0.92 mmol), imidazole (63 mg, 0.92 mmol), CuI (17.5 mg, 0.09 mmol) and KCO (383 mg, 2.77 mmol) in DMF (5 mL) was heated to 125 °C overnight. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and the solvent evaporated in vacuo. The resulting crude residue was purified by flash chromatography on Biotage Laolera (230-400 mesh silica gel, eluted with 10%-50% EtOAc / petroleum ether) to give the title compound. Yield: 29% (0.1 g, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ8.63(d,J=8.0Hz,1H),8.56(s,1H),8.09(s,1H),7.98(d,J=1.2Hz,1H),7.78(s,1H),7.16(s,1H),3.79 -3.72(m,1H),3.55-3.53(m,2H),3.44-3.41(m,2H),3.31-3.25(m,4H),2.04-2.01(m,2H),1.92-1.89(m,2H),1.39-1.23(m,4H). LCMS: (Method C) 379.1[M+H], Rt.1.25min.

[0231] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(1H-imidazol-1-yl)isonicotinamide

[0232]

[0233] To a stirred solution of 2-chloro-6-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (0.1 g, 0.26 mmol) in ethanol (5 mL) and water (0.5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)thiazole (73 mg, 0.34 mmol) and KCO (0.11 g, 0.79 mmol) at RT and the mixture was purged with nitrogen for 5 min at RT. Pd(dppf)Cl.DCM (9 mg, 0.01 mmol) and CuI (5 mg, 0.02 mmol) were then added and the reaction mixture was heated at 95 °C overnight. After completion (monitored by TLC), the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The resulting crude material was purified by flash chromatography on Biotage Isolera to give the title compound. Yield: 47% (53 mg, light yellow solid). 1 H NMR (400MHz, DMSO-d6): δ9.26(s,1H),8.78(s,1H),8.64(br s,1H),8.60(d,J=7.6Hz,1H),8.20(s,1H),8.05(s,1H),8.00(s,1H),7.19(s,1H),3.85-3.77(m,1H),3.56- 3.54(m,2H),3.44-3.42(m,2H),3.31-3.25(m,4H),2.06-2.03(m,2H),1.96-1.93(m,2H),1.46-1.23(m,4H). LCMS: (Method A) 428.2[M+H], Rt.1.64min. HPLC: (Method A) Rt. 2.34 min.

[0234] Example 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)isonicotinamide

[0235]

[0236] A solution of 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (351 mg, 1.01 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)thiazole (533 mg, 2.52 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was deoxygenated by purging nitrogen over a period of 5 min. Afterwards, K2CO3 (558 mg, 4.04 mmol), CuI (19.23 mg, 0.10 mmol) were added followed by Pd(dppf)Cl2.DCM (82.4 mg, 0.10 mmol), and the resulting mixture was heated at 115°C for 16 h. After completion, the reaction mixture was filtered through a pad of celite and washed with 10% MeOH / DCM (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product. The crude residue was then purified by reverse phase chromatography (Method A) and the collected fractions were concentrated under reduced pressure, the obtained product was redissolved in 10% MeOH / DCM (10 mL), washed with 10% NaHCO3 solution (50 mL) and water (2×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound. Yield: 59% (264.64 mg, off-white solid); 1 HNMR (400 MHz, DMSO-d6): δ9.22 (d, J=0.4 Hz, 2H), 8.72 (d, J=0.8 Hz, 2H), 8.60 (d, J=7.6 Hz, 1H), 8.22 (s, 2H), 3.85-3.70 (m, 1H), 3.60-3.56 (m, 2H), 3.55-3.50 (m, 2H), 3.43-3.20 (m, 4H), 2.06-2.00 (m, 2H), 1.96-1.90 (m, 2H), 1.46-1.38 (m, 2H), 1.32-1.23 (m, 2H); LCMS: (Method C) 445.0 [M+H], Rt. 1.77 min; HPLC: (Method A) Rt. 3.48 min.

[0237] Example 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)isonicotinamide

[0238]

[0239] Step 1: 2-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)isonicotinamide

[0240]

[0241] A solution of 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (989 mg, 2.84 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (414 mg, 1.99 mmol) in a mixture of 1,4-dioxane (10 mL) and water (1 mL) was deoxygenated by purging nitrogen for 5 min. K2CO3 (786 mg, 5.69 mmol) and Pd(dppf)Cl2.DCM (232 mg, 0.28 mmol) were then added and the resulting mixture was heated at 90°C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite and washed with 10% MeOH / DCM (100 mL). The filtrate was washed with water (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was then purified by Grace normal phase chromatography (100-200 mesh silica gel, eluent: 2%-5% MeOH / DCM) to afford the title compound. Yield: 54.5% (610 mg, brown gummy solid). 1 HNMR (400MHz, DMSO-d6): δ8.54(d,J=7.6Hz,1H),8.39(s,1H),8.04(d,J=0.4Hz,1H ),7.93(d,J=1.2Hz,1H),7.57(d,J=0.8Hz,1H),3.9(s,3H),3.83-3.79(m,1H),3.56 -3.50 (m, 2H), 3.45-3.40 (m, 2H), 3.29-3.20 (m, 4H), 2.05-2.00 (m, 2H), 1.94-1.91 (m, 2H), 1.45-1.37 (m, 2H), 1.30-1.22 (m, 2H), LCMS: (Method C) 393.2 [M+H], Rt. 1.73 min.

[0242] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)isonicotinamide

[0243]

[0244] A solution of 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)isonicotinamide (513 mg, 1.30 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)thiazole (413 mg, 1.95 mmol) in 1,4 dioxane (5 mL) and water (0.5 mL) was deoxygenated by purging nitrogen for 5 min. K2CO3 (448 mg, 3.25 mmol), CuI (24.7 mg, 0.13 mmol) were then added followed by Pd(dppf)Cl2.DCM (106 mg, 0.13 mmol) and heated at 110°C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite, washed with 10% MeOH / DCM (100 mL). The filtrate was washed with water (2×50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The crude residue was then purified by Grace reverse phase chromatography (Method A). The collected fractions were concentrated under reduced pressure and the obtained product was redissolved in 10% MeOH / DCM (50 mL), washed with 10% NaHCO3 solution (20 mL) and water (2×50 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried by lyophilization to give the title compound. Yield: 83.9% (484 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ9.19(s,1H),8.67(d,J=0.8Hz,1H),8.51(d,J=7.6Hz,1H),8.38(s,1H), 8.08(d,J=0.4Hz,1H),8.00(d,J=1.6Hz,1H),7.90(d,J=1.2Hz,1H),3.9(s,3H),3.83-3.75(m,1H), 3.57-3.55 (m, 2H), 3.54-3.44 (m, 2H), 3.33-2.53 (m, 4H), 2.06-1.95 (m, 2H), 1.94-1.90 (m, 2H), 1.46-1.43 (m, 2H), 1.39-1.31 (m, 2H); LCMS: (Method C) 442.2 [M+H], Rt. 1.70 min; HPLC: (Method A) Rt. 3.27 min.

[0245] Example 4: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(trifluoromethyl)isonicotinamide

[0246]

[0247] Step 1: 2-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)isonicotinamide

[0248]

[0249] To a stirred solution of 2-chloro-6-(trifluoromethyl)isonicotinic acid (200 mg, 0.888 mmol) in DMF (5 mL) was added HATU (506.6 mg, 1.33 mmol) and DIPEA (0.46 mL, 2.66 mmol) at RT. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (230.1 mg, 1.33 mmol) in DMF (0.5 mL) was added at the same temperature. The reactant was further stirred overnight at RT. The reaction mixture was monitored by TLC. The reaction mixture was quenched with water (25 mL). The resulting suspension was extracted with DCM (3×25 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The resulting crude product was purified by Biotage Isolera column chromatography (100-200 mesh silica gel, eluted with 10%-50% EtOAc / petroleum ether) to afford the title compound. Yield: 32% (109 mg, white solid). 1 HNMR (300MHz, DMSO-d6): δ8.79(d,J=7.2Hz,1H),8.24(s,1H),8.20(s,1H),3.76-3.75(m,1H),3.54-3 .52(m,2H),3.47-3.41(m,2H),3.18(s,4H),2.04-2.02(m,2H),1.99-1.91(m,2H),1.87-1.22(m,4H). LCMS: (Method C) 379.0 (MH), Rt. 2.278 min.

[0250] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(trifluoromethyl)isonicotinamide

[0251]

[0252] After purging nitrogen for 5 min, a mixture of 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)isonicotinamide (100 mg, 0.263 mmol), 5-(tributyltinyl)thiazole (147.63 mg, 0.394 mmol), Pd(dppf)Cl2.DCM (21.47 mg, 0.0263 mmol) in DMA (3 mL) was added at RT. The reaction mixture was then heated at 80 ° C in a sealed tube overnight. The reaction mixture was quenched with water (10 mL). The resulting suspension was extracted with DCM (3×15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to give a crude compound, which was purified by preparative HPLC (Method A). The preparative fractions were concentrated to an aqueous phase, DCM was added and neutralized with a 10% aqueous NaHCO3 solution. The phases were separated. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to give the title compound. Yield: 44% (50.1 mg, off-white solid). 1 HNMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.81 (s, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.60 (s, 1H), 8.12 (s, 1H), 3.83-3.79 (m, 1H), 3.56-3.54 (m, 2H), 3.44-3.42 (m, 2H), 3.26 (s, 4H), 2.05-2.03 (m, 2H), 1.95-1.92 (m, 2H), 1.45-1.36 (m, 2H), 1.31-1.22 (m, 2H). LCMS: (Method C) 430.2 [M+H], Rt. 1.632 min, HPLC: (Method A) Rt. 4.118 min.

[0253] Example 5: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)pyrimidine-4-carboxamide

[0254]

[0255] Step 1: Methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate

[0256]

[0257] To a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (2.0 g, 96.62 mmol) in THF (25 mL) was added an aqueous solution of NaSMe (676 mg, 96.62 mmol) at RT and the reaction mixture was stirred for 3 h at RT. After completion (monitored by TLC), the reaction mixture was diluted with water (100 mL) and the resulting suspension was extracted with ether (2×150 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the title compound. Yield: 66% (1.4 g, yellow solid). 1 H NMR (400 MHz, DMSO-d6) : δ 7.95 (s, 1H), 3.91 (s, 3H), 2.61 (s, 3H). LCMS: (Method C) 218.8 [M+H], Rt. 2.00 min.

[0258] Step 2: 2,6-di(thiazol-5-yl)pyrimidine-4-carboxylic acid and 6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid

[0259]

[0260] To a stirred solution of methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate (0.50 g, 2.30 mmol) in 1,4-dioxane (12 mL) and water (2 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)thiazole (729 mg, 3.45 mmol) and potassium carbonate (0.95 g, 6.90 mmol) at RT, and nitrogen was purged through the reaction mixture for 5 min. Pd(dppf)Cl2.DCM (188 mg, 0.23 mmol) and CuI (43 mg, 0.23 mmol) were then added and the reaction mixture was heated at 110 °C overnight. After completion (monitored by TLC), the reaction mixture was diluted with 5% methanol / DCM and filtered through celite. The filtrate was concentrated in vacuo to give a mixture of the title compounds, which was used in the next step without further purification. Crude yield: 0.56 g, black solid. LCMS: (Method C) 290.8 [M+H], Rt. 1.28 min, 253.9 [M+H], Rt. 1.44 min.

[0261] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)pyrimidine-4-carboxamide

[0262]

[0263] To a stirred solution of the above crude mixture containing 2,6-di(thiazol-5-yl)pyrimidine-4-carboxylic acid and 6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid (540 mg, 0.96 mmol) in DMF (12 mL) was added EDC.HCl (612 mg, 3.20 mmol), HOBt (432 mg, 3.20 mmol), DIPEA (0.87 mL, 6.40 mmol) and (1r, 4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (553 mg, 3.20 mmol) at RT, and the reaction mixture was stirred overnight at RT. The reaction mixture was monitored by TLC. After completion, the reaction mixture was diluted with water (50 mL), and the resulting suspension was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The resulting crude residue was purified by preparative HPLC (Method A). The preparative fractions from preparative HPLC were made slightly alkaline using aqueous NaHCO3 and concentrated under reduced pressure to remove acetonitrile. The residual aqueous layer was extracted with 5% methanol / DCM (2×100 mL). The combined organic layers were washed with water (2×30 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was finally lyophilized from water-acetonitrile to give the title compound. Yield: (21 mg, gray solid). 1 H NMR (400 MHz, DMSO-d6): δ 9.37-9.33 (m, 2H), 9.11-9.10 (m, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 3.88-3.82 (m, 1H), 3.58-3.55 (m, 2H), 3.45-3.43 (m, 2H), 3.31-3.25 (m, 4H), 2.07-2.04 (m, 2H), 1.90-1.88 (m, 2H), 1.65-1.58 (m, 2H), 1.33-1.24 (m, 2H). LCMS: (Method A) 446.1 [M+H], Rt. 1.97 min. HPLC: (Method A) Rt. 3.76 min.

[0264] Example 6: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxamide

[0265]

[0266] Step 1: Methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate

[0267]

[0268] To a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g, 9.66 mmol) in THF (25 mL) was added an aqueous solution of NaSMe (676 mg, 9.66 mmol) at RT and stirred at the same temperature for 3 h. The reaction mixture was monitored by TLC and quenched with water (100 mL). The resulting suspension was extracted with ether (2×150 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and the solvent evaporated in vacuo to give the title compound. Yield: 66% (1.4 g, yellow solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 3.91 (s, 3H), 2.61 (s, 3H). LCMS: (Method C) 218.8 (M+H), Rt. 1.99 min.

[0269] Step 2: 2-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid methyl ester

[0270]

[0271] A stirred solution of methyl 6-chloro-2-(methylthio)pyrimidine-4-carboxylate (3 g, 13.76 mmol) in 1,4-dioxane (30 mL) was purged with N gas for 10 min before 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (5.72 g, 27.52 mmol), copper thiophene-2-carboxylate (1) (5.24 g, 27.52 mmol) and Pd(PPh3)4 (1.56 g, 1.37 mmol) were added at RT. The reaction was then stirred at 85 °C for 6 h. The reaction mass was diluted with 5% methanol / DCM (150 mL) and filtered through a celite bed. The filtrate was concentrated in vacuo and the resulting crude product was purified by flash chromatography (230-400 mesh silica gel, eluted with 0-5% methanol / DCM) to give the title compound. Yield: 35% (1.2 g, yellow solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H). LCMS: (Method A) 253.2 (M+H), Rt. 1.53 min.

[0272] Step 3: 6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid

[0273]

[0274] To a stirred solution of 2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid methyl ester (1.0 g, 3.95 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)thiazole (1.08 g, 5.14 mmol), CuI (75 mg, 0.39 mmol) and potassium carbonate (1.63 g, 11.87 mmol) at RT, and nitrogen was purged through the reaction mixture for 5 min. Pd(dppf)Cl2.DCM (161 mg, 0.19 mmol) was then added and the reaction mixture was heated at 110 °C overnight. The reaction mixture was diluted with water, stirred at 50 °C for 10 min and filtered. The filtrate was acidified using HCl (1.5 M) aqueous solution and the resulting solid was filtered and washed with water to give the title compound. Yield: 23% (0.28 g, brown solid). 1 HNMR (400 MHz, DMSO-d6): δ 14.0 (s, 1H), 9.36 (s, 1H), 8.81 (s, 1H), 8.78 (s, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 3.91 (s, 3H). LCMS: (Method C) 288.0 (M+H), Rt. 1.29 min.

[0275] Step 4: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxamide

[0276]

[0277] To a stirred solution of 6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid (150 mg, 0.52 mmol) in DMF (2.5 mL) was added EDC.HCl (150 mg, 0.78 mmol), HOBt (106 mg, 0.78 mmol) and DIPEA (202 mg, 1.56 mmol) and (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (118 mg, 0.68 mmol) at RT, and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), purified by anhydrous NaS O4Dry and concentrate in vacuo. The crude residue obtained was purified by flash chromatography on Biotage Isolera (230-400 mesh silica gel, eluent: 0-5% methanol / DCM) to give the title compound. Yield: 32% (73 mg, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ9.30 (d, J = 0.4Hz, 1H), 9.08 (d, J = 0.8Hz, 1H), 8.70 (s,1H),8.6(d,J=8.8Hz,1H),8.3(d,J=0.4Hz,1H),8.0(s,1H),3.9(s,3H),3 .80-3,77(m,1H),3.57-3.55(m,2H),3.45-3.43(m,2H),3.34-3.31(m,4H), 2.06-2.04(m,2H),1.89-1.87(m,2H),1.59-1.56(m,2H),1.30-1.24(m,2H). LCMS: (Method C) 443.2 (M+H), Rt. 1.83 min. HPLC: (Method A) Rt. 3.45 min.

[0278] Example 7: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxamide

[0279]

[0280] Step 1: Methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate

[0281]

[0282] To a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g, 96.62 mmol) in THF (25 mL) was added an aqueous solution of NaSMe (676 mg, 96.62 mmol) at RT and stirred at the same temperature for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with diethyl ether (2×150 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the title compound. Yield: 66% (1.4 g, yellow solid). 1 HNMR (400MHz, DMSO-d6) : δ 8.0 (s, 1H), 3.9 (s, 3H), 2.6 (s, 3H). LCMS: (Method C) 218.8 [M+H], Rt. 1.99 min.

[0283] Step 2: 6-(Methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid

[0284]

[0285] To a stirred solution of methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate (0.50 g, 2.30 mmol) in dioxane (12 mL) and water (2 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)thiazole (729 mg, 3.45 mmol), CuI (43 mg, 0.23 mmol) and K2CO3 (0.95 g, 6.90 mmol) at RT, and nitrogen was purged through the reaction mixture for 5 min. Pd(dppf)Cl2.DCM (188 mg, 0.23 mmol) was then added and the reaction mixture was heated at 110°C overnight. The reaction mixture was diluted with 5% methanol / DCM and filtered through celite. The combined filtrate was concentrated in vacuo and the resulting crude material was used as is in the other steps. Yield: 96% (0.56 g, black solid, crude material). LCMS: (Method C) 353.9 [M+H], Rt. 1.44 min.

[0286] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxamide

[0287]

[0288] To a stirred solution of crude 6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid (540 mg, 0.75 mmol) in DMF (12 mL) was added EDC.HCl (612 mg, 3.20 mmol), HOBt (432 mg, 3.20 mmol) and DIPEA (826 mg, 6.40 mmol), followed by (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (553 mg, 3.20 mmol), and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo. The resulting crude product was purified by preparative HPLC (Method A). The fractions from preparative HPLC were made slightly alkaline with aqueous NaHCO3 solution and the ACN was removed under reduced pressure on a rota vapour. The aqueous layer was extracted with 5% methanol / DCM (2×100 mL). The combined organic layers were washed with water (2×30 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated and lyophilized to give the title compound. Yield: 5% (35 mg, gray solid). 1 HNMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 9.0 (s, 1H), 8.5 (d, J = 8.4 Hz, 1H), 8.2 (s, 1H), 3.81-3.79 (m, 1H), 3.55-3.53 (m, 2H), 3.44-3.42 (m, 2H), 3.34-3.32 (m, 4H), 2.6 (s, 3H), 2.03-2.00 (m, 2H), 1.86-1.83 (m, 2H), 1.54-1.51 (m, 2H), 1.30-1.27 (m, 2H). LCMS: (Method A) 409.1 [M+H], Rt. 2.20 min. HPLC: (Method A) Rt. 4.02 min.

[0289] Example 8: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)picolinamide

[0290]

[0291] Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0292]

[0293] To a stirred solution of 4,6-dichloropicolinic acid (3.0 g, 15.62 mmol) in DMF (30 mL) was added DIPEA (8.39 mL, 46.87 mmol) and HATU (8.90 g, 23.43 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (3.24 g, 18.75 mmol) in DMF (5.0 mL) was added at the same temperature. The reaction mixture was stirred for 16 h at RT. The reaction mixture was monitored by TLC. After the reaction was completed, it was quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 77% (4.2 g, yellow solid). 1 HNMR 300MHz, DMSO-d6): δ8.46 (d, J=8.1Hz, 1H), 8.01-7.98 (m, 2H), 3.76-3.73 (m, 1H), 3.52-3.50 (m, 2H), 3.42-3.40 (m, 2H), 3.23 (s, 4H), 2.00-197 (m, 2H), 1.80-1.76 (m, 2H), 1.55-1.44 (m, 2H), 1.26-1.19 (m, 2H). LCMS: (Method C) 347.0 [M+H], Rt. 2.15 min

[0294] Step 2: 4-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide

[0295]

[0296] 5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)thiazole (364.9 mg, 1.729 mmol), CuI (27.37 mg, 0.144 mmol), potassium carbonate (497.1 mg, 3.602 mmol), Pd(dppf)Cl2.DCM (58.83 mg, 0.0724 mmol) were added to a stirred solution of 4,6-dichloro-N-((1r, 4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (500 mg, 1.440 mmol) in 9.0 mL ethanol and water (1.0 mL) placed in a sealed tube at RT, and nitrogen was purged through the reaction mixture for 5 min. The reaction mixture was heated at 95 ° C for 16 h. After the reaction was completed, it was filtered through diatomaceous earth and washed with DCM (20 mL). The solvent was evaporated in vacuo to give a crude compound. The resulting crude product was purified by column chromatography on Biotage isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM) to afford the title compound. Yield: 55.5% (290 mg, light brown solid). 1 HNMR (400MHz, DMSO-d6): δ9.26(s,1H),8.87(s,1H),8.37(d,J==1.6Hz,1H),8.30(d,J=8.4Hz,1H),7.91(d,J=1.6Hz,1H),3.81-3.78( m,1H),3.55-3.53(m,2H),3.44-3.42(m,2H),3.25(s,4H),2.03-2.00(m,2H),1.99-1.89(m,2H),1.56-1.48(m,2H),1.29-1.23(m,2H). LCMS: (Method A) 396.1[M+H], Rt.1.912min.

[0297] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)picolinamide

[0298]

[0299] A stirred mixture of 4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide (280 mg, 0.705 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (176.9 mg, 0.850 mmol), KCO (244.5 mg, 1.772 mmol), Pd(dppf)Cl.DCM (72.36 mg, 0.0886 mmol) in 4.5 mL of dioxane and water (0.5 mL) placed in a sealed tube was purged with N for 5 min. The reaction mixture was heated at 97 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was complete, it was filtered through celite and washed with DCM (20 mL). The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC (Method A). The preparative fractions were concentrated, diluted with DCM and neutralized with 10% aqueous NaHCO3. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to give the title compound. Yield: 45% (141.7 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ9.22(s,1H),8.84(s,1H),8.60(s,1H),8.33(d,J= 1.2Hz,1H),8.26(s,1H),8.20(d,J=8.4Hz,1H),8.06(d,J=1.6Hz,1H),3.91( s,3H),3.85-3.80(m,1H),3.56-3.54(m,2H),3.45-3.42(m,2H),3.26(s,4H) ,2.03-2.00(m,2H),1.92-1.89(m,2H),1.55-1.47(m,2H),1.33-1.25(m,2H). LCMS: (Method A) 441.9 [M+H], Rt. 2.02 min, HPLC: (Method A) Rt. 3.54 min.

[0300] Example 9: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide

[0301]

[0302]

[0303] Step 1: 6-Bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0304]

[0305] To a stirred solution of 6-bromopicolinic acid (415 mg, 2.05 mmol) in DMF (4 mL) was added HATU (1.17 g, 4.46 mmol) followed by DIPEA (0.94 mL, 5.12 mmol) at 0 °C under nitrogen atmosphere and the resulting mixture was stirred for 15 min. After 15 min, (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (533 mg, 3.08 mmol) was added and stirred at RT for 16 h. Upon completion, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (50 mL). The ethyl acetate layer was washed with water (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound. Yield: 69.9% (510 mg, brown gummy solid). 1 H NMR (400MHz, DMSO-d6): δ8.32(d,J=10.80Hz,1H),8.1-8.00(m,1H),7.95-7.90(m,1H),7.89-7.82(m,1H),3.75-3.70(m,1H),3.5 3-3.50(m,2H),3.42-3.40(m,2H),3.25-3.16(m,4H),2.20-1.86(m,4H),1.39-1.22(m,4H), LCMS: (Method C) 360.0[M+H], Rt.1.94min.

[0306] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide

[0307]

[0308] A solution of 6-bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (210 mg, 0.58 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)thiazole (186 mg, 0.88 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was deoxygenated by purging nitrogen for 10 min. KCO (162 mg, 1.17 mmol) was then added followed by CuI (11.1 mg, 0.058 mmol) and Pd(dppf)Cl.DCM (47.3 mg, 0.058 mmol) and the resulting mixture was heated at 110° C. for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite and washed with 10% MeOH / DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude residue. The crude product obtained was then purified by Grace reverse phase chromatography (Method A), the collected fractions were concentrated under reduced pressure, the obtained product was redissolved in 10% MeOH / DCM (50 mL), washed with 10% NaOH solution (20 mL), and then with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further dried using lyophilization to give the title compound. Yield: 66.12% (140.5 mg, white solid); 1 HNMR (400MHz, DMSO-d6): δ9.22 (s, 1H), 8.79 (s, 1H), 8.23 ​​(d, J = 8.4Hz, 1H), 8.15-8.10 (m, 1H),8.09-8.05(m,1H),7.96-7.90(m,1H),3.83-3.80(m,1H),3.56-3.50(m,2H),3.45-3.4 0 (m, 2H), 3.38-3.33 (m, 1H), 3.30 (s, 3H), 2.03-2.00 (m, 2H), 1.91-1.88 (m, 2H), 1.57-1.50 (m, 2H), 1.48-1.24 (m, 2H); LCMS: (Method D) 362.2 [M+H], Rt. 2.29 min; HPLC: (Method A) Rt. 3.26 min.

[0309] Example 10: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide

[0310]

[0311] Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0312]

[0313] To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.8 mmol) in DMF (15 mL) was added DIPEA (4.19 mL, 23.43 mmol) and HATU (5.93 g, 15.62 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reactant was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After the reaction was completed, it was quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 49% (1.35 g, yellow solid). 1 HNMR 400MHz, DMSO-d6): δ8.49(d,J=8.4Hz,1H),8.03(d,J=1.6Hz,1H),8.00(d,J=1.6Hz,1H),3.87-3.81(m,1H),3.54-3.5 2(m,2H),3.44-3.40(m,2H),3.20(s,4H),2.01-198(m,2H),1.81-1.78(m,2H),1.53-1.49(m,2H),1.25-1.21(m,2H). LCMS: (Method C) 347.1. [M+H], Rt. 2.27 min.

[0314] Step 2: 4-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide

[0315]

[0316] 5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)thiazole (145.93 mg, 0.691 mmol), CuI (10.95 mg, 0.0576 mmol), potassium carbonate (159.0 mg, 1.15 mmol), Pd(dppf)Cl2.DCM (23.53 mg, 0.028 mmol) were added to a stirred solution of 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.576 mmol) in 4.5 mL of ethanol and water (0.5 mL) placed in a sealed tube at RT, and nitrogen was purged through the reaction mixture for 5 min. The reaction mixture was then heated at 100 ° C for 16 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth and washed with DCM (20 mL). The solvent was evaporated in vacuo to give a crude compound. The resulting crude product was purified by column chromatography on Biotage isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM) to afford the title compound. Yield: 35.2% (80 mg, light brown solid). 1 HNMR (400MHz, DMSO-d6): δ9.26(s,1H),8.87(s,1H),8.37(d,J=2.0Hz,1H),8.29(d,J=8.4Hz,1H),7.91(d,J=1.6Hz,2H),3.93-3.79(m ,1H),3.55-3.53(m,2H),3.44-3.42(m,2H),3.25(s,4H),2.03-2.00(m,2H),1.89-1.86(m,2H),1.54-1.50(m,2H),1.32-1.24(m,2H). LCMS: (Method A) 395.8[M+H], Rt. 2.584min.

[0317] Step 3: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide

[0318]

[0319] A mixture of 4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide (80 mg, 0.202 mmol), imidazole (41.31 mg, 0.607 mmol), copper iodide (3.8 mg, 0.0202 mmol) and K2CO3 (83.84 mg, 0.607 mmol) in DMF (2 mL) placed in a sealed tube was purged with N2 for 5 min. The reaction mixture was heated at 125 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth and washed with DCM (10 mL). The filtrate was evaporated in vacuo to obtain a crude product, which was purified by preparative HPLC (method A). The preparative fraction was concentrated, diluted with DCM and neutralized with a 10% NaHCO3 aqueous solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to obtain the title compound. Yield: 19.7% (17.02 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ9.25 (s, 1H), 8.92 (d, J = 0.4Hz, 1H), 8.75 (s, 1H), 8.47(d,J=2.4Hz,1H),8.30(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,2H),7.22(s, 1H),3.85-3.81(m,1H),3.56-3.54(m,2H),3.45-3.42(m,2H),3.26(s,4H), 2.03-2.01(m,2H),1.93-1.89(m,2H),1.58-1.49(m,2H),1.34-1.23(m,2H). LCMS: (Method C) 427.9 [M+H], Rt. 1.193 min. HPLC: (Method A) Rt. 2.439 min.

[0320] Example 11: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0321]

[0322] Step 1: 6-(1H-imidazol-1-yl)picolinic acid

[0323]

[0324] The solution of 6-bromopicolinic acid methyl ester (502mg, 2.32mmol) and 1H-imidazole (474mg, 6.97mmol) in DMF (5mL) is deoxygenated by purging nitrogen for 5min. After 5min, KCO (801mg, 5.80mmol) is added, followed by CuI (44.2mg, 0.23mmol) and heated at 140°C for 16h. After completion, the reaction mixture is filtered through a diatomaceous earth pad and washed with EtOAc (200mL) and water (50mL). The water layer is acidified with 1.5N HCl and evaporated in vacuo. And washed with EtOAc (200mL) and water (50mL). The water layer is acidified with 1.5N HCl and evaporated in vacuo. The crude product is used for other steps without any purification. Yield: 44.5% (210 mg, white solid); LCMS: (Method B) 190.1 [M+H], Rt. 0.56 min.

[0325] Step 2: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0326]

[0327] To a stirred solution of 6-(1H-imidazole-1-yl)picolinic acid (102 mg, 0.53 mmol) in DMF (7 mL) was added HATU (307 mg, 0.80 mmol) at 0 ° C under nitrogen atmosphere, followed by DIPEA (0.37 mL, 2.02 mmol) and stirred for 5 min. Afterwards, (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (146 mg, 0.80 mmol) was added and the resulting mixture was stirred for 16 h at RT. After completion, water (50 mL) was added to the reaction mixture and extracted with EtOAc (100 mL). (Too much solvent for 100 mg scale) The organic layer was washed with water (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The obtained crude residue was purified by Grace reverse phase chromatography (Method B). The collected fractions were concentrated under reduced pressure, and the obtained product was redissolved in 10% MeOH / DCM (50 mL), and washed with 10% aqueous NaHCO3 (20 mL), followed by water (2×25 mL). (Some insoluble particles that were not soluble in the organic layer were observed. These particles dissolved excess water) The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further dried by lyophilization to give the title compound. Yield: 56.7% (105.39 mg, off-white solid); 1HNMR (400MHz, DMSO-d6): δ8.95(s,1H),8.56(d,J=8.8Hz,1H),8.26(s,1H),8.15(d,J=7 .6Hz,1H),8.00(d,J=8.0Hz,1H),7.16(s,1H),3.86-3.80(m,1H),3.57-3.55(m,2H),3.5 5-3.54 (m, 2H), 3.44-3.26 (m, 4H), 2.05-2.030 (m, 2H), 1.84-1.81 (m, 2H), 1.62-1.53 ​​(m, 2H), 1.29-1.21 (m, 2H); LCMS: (Method C) 345.2 [M+H], Rt. 0.95 min; HPLC: (Method A) Rt. 2.01 min.

[0328] Example 12: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)picolinamide

[0329]

[0330]

[0331] Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0332]

[0333] To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.8 mmol, CAS No. 88912-25-8) in DMF (15 mL) was added DIPEA (4.19 mL, 23.43 mmol) and HATU (5.93 g, 15.62 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction mixture was stirred for 16 h at RT. The reaction mixture was monitored by TLC. After the reaction was completed, it was quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 49% (1.35 g, yellow solid).1 HNMR 400MHz, DMSO-d6): δ8.49(d,J=8.4Hz,1H),8.03(d,J=1.6Hz,1H),8.00(d,J=1.6Hz,1H),3.87-3.81(m,1H),3.54-3.5 2(m,2H),3.44-3.40(m,2H),3.20(s,4H),2.01-198(m,2H),1.81-1.78(m,2H),1.53-1.49(m,2H),1.25-1.21(m,2H). LCMS: (Method C) 347.1. [M+H], Rt. 2.27 min.

[0334] Step 2: 6-Chloro-4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide and 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0335]

[0336] A mixture of 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (700 mg, 2.017 mmol), imidazole (123.4 mg, 1.81 mmol), copper iodide (38.32 mg, 0.201 mmol) and K2CO3 (417.5 mg, 3.025 mmol) in DMF (15 mL) placed in a sealed tube was purged with N2 for 5 min. The reaction mixture was heated at 90 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, it was filtered through a diatomaceous earth bed and washed with DCM (10 mL). The filtrate was evaporated in vacuo to obtain a crude product, which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM). Yield 80% (610.1 mg, colloidal solid). 1HNMR (400MHz, DMSO-d6): δ8.71(s,1H),8.45(d,J==8.4Hz,1H),8.27(d,J=2.8Hz,1H),8.19(d,J=2.0Hz,1H),8.14(s,1H),7.19(s,1H),3.81- 3.78(m,1H),3.56-3.52(m,2H),3.44-3.41(m,2H),3.23(s,4H),2.02- 2.00(m,2H),1.84-1.81(m,2H),1.58-1.48(m,2H),1.20-1.29(m,2H). LCMS: (Method C) 379.2 [M+H], Rt. 1.13 min, 379.2 [M+H], Rt. 1.02 min.

[0337] Step 3: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)picolinamide

[0338]

[0339] 6-Chloro-4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide and 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (280 mg, 0.740 mmol, 55% major isomer and 26% minor isomer), 1-methyl A mixture of -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (184.88 mg, 0.888 mmol), K2CO3 (255.5 mg, 1.851 mmol), Pd(dppf)Cl2.DCM (30.24 mg, 0.0370 mmol) in 4.5 mL of dioxane and water (0.5 mL) was purged with N2 for 5 min. The reaction mixture was heated at 97 °C for 16 h. The reaction was monitored by LCMS. After completion of the reaction, it was filtered through celite and washed with DCM (20 mL). The filtrate was evaporated in vacuo to give a crude product, which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM) to give the title compound, which was further purified by preparative HPLC (Method A). The preparative fraction of the minor isomer was concentrated, diluted with DCM and neutralized with 10% aqueous NaHCO3 solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to give the title compound. Yield: 8% (28.1 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ8.97(s,1H),8.60(s,1H),8.52(d,J=8.4Hz,1H),8.31- 8.30(m,1H),8.27(s,1H),8.14(,J=1.2Hz,1H),8.07(d,J=1.2Hz,1H),7.18(s,1H ),3.94(s,3H),3.86-3.83(m,1H),3.56-3.54(m,2H),3.45-3.42(m,2H),3.24(s, 4H),2.06-2.03(m,2H),1.86-1.83(m,2H),1.63-1.53(m,2H),1.31-1.25(m,2H). LCMS: (Method A) 425.2 [M+H], Rt. 1.54 min, HPLC: (Method A) Rt. 2.48 min.

[0340] Example 13: 6-(1H-imidazol-1-yl)-4-(1-isopropyl-1H-pyrazol-4-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0341]

[0342]

[0343] Step 1: 6-Bromo-4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0344]

[0345] To a stirred solution of 6-bromo-4-chloropicolinic acid (3.0 g, 12.71 mmol) in DMF (30 mL) was added DIPEA (6.60 mL, 38.13 mmol) and HATU (7.23 g, 19.06 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (2.85 g, 16.52 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction mixture was stirred overnight at RT. After completion (monitored by TLC), the reaction mixture was diluted with water (45 mL). The resulting suspension was extracted with EtOAc (3×45 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue obtained was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to afford the title compound. Yield: 43% (2.1 g, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ8.44(d,J=8.4Hz,1H),8.14(d,J=1.6Hz,1H),8.00(d,J=2.0Hz,1H),3.78-3.71(m,1H),3.55-3.5 2(m,2H),3.43-3.41(m,2H),3.24-3.18(m,4H),2.01-198(m,2H),1.81-1.78(m,2H),1.54-1.49(m,2H),1.26-1.21(m,2H). LCMS: (Method C) 391.0 [M+H], Rt. 2.20min.

[0346] Step 2: 4-Chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0347]

[0348] A mixture of 6-bromo-4-chloro-N-((1r, 4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.510 mmol), imidazole (31.2 mg, 0.459 mmol), K2CO3 (105.69 mg, 0.765 mmol), copper iodide (9.7 mg, 0.0510 mmol) in DMF (15 mL) placed in a sealed tube was purged with N2 for 5 min. The reaction mixture was heated at 90 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, it was filtered through diatomaceous earth and washed with DCM (10 mL). The filtrate was evaporated in vacuo to obtain a crude product, which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM). Yield 65% (125.1 mg, colloidal solid). 1 HNMR (400MHz, DMSO-d6): δ8.99(s,1H),8.63(d,J=8.4Hz,1H),8.30(d,J=1.6Hz,1H),8.26(d,J=1.6Hz,1H),7.92(d,J=2.0Hz,1H),7.16(s,1H),3 .86-3.82(m,1H),3.55-3.54(m,2H),3.44-3.43(m,2H),3.26(s,4H),2.0 6-2.03(m,2H),1.84-1.81(m,2H),1.62-1.52(m,2H),1.29-1.20(m,2H). LCMS: (Method C) 379.2 [M+H], Rt. 1.37 min.

[0349] Step 3: 6-(1H-imidazol-1-yl)-4-(1-isopropyl-1H-pyrazol-4-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0350]

[0351] A mixture of 4-chloro-6-(1H-imidazole-1-yl)-N-((1r, 4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (120 mg, 0.3177 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1H-pyrazole (89.9 mg, 0.3809 mmol), NaHCO (80.01 mg, 0.9523 mmol), Pd(PPh) (36.66 mg, 0.03177 mmol) in 2.0 mL DMF and 0.1 mL water in a sealed tube was purged with nitrogen for 5 min. The reaction mixture was heated at 100 ° C for 16 h. After the reaction was completed, it was filtered through diatomaceous earth and washed with DCM (10 mL). The solvent was evaporated in vacuo to give a crude compound. The resulting crude product was purified by column chromatography on Biotage isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM) to give the title compound, which was further purified by preparative HPLC (method TFA). The preparative fractions were concentrated, diluted with DCM and neutralized with 10% NaHCO3 aqueous solution. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and lyophilized to give the title compound. Yield: 28% (40 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ8.97(s,1H),8.71(s,1H),8.52(d,J=8.4Hz,1H),8.31-8.30(m ,1H),8.28(s,1H),8.15(d,J=1.2Hz,1H),8.11(d,J=1.2Hz,1H),7.19(s,1H),4.58-4.54 (m, 1H), 3.89-3.85 (m, 1H), 3.57-3.51 (m, 2H), 3.45-3.42 (m, 2H), 3.26 (s, 4H), 2.08-2.03 (m, 2H), 1.86-1.83 (m, 2H), 1.60-1.56 (m, 2H), 1.49 (d, J = 6.4 Hz, 6H), 1.28-1.24 (m, 2H). LCMS: (Method C) 453.2 [M+H], Rt. 1.47 min, HPLC: (Method A) Rt. 2.80 min.

[0352] Example 14: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)picolinamide

[0353]

[0354] To a stirred solution of 4-chloro-6-(1H-imidazole-1-yl)-N-((1r, 4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (90 mg, 0.24 mmol) in DMF (3.0 mL) and water (one drop) was added 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1H-pyrazole (67 mg, 0.28 mmol) and NaHCO (59 mg, 0.71 mmol) at RT and the mixture was purged with N (gas) for 5 min. Pd(PPh) (27.4 mg, 0.02 mmol) was then added at RT and the reaction mixture was heated at 100 ° C in a sealed tube for 16 h. After completion (monitored by TLC), the reaction mixture was filtered through a bed of celite and the bed was washed with DCM (10 mL). The filtrate was concentrated in vacuo and the resulting crude material was purified by preparative HPLC (Method A). The preparative fractions were concentrated in vacuo. DCM was added to the residue and neutralized with 10% aqueous NaHCO3. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and lyophilized to give the title compound. Yield: 46% (50.1 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ8.98 (s, 1H), 8.58 (d, J = 8.8Hz, 1H), 8.31-8.30 (m, 1 H),7.81-7.79(m,2H),7.17-7.16(m,1H),3.89-3.83(m,1H),3.76(s,3H),3.5 7-3.55(m,2H),3.45-3.43(m,2H),3.31-3.24(m,4H),2.34(s,3H),2.24(s,3H ),2.07-2.04(m,2H),1.87-1.83(m,2H),1.61-1.57(m,2H),1.28-1.24(m,2H). LCMS: (Method C) 453.2 [M+H], Rt. 1.39 min, HPLC: (Method A) Rt. 2.53 min.

[0355] Example 15: 4-amino-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0356]

[0357] Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0358]

[0359] To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.8 mmol) in DMF (15 mL) was added DIPEA (4.19 mL, 23.43 mmol) and HATU (5.93 g, 15.62 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reactant was further stirred overnight at RT. The reaction mixture was monitored by TLC and quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the crude compound which was purified by Biotage Isolera column chromatography (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 49% (1.35 g, yellow solid). 1 HNMR (400 MHz, DMSO-d6): δ 8.49 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 3.87-3.81 (m, 1H), 3.54-3.52 (m, 2H), 3.44-3.40 (m, 2H), 3.21-3.20 (m, 4H), 2.01-198 (m, 2H), 1.81-1.78 (m, 2H), 1.53-1.49 (m, 2H), 1.25-1.21 (m, 2H). LCMS: (Method C) 347.1. [M+H] 349.1 and [M+H], Rt. 2.27 min.

[0360] Step 2: 6-Chloro-4-((2,4-dimethoxybenzyl)amino)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0361]

[0362] To a mixture of 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (1.5 g, 4.32 mmol) in NMP (10 mL) was added (2,4-dimethoxyphenyl)methylamine (794.1 mg, 4.75 mmol), DIPEA (1.50 mL, 8.646 mmol), and purged with N2 for 5 min. The reaction mixture was then heated at 80 °C in a sealed tube overnight. The reaction mixture was quenched with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the crude compound, which was purified by Biotage Isolera column chromatography (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 65% (1.30 g, yellow solid). 1 HNMR (300MHz, DMSO-d6): δ8.00 (d, J=8.4Hz, 1H), 7.57-7.56 (m, 1H), 7.21 (s, 1H), 7.10(d,J=8.1Hz,1H),6.58(s,2H),6.48(d,J=8.4Hz,1H),4.21(d,J=5.4Hz,2H),3 .82 (s, 3H), 3.78-3.68 (m, 4H), 3.54-3.51 (m, 2H), 3.43-3.40 (m, 2H), 3.24-3.22 (m, 4H), 1.99-1.90 (m, 2H), 1.80-1.76 (m, 2H), 1.46-1.42 (m, 2H), 1.26-1.19 (m, 2H). LCMS: (Method C) 478.2 [M+H], Rt. 1.29 min.

[0363] Step 3: 4-Amino-6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide.

[0364]

[0365] To a stirred solution of 6-chloro-4-((2,4-dimethoxybenzyl)amino)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (1.3 g, 2.726 mmol) was added TFA (9.39 mL 122.641 mol) at 0°C and continued for 3 h at RT. After completion of the reaction, the reaction mixture was cooled to 0°C and ice-cold water was slowly added before neutralization with a saturated solution of Na2CO3. The solid formed during the neutralization was filtered, washed with water, hexane and dried to obtain the title compound. Yield: 96% (860 mg, off-white solid). 1 HNMR (300MHz, DMSO-d6): δ7.99(d,J=8.4Hz,1H),7.18(d,J=2.1Hz,1H),6.71(s,2H),6.58(d,J=2.1Hz,1H),3.81-3.75(m,1H),3.5 2-3.51(m,2H),3.43-3.41(m,2H),3.24-3.21(m,4H),1.99-1.96(m,2H),1.80-1.77(m,2H),1.47-1.43(m,2H),1.24-1.20(m,2H). LCMS: (Method C) 328.2[M+H], Rt.1.74min.

[0366] Step 4: 4-amino-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0367]

[0368] A mixture of 4-amino-6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.611 mmol), imidazole (124.7 mg, 1.834 mmol), KCO (253.2 mg, 1.834 mmol), copper iodide (11.6 mg, 0.0611 mmol) in DMF (4 mL) was purged with N for 5 min, and then the reaction mixture was heated at 140 °C in a sealed tube for 48 h. The reaction mixture was filtered through a bed of celite and washed with DCM (10 mL). The filtrate was evaporated in vacuo to give the crude product, which was further purified by preparative HPLC (Method A). The preparative fractions were concentrated to remove ACN, and the resulting fractions were neutralized with 10% aqueous NaHCO and extracted with DCM. The organic phase was washed with water, brine, dried over anhydrous NaSO and evaporated to give the title compound. Yield 13% (30.1 mg, off-white solid). 1HNMR (400MHz, DMSO-d6): δ8.71 (s, 1H), 8.31 (d, J = 8.8Hz, 1H), 7.94 (s, 1H) ,7.19(d,J=1.6Hz,1H),7.09(s,1H),6.79(d,J=1.6Hz,1H),6.64(s,2H),3. 81-3.75(m,1H),3.54-3.53(m,2H),3.44-3.42(m,2H),3.25-3.21(m,4H),2 .04-2.01(m,2H),1.82-1.79(m,2H),1.57-1.47(m,2H),1.28-1.19(m,2H). LCMS: (Method A) 360.3 [M+H], Rt. 1.13 min. HPLC: (Method A) Rt. 2.03 min.

[0369] Example 16: 4,6-di(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0370]

[0371] Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0372]

[0373] To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.80 mmol) in DMF (15 mL) was added DIPEA (4.19 mL, 23.43 mmol) and HATU (5.93 g, 15.62 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After completion, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 49% (1.35 g, yellow solid). 1H NMR (400MHz, DMSO-d6): δ8.49(d,J=8.4Hz,1H),8.03(d,J=1.6Hz,1H),8.00(d,J=1.6Hz,1H),3.87-3.81(m,1H),3.54-3.5 2(m,2H),3.44-3.40(m,2H),3.31-3.25(m,4H),2.01-198(m,2H),1.81-1.78(m,2H),1.53-1.49(m,2H),1.25-1.21(m,2H). LCMS: (Method C) 347.1[M+H], 349.1[M+H], Rt.2.27min.

[0374] Step 2: 4,6-di(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0375]

[0376] A mixture of 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (0.1 g, 0.29 mmol), imidazole (17.63 mg, 0.259 mmol) and KCO (59.65 mg, 0.43 mmol) in DMF (2 mL) in a sealed tube was purged with N for 5 min. Copper iodide (5.4 mg, 0.03 mmol) was subsequently added, the tube was sealed, and the reaction mixture was heated at 125 ° C overnight. The reaction was monitored by LCMS. After completion, the reaction mixture was filtered through diatomaceous earth and the diatomaceous earth bed was washed with DCM (10 mL). The filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC (method A). The preparative fraction was concentrated, diluted with DCM and neutralized with a 10% NaHCO aqueous solution. The organic layer was washed with water, brine, dried over anhydrous NaSO and concentrated to give the title compound. Yield: 16% (19.2 mg, off-white solid). 1H NMR (400MHz, DMSO-d6): δ9.03 (s, 1H), 8.75 (s, 1H), 8.64 (d, J = 8.8Hz, 1H), 8.36-8.3 5(m,1H),8.27-8.26(m,1H),8.22-8.21(m,1H),8.20-8.19(m,1H),7.23-7.22(m,1H ), 7.20 (s, 1H), 3.89-3.81 (m, 1H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 2H), 3.31-3.22 (s, 4H), 2.07-2.04 (m, 2H), 1.86-1.84 (m, 2H), 1.64-1.55 (m, 2H), 1.32-1.23 (m, 2H). LCMS: (Method A) 411.2 [M+H], Rt. 1.25 min. HPLC: (Method B) Rt. 4.07 min.

[0377] Example 17: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide

[0378]

[0379] Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0380]

[0381] To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.8 mmol) in DMF (15 mL) was added DIPEA (4.19 mL, 23.43 mmol) and HATU (5.93 g, 15.62 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction mixture was stirred for 16 h at RT. The reaction mixture was monitored by TLC. After the reaction was completed, it was quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 49% (1.35 g, yellow solid). 1HNMR 400MHz, DMSO-d6): δ8.49(d,J=8.4Hz,1H),8.03(d,J=1.6Hz,1H),8.00(d,J=1.6Hz,1H),3.87-3.81(m,1H),3.54-3.5 2(m,2H),3.44-3.40(m,2H),3.20(s,4H),2.01-198(m,2H),1.81-1.78(m,2H),1.53-1.49(m,2H),1.25-1.21(m,2H). LCMS: (Method C) 347.1. [M+H], Rt. 2.27 min.

[0382] Step 2: 6-Chloro-4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide and 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0383]

[0384] A mixture of 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (700 mg, 2.017 mmol), imidazole (123.4 mg, 1.81 mmol), copper iodide (38.32 mg, 0.201 mmol) and K2CO3 (417.5 mg, 3.025 mmol) in DMF (15 mL) placed in a sealed tube was purged with N2 for 5 min. The reaction mixture was heated at 90 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, it was filtered through a diatomaceous earth bed and washed with DCM (10 mL). The filtrate was evaporated in vacuo to obtain a crude product, which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM). Yield 80% (610.1 mg, colloidal solid). 1HNMR (400MHz, DMSO-d6): δ8.71(s,1H),8.45(d,J==8.4Hz,1H),8.27(d,J=2.8Hz,1H),8.19(d,J=2.0Hz,1H),8.14(s,1H),7.19(s,1H),3.81- 3.78(m,1H),3.56-3.52(m,2H),3.44-3.41(m,2H),3.23(s,4H),2.02- 2.00(m,2H),1.84-1.81(m,2H),1.58-1.48(m,2H),1.20-1.29(m,2H). LCMS: (Method C) 379.2 [M+H], Rt. 1.13 min, 379.2 [M+H], Rt. 1.02 min.

[0385] Step 3: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide

[0386]

[0387] 6-Chloro-4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide and 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (600 mg, 1.587 mmol, 72.56% and 25.7% isomer ratio), 5-(4,4,5,5-tetramethyl-1,3, A mixture of 2-(2-dioxaborin-2-yl)thiazole (401.9 mg, 1.904 mmol), CuI (30.15 mg, 0.1587 mmol), potassium carbonate (547.61 mg, 3.968 mmol), Pd(dppf)Cl2.DCM (64.81 mg, 0.0793 mmol) in 9.0 mL of ethanol and water (1.0 mL) was placed in a sealed tube and nitrogen was purged through the reaction mixture for 5 min. The reaction mixture was then heated at 100 °C for 16 h. After completion of the reaction, it was filtered through celite and washed with DCM (20 mL). The solvent was evaporated in vacuo to give the crude compound. The crude product was purified by column chromatography on Biotage isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM) to give the title compound, which was further purified by preparative HPLC (Method HCOOH). The preparative fraction of the minor isomer was concentrated, diluted with DCM and neutralized with 10% aqueous NaHCO3. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to give the title compound. Yield: 3.2% (21 mg, off-white solid) 1 HNMR (400MHz, DMSO-d6): δ9.33(d,J=0.4Hz,1H),9.03(s,1H),8.84(d,J=0.4Hz,1H ),8.61(d,J=8.8Hz,1H),8.38-8.37(m,1H),8.31(d,J=1.6Hz,1H),8.09(d,J=1.2Hz , 1H), 7.19 (s, 1H), 3.87-3.84 (m, 1H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 2H), 3.24 (s, 4H), 2.06-2.03 (m, 2H), 1.86-1.83 (m, 2H), 1.61-1.54 (m, 2H), 1.31-1.23 (m, 2H). LCMS: (Method C) 428.4 [M+H], Rt. 1.18 min, HPLC: (Method A) Rt. 2.306 min.

[0388] Example 18: 4-Chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-picolinamide

[0389]

[0390] A mixture of 6-bromo-4-chloro-N-((1r, 4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.510 mmol), imidazole (31.2 mg, 0.459 mmol), K2CO3 (105.69 mg, 0.765 mmol), copper iodide (9.7 mg, 0.0510 mmol) in DMF (15 mL) placed in a sealed tube was purged with N2 for 5 min. The reaction mixture was heated at 90 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, it was filtered through diatomaceous earth and washed with DCM (10 mL). The filtrate was evaporated in vacuo to obtain a crude product, which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM). Yield 65% (125.1 mg, colloidal solid). 1 HNMR (400MHz, DMSO-d6): δ8.99(s,1H),8.63(d,J=8.4Hz,1H),8.30(d,J=1.6Hz,1H),8.26(d,J=1.6Hz,1H),7.92(d,J=2.0Hz,1H),7.16(s,1H),3 .86-3.82(m,1H),3.55-3.54(m,2H),3.44-3.43(m,2H),3.26(s,4H),2.0 6-2.03(m,2H),1.84-1.81(m,2H),1.62-1.52(m,2H),1.29-1.20(m,2H). LCMS: (Method C) 379.2 [M+H], Rt. 1.37 min.

[0391] Example 19: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide

[0392]

[0393] Step 1: Methyl 4-(trifluoromethyl)picolinate

[0394]

[0395] To a stirred solution of 4-(trifluoromethyl)picolinic acid (1 g, 5.23 mmol) in MeOH (10 mL) was slowly added thionyl chloride (1.15 mL, 15.69 mmol) over 5 min at 0 ° C and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was neutralized with saturated NaHCO3 solution (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo to give the title compound. Yield: 75% (0.8 g, light yellow liquid). 1 HNMR (400 MHz, DMSO-d6): δ 8.98 (d, J = 5.2 Hz, 1H), 8.39-8.39 (m, 1H), 7.75-7.73 (m, 1H), 4.08 (s, 3H). LCMS: (Method C) 206.0 [M+H], Rt. 1.809 min.

[0396] Step 2: 2-(Methoxycarbonyl)-4-(trifluoromethyl)pyridine 1-oxide

[0397]

[0398] To a stirred solution of methyl 4-(trifluoromethyl)picolinate (0.6 g, 2.92 mmol) in DCM (20 mL) was added urea peroxide (0.55 g, 5.84 mmol) and TFAA (1.22 g, 5.84 mmol) and stirred at RT for 16 h. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM (2×20 mL). The combined organic layers were washed with brine solution (20 mL), water (20 mL), dried over anhydrous Na2SO4, filtered and dried in vacuo to give the title compound. Yield: 94% (0.61 g, light yellow liquid). 1HNMR 400 MHz, DMSO-d6: δ 8.33 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.59-7.56 (m, 1H), 4.05 (s, 3H). LCMS: (Method C) 222.0 [M+H], Rt. 1.286 min.

[0399] Step 3: Methyl 6-chloro-4-(trifluoromethyl)picolinate

[0400]

[0401] A solution of methyl 2-(methoxycarbonyl)-4-(trifluoromethyl)pyridine 1-oxide (0.6 g) and POCl3 (10 mL) was heated to 70°C overnight. The reaction mixture was concentrated under reduced pressure. The resulting crude material was dissolved in EtOAc (25 mL) and neutralized with saturated NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound. Yield: 92% (0.6 g, off-white solid). 1 HNMR (400 MHz, CDCl3): δ 8.30 (d, J = 0.4 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 4.07 (s, 3H). LCMS: (Method C) 220.0 [MH], Rt. 2.197 min.

[0402] Step 4: 6-Chloro-4-(trifluoromethyl)picolinic acid

[0403]

[0404] To a solution of methyl 6-chloro-4-(trifluoromethyl)picolinate (0.6 g, 2.51 mmol) in THF (12 mL) and water (4 mL) was added NaOH (0.301 g, 7.53 mmol) at RT and stirred overnight at the same temperature. The reaction mixture was evaporated in vacuo and acidified with 1.5 N HCl solution to adjust the pH to about 2.0 and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to give the title compound. Yield: 88% (0.5 g, light brown liquid). 1 HNMR 400 MHz, DMSO-d6): δ 14.11 (s, 1H), 8.31-8.31 (m, 1H), 8.24 (d, J=0.4 Hz, 1H). LCMS: (Method C) 226.2 [M+H], Rt. 1.547 min.

[0405] Step 5: 6-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide

[0406]

[0407] To a stirred solution of 6-chloro-4-(trifluoromethyl)picolinic acid (0.5 g, 2.22 mmol) in DMF (10 mL) was added DIPEA (1.19 mL, 6.66 mmol) and HATU (1.26 g, 3.33 mmol) at RT. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (0.461 g, 2.66 mmol) was added at the same temperature. The reactant was further stirred overnight at RT. The reaction mixture was monitored by TLC and quenched with water (20 mL). The resulting suspension was extracted with EtOAc (2×10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The crude product was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 16%-20% EtOAc / petroleum ether) to give the title compound. Yield: 62% (0.52 g, yellow gummy solid). LCMS: (Method C) 381.2 [M+H], Rt. 2.298 min.

[0408] Step 6: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide

[0409]

[0410] A mixture of 6-chloro-N-((1r, 4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide (0.2 g, 0.52 mmol), imidazole (107 mg, 1.57 mmol), copper iodide (9.9 mg, 0.05 mmol) and KCO (217 mg, 1.57 mmol) in DMF (4 mL) was purged with N for 2 min, and the reaction mixture was then heated in a sealed tube at 120 ° C overnight. The reaction mixture was diluted with EtOAc (10 mL) and filtered through a diatomaceous earth bed. The filtrate was evaporated in vacuo and the resulting crude product was purified by preparative HPLC (method C). The preparative fractions were collected and concentrated under reduced pressure to give the product. The product was then dissolved in 10% MeOH / DCM (10 mL) and neutralized with 10% NaHCO solution (4 mL), followed by washing with brine solution and water. The organic layer was dried over anhydrous Na2SO4, filtered, dried under reduced pressure and lyophilized to give the product. Yield: 44% (95.53 mg, white gummy solid). 1HNMR (400MHz, DMSO-d6): δ9.09-9.09(m,1H),8.73(d,J=8.4Hz,1H),8.45(s,1H),8.43-8.42(m,1H),8.12(d,J=0.4Hz,1H),7.20-7.20(m,1H),3.89 -3.83(m,1H),3.57-3.55(m,2H),3.45-3.42(m,2H),3.33-3.26(m,4H),2. 07-2.04(m,2H),1.86-1.83(m,2H),1.65-1.54(m,2H),1.32-1.22(m,2H). LCMS: (Method A) 413.0 [M+H], Rt. 1.902 min, HPLC: (Method A) Rt. 2.611 min.

[0411] Example 20: 4-Fluoro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0412]

[0413] Step 1: 4-Chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0414]

[0415] A mixture of 6-bromo-4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (620 mg, 1.585 mmol), imidazole (97.04 mg, 1.427 mmol), copper iodide (27.10 mg, 0.142 mmol), L-proline (32.8 mg, 0.285 mmol) and KCO (395.9 mg, 2.86 mmol) in DMSO (5 mL) was purged with N for 5 min and then the reaction mixture was heated in a sealed tube at 65 °C for 48 h. The reaction was monitored by LCMS and after completion of the reaction, the reaction mixture was filtered through a celite bed and washed with DCM (10 mL). The filtrate was evaporated in vacuo to give the crude product which was purified by Biotage Isolera column chromatography (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM). Yield 35% (210 mg, gummy solid). 1HNMR (300MHz, DMSO-d6): δ8.99(s,1H),8.63(d,J=8.7Hz,1H),8.29(d,J=4.5Hz,1H),8.26(d,J=1.5Hz,1H),7.92(d,J=1.5Hz,1H),7.17(s,1H),3 .89-3.88(m,1H),3.57-3.53(m,2H),3.45-3.43(m,2H),3.18(s,4H),2.0 6-2.03(m,2H),1.84-1.81(m,2H),1.60-1.51(m,2H),1.31-1.23(m,2H). LCMS: (Method C) 379.2 [M+H], Rt. 1.44 min.

[0416] Step 2: 4-Fluoro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0417]

[0418] To a mixture of 4-chloro-6-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.529 mmol) in DMSO (4.0 mL) was added cesium fluoride (200.91 mg, 1.322 mmol) at RT, and nitrogen was purged through the reaction mixture for 5 min. The reaction mixture was then heated in a sealed tube at 100 °C for 3 h. The reaction mixture was monitored by TLC and quenched with water (15 mL). The resulting suspension was extracted with DCM (3×25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo to give the crude compound, which was purified by preparative HPLC (Method C). The preparative fractions were concentrated to remove ACN, and the resulting aqueous layer was neutralized with 10% NaHCO3. It was then extracted with DCM (25 mL) and the DCM layer was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to give the title compound. Yield: 21% (41.1 mg, off-white solid). 1HNMR (400MHz, DMSO-d6): δ8.99(s,1H),8.63(d,J=8.8Hz,1H),8.28-8.27(m,1H),8.08-8.05(m,1H),7.76-7.73(m,1H),7.17(s,1H),3.86-3 .82(m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.23(s,4H),2.06- 2.03(m,2H),1.84-1.81(m,2H),1.62-1.54(m,2H),1.30-1.21(m,2H). LCMS: (Method C) 363.0 [M+H], Rt. 1.18 min, HPLC: (Method A) Rt. 2.217 min.

[0419] Example 21: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0420]

[0421] Step 1: 2-Bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0422]

[0423] To a stirred solution of 2-bromoisonicotinic acid (510 mg, 2.52 mmol) in DMF (5 mL) was added HATU (1.43 g, 3.78 mmol) at 0 ° C under nitrogen atmosphere, followed by DIPEA (1.16 mL, 6.30 mmol) and stirred for 5 min. After 5 min, (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (656 mg, 3.78 mmol) was added and stirred at RT for 16 h. After completion, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (50 mL). The ethyl acetate layer was washed with water (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound. Yield: 48.2% (435 mg, yellow solid). 1HNMR (400MHz, DMSO-d6): δ8.59(d,J=7.60Hz,1H),8.53(d,J=5.20Hz,1H),7. 99(s,1H),7.78(dd,J=6.40,1.2Hz,1H),3.84-3.79(m,1H),3.57-3.50(m,2H) ,3.45-3.40(m,2H),3.30-3.20(m,4H),2.06-2.00(m,2H),1.84-1.80(m,2H) ,1.61-1.50(m,2H),1.30-1.20(m,2H), LCMS: (Method A) 357.0[M+H], Rt.1.86min.

[0424] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0425]

[0426] A solution of 2-bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (191 mg, 0.55 mmol) and 1H-imidazole (113 mg, 1.66 mmol) in DMF (3 mL) was deoxygenated for 5 min by purging with nitrogen. After 5 min, KCO (151 mg, 1.10 mmol) was added at RT, followed by CuI (10.4 mg, 0.05 mmol), and the resulting mixture was heated at 140 ° C for 16 h. After completion, the reaction mixture was filtered through a celite pad and washed with 10% MeOH / DCM (50 mL). The combined filtrate was evaporated in vacuo to give the crude product, and the crude residue was purified by Grace normal phase chromatography (eluent: 2%-3% MeOH / DCM). The collected fractions were concentrated under reduced pressure, then redissolved in 10% MeOH / DCM (50 mL), washed with 10% aqueous NaHCO3 (20 mL), and then washed with water (2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further dried by lyophilization to give the title compound. Yield: 11.3% (20.89 mg, white solid); 1HNMR(400MHz,DMSO-d6):8.61(d,J=5.2Hz,1H),8.58-8.55(m,2H),8.08(s,1H),8.00 (s,1H),7.70-7.68(m,1H),7.16(s,1H),3.80-3.78(m,1H),3.77-3.56(m,2H),3.55-3 .50 (m, 2H), 3.43-3.29 (m, 4H), 2.05-2.00 (m, 2H), 1.93-1.90 (m, 2H), 1.41-1.38 (m, 2H), 1.35-1.24 (m, 2H); LCMS: (Method C) 345.2 [M+H], Rt. 1.03 min; HPLC: (Method A) Rt. 1.87 min.

[0427] Example 22: 2,6-Di(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0428]

[0429]

[0430] A solution of 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (72 mg, 0.20 mmol) and 1H-imidazole (84.7 mg, 1.24 mmol) in DMF (2 mL) was deoxygenated by purging nitrogen for 5 min. Afterwards, K2CO3 (143 mg, 1.03 mmol) and CuI (3.9 mg, 0.02 mmol) were added and the reaction mixture was heated at 130 ° C for 16 h. After completion, the reaction mixture was filtered through a celite pad and washed with 10% MeOH / DCM (50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue obtained was purified by Grace reverse phase chromatography (Method A). The collected fractions were concentrated under reduced pressure, diluted with 10% MeOH / DCM (50 mL), washed with 10% aqueous NaHCO3 (20 mL), water (20 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and dried by lyophilization to give the title compound. Yield: 62.8% (53.57 mg, off-white solid); 1HNMR (400 MHz, DMSO-d6): δ 8.79 (t, J = 1.2 Hz, 2H), 8.56 (d, J = 7.6 Hz, 1H), 8.17 (t, J = 1.6 Hz, 2H), 7.99 (s, 2H), 7.18 (t, J = 1.2 Hz, 2H), 3.82-3.78 (m, 1H), 3.56-3.54 (m, 2H), 3.45-3.26 (m, 4H), 2.07-2.00 (m, 2H), 1.97-1.90 (m, 2H), 1.46-1.40 (m, 2H), 1.37-1.27 (m, 2H). LCMS: (Method C) 411.0 [M+H], Rt. 0.73 min; HPLC: (Method B) Rt. 4.12 min.

[0431] Example 23: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)isonicotinamide

[0432]

[0433] A solution of 2-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (215 mg, 0.56 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (177 mg, 0.85 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was deoxygenated by purging nitrogen for 5 min. K2CO3 (195 mg, 1.41 mmol) and Pd(dppf)Cl2.DCM (46.3 mg, 0.05 mmol) were then added and the resulting reaction mixture was heated at 100°C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite and washed with 10% MeOH / DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue obtained was further purified by Grace reverse phase chromatography (Method A) and by preparative HPLC using Method A. The collected fractions were concentrated under reduced pressure, and the obtained product was redissolved in 10% MeOH / DCM (50 mL) and washed with 10% NaHCO3 aqueous solution (20 mL) and then with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further dried by lyophilization to obtain the title compound. Yield: 12.3% (29.80 mg, off-white solid); 1HNMR (400MHz, DMSO-d6): δ8.69(s,1H),8.50(d,J=8.0Hz,2H),8.17(d,J=0.8Hz,1H),8.09(t,J=1.6H z,1H),7.87(d,J=1.2Hz,1H),7.80(d,J=0.8Hz,1H),7.16(t,J=1.2Hz,1H),3.92(s,3H),3.82-3.80(m , 1H), 3.57-3.55 (m, 2H), 3.54-3.51 (m, 2H), 3.44-3.33 (m, 4H), 2.06-2.03 (m, 2H), 1.95-1.93 (m, 2H), 1.42-1.39 (m, 2H), 1.31-1.24 (m, 2H); LCMS: (Method C) 425.3 [M+H], Rt. 1.20 min; HPLC: (Method A) Rt. 2.37 min.

[0434] Example 24: 2-(1-ethyl-1H-pyrazol-4-yl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0435]

[0436]

[0437] A solution of 2-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (113 mg, 0.29 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (99.38 mg, 0.44 mmol) in 1,4-dioxane (2 mL) and water (0.13 mL) was purged with nitrogen for 5 min. After 5 min, K2CO3 (102.8 mg, 0.74 mmol) and PdCl2(dppf).DCM (24.3 mg, 0.02 mmol) were added and the resulting mixture was heated at 100°C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite and washed with 10% MeOH / DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude compound obtained was then purified by Grace reverse phase chromatography (Method A). The collected fractions were concentrated, and the product was redissolved in 10% MeOH / DCM (50 mL), washed with 10% NaHCO3 aqueous solution (20 mL), and then washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further dried by lyophilization to obtain the title compound. Yield: 24% (31.5 mg, off-white solid); 1 HNMR (400MHz, DMSO-d6): δ8.90(s,1H),8.57-8.51(m,2H),8.19-8.17(m,2H),7.91(s,1H) ),7.85(s,1H),7.27(s,1H),4.21(q,J=7.2Hz,2H),3.81-3.75(m,1H),3.56-3.54(m,2H), 3.44-3.42 (m, 2H), 3.27-3.25 (m, 4H), 2.05-2.03 (m, 2H), 1.95-1.92 (m, 2H), 1.46-1.37 (m, 5H), 1.31-1.26 (m, 2H); LCMS: (Method C) 439.2 [M+H], Rt. 1.34 min; HPLC: (Method A) Rt. 2.66 min.

[0438] Example 25: 2-(1H-imidazol-1-yl)-6-(1-isopropyl-1H-pyrazol-4-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0439]

[0440]

[0441] A solution of 2-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (102 mg, 0.26 mmol) and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (95.3 mg, 0.40 mmol) in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL) was deoxygenated by purging nitrogen for 5 min. K2CO3 (92.87 mg, 0.67 mmol) and Pd(dppf)Cl2.DCM (21.96 mg, 0.02 mmol) were then added and the reaction mixture was heated at 100°C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite and washed with 10% MeOH / DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude residue which was subsequently purified by Grace reverse phase chromatography (Method A). The collected fractions were concentrated under reduced pressure and the obtained product was redissolved in 10% MeOH / DCM (50 mL). The layer was washed with 10% NaHCO3 solution (20 mL), water (20 mL), and dried over anhydrous Na2SO4, concentrated under reduced pressure, and further dried by lyophilization to give the title compound. Yield: 42.5% (51.88 mg, light yellow solid); 1 HNMR (400MHz, DMSO-d6): δ8.73-8.72(m,1H),8.59(s,1H),8.50(d,J=7.6Hz,1H),8.18(d,J=0.4Hz,1H),8.11- 8.10(m,1H),7.90(d,J=0.8Hz,1H),7.80(d,J=1.2Hz,1H),7.17-7.10(m,1H),4.59-4.50(m,1H),3.59-3.55(m , 1H), 3.55-3.45 (m, 2H), 3.45-3.26 (m, 2H), 3.36-3.32 (m, 4H), 2.06-2.00 (m, 2H), 1.95-1.90 (m, 2H), 1.50 (d, J = 6.8 Hz, 6H), 1.40 (m, 2H), 1.32-1.25 (m, 2H); LCMS: (Method C) 453.0 [M+H], Rt. 1.26 min; HPLC: (Method A) Rt. 2.85 min.

[0442] Example 26: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-3-yl)isonicotinamide

[0443]

[0444] Step 1: 2-Chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide

[0445]

[0446] A stirred solution of 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (950 mg, 2.73 mmol) in DMF (100 mL) and 1H-imidazole (558 mg, 8.20 mmol) was degassed for 10 min before potassium carbonate (1.13 g, 8.20 mmol) was added followed by CuI (51.9 mg, 0.27 mmol) at RT. The reaction mixture was heated at 100 °C for 16 h. Upon completion, the reaction mixture was filtered through celite and washed with 5% MeOH / DCM (200 mL). The combined organic layers were washed with 10% NaHCO3 solution (50 mL) followed by water (2 x 50 mL). The combined organic layers were evaporated in vacuo and the resulting crude material was purified by grace chromatography using silica gel (100-200 mesh, 2%-3% MeOH / DCM) to give the title compound. Yield: 40% (410 mg, brown solid). LCMS: (Method C) 378.9 [M+H], Rt 1.26 min.

[0447] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-3-yl)isonicotinamide

[0448]

[0449] To a stirred solution of 2-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (100 mg, 0.26 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (80 mg, 0.39 mmol) in a mixture of 1,4-dioxane (2.5 mL) and water (0.25 mL) was purged with nitrogen through the reaction mixture for 5 min before adding K2CO3 (110 mg, 0.78 mmol) followed by Pd(dppf)Cl2.DCM (20 mg, 0.02 mmol) at RT. The reaction mixture was heated at 100°C for 16 h. Upon completion, the reaction mixture was filtered through celite and washed with 10% MeOH / DCM (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC (Method A). The preparative fractions were collected, concentrated under reduced pressure, diluted with 10% MeOH / DCM (50 mL), and washed with 10% NaHCO3 solution (20 mL), followed by water (2×20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and lyophilized to give the title compound. Yield: 52% (58.41 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ9.20(s,1H),8.73(d,J=7.6Hz,1H),8.30(s,1H),8.25(d,J=1.2Hz,1H ),8.06(d,J=1.2Hz,1H),7.90(d,J=2.0Hz,1H),7.50(s,1H),7.10(d,J=2.4Hz,1H),4.00(s,3H) ,3.85-3.80 (m, 1H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 2H), 3.30-3.24 (m, 4H), 2.06-2.03 (m, 2H), 1.93-1.91 (m, 2H), 1.45-1.38 (m, 2H), 1.32-1.25 (m, 2H), LCMS: (method C) 425.2 [M+H], Rt. 1.20 min. HPLC: (method A) Rt. 2.33 min.

[0450] Example 27: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxamide

[0451]

[0452] Step 1: 2-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid methyl ester

[0453]

[0454] A solution of methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate (1.0 g, 4.58 mmol) in dioxane (15 mL) was purged with nitrogen for 15 min, and then copper thiophene-2-carboxylate (1) (1.75 g, 9.17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (1.9 g, 9.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.53 g, 0.46 mmol) were charged at RT and heated at 85 °C for 6 h. The reaction mixture was diluted with 5% methanol / DCM and filtered through celite. The combined filtrate was concentrated in vacuo, and the resulting crude material was purified by flash chromatography on a Biotage Isolera to give the title compound. Yield: 28% (0.32 g, yellow solid). 1 HNMR (400 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.3 (s, 1H), 8.2 (s, 1H), 3.9 (s, 3H), 3.9 (s, 3H). LCMS: (Method A) 253.0 [M+H], 1.50 min.

[0455] Step 2: 2-(1H-imidazol-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid

[0456]

[0457] The reaction mixture of 2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid methyl ester (0.31 g, 1.23 mmol), imidazole (0.33 mg, 4.92 mmol), CuI (233 mg, 1.23 mmol) and KCO (0.68 g, 4.92 mmol) in DMF (3 mL) was heated to 120 ° C overnight. The reaction mixture was diluted with water (20 mL) and filtered through a celite bed. The filtrate was concentrated to give the crude title compound, which was used as is in the next step. 1 HNMR (400 MHz, DMSO-d6): δ12.1 (s, 1H), 8.6 (s, 1H), 8.3 (s, 1H), 8.0 (s, 1H), 7.7 (s, 1H), 7.6 (s, 1H), 3.9 (s, 3H). LCMS (reaction mixture): (Method A) 271.0 [M+H], 0.22 min.

[0458] Step 3: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxamide

[0459]

[0460] To a stirred solution of 2-(1H-imidazole-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid (28 mg, 0.10 mmol) in DMF (1 mL) was added EDC.HCl (30 mg, 0.15 mmol), HOBt (21 mg, 0.15 mmol) and DIPEA (40 mg, 0.31 mmol) followed by (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (23 mg, 0.13 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (10 mL) and extracted with 5% methanol / DCM (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude residue was purified by preparative HPLC (Method A). Fractions from preparative HPLC were made slightly basic with aqueous NaHCO3 solution, and ACN was removed under reduced pressure on a rotavapour. The aqueous layer was extracted with 5% methanol / DCM (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo to give the title compound. Yield: 23% (10 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ9.04(s,1H),8.83(s,1H),8.76(d,J=8.80Hz,1H),8.43(s,1H),8.3(s,1H),8.1(s,1H),7.2(s,1H),3.9(s,3H),3.8 0-0.00(m,1H),3.57-3.56(m,2H),3.45-3.43(m,2H),3.2(s,4H),2.07 -2.04(m,2H),1.87-1.84(m,2H),1.60-1.56(m,2H),1.25-1.24(m,2H). LCMS: (Method A) 426.2 [M+H], Rt. 1.34 min, 98.56%. HPLC: (Method A) Rt. 2.34 min.

[0461] Example 28: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0462]

[0463] Step 1: 2-Chloropyrimidine-4-carbonyl chloride

[0464]

[0465] To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (1 g, 6.3 mmol) and 2 drops of DMF / DCM (20 ml) was added oxalyl chloride (1.20 g, 9.46 mmol) at 0°C and stirred at RT for 2 h. The reaction mixture was dried in vacuo to give the desired product. Yield: 98% (1 g, light brown gum).

[0466] Step 2: 2-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0467]

[0468] To a stirred solution of 2-chloropyrimidine-4-carbonyl chloride (1 g, 5.65 mmol) and TEA (2.37 mL, 16.95 mmol) in THF (20 mL) at 0°C was added (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (0.977 g, 5.65 mmol) at the same temperature and stirred overnight at RT. The reaction mixture was quenched with saturated NaHCO3 solution (20 mL). The resulting suspension was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo to give the title compound. Yield: 84% (1.5 g, light brown gummy solid). LCMS: (Method C) 314.2 [M+H], Rt. 1.615 min.

[0469] Step 3: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0470]

[0471] A mixture of 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide (1.5 g, 4.78 mmol), imidazole (975 mg, 14.34 mmol), copper iodide (90.5 mg, 0.478 mmol) and KCO (1.97 g, 14.34 mmol) in DMF (20 mL) was purged with N for 5 min, and the reaction mixture was then heated in a sealed tube at 120 ° C overnight. The reaction mixture was diluted with DCM and filtered through a celite bed. The filtrate was evaporated in vacuo and the resulting crude product was purified by preparative HPLC (method A). The preparative fractions were concentrated under reduced pressure to give the product. The product was then dissolved in 10% MeOH / DCM (20 mL) and neutralized with 10% NaHCO solution (10 mL), followed by washing with brine solution and water. The organic layer was dried over anhydrous Na2SO4, filtered, dried under reduced pressure and lyophilized to give the product. Yield: 38% (635.57 mg, light yellow gummy solid). 1 HNMR(400MHz, DMSO-d6: δ9.06(d,J=4.8Hz,1H),8.97(s,1H),8.85(d,J=8.8Hz,1H),8.23(s,1 H),7.91(d,J=5.2Hz,1H),7.19(s,1H),7.33(d,J=8.4Hz,1H),3.89-3.81(m,1H),3.57-3.54( m, 2H), 3.45-3.42 (m, 2H), 3.34-3.26 (m, 4H), 2.07-2.04 (m, 2H), 1.86-1.83 (m, 2H), 1.62-1.52 (m, 2H), 1.31-1.21 (m, 2H). LCMS: (Method C) 346.0 [M+H], Rt. 1.336 min. HPLC: (Method A) Rt. 2.006 min.

[0472] Example 29: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide

[0473]

[0474] Step 1: 6-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide

[0475]

[0476] To a stirred solution of 6-chloro-4-methylpicolinic acid (511 mg, 2.97 mmol) in DMF (5 mL) at 0 ° C under nitrogen atmosphere was added EDC.HCl (856 mg, 4.46 mmol), HOBt (603 mg, 4.46 mmol), followed by DIPEA (1.37 mL, 7.44 mmol) and the resulting mixture was stirred for 5 min. After 5 min, (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (774 mg, 4.46 mmol) was added and stirred at RT for 16 h. After completion, the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (50 mL), washed with water (2×20 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the title compound. Yield: 77.05% (750 mg, brown solid); 1 H NMR (400MHz, DMSO-d6): δ11.99(s,1H),8.18(d,J=7.6Hz,1H),7.61(d,J=8.0Hz,1H),7.54(d,J=16.4Hz,1H),6.91(s,1H),3.75-3.70(m,1 H),3.53-3.50(m,2H),3.42-3.40(m,2H),3.25-3.16(m,4H),2.20-1.86(m,4H),1.39-1.22(m,4H), LCMS: (Method C) 327.2[M+H], Rt.2.10min.

[0477] Step 2: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide

[0478]

[0479] To a solution of 6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide (210 mg, 0.64 mmol) and 1H-imidazole (131 mg, 1.92 mmol) in DMF (3 mL) was added KCO (266 mg, 1.92 mmol), followed by CuI (12.2 mg, 0.06 mmol) and the resulting reaction mixture was heated at 130 °C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite and washed with DCM (50 mL), and the filtrate was evaporated in vacuo to give the crude product. The crude product was then purified by Grace reverse phase chromatography (Method A), and the collected fractions were concentrated under reduced pressure. The obtained product was redissolved in 10% MeOH / DCM (50 mL), washed with 10% aqueous NaHCO3 solution (20 mL), water (2×20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. Yield: 33.5% (77.29 mg, off-white solid); 1 HNMR (400MHz, DMSO-d6): δ8.91(s,1H),8.52(d,J=8.8Hz,1H),8.22(t,J=1.2Hz,1H),7.88( s,1H),7.82(s,1H),7.15(s,1H),3.84-3.79(m,1H),3.57-3.50(m,2H),3.45-3.40(m,2H),3 .30 (s, 3H), 3.26-3.20 (m, 1H), 2.5 (s, 3H), 2.06-2.00 (m, 2H), 1.84-1.80 (m, 2H), 1.61-1.50 (m, 2H), 1.30-1.20 (m, 2H); LCMS: (Method A) 359.2 [M+H], Rt. 1.19 min; HPLC: (Method A) Rt. 2.29 min.

[0480] Example 30: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide

[0481]

[0482]

[0483] Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0484]

[0485] To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.8 mmol, CAS No. 88912-25-8) in DMF (15 mL) was added DIPEA (4.19 mL, 23.43 mmol) and HATU (5.93 g, 15.62 mmol) at 0 ° C. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reactant was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After the reaction was completed, it was quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 49% (1.35 g, yellow solid). 1 HNMR 400MHz, DMSO-d6): δ8.49(d,J=8.4Hz,1H),8.03(d,J=1.6Hz,1H),8.00(d,J=1.6Hz,1H),3.87-3.81(m,1H),3.54-3.5 2(m,2H),3.44-3.40(m,2H),3.20(s,4H),2.01-198(m,2H),1.81-1.78(m,2H),1.53-1.49(m,2H),1.25-1.21(m,2H). LCMS: (Method C) 347.1. [M+H], Rt. 2.27 min.

[0486] Step 2: 6-Chloro-4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide and 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0487]

[0488] A mixture of 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (400 mg, 1.15 mmol), imidazole (70.53 mg, 1.037 mmol), copper iodide (21.90 mg, 0.01152 mmol) and K2CO3 (397.69 mg, 2.88 mmol) in DMF (2 mL) placed in a sealed tube was purged with N2 for 5 min. The reaction mixture was heated at 95 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, it was filtered through diatomaceous earth and washed with DCM (10 mL). The filtrate was evaporated in vacuo to give a crude product, which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM) to give the title compound. Accompanying 55 yield: 71% (310.1 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ8.61(d,J=8.0Hz,1H),8.44(d,J=8.0Hz,1H),8.29(s,1H),8.21(s,1H),7.96(s,1H),7.93(s,1H),3.81-3.77 (m,1H),3.56-3.52(m,2H),3.44-3.41(m,2H),3.20(s,4H),2.09-2.02(m,2H),1.84-1.81(m,2H),1.58-1.48(m,2H),1.20-1.29(m,2H). LCMS: (Method C) 379.2 [M+H], Rt. 1.25 min, 379.2 [M+H], Rt. 1.20 min.

[0489] Step 3: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide

[0490]

[0491] 6-Chloro-4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide and 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (280 mg, 0.740 mmol, 55% major isomer and 26% minor isomer), 1-methyl-4-(4,4, A mixture of 5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (184.88 mg, 0.888 mmol, Cas No. 761446-44-0), K2CO3 (255.5 mg, 1.851 mmol), Pd(dppf)Cl2.DCM (30.24 mg, 0.0370 mmol) in 4.5 mL of dioxane and water (0.5 mL) was purged with N2 for 5 min. The reaction mixture was heated at 97 ° C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, it was filtered through diatomaceous earth and washed with DCM (20 mL). The filtrate was evaporated in vacuo to give a crude product, which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM) to give the title compound, which was further purified by preparative HPLC (method A). The preparative fractions were concentrated, dissolved with DCM and neutralized with 10% aqueous NaHCO3 solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to give the title compound. Yield: 15% (48.1 mg, off-white solid). 1 HNMR (400MHz, DMSO-d6): δ8.72(s,1H),8.60(s,1H),8.48(d,J=8.4Hz,1H),8.36(d ,J=0.4Hz,1H),8.16(d,J=2.0Hz,1H),8.13(s,1H),8.04(d,J=2.0Hz,1H),7.23(s, 1H), 3.94 (s, 3H), 3.86-3.82 (m, 1H), 3.57-3.55 (m, 2H), 3.45-3.42 (m, 2H), 3.26 (s, 4H), 2.08-2.03 (m, 2H), 1.90-1.87 (m, 2H), 1.62-1.53 ​​(m, 2H), 1.34-1.24 (m, 2H). LCMS: (Method A) 425.2 [M+H], Rt. 1.56 min, HPLC: (Method A) Rt. 2.53 min.

[0492] Example 31: N-((1r,4r)-4-hydroxycyclohexyl)-6-(1H-imidazol-1-yl)picolinamide

[0493]

[0494]

[0495] Step 1: Methyl 6-(1H-imidazol-1-yl)picolinate

[0496]

[0497] The solution of 6-bromopicolinic acid methyl ester (1.23g, 5.69mmol, CAS No. 26218-75-7) and 1H-imidazole (1.16g, 17.08mmol) in DMF (20mL) was deoxygenated by purging nitrogen for 10min. After 10min, K2CO3 (1.96g, 14.23mmol) and CuI (108mg, 0.56mmol) were added and the resulting mixture was heated at 120°C for 16h. After completion, the reaction mixture was filtered through a diatomaceous earth pad and washed with 10%MeOH / DCM (200mL). The combined filtrate was concentrated in vacuo to obtain a crude product, which was then purified by Grace chromatography using silica gel (100-200 mesh, 70%-100%EtOAc / petroleum ether) to obtain the title compound. Yield: 81.2% (940mg, light yellow solid). LCMS: (Method B)204.1[M+H],Rt.1.44min, 1 HNMR (400MHz, DMSO-d6): δ8.57(t,J=1.20Hz,1H),8.24-8.20(m,1H),8.11-8.09(m,1H),8.03-7.99(m,2H),7.17-7.16(m,1H),3.9(s,3H).

[0498] Step 2: 6-(1H-imidazol-1-yl)picolinic acid

[0499]

[0500] Methyl 6-(1H-imidazol-1-yl)picolinate (937 mg, 4.61 mmol) was dissolved in THF (5 mL) and MeOH (5 mL), then 3N NaOH aqueous solution (5 mL) was added at RT and the resulting mixture was stirred for 16 h. After completion, the solvent was evaporated in vacuo, the residue was acidified with 4M HCl / 1,4-dioxane, and then concentrated in vacuo to give the title compound. Yield: crude material (950 mg, yellow solid). LCMS: (Method C) 190.2 [M+H], Rt. 0.19 min, 1HNMR (400MHz, DMSO-d6): δ9.39 (s, 1H), 8.33-8.28 (m, 2H), 8.22 (d, J = 8.0Hz, 1H), 8.11 (d, J = 7.6Hz, 1H), 7.55 (s, 1H).

[0501] Step 3: N-((1r,4r)-4-hydroxycyclohexyl)-6-(1H-imidazol-1-yl)picolinamide

[0502]

[0503] To a stirred solution of 6-(1H-imidazole-1-yl)picolinic acid (110 mg, 0.58 mmol) in DMF (3 mL) was added HATU (331 mg, 0.87 mmol) at 0 ° C under nitrogen atmosphere, followed by DIPEA (0.26 mL, 1.45 mmol) and the resulting mixture was stirred for 10 min. After 10 min, (1r, 4r)-4-aminocyclohexan-1-ol (100 mg, 0.87 mmol) was added and stirred at RT for 16 h. After completion, the reaction mixture was concentrated to give the crude product, which was subsequently purified by Grace reverse phase chromatography (Method B). The collected fractions were concentrated under reduced pressure, and the obtained product was redissolved in 10% MeOH / DCM (20 mL), washed with 10% NaHCO3 aqueous solution (10 mL), and then washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further dried by lyophilization to give the title compound. Yield: 85.2% (141.9 mg, brown solid); 1 HNMR (400MHz, DMSO-d6): δ8.94(t,J=0.8Hz,1H),8.53(d,J=8.8Hz,1H),8.26(t,J=1.6H z,1H),8.16(t,J=8.0Hz,1H),8.01-7.94(m,2H),7.20(t,J=1.2Hz,1H),4.60(s,1H),3. 83-3.79 (m, 1H), 3.46-3.40 (m, 1H), 1.90-1.87 (m, 2H), 1.80-1.70 (m, 2H), 1.63-1.60 (m, 2H), 1.53-1.29 (m, 2H); LCMS: (Method D) 287.2 [M+H], Rt. 1.46 min; HPLC: (Method B) Rt. 3.13 min.

[0504] Example 32: N-cyclohexyl-6-(1H-imidazol-1-yl)picolinamide

[0505]

[0506] To a stirred solution of 6-(1H-imidazole-1-yl)picolinic acid (110 mg, 0.58 mmol) in DMF (3 mL) was added HATU (331 mg, 0.87 mmol) and DIPEA (0.26 mL, 1.45 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 10 min, after which cyclohexylamine (57.7 mg, 0.87 mmol) was added and stirred at RT for 16 h. Upon completion, the reaction mixture was quenched with ice-cold water (50 mL) and then extracted with EtOAc (50 mL). The combined extracts were washed with water (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude compound was then purified by Grace reverse phase purification (Method B) and the collected fractions were concentrated under reduced pressure. The obtained product was redissolved in 10% MeOH / DCM (50 mL), washed with 10% aqueous NaHCO3 solution (20 mL), water (20 mL), dried over anhydrous Na2SO4 and filtered. After evaporation of the solvent, the residue was further dried by lyophilization to obtain the title compound. Yield: 98.9% (157.67 mg, brown solid); 1 HNMR (400 MHz, DMSO-d6): δ8.95 (s, 1H), 8.57 (d, J=8.4 Hz, 1H), 8.26 (t, J=1.2 Hz, 1H), 8.17 (t, J=7.6 Hz, 1H), 8.01-7.95 (m, 2H), 7.16 (t, J=1.2 Hz, 1H), 3.85-3.80 (m, 1H), 1.82-1.63 (m, 4H), 1.56-1.50 (m, 1H), 1.49-1.40 (m, 2H), 1.38-1.33 (m, 2H), 1.32-1.21 (m, 1H); LCMS: (Method D) 271.2 [M+H], Rt. 2.49 min; HPLC: (Method A) Rt. 2.54 min.

[0507] Example 33: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)picolinamide

[0508]

[0509] Step 1: (1r,4r)-N,N-diphenylmethyl-4-methoxycyclohexyl-1-amine

[0510]

[0511] To a stirred solution of (1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol (710 mg, 2.40 mmol) in THF (10 mL) was added sodium hydride (240 mg, 6.00 mmol) at 0°C under nitrogen atmosphere. After 10 min, iodomethane (0.37 mL, 6.00 mmol) was added and the resulting reaction mixture was stirred at RT for 5 h. Upon completion, the reaction mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with water (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude compound. The resulting crude residue was purified by Grace normal phase chromatography (100 to 200 mesh silica gel, eluent: 5%-10% EtOAc / petroleum ether) to give the title compound. Yield: 70% (520 mg, colorless liquid; LCMS: (Method C) 310.2 [M+H], Rt. 1.38 min.

[0512] Step 2: (1r,4r)-4-methoxycyclohexan-1-amine

[0513]

[0514] To a stirred solution of (1r,4r)-N,N-dibenzhydryl-4-methoxycyclohexan-1-amine (510 mg, 1.64 mmol) in pure ethanol (10 mL) was added 20% Pd(OH)2 / C (50 mg) at RT and the mixture was stirred under hydrogen overnight at RT. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with methanol (50 mL). The filtrate was evaporated in vacuo to give the title compound. This product was used in the next step without further purification. Yield: 100% yield was 215 mg (310 mg, yellow liquid). Crude product (310 mg, yellow liquid). LCMS: (Method A) 130.3 [M+H], Rt 0.52 min.

[0515] Step 3: 6-(1H-imidazol-1-yl)picolinic acid

[0516]

[0517] To a stirred solution of methyl 6-bromopicolinate (450 mg, 2.08 mmol) in DMF (5 mL) and 1H-imidazole (425 mg, 6.24 mmol) was added K2CO3 (863 mg, 6.24 mmol), followed by CuI (39.6 mg, 0.20 mmol), and the resulting reaction mixture was heated at 140 ° C for 16 h. After completion, the reaction mixture was filtered through a celite pad and washed with DCM (50 mL) and water (25 mL). The aqueous layer was separated from the filtrate and acidified with 1.5 N HCl, then concentrated under reduced pressure to give the title compound in the form of a hydrochloride salt. Yield: 100% yield (395 mg, light blue solid); LCMS: (Method C) 190.0 [M + H], Rt. 0.18 min.

[0518] Step 4: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)picolinamide

[0519]

[0520] To a stirred solution of 6-(1H-imidazole-1-yl)picolinic acid (120 mg, 0.63 mmol) in DMF (3 mL) was added HOBt (128 mg, 0.95 mmol), EDC.HCl (182 mg, 0.95 mmol) followed by DIPEA (0.29 mL, 1.58 mmol) and the resulting mixture was stirred at 0 °C for 5 min. After 5 min, (1r,4r)-4-methoxycyclohexan-1-amine (123 mg, 0.95 mmol) was added and stirred at RT for 16 h. Upon completion, water (20 mL) was added to the reaction mixture and the aqueous layer was extracted with EtOAc (50 mL). The combined extracts were washed with water (2×15 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was then purified by Grace reverse phase chromatography (Method C) and the collected fractions were concentrated under reduced pressure. This product was redissolved in 10% MeOH / DCM (20 mL), washed with 10% NaHCO3 solution (10 mL), water (10 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. Yield: 76% (145 mg, off-white solid); 1HNMR (400MHz, DMSO-d6): δ8.95 (s, 1H), 8.57 (d, J = 8.4Hz, 1H), 8.26-8.25 (m, 1H), 8 .18-8.14(m,1H),8.01-7.90(m,2H),7.16(t,J=1.2Hz,1H),3.88-3.70(m,1H),3.30 (s, 3H), 3.16-3.05 (m, 1H), 2.08-2.00 (m, 2H), 1.86-1.80 (m, 2H), 1.63-1.53 ​​(m, 2H), 1.28-1.18 (m, 2H); LCMS: (Method C) 301.2 [M+H], Rt. 0.80 min; HPLC: (Method A) Rt. 1.96 min.

[0521] Example 34: N-((1r,4r)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0522]

[0523] Step 1: 2-Chloropyrimidine-4-carbonyl chloride

[0524]

[0525] To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (300 mg, 1.89 mmol) and 1 drop of DMF in DCM (10 mL) was added oxalyl chloride (359 mg, 2.84 mmol) at 0 ° C, and the reaction mixture was stirred for 3 h at RT. The reaction mixture was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to give the title compound in the form of a crude substance, which was used in the next step without any purification. Yield: 95% (320 mg, light brown gum).

[0526] Step 2: 2-Chloro-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide

[0527]

[0528] To a stirred solution of 2-chloropyrimidine-4-carbonyl chloride (320 mg, 1.80 mmol) and TEA (0.75 mL, 5.42 mmol) in THF (10 mL) at 0 ° C. was added (1r, 4r)-4-aminocyclohexan-1-ol (249 mg, 2.17 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After completion, the reaction mixture was quenched with saturated aqueous NaHCO3 solution (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound, which was used in the next step without further purification. Yield: 62% (260 mg, brown gum). LCMS: (Method C) 256.2 [M+H], Rt. 0.97 min.

[0529] Step 3: N-((1r,4r)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0530]

[0531] A suspension of 2-chloro-N-((1r, 4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide (250 mg, 0.98 mmol), imidazole (200 mg, 2.94 mmol), copper iodide (18 mg, 0.10 mmol) and KCO (405 mg, 2.94 mmol) in DMF (3 mL) was purged with N for 2 min and the reaction mixture was heated overnight at 140 ° C in a sealed tube. After completion (the reaction was monitored by TLC), the reaction mixture was diluted with DCM. The resulting mixture was filtered through a diatomaceous earth bed, the filtrate was concentrated in vacuo, and the resulting crude material was purified by preparative HPLC (method B). The preparative fractions were concentrated under reduced pressure. The residue was diluted with 10% MeOH / DCM (10 mL) and neutralized with 10% NaHCO aqueous solution (4 mL). The organic layer was separated and washed with brine and water. The organic layer was then dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 12% (33.1 mg, off-white solid). 1H NMR (400MHz, DMSO-d6): δ9.06(d,J=4.8Hz,1H),8.97-8.96(m,1H),8.84(d,J=8.4Hz,1H),8.24-8.23(m,1H),7.91(d,J=4.8Hz,1H),7.19-7.18( m,1H),4.63(d,J=4.4Hz,1H),3.83-3.80(m,1H),3.49-3.42(m,1H),1.9 1-1.88(m,2H),1.81-1.79(m,2H),1.59-1.50(m,2H),1.29-1.26(m,2H). LCMS: (Method B) 288.4 [M+H], Rt. 1.44 min. HPLC: (Method B) Rt. 3.20 min.

[0532] Example 35: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0533]

[0534] Step 1: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid

[0535]

[0536] To a stirred solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (52 mg, 0.30 mmol, CAS No. 89581-58-8) (2 mL) and 1H-imidazole (62 mg, 0.90 mmol) in DMF, KCO (124 mg, 0.90 mmol) was added, followed by CuI (5.78 mg, 0.03 mmol), and the resulting mixture was heated at 120 ° C for 16 h. After completion, the reaction mixture was filtered through a celite pad and washed with methanol (20 mL) and water (10 mL). All layers were concentrated under reduced vacuum to give a crude product. The crude compound was redissolved in 1,4 dioxanes and acidified with 4M HCl / 1,4 dioxanes (3 mL). The solvent was then evaporated under reduced pressure to give the title compound in the form of a hydrochloride salt. Yield: crude product (75 mg, yellow solid). LCMS: (Method D) 205.1 [M+H], Rt. 0.52 min.

[0537] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0538]

[0539] To a stirred solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (71 mg, 0.34 mmol) in DMF (3 mL) was added HOBt (70 mg, 0.52 mmol), EDC.HCl (99.9 mg, 0.52 mmol) and DIPEA (0.16 mL, 0.86 mmol) at 0°C under nitrogen atmosphere. (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (90 mg, 0.52 mmol) was then added and stirred at RT for 16 h. Upon completion, water (30 mL) was added to the reaction mixture and extracted with 10% MeOH / DCM (50 mL), washed with water (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC (Method A) and the collected fractions were concentrated under reduced pressure. The obtained product was redissolved in 10% MeOH / DCM (35 mL), washed with 10% NaHCO3 solution (15 mL), water (2×20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound. Yield: 25% (31.36 mg, light brown solid); 1 HNMR (400MHz, DMSO-d6): δ8.94(t,J=1.2Hz,1H),8.79(d,J=8.8Hz,1H),8.20(t,J=1. 2Hz,1H),7.83(s,1H),7.17-7.16(m,1H),3.86-3.80(m,1H),3.57-3.50(m,2H),3.45- 3.39 (m, 2H), 3.34-3.24 (m, 4H), 2.08-2.00 (m, 2H), 1.85-1.80 (m, 2H), 1.61-1.52 (m, 2H), 1.30-1.22 (m, 2H); LCMS: (Method C) 360.0 [M+H], Rt. 1.9 min; HPLC: (Method A) Rt. 2.22 min.

[0540] The final product was characterized by X-ray powder diffraction, thermogravimetric analysis, and differential scanning calorimetry (DSC). The characterization results indicated that the product was crystalline, referred to herein as polymorph Form A, which was further identified as an anhydrate. The X-ray diffraction diagram is shown in Figure 1 The X-ray diffraction peaks are listed in Table 1 below.

[0541] Table 1. Raw XRD diffraction data of polymorph A

[0542]

[0543]

[0544] The results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) are shown in Figure 2 The TGA (top curve, left axis) shows a small weight loss before decomposition, and the DSC (bottom curve, right axis) shows a sharp melting peak at 136.4°C (onset) before decomposition, indicating that the material is anhydrous.

[0545] Polymorph Form A can also be obtained by dissolving about 15 mg of the compound in 0.4-3.0 mL of methanol, ethanol, acetone, THF, 1,4-dioxane, ACN, DMF or DMSO to obtain a clear solution. The solution was stirred magnetically, and then 0.2 to 0.5 mL of water was gradually added as an anti-solvent until precipitation occurred or the total amount of anti-solvent reached 15.0 mL. Alternatively, a clear solution was obtained in isopropanol, acetone, MIBK, EtOAc, THF, DCM, MTBE or toluene; and n-heptane was used as an anti-solvent. Alternatively, a clear solution was obtained in ethanol, MEK, isopropanol, CPME, 2-MeTHF, chloroform and anisole 3:1, and n-hexane was used as an anti-solvent. XRPD showed that in all cases, polymorph Form A was obtained.

[0546] Polymorphic Form A can also be obtained by dissolving about 15 mg of the starting material in 0.6 to 2.0 mL of solvent in a 4 mL glass vial. The solvents used were methanol, ethanol, acetone, ethyl acetate, THF, MTBE, ACN, and DCM / n-heptane (3:1). If dissolution was not achieved, the suspension was filtered using a nylon membrane (pore size 0.22 μm) and the filtrate was used in the following step. The suspension was then filtered through a 4 to 8 pinhole filter. The visually clear solutions were covered and evaporated at RT. XRPD showed that in all cases polymorph Form A was obtained.

[0547] The second polymorphic form, referred to herein as polymorph Form B, was produced via reverse anti-solvent addition of the compound in a toluene / n-heptane system at room temperature. The X-ray diffraction pattern is shown in Figure 3 The X-ray diffraction peaks are shown in Table 2 below.

[0548] Table 2. Raw XRD diffraction data of polymorph B

[0549]

[0550] exist Figure 4 In the Figure, polymorph Form B exhibits negligible weight loss before decomposition by TGA (top curve, left axis), and DSC (bottom curve, right axis) shows two endothermic peaks at 123.8° C. and 137.9° C. (onset) and an exothermic peak at 125.6° C. (onset). All data indicate that polymorph Form B is anhydrous.

[0551] Example 36: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide

[0552]

[0553] Step 1: 2-(1H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylic acid

[0554]

[0555] To a stirred solution of 2-chloro-6-(trifluoromethyl)pyrimidine-4-carboxylic acid (71 mg, 0.31 mmol) and 1H-imidazole (64 mg, 0.94 mmol) in DMF (2 mL) was added KCO (129 mg, 0.94 mmol), followed by CuI (5.96 mg, 0.03 mmol), and the resulting mixture was heated at 120 ° C for 16 h. After completion, the reaction mixture was filtered through a celite pad and washed with methanol (50 mL) and water (10 mL). All layers were concentrated under reduced vacuum to give a crude product. The crude product was redissolved in 1,4-dioxane (2 mL), 4M HCl / 1,4-dioxane solution (5 mL) was added, and the solvent was evaporated to give the title compound in the form of a hydrochloride salt. Yield: crude product (75 mg, yellow solid). LCMS: (Method D) 259.0 [M + H], Rt. 1.30 min.

[0556] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide

[0557]

[0558] To a stirred solution of 2-(1H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylic acid (71 mg, 0.27 mmol) in DMF (2 mL) was added EDC.HCl (79 mg, 0.41 mmol), HOBt (55 mg, 0.41 mmol) followed by DIPEA (0.12 mL, 0.68 mmol) at 0°C under nitrogen atmosphere. After that, (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (57 mg, 0.33 mmol) was added and stirred for 16 h. Upon completion, water (30 mL) was added to the reaction mixture and extracted with 10% MeOH / DCM (50 mL), washed with water (3×30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC (Method A), and the collected fractions were concentrated under reduced pressure. The obtained product was redissolved in 10% MeOH / DCM (35 mL), washed with 10% NaHCO3 solution (15 mL), water (2×20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compound. Yield: 20% (23.26 mg, light brown solid); 1 HNMR (400 MHz, DMSO-d6): δ 9.07 (s, 1H), 9.01 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.25 (s, 1H), 3.90-3.86 (m, 1H), 3.57-3.55 (m, 2H), 3.51-3.42 (m, 2H), 3.36-3.26 (m, 4H), 2.08-2.05 (m, 2H), 1.87-1.80 (m, 2H), 1.63-1.54 (m, 2H), 1.32-1.24 (m, 2H); LCMS: (method C) 414.0 [M+H], Rt. 1.84 min. HPLC: (method A) Rt. 2.74 min.

[0559] Example 37: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylthio)picolinamide

[0560]

[0561]

[0562] Step 1: Methyl 4-bromo-6-fluoropicolinate

[0563]

[0564] To a stirred solution of methyl 4-bromopicolinate (2.7 g, 12.5 mmol) in acetonitrile (30 mL) was added AgF2 (5.46 g, 37.5 mmol) at once and stirred at the same RT for 16 h. The reaction progress was monitored by TLC and quenched with 10% NaHCO3 aqueous solution (20 mL). The resulting suspension was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-10% EtOAc / petroleum ether) to obtain the title compound. Yield: 27% (860 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.18-8.17 (m, 1H), 7.98-7.97 (m, 1H), 3.93 (s, 3H). LCMS: (Method C) 233.9 (M+H) and 235.9 (M+H), Rt. 2.02 min.

[0565] Step 2: Methyl 4-bromo-6-(1H-imidazol-1-yl)picolinate

[0566]

[0567] To a stirred solution of 4-bromo-6-fluoropicolinic acid methyl ester (850 mg, 3.63 mmol) in NMP (10 mL) was added imidazole (988.0 mg, 14.52 mmol), followed by DIPEA (1.89 mL, 10.89 mmol), and the reaction mixture was heated at 80 ° C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with water (10 mL). The resulting suspension was extracted with DCM (3×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100 to 200 mesh silica gel, eluted with 0-10% MeOH / DCM) to give the title compound. Yield: 54% (550.1 mg, solid). 1 H NMR (400MHz, DMSO-d6): δ8.60-8.59(m,1H),8.49(d,J=1.6Hz,1H),8.14(d,J=1.6Hz,1H),8.02-8.01(m,1H),7.17-7.16(m,1H),3.93(s,3H). LCMS: (Method C) 283.9 (M+H), Rt.0.70min.

[0568] Step 3: 4-Bromo-6-(1H-imidazol-1-yl)picolinic acid

[0569]

[0570] To a stirred solution of 4-bromo-6-(1H-imidazole-1-yl)picolinic acid methyl ester (540mg, 1.91mmol) in MeOH (3mL), THF (3mL) and water (2mL) was added NaOH (229.7mg, 5.74mmol) at RT, and the reaction mixture was stirred for 4h at the same temperature. The reaction process was monitored by TLC, and the starting material was observed to be completely consumed. The reaction mixture was concentrated in vacuo and acidified with 3N HCl solution (20mL). The resulting solid was collected by filtration and dried to obtain the title compound. Yield: 66% (340.1mg, solid). 1 H NMR (400MHz, DMSO-d6): δ13.70 (bs, 1H), 8.67 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 8.08 (d, J = 1.2 Hz, 1H), 7.16 (s, 1H). LCMS: (Method C) 269.9 (M+H), Rt.0.24min.

[0571] Step 4: 4-Bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0572]

[0573] To a stirred solution of 4-bromo-6-(1H-imidazole-1-yl)picolinic acid (330 mg, 1.231 mmol) in DMF (3 mL) was added DIPEA (0.64 mL, 3.69 mmol) and HATU (701.8 mg, 1.847 mmol) at RT. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (255.6 mg, 1.477 mmol) in DMF (0.5 mL) was added at the same temperature. In addition, the reactants were stirred for 16 h at RT. The progress of the reaction was monitored by TLC, and the reaction mixture was diluted with water (25 mL). The resulting suspension was extracted with EtOAc (3×25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100 to 200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 53% (280 mg, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ8.99(s,1H),8.62(d,J=8.7Hz,1H),8.39(d,J=1.5Hz,1H),8.31(d,J=1.2Hz,1H),8.04(d,J=1.2Hz,1H),7.17(s,1H),3.89 -3.83(m,1H),3.57-3.50(m,2H),3.44-3.41(m,2H),3.33-3.23(m,4H),2. 06-2.02(m,2H),1.84-1.81(m,2H),1.59-1.55(m,2H),1.30-1.24(m,2H). LCMS: (Method C) 423.0 (M+H) and 425.0 (M+H), Rt. 1.27 min.

[0574] Step 5: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylthio)picolinamide

[0575]

[0576] To a stirred solution of 4-bromo-6-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (100 mg, 0.236 mmol) in DMF (12 mL) was added sodium thiomethoxide (33.13 mg, 0.47 mmol) and the reaction mixture was heated at 75 °C for 6 h, the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 mL). The resulting suspension was extracted with DCM (3×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The crude residue was purified by preparative HPLC (Method A). The preparative fractions were concentrated to an aqueous phase, DCM was added and neutralized with a 10% aqueous NaHCO3 solution. The phases were separated. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to give the title compound. Yield: 34% (32 mg, gummy solid), 1 H NMR (400MHz, DMSO-d6): δ8.95 (s, 1H), 8.54 (d, J = 8.0Hz, 1H), 8.29-8.28 (m, 1H),7.77(d,J=1.6Hz,1H),7.73(d,J=1.2Hz,1H),7.14(s,1H),3.83-3.81(m ,1H),3.56-3.54(m,2H),3.44-3.42(m,2H),3.30-3.23(m,4H),2.67(s,3H), 2.05-2.02(m,2H),1.84-1.81(m,2H),1.61-1.52(m,2H),1.29-1.23(m,2H). LCMS: (Method C) 391.0 (M+H), Rt. 1.23 min. HPLC: (Method A) Rt. 2.53 min.

[0577] Example 38: 4-(1-Hydroxyethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0578]

[0579] Step 1: Methyl 4-bromopicolinate

[0580]

[0581] To a stirred solution of 4-bromopicolinic acid (10 g, 49.50 mmol) in DMF (80 mL), KCO (20.49 g, 148.51 mmol) was added once, and the reaction mixture was stirred at RT for 10 min, then MeI (42.17 g, 297.0 mmol) was slowly added and the reaction mixture was stirred in a sealed tube at RT for 30 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water (150 mL). The resulting suspension was extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (100-200 mesh silica gel, eluted with 0-20% EtOAc / petroleum ether) on Biotage Isolera to obtain the title compound. Yield: 77% (8.23 g, white solid). 1 H NMR (300 MHz, DMSO-d6): δ 8.61 (d, J = 5.1 Hz, 1H), 8.21-8.20 (m, 1H), 7.98-7.96 (m, 1H), 3.90 (s, 3H). LCMS: (Method C) 218.0 (M+H), Rt. 1.33 min.

[0582] Step 2: Methyl 4-bromo-6-fluoropicolinate

[0583]

[0584] To a stirred solution of 4-bromopicolinic acid methyl ester (3.3g, 15.27mmol) in acetonitrile (40mL), AgF2 (6.68g, 45.83mmol) was added once, and the reaction mixture was stirred at RT for 6h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with 10% NaHCO3 aqueous solution (20mL). The resulting suspension was extracted with EtOAc (3×100mL). The combined organic layer was washed with water (100mL), brine (100mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (100-200 mesh silica gel, eluted with 0-10% EtOAc / petroleum ether) on BiotageIsolera to obtain the title compound. Yield 34% (1.23g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.18-8.17 (m, 1H), 7.98-7.97 (m, 1H), 3.90 (s, 3H). LCMS: (Method C) 233.9 (M+H), Rt. 1.81 min.

[0585] Step 3: Methyl 4-bromo-6-(1H-imidazol-1-yl)picolinate

[0586]

[0587] To a stirred solution of 4-bromo-6-fluoropicolinic acid methyl ester (1.8 g, 7.69 mmol) in NMP (10 mL) was added imidazole (2.09 g, 30.76 mmol), followed by DIPEA (4.0 mL, 23.07 mmol), and the reaction mixture was heated at 80 ° C for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with water (10 mL). The resulting suspension was extracted with DCM (3 × 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100 to 200 mesh silica gel, eluted with 0-10% MeOH / DCM) to obtain the title compound. Yield 74% (1.6 g, solid). 1 H NMR (400MHz, DMSO-d6): δ8.60-8.59(m,1H),8.49(d,J=1.2Hz,1H),8.14(d,J=1.6Hz,1H),8.02-8.01(m,1H),7.17-7.16(m,1H),3.93(s,3H). LCMS: (Method A) 283.9 (M+H), Rt.0.54min.

[0588] Step 4: 4-Bromo-6-(1H-imidazol-1-yl)picolinic acid

[0589]

[0590] To a stirred solution of 4-bromo-6-(1H-imidazole-1-yl)picolinic acid methyl ester (1.56g, 5.53mmol) in MeOH (9mL), THF (9mL) and water (6mL) was added NaOH (664mg, 16.59mmol) at RT and the reaction mixture was stirred for 4h at the same temperature. The reaction mixture was monitored by TLC and the starting material was consumed. The reaction mixture was concentrated in vacuo and acidified with 3N HCl aqueous solution (20mL). The resulting solid was collected by filtration and dried to obtain the title compound. Yield: 94% (1.39g, solid). 1H NMR (300MHz, DMSO-d6): δ9.94 (s, 1H), 8.72 (d, J = 1.5 Hz, 1H), 8.50-8.49 (m, 1H), 8.32 (d, J = 1.5 Hz, 1H), 7.84 (s, 1H). LCMS: (Method B) 270.6 (M+H), Rt.1.02min.

[0591] Step 5: 4-Bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0592]

[0593] To a stirred solution of 4-bromo-6-(1H-imidazole-1-yl)picolinic acid (1.35 g, 5.04 mmol) in DMF (20 mL) was added DIPEA (2.64 mL, 15.10 mmol) and HATU (2.87 g, 7.553 mmol) at RT. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (1.3 g, 7.55 mmol) in DMF (0.5 mL) was added and the reaction mixture was stirred for 16 h at RT. The reaction mixture was monitored by TLC and diluted with water (25 mL) after completion. The resulting suspension was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 52% (1.2 g, yellow solid). 1 H NMR (300MHz, DMSO-d6): δ8.98(s,1H),8.62(d,J=8.7Hz,1H),8.39(d,J=1.5Hz,1H),8.31-8.30(m,1H),8.04(d,J=1.5Hz,1H),7.17(s,1H),3.8 4-3.80(m,1H),3.56-3.50(m,2H),3.44-3.41(m,2H),3.23(s,4H),2.05 -2.03(m,2H),1.83-1.80(m,2H),1.62-1.51(m,2H),1.29-1.23(m,2H). LCMS: (Method C) 425.0 (M+H), Rt. 1.21min.

[0594] Step 6: 4-acetyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-ethoxyethoxy)cyclohexyl)picolinamide

[0595]

[0596] A mixture of 4-bromo-6-(1H-imidazole-1-yl)-N-((1r, 4r)-4-(2-ethoxyethoxy)cyclohexyl)picolinamide (400 mg, 0.95 mmol) and tributyl(1-ethoxyvinyl)tin (409 mg, 1.13 mmol) in toluene (8 mL) at RT was purged with nitrogen for 5 min. Pd(PPh3)2Cl2 (28.9 mg, 0.04 mmol) was subsequently added and the reaction mixture was heated at 90 °C for 16 h. The reaction was monitored by TLC and the starting material was observed to be completely converted. The reaction mixture was filtered through a diatomaceous earth bed and washed with DCM (20 mL). The solvent was evaporated in vacuo and the crude residue was purified by column chromatography (100 to 200 mesh silica gel, eluted with 0-10% MeOH / DCM) on Biotage Isolera to obtain the title compound. Yield: 87% (320 mg, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ9.05(d,J=0.8Hz,1H),8.63(d,J=8.8Hz,1H),8.40-8 .39(m,1H),8.34(d,J=1.2Hz,1H),8.27-8.25(m,1H),7.19(s,1H),3.88-3.85 (m,1H),3.57-3.55(m,2H),3.45-3.43(m,2H),3.31-3.24(m,4H),2.74(s,3H) ,2.07-2.04(m,2H),1.91-1.84(m,2H),1.61-1.57(m,2H),1.31-1.25(m,2H). LCMS: (Method C) 387.2 (M+H), Rt. 1.04 min.

[0597] Step 7: 4-(1-Hydroxyethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0598]

[0599] To a stirred solution of 4-acetyl-6-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (110 mg, 0.28 mmol) in MeOH (5 mL) was slowly added NaBH4 (16.20 mg, 0.43 mmol) at 0 ° C. After completion of the addition, the reaction mixture was stirred at RT for 1.5 h. The reaction was monitored by TLC and complete conversion of the starting material was observed. The reaction mixture was then cooled to 0 ° C and quenched with water (2 mL). The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 mL), stirred for 5 min, then DCM (10 mL) was added, and the mixture was stirred at RT for 10 min. The mixture was extracted with DCM (2×10 mL). The combined organic phases were washed with water followed by brine, dried over anhydrous Na2SO4, concentrated in vacuo and the crude residue was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM as gradient) to give the title compound. Yield: 38% (42.0 mg, gummy solid). 1 H NMR (400MHz, DMSO-d6): δ8.93 (s, 1H), 8.53 (d, J = 7.6Hz, 1H), 8.25-8.24 (m, 1H), 7. 99(s,1H),7.90(s,1H),7.15(s,1H),5.64(d,J=4.4Hz,1H),4.89-4.87(m,1H),3.8 5-3.83 (m, 1H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 2H), 3.24 (s, 4H), 2.05-2.03 (m, 2H), 1.85-1.82 (m, 2H), 1.59-1.52 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H), 1.31-1.21 (m, 2H). LCMS: (Method A) 389.3 (M+H), Rt. 1.26 min. HPLC: (Method C) Rt. 4.01 min.

[0600] Example 39: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylsulfonyl)picolinamide

[0601]

[0602]

[0603] To a stirred solution of 4-bromo-6-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (150 mg, 0.35 mmol) in DMSO (3 mL) was added sodium methanesulfinate (54.25 mg, 0.53 mmol), CuI (6.73 mg, 0.03 mmol) and sodium proline (9.73 mg, 0.07 mmol) and the reaction mixture was heated at 90 °C for 16 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 mL). The resulting suspension was extracted with DCM (3 x 25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude compound, which was purified by preparative HPLC (Method A). The preparative fractions were concentrated to an aqueous phase, DCM was added and neutralized with 10% aqueous NaHCO3. The phases were separated. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the title compound. Yield: 27% (41.5 mg, white solid). 1 H NMR (400MHz, DMSO-d6): δ9.08-9.07(m,1H),8.73(d,J=8.8Hz,1H),8.46(d, J=1.2Hz,1H),8.41-8.40(m,1H),8.29(d,J=1.2Hz,1H),7.21-7.20(m,1H),3 .92-3.84(m,1H),3.57-3.55(m,2H),3.45-3.42(m,5H),3.30-3.25(m,4H), 2.07-2.04(m,2H),1.86-1.83(m,2H),1.64-1.55(m,2H),1.32-1.23(m,2H). LCMS: (Method C) 423.0 (M+H), Rt. 1.24 min. HPLC: (Method B) Rt. 4.20 min.

[0604] Example 40: 4-(2-Hydroxypropan-2-yl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0605]

[0606] To a stirred solution of 4-acetyl-6-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.52 mmol) in anhydrous THF (5 mL) was added MeMgBr (0.51 mL, 1.55 mmol, 3 M solution in THF) dropwise over a 5 min period at -40 °C. After the addition was complete, the reaction mixture was warmed to RT and stirred at RT for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and saturated NH4Cl aqueous solution (5 mL) was slowly added, and the reaction mixture was stirred for 10 min. DCM (20 mL) was then added and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The organic phase was washed with water followed by brine, dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to give a crude product which was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 0-10% MeOH / DCM as a gradient) to give the title compound. Yield: 27% (56 mg, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ8.95 (s, 1H), 8.53 (d, J = 8.8Hz, 1H), 8.28-8.27 (m, 1H), 8.10(d,J=1.2Hz,1H),7.92(d,J=1.2Hz,1H),7.16-7.15(m,1H),5.52(s,1H),3.8 6-3.77(m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.30-3.24(m,4H),2.05-2. 03(m,2H),1.85-1.82(m,2H),1.61-1.52(m,2H),1.50(s,6H),1.31-1.21(m,2H). LCMS: (Method C) 403.2 (M+H), Rt. 1.18 min. HPLC: (Method B) Rt. 4.23 min.

[0607] Example 41: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0608]

[0609] Step 1: (1r,4r)-N,N-diphenylmethyl-4-(difluoromethoxy)cyclohexan-1-amine

[0610]

[0611] To a stirred solution of (1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol (2.03 g, 6.87 mmol) in ACN (100 mL) was added CuI (261 mg, 1.37 mmol) at RT. The reaction mass was then heated to 45°C. At this temperature, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.57 mL, 24.93 mmol) was added and the reaction mixture was stirred at 45°C for 1 h. After 1 h, TLC showed unreacted (1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol. Another portion of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.15 mL, 11.19 mmol) was added at 45°C and the reaction mixture was stirred at 45°C for another 1 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated in vacuo. Under continuous stirring, the crude residue was slowly diluted with water (30mL), 10% NaHCO aqueous solution (30mL) and EtOAc (100mL). The suspension was filtered through a diatomaceous earth bed. The layers of the filtrate were separated. The combined organic layer was washed with brine (30mL), then washed with water (30mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by Grace normal phase purification using silica gel (100-200 mesh, 2%-5% EtOAc / petroleum ether) to obtain the title compound. Yield: 51% (1.21g, white solid). 1 H NMR (400MHz, DMSO-d6): δ7.35-7.18(m,10H),6.67(t,J=76.8Hz,1H),4.01-3.94(m,1H),3.57(s,4H),2.51-2.40(m,1 H), 2.00-1.97(m,2H), 1.85-1.82(m,2H), 1.54-1.40(m,2H), 1.27-1.21(m,2H), LCMS: (Method D) 346.5(M+H), Rt.2.74min.

[0612] Step 2: (1r,4r)-4-(difluoromethoxy)cyclohexan-1-amine

[0613]

[0614] To a stirred solution of (1r,4r)-N,N-dibenzhydryl-4-(difluoromethoxy)cyclohexan-1-amine (610 mg, 1.76 mmol) in absolute ethanol (6 mL) was added Pd(OH)2 / C (60 mg, 20%) at RT and the mixture was stirred under hydrogen (balloon reaction) for 16 h at RT. After completion, the reaction mixture was filtered through a celite bed and the bed was washed with MeOH (50 mL). The filtrate was evaporated in vacuo and the residue was co-distilled with toluene (2×20 mL) to give the title compound. Yield: 72% (210 mg, colorless liquid). LCMS: (Method A) 166.2 (M+H), 1.15 min.

[0615] Step 3: 2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid

[0616]

[0617] A stirred solution of 2-chloropyrimidine-4-formic acid methyl ester (510 mg, 2.95 mmol) and 1H-imidazole (612 mg, 8.86 mmol) in DMF (5 mL) was degassed for 5 min at RT, followed by the addition of potassium carbonate (1.22 g, 8.86 mmol) and CuI (56.2 mg, 0.29 mmol). The reaction mixture was heated at 120 ° C for 16 h. After completion, the reaction mixture was filtered through diatomaceous earth, and the diatomaceous earth bed was washed with 10% MeOH / DCM (20 mL) and then MeOH (20 mL). The combined filtrate was concentrated under reduced pressure. The crude residue was dissolved in 1,4-dioxane (10 mL), acidified with HCl / 1,4-dioxane (4 M, 5 mL), and then concentrated in vacuo to give the title compound in the form of hydrochloride. Yield: 98% (550 mg, yellow solid). LCMS: (Method C) 191.1 (M+H), Rt. 0.43 min.

[0618] Step 4: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0619]

[0620] To a stirred solution of 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (195 mg, 1.02 mmol) in DMF (10 mL) was added EDC.HCl (294 mg, 1.53 mmol), HOBt (207 mg, 1.53 mmol) and DIPEA (0.47 mL, 2.56 mmol) at 0 ° C under a nitrogen atmosphere. (1r, 4r)-4-(difluoromethoxy)cyclohexan-1-amine (203 mg, 1.23 mmol) was then added and the reaction mixture was stirred at RT for 16 h. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (20 mL) and then extracted with 10% MeOH / DCM (50 mL). The resulting organic solution was washed with water (2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting crude residue was purified by Grace reverse phase purification (method A). The preparative fraction was concentrated under reduced pressure, and the residue was diluted with 10% MeOH / DCM (30 mL) and washed with 10% aqueous NaHCO3 (10 mL) followed by water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 42% (145.33 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): 9.07-9.06 (m, 1H), 8.97 (s, 1H), 8.87 (d, J = 8.8 Hz, 1H), 8.23-8.22 (m, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.19-7.18 (m, 1H), 6.76 (t, J = 76.8 Hz, 1H), 4.09-4.02 (m, 1H), 3.92-3.84 (m, 1H), 2.05-2.02 (m, 2H), 1.90-1.86 (m, 2H), 1.67-1.48 (m, 4H), LCMS: (Method A) 337.9 (M+H), Rt. 1.92 min. HPLC: (Method A) Rt. 2.63 min.

[0621] Example 42: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide

[0622]

[0623] Step 1: (1r,4r)-4-(difluoromethoxy)cyclohexan-1-amine

[0624]

[0625] To a stirred solution of (1r,4r)-N,N-dibenzhydryl-4-(difluoromethoxy)cyclohexan-1-amine (610 mg, 1.76 mmol) in absolute ethanol (6 mL) was added Pd(OH)2 / C (61 mg, 20%) at RT and the mixture was stirred under hydrogen (balloon reaction) for 16 h at RT. After completion, the reaction mixture was filtered through a celite bed and the bed was washed with MeOH (100 mL). The combined filtrates were concentrated in vacuo and the residue was co-distilled with toluene (2×50 mL) to give the title compound. Yield: crude material (310 mg, colorless liquid). LCMS: (Method A) 166.2 (M+H), Rt. 1.16 min.

[0626] Step 2: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid

[0627]

[0628] A stirred solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (210 mg, 1.12 mmol) and 1H-imidazole (233 mg, 3.37 mmol) in DMF (3 mL) was degassed for 5 min at RT, followed by the addition of potassium carbonate (466 mg, 3.37 mmol) at RT, followed by the addition of CuI (21.4 mg, 0.11 mmol). The reaction mixture was heated at 120 ° C for 16 h. After completion, the reaction mixture was filtered through diatomaceous earth, and the bed was washed with methanol (20 mL) and water (10 mL). The combined filtrate was concentrated in vacuo. The crude residue was dissolved in 1,4-dioxane (5 mL) and then acidified with HCl / 1,4-dioxane (5 mL, 4 M). The mixture was concentrated in vacuo to give the title compound in the form of a hydrochloride salt. Yield: crude material (220 mg, yellow solid). LCMS: (Method C) 205.1 (M+H), Rt.0.40 min.

[0629] Step 3: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide

[0630]

[0631] To a stirred solution of 2-(1H-imidazole-1-yl)-6-methylpyrimidine-4-carboxylic acid (210 mg, 1.02 mmol) in DMF (3 mL) was added HATU (585 mg, 1.54 mmol) and DIPEA (0.47 mL, 2.57 mmol) at 0 ° C under nitrogen atmosphere. (1r, 4r)-4-(difluoromethoxy)cyclohexan-1-amine (203 mg, 1.23 mmol) was then added and the reaction mixture was stirred at RT for 16 h. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (30 mL) and then extracted with 10% MeOH / DCM (50 mL). The resulting organic solution was washed with water (3×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting crude product was purified by reverse phase purification. The preparative fraction was concentrated under reduced pressure, the residue was diluted with 10% MeOH / DCM (50 mL) and washed with 10% aqueous NaHCO3 solution (15 mL) followed by water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 39% (140.69 mg, light yellow solid). 1 H NMR (400 MHz, DMSO-d6): 8.94 (s, 1H), 8.81 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.84 (s, 1H), 7.17 (s, 1H), 6.95-6.76 (m, 1H), 4.08-4.02 (m, 1H), 3.89-3.80 (m, 1H), 2.63 (s, 3H), 2.05-2.00 (m, 2H), 1.89-1.86 (m, 2H), 1.67-1.48 (m, 4H). LCMS: (Method D) 352.2 (M+H), Rt. 2.03 min. HPLC: (Method A) Rt. 2.89 min.

[0632] Example 43: 4-cyano-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0633]

[0634] Step 1: Methyl 4-bromo-6-fluoropicolinate

[0635]

[0636] To a stirred solution of methyl 4-bromopicolinate (10.0 g, 46.29 mmol) in acetonitrile (90 mL) was added AgF2 (20.0 g, 138.88 mmol) at once, and the reaction mixture was stirred at RT for 6 h. The reaction was monitored by TLC and quenched with 10% NaHCO3 aqueous solution (20 mL). The resulting suspension was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by Biotage Isolera column chromatography (100-200 mesh silica gel, eluted with 0-10% EtOAc / petroleum ether) to obtain the title compound. Yield: 38% (4.13 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.18-8.17 (m, 1H), 7.98-7.97 (m, 1H), 3.90 (s, 3H). LCMS: (Method C) 234.0 (M+H), 236.0 (M+H), Rt. 1.61 min.

[0637] Step 2: Methyl 4-bromo-6-(1H-imidazol-1-yl)picolinate

[0638]

[0639] To a stirred solution of 4-bromo-6-fluoropicolinic acid methyl ester (4.1 g, 17.51 ​​mmol) in NMP (30 mL) was added imidazole (4.76 g, 70.08 mmol), followed by DIPEA (9.1 mL, 52.56 mmol), and the reaction mixture was heated at 80 ° C for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with water (10 mL). The resulting suspension was extracted with DCM (3 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100 to 200 mesh silica gel, eluted with 0-10% MeOH / DCM) to obtain the title compound. Yield: 55% (2.76 g, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ8.60-8.59(m,1H),8.49(d,J=1.6Hz,1H),8.14(d,J=1.6Hz,1H),8.02-8.01(m,1H),7.17-7.16(m,1H),3.93(s,3H). LCMS: (Method A) 284.0 (M+H), Rt. 1.88min.

[0640] Step 3: 4-Bromo-6-(1H-imidazol-1-yl)picolinic acid

[0641]

[0642] To a stirred solution of 4-bromo-6-(1H-imidazoles-1-yl)picolinic acid methyl esters (2.71 g, 9.60 mmol) in MeOH (18 mL), THF (18 mL) and water (12 mL) was added NaOH (1.15 g, 28.88 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was monitored by TLC and the starting material was consumed. The reaction mixture was concentrated in vacuo and acidified with HCl solution (20 mL, 3 N). The resulting solid was collected by filtration and dried to give the title compound. Yield: 88% (2.27 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 13.61 (bs, 1H), 8.67 (d, J = 0.8 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 8.09-8.08 (m, 1H), 7.17-7.16 (m, 1H). LCMS: (Method D) 268.0 and 270.0 (M+H), Rt. 0.98 min.

[0643] Step 4: 4-Bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0644]

[0645] To a stirred solution of 4-bromo-6-(1H-imidazole-1-yl)picolinic acid (2.30 g, 8.58 mmol) in DMF (30 mL) was added DIPEA (4.50 mL, 25.74 mmol) and HATU (4.89 g, 12.87 mmol) at RT. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (2.2 g, 12.87 mmol) in DMF (0.5 mL) was added and the reaction mixture was stirred for 16 h at RT. The reaction mixture was monitored by TLC and diluted with water (25 mL). The resulting suspension was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc / petroleum ether) to give the title compound. Yield: 66% (2.4 g, yellow solid). 1H NMR (300MHz, DMSO-d6): δ8.99(s,1H),8.62(d,J=8.7Hz,1H),8.39(d,J=1.5Hz,1H),8.31-8.30(m,1H),8.04(d,J=1.5Hz,1H),7.17(s,1H),3.88-3 .80(m,1H),3.56-3.50(m,2H),3.44-3.41(m,2H),3.29-3.23(m,4H),2.0 5-2.03(m,2H),1.83-1.80(m,2H),1.62-1.51(m,2H),1.29-1.23(m,2H). LCMS: (Method C) 425.0 (M+H), Rt. 1.01 min.

[0646] Step 5: 4-cyano-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0647]

[0648] To a mixture of 4-bromo-6-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (150 mg, 0.35 mmol), Zn(CN)2 (63.0 mg, 0.53 mmol) in DMF (3 mL) was added Pd(PPh3)4 (41.0 mg, 0.035 mmol) at RT, and the reaction mixture was purged with nitrogen for 5 min. The reaction mixture was heated at 80 °C for 24 h. After completion (reaction monitored by LCMS), the reaction mixture was filtered through a celite bed and the bed was washed with DCM (20 mL). The combined filtrate was concentrated in vacuo to give the crude compound, which was purified by preparative HPLC (Method A). The preparative fractions were concentrated. DCM was added to the residual aqueous phase and neutralized with 10% NaHCO3 aqueous solution. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound. Yield: 44% (60 mg, off-white solid). 1H NMR (400MHz, DMSO-d6): δ9.01(s,1H),8.69(d,J=8.4Hz,1H),8.59(d,J=1.2Hz,1H),8.33-8.31(m,1H),8.24(d,J=1.2Hz,1H),7.20(s,1H),3.89-3 .81(m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.29-3.25(m,4H),2.0 6-2.03(m,2H),1.84-1.82(m,2H),1.62-1.53(m,2H),1.30-1.21(m,2H). LCMS: (Method D) 370.1 (M+H), Rt. 1.75 min. HPLC: (Method A) Rt. 2.16 min.

[0649] Example 44: N-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide

[0650]

[0651] Step 1: 2-(((1r,4r)-4-(Benzhydrylamino)cyclohexyl)oxy)ethan-1-ol

[0652]

[0653] To a stirred solution of (1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol (2.10 g, 7.10 mmol) in DMPU (20 mL) was added NaH (60% suspension, 355 mg, 8.88 mmol) at 0°C followed by 1,3,2-dioxathiolane 2,2-dioxide (1.14 g, 8.88 mmol) and the reaction mixture was stirred at RT for 16 h. After 16 h, TLC showed unreacted (1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol. An additional portion of NaH (60% suspension, 355 mg, 8.88 mmol) was added followed by 1,3,2-dioxathiolane 2,2-dioxide (1.14 g, 8.88 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and LCMS. After the starting material is completely consumed, the reaction mixture is quenched by adding water (2.5mL) and concentrated H2SO4 (2.5mL), and the reaction mixture is stirred at 70 ℃ for 16h. The reaction mixture is monitored by TLC and LCMS. After completion, the reaction mixture is diluted with 10% NaHCO3 aqueous solution (50mL), and then extracted with EtOAc (3 × 100mL). The organic layer is combined with saline solution (50mL), then washed with water (2 × 50mL). Make the organic layer through anhydrous Na2SO4 dry, filter and vacuum concentrate the filtrate. By Grace normal phase, silica gel (100-200 mesh, 20%-30% EtOAc / petroleum ether) is used to purify the obtained crude residue to obtain the title compound. Yield: 50% (1.22g, white solid). 1 HNMR (400 MHz, DMSO-d6): δ 7.34-7.27 (m, 8H), 7.22-7.18 (m, 2H), 4.52-4.49 (m, 1H), 3.57 (s, 4H), 3.45-3.34 (m, 4H), 3.19-3.12 (m, 1H), 2.44-2.34 (m, 1H), 2.02-1.99 (m, 2H), 1.83-1.80 (m, 2H), 1.50-1.35 (m, 2H), 1.03-0.91 (m, 2H). LCMS: (Method A) 340.9 (M+H), Rt 1.70 min.

[0654] Step 2: 2-(((1r,4r)-4-aminocyclohexyl)oxy)ethan-1-ol

[0655]

[0656] To a stirred solution of 2-(((1r,4r)-4-(benzhydrylamino)cyclohexyl)oxy)ethan-1-ol (1.21 g, 3.56 mmol) in absolute ethanol (50 mL) was added Pd(OH)2 / C (150 mg, 20 wt%) at RT and the mixture was stirred under hydrogen atmosphere for 16 h at RT. After completion, the reaction mixture was filtered through a celite bed and the celite bed was washed with methanol (100 mL). The combined filtrates were concentrated in vacuo to afford the title compound which was used in the next step without further purification. Yield: crude material (612 mg, colorless liquid). LCMS: (Method A), 160.2 (M+H), Rt. 0.58 min, 59.16% (ELSD) and Rt. 0.51 min.

[0657] Step 3: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid

[0658]

[0659] To a stirred solution of ethyl 2-(1H-imidazole-1-yl)-6-methylpyrimidine-4-carboxylate (975 mg, 4.19 mmol) in a mixture of 1,4-dioxane (7.25 mL) and water (2.5 mL) was added NaOH (184 mg, 4.61 mmol) at RT, and the reaction mixture was stirred for 16 h at RT. After completion (starting material was consumed according to TLC), 1,4-dioxane was concentrated in vacuo. To this residue was added water (15 mL) and the aqueous layer was washed with DCM (2×10 mL). The aqueous layer was separated and concentrated under reduced pressure. The resulting solid was co-distilled with toluene (2×10 mL) to give the title compound. Yield: 92% (870 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.11 (s, 1H). LCMS: (Method B) 205.3 (M+H), Rt. 0.88 min.

[0660] Step 4: N-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide

[0661]

[0662] To a stirred solution of sodium 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylate (205 mg, 0.90 mmol) in DMF (3Ml) was added DIPEA (0.15 mL, 0.90 mmol), HOBt (183 mg, 1.35 mmol), EDC.HCl (347 mg, 1.81 mmol) followed by 2-(((1r,4r)-4-aminocyclohexyl)oxy)ethan-1-ol (144 mg, 0.90 mmol) at RT under nitrogen atmosphere and the reaction mixture was stirred at RT for 16 h. After completion (consumption of starting material according to TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The resulting organic solution was washed with 10% aqueous NaHCO3 solution (10 mL) and water (2×10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The resulting crude residue was purified by preparative HPLC. The preparative fraction was concentrated under reduced pressure, diluted with DCM (20 mL) and washed with brine solution (10 mL) followed by water (2×10 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound. Yield: 41% (121.1 mg, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ8.94-8.93(m,1H),8.78(d,J=8.4Hz,1H),8.20-8.19(m,1H),7.83(s,1H),7.17-7.16(m,1H),4.57-4.54(m,1H),3.89 -3.80(m,1H),3.51-3.44(m,4H),3.29-3.23(m,1H),2.63(s,3H),2.07 -2.04(m,2H),1.86-1.83(m,2H),1.61-1.52(m,2H),1.32-1.20(m,2H). LCMS: (Method A) 346.0 (M+H), Rt. 1.54min. HPLC: (Method A) Rt. 1.83 min.

[0663] Example 45: 2-(1 H-Imidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide.

[0664]

[0665] To a mixture of 2-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide (1.0 g, 2.78 mmol) in pyridine (10 mL) was added SeO2 (1.08 g, 9.73 mmol) and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was monitored by TLC, which showed a 10% conversion. The reaction mixture was concentrated in vacuo and the obtained crude residue was diluted with EtOAc (50.0 mL). The resulting mixture was filtered through a bed of celite, washed with EtOAc (15.0 mL) and the solvent was evaporated in vacuo. The crude residue was purified by preparative HPLC. The preparative fractions were concentrated to an aqueous phase, DCM was added and then neutralized with a 10% aqueous NaHCO3 solution. The organic phase was washed with brine, water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound. Yield: 7% (70.0 mg, off-white solid). 1 H NMR (400 MHz, MeOD): δ 9.47 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 7.40 (s, 1H), 4.03-3.92 (m, 1H), 3.69-3.66 (m, 2H), 3.57-3.54 (m, 2H), 3.45-3.36 (m, 4H), 2.20-2.17 (m, 2H), 2.07-2.04 (m, 2H), 1.64-1.58 (m, 2H), 1.47-1.40 (m, 2H). LCMS: (Method A) 390.3 (M+H), Rt. 1.11 min. HPLC: (Method A) Rt. 1.77 min.

[0666] Example 46: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide

[0667]

[0668] Step 1: 2-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide

[0669]

[0670] To a stirred solution of 2-chloro-6-methylisonicotinic acid (210 mg, 1.22 mmol) in DMF (3 mL) was added EDC.HCl (351.9 mg, 1.83 mmol), HOBt (248 mg, 1.83 mmol) at 0 ° C under a nitrogen atmosphere, followed by DIPEA (0.53 mL, 3.05 mmol), and the reaction mixture was stirred at 0 ° C for 5 min. (1r, 4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (212 mg, 1.22 mmol) was then added, and the reaction mixture was stirred at RT for 16 h. After completion (according to TLC, the starting material was consumed), the reaction mixture was diluted with water (30 mL) and then extracted with EtOAc (50 mL). The resulting organic solution was washed with 10% NaHCO3 aqueous solution (15 mL) and then with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by chromatography using silica gel (100-200 mesh, 50%-70% EtOAc / petroleum ether) to afford the title compound. Yield: 37% (151 mg, yellow solid). LCMS: (Method A) 327.0 (M+H), Rt 2.09 min.

[0671] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide

[0672]

[0673] A stirred solution of 5-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (145 mg, 0.44 mmol) and 1H-imidazole (90.6 mg, 1.33 mmol) in DMF (3 mL) was purged with nitrogen for 5 min. K2CO3 (183 mg, 1.33 mmol) was added at RT, followed by CuI (8.4 mg, 0.04 mmol), and the reaction mixture was heated at 120 ° C for 16 h. After completion, the reaction mixture was filtered through diatomaceous earth and washed with 5% MeOH / DCM (50 mL). The combined organic layers were washed with 10% NaHCO3 aqueous solution (20 mL) and water (2×15 mL), and then concentrated in vacuo. The resulting crude residue was purified by preparative HPLC. The preparative fraction was concentrated under reduced pressure, the residue was diluted with DCM (20 mL) and washed with 10% aqueous NaHCO3 solution (10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 28% (45.48 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.49 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.10 (s, 1H), 3.81-3.75 (m, 1H), 3.56-3.53 (m, 2H), 3.44-3.40 (m, 2H), 3.30-3.24 (m, 4H), 2.57 (s, 3H), 2.04-2.01 (m, 2H), 1.92-1.89 (m, 2H), 1.40-1.24 (m, 4H). LCMS: (Method A) 359.0 (M+H), Rt. 1.69 min. HPLC: (Method A) Rt. 2.23 min.

[0674] Example 47: 6-Cyano-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0675]

[0676]

[0677] Step 1: 2-(1H-imidazol-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylic acid.

[0678]

[0679] To a stirred solution of methyl 2-(1H-imidazole-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylate (800 mg, 1.98 mmol) in a mixture of THF:water (1:1, 8 mL) was added DIPEA (768.82 mg, 5.94 mmol) and the reaction mixture was stirred at RT for 30 min. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (25 mL) and the resulting suspension was extracted with EtOAC (30 mL). The aqueous layer was evaporated in vacuo to give the resulting crude product, which was used as is in the next step. Yield 52% (0.4 g, light brown solid). LCMS: (Method C) 390.1 (M+H), Rt. 0.93 min.

[0680] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4,6-dicarboxamide.

[0681]

[0682] To a stirred solution of 2-(1H-imidazole-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylic acid (0.4 g, 1.02 mmol) in DCM (4 mL) containing a catalytic amount of DMF (0.05 mL) at 0°C was slowly added (COCl) (0.12 mL, 1.33 mmol) and the reaction mixture was slowly warmed to RT and stirred at RT for 2 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was treated with a solution of NH in THF (40 mL, 10 volumes) at 0°C and the reaction mixture was stirred at RT for 30 min. The reaction mixture was filtered through a bed of celite and the bed was washed with DCM (20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous NaSO, filtered, and the solvent evaporated in vacuo to give the crude compound, which was used as is in the next step. Yield: 100% (0.4 g, brown solid). LCMS: (Method C) 389.1 (M+1), Rt. 1.08 min.

[0683] Step 3: 6-cyano-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0684]

[0685] To a mixture of 2-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4,6-dicarboxamide (400 mg, 1.03 mmol) in DCM (4.0 mL) was added TEA (0.28. mL, 2.06 mmol) at -20 °C, followed by the slow addition of TFAA (0.18. mL, 1.32 mmol). After the addition was complete, the reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was slowly quenched with ice-cold water (15 mL) and diluted with DCM (20.0 mL). The mixture was stirred for 10 min at RT, the layers were separated, and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were washed with 10% aqueous NaHCO3 (10.0 mL), brine (10.0 mL), water (10.0 mL), dried over anhydrous Na2SO4, and the solvent evaporated in vacuo. The resulting crude residue was purified by preparative HPLC (neutral method, ACN-water) to give the title compound. Yield: 29% (110 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.97 (d, J = 8.8 Hz, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 7.22 (s, 1H), 3.89-3.82 (m, 1H), 3.57-3.54 (m, 2H), 3.44-3.42 (m, 2H), 3.30-3.24 (m, 4H), 2.07-2.04 (m, 2H), 1.86-1.83 (m, 2H), 1.62-1.53 ​​(m, 2H), 1.31-1.22 (m, 2H). LCMS: (Method C) 371.0 (M+H), Rt. 1.60 min. HPLC: (Method A) Rt. 2.22 min.

[0686] Example 48: 2-(1 H-Imidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4,6-dicarboxamide.

[0687]

[0688] To a mixture of 2-(1H-imidazole-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylic acid (50 mg, 0.13 mmol) in DCM (1.0 mL) was slowly added (COCl) (0.02 mL, 0.19 mmol) at 0 ° C and the reaction mixture was stirred for 1 h at RT. The reaction was monitored by TLC. After the completion of the starting material, the reaction mixture was treated with a solution of NH3 in THF (1.0 mL, 0.5 M) at RT, and the reaction mixture was stirred for 30 min at RT. The reaction mixture was concentrated in vacuo. The resulting crude residue was purified by preparative HPLC to give the title compound. Yield: 40% (20.0 mg, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ9.23-9.22(m,1H),8.90(d,J=8.8Hz,1H),8.80(s ,1H),8.56-8.55(m,1H),8.29(s,1H),8.16(s,1H),7.20-7.19(m,1H),3.8 9-3.81(m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.30-3.25(m,4H),2 .07-2.05(m,2H),1.87-1.84(m,2H),1.62-1.52(m,2H),1.31-1.21(m,2H). LCMS: (Method A) 389.3 (M+H), Rt. 1.17 min. HPLC: (Method A) Rt. 1.89 min.

[0689] Example 49: 6-((Hydroxymethyl))-2-(1 H-imidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide.

[0690]

[0691]

[0692] To a suspension of methyl 2-(1H-imidazole-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylate (0.8 g, 1.98 mmol) in MeOH (16 mL) was slowly added NaBH4 (98 mg, 2.57 mmol) at 0°C and the reaction mixture was stirred at 0°C for 1 h. After the starting material was consumed (monitored by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and stirred at RT for 10 min. EtOAc (40.0 mL) was then added and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic phase was washed with water (10 mL) followed by brine (10 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The resulting crude residue was purified by preparative HPLC to give the title compound. Yield: 54% (400 mg, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ8.95(s,1H),8.83(d,J=8.4Hz,1H),8.20(s,1H),8.00(s,1H),7.17(s,1H),5.90-5.87(m,1H),4.68(d,J=5.6Hz,2H),3.90 -3.81(m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.30-3.25(m,4H),2. 07-2.04(m,2H),1.87-1.84(m,2H),1.62-1.52(m,2H),1.31-1.22(m,2H). LCMS: (Method D) 376.1 (M+H), Rt. 1.55 min. HPLC: (Method A) Rt. 1.85 min.

[0693] Example 50: 2-(1H-imidazol-1-yl-d3)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0694]

[0695]

[0696] Step 1: Ethyl 2-(1H-imidazol-1-yl-d3)-6-methylpyrimidine-4-carboxylate

[0697]

[0698] Commercial 1H-imidazole-d4 (500 mg, 6.944 mmol) was treated with 10% DIPEA / EtOH (4×8 mL) and the mixture was concentrated in vacuo. The residue was co-distilled with ACN (4×8 mL) to give 1H-imidazole-d3 (500 mg) which was used as such in the following reaction.

[0699] To a stirred solution of 1H-imidazole-d3 (500mg, 6.94mmol) and 6-methyl-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (1.86g, 7.64mmol) in ACN (10mL) was added DIPEA (3.0mL, 17.36mmol) at RT and the reaction mixture was heated at 60°C for 14h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50mL) and washed with water (20mL) and brine solution (20mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The obtained crude residue was wet-ground with petroleum ether to obtain the title compound. Yield: 78% (1.28g, brown solid). 1 H NMR (400 MHz, CD3OD): δ 7.88 (s, 1H), 4.51 (q, J = 7.2 Hz, 2H), 2.70 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). (1H NMR showed the presence of trace amounts of D2-analogs). LCMS: (Method C) 236.1 (M+H), Rt. 0.93 min.

[0700] Step 2: Ethyl 2-(1H-imidazol-1-yl-d3)-6-methylpyrimidine-4-carboxylate

[0701]

[0702] The ethyl 2-(1H-imidazol-1-yl-d3)-6-methylpyrimidine-4-carboxylate (1.2 g, 5.10 mmol) obtained in step 1 was dissolved in a mixture of D2O (12 mL) and 1,4-dioxane (4.0 mL) and the mixture was heated at 80°C for 16 h. The reaction mixture was concentrated in vacuo and the resulting solid was dissolved in EtOAc (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the compound. Yield: 88% (1.06 g, brown solid). 1H NMR (400 MHz, CD3OD): δ 7.89 (s, 1H), 4.51 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). LCMS: (Method C) 236.1 (M+H), Rt. 1.45 min.

[0703] Step 3: Sodium 2-(1H-imidazol-1-yl-d3)-6-methylpyrimidine-4-carboxylate

[0704]

[0705] To a stirred solution of ethyl 2-(1H-imidazole-1-yl-d3)-6-methylpyrimidine-4-carboxylate (1.05 g, 4.46 mmol) in a mixture of 1,4-dioxane (7.0 mL) and water (3.0 mL) was added NaOH (196.59 mg, 4.91 mmol) at RT, and the reaction mixture was stirred for 3 h at RT. After completion (the starting material was consumed according to TLC), 1,4-dioxane was evaporated in vacuo. Water (5 mL) was added to the resulting residue, and the aqueous layer was washed with DCM (25 mL). The aqueous layer was separated and concentrated under reduced pressure. The resulting solid was co-distilled with toluene (3×10 mL) to give the title compound (1HNMR showed the presence of trace amounts of D2 analogs). Yield: 100% (1.025 g, white solid). 1 H NMR (400 MHz, CD3OD): δ 7.73 (s, 1H), 2.64 (s, 3H). LCMS: (Method A) 208.1 (M+H), Rt. 0.79 min.

[0706] Step 4: 2-(1H-imidazol-1-yl-d3)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0707]

[0708] To a stirred solution of sodium 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylate (1.0 g, 4.36 mmol) in DMF (10 mL) was added DIPEA (0.76 mL, 4.363 mmol), HOBt (885.1 mg, 6.544 mmol), EDC.HCl (1.68 g, 8.726 mmol) and (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (830 mg, 4.80 mmol) at RT under nitrogen atmosphere, and the reaction mixture was stirred at RT for 16 h. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (20 mL) and then extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine solution (50 mL), water (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The crude residue was purified by flash column chromatography on a Biotage Isolera using silica gel (230-400 mesh, 5%-100% EtOAc / petroleum ether) to give the title compound. Yield: 55% (960 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.79 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 3.88-3.81 (m, 1H), 3.57-3.54 (m, 2H), 3.44-3.42 (m, 2H), 3.30-3.22 (m, 4H), 2.63 (s, 3H), 2.06-2.03 (m, 2H), 1.85-1.83 (m, 2H), 1.61-1.51 (m, 2H), 1.31-1.21 (m, 2H). LCMS: (Method C) 363.2 (M+H), Rt. 1.02 min. HPLC: (Method A) Rt. 2.34 min. HRMS: C18H25N5O3 (0%), C18H24DN5O3 (0.14%), C18H23D2N5O3 (6.74%), C18H22D3N5O3 (91.95%), C18H21D4N5O3 (1.17%).

[0709] Example 51: 6-(Fluoromethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0710]

[0711]

[0712] To a mixture of 6-((hydroxymethyl))-2-(1H-imidazole-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide (150 mg, 0.40 mmol) in DCM (1.5 mL) was added DAST (161 mg, 1.00 mmol) followed by the slow addition of triethylamine trihydrofluoride (161.0 mg, 1.00 mmol) at -78 °C. After the addition was complete, the reaction mixture was stirred at -78 °C for 30 min while being monitored by TLC. After the starting material was consumed (as analyzed by TLC), the reaction mixture was slowly quenched with 10% NaHCO3 aqueous solution (5 mL), and the reaction mixture was stirred at RT for 10 min. DCM (20.0 mL) was subsequently added and the mixture was stirred for an additional 10 min. The layers were separated, and the aqueous layer was extracted with DCM (2×15 mL). The organic phase was washed with water (10.0 mL) followed by brine (10.0 mL), dried over anhydrous Na2SO4, and the solvent evaporated in vacuo. The resulting crude residue was purified by flash column chromatography on Biotage Isolera (using 230-400 mesh silica gel, eluting with 0-10% MeOH / DCM as a gradient) to give the title compound. Yield: 14% (20.61 mg, light yellow solid). 1 H NMR (400MHz, DMSO-d6): δ8.97(s,1H),8.88(d,J=8.8Hz,1H),8.20(s,1H),7.91(s,1H),7.19(s,1H),5.73(s,1H),5.62(s,1H),3.90-3.82(m ,1H),3.57-3.54(m,2H),3.52-3.49(m,2H),3.30-3.25(m,4H),2.07- 2.04(m,2H),1.87-1.84(m,2H),1.62-1.53(m,2H),1.31-1.20(m,2H). LCMS: (Method A) 378.0 (M+H), Rt. 1.76min. HPLC: (Method A) Rt. 2.22 min.

[0713] Example 52: 6-(Difluoromethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0714]

[0715]

[0716] Step 1: 6-Formyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide.

[0717]

[0718] To a mixture of 6-((hydroxymethyl))-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide (450 mg, 1.20 mmol) in DCM (9.0 mL) was slowly added Dess-Martin periodinane (610.0 mg, 1.44 mmol) at 0°C. After the addition was complete, the reaction mixture was stirred at 0°C for 1.5 h. The reaction was monitored by TLC and the starting material was consumed. The reaction mixture was quenched by the addition of 10% Na2S2O3 aqueous solution (15 mL) and the slow addition of 10% NaHCO3 solution (15 mL). The reaction mixture was stirred for 10 min, DCM (50 mL) was added and the mixture was stirred for an additional 10 min. The layers were separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organic phases were washed with water (35 mL), brine (35 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to give the title compound. Yield: 100% (450 mg, light yellow solid). LCMS: (Method C) 374.0 (M+H), Rt. 1.06 min.

[0719] Step 2: 6-(Difluoromethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0720]

[0721] To a mixture of 6-formyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide (450 mg, 1.20 mmol) in DCM (9.0 mL) was slowly added DAST (485.62 mg, 3.01 mmol) at -78 °C followed by triethylamine trihydrofluoride (485.62 mg, 3.01 mmol) and the reaction mixture was stirred at -78 °C for 1 h. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was slowly quenched with 10% aqueous NaHCO3 solution (5 mL). The mixture was stirred at RT for 10 min, and then DCM (200 mL) was added, and the mixture was stirred for another 10 min. The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic phases were washed with water followed by brine, dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The resulting crude residue was purified by preparative HPLC (Method A). The preparative fractions were concentrated to an aqueous phase. DCM was added to this residue and neutralized with 10% aqueous NaHCO3. The organic phase was washed with brine, water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound. Yield: 6% (27.03 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.94 (d, J = 8.8 Hz, 1H), 8.22-8.21 (m, 1H), 8.07 (s, 1H), 7.27-7.00 (m, 2H), 3.92-3.82 (m, 1H), 3.57-3.55 (m, 2H), 3.45-3.43 (m, 2H), 3.30-3.25 (m, 4H), 2.07-2.05 (m, 2H), 1.87-1.85 (m, 2H), 1.62-1.53 ​​(m, 2H), 1.32-1.23 (m, 2H). LCMS: (Method A) 396.0 (M+H), Rt. 1.85 min, HPLC: (Method A) Rt. 2.40 min.

[0722] Example 53: N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0723]

[0724] Step 1: tert-Butyl ((1r,4r)-4-(ethylsulfonamido)cyclohexyl)carbamate

[0725]

[0726] To a stirred solution of tert-butyl ((1r, 4r)-4-aminocyclohexyl)carbamate (0.5 g, 2.33 mmol, Cas No. 177906-48-8) in DCM (10 mL) was added triethylamine (472 mg, 4.66 mmol) at 0 ° C, followed by ethanesulfonyl chloride (449 mg, 3.49 mmol), and the reaction mixture was stirred overnight at RT. After completion (TLC), the reaction mixture was quenched with water (20 mL), and the suspension was extracted with DCM (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound. Yield: 735 mg (white solid). 1 H NMR (400MHz, DMSO-d6): δ7.00(d,J=10.0Hz,1H),6.72(d,J=10.0Hz,1H),3. 15-3.04(m,1H),3.01-2.89(m,3H),1.90-1.68(m,4H),1.39-1.12(m,16H). LCMS: (Method A)207.2(M-Boc),Rt.2.00min

[0727] Step 2: N-((1r,4r)-4-aminocyclohexyl)ethanesulfonamide hydrochloride

[0728]

[0729] To a stirred solution of tert-butyl ((1r, 4r)-4-(ethylsulfonamido) cyclohexyl)carbamate (335 mg, 1.09 mmol) in DCM (20 mL) was added TFA (0.41 mL, 5.46 mmol) at 0 ° C under a nitrogen atmosphere. After the reaction mixture was stirred at RT for 4 h, no reaction was observed by LCMS analysis of the crude material. The reaction mixture was then concentrated in vacuo. The residue was dissolved in 1,4-dioxane (5 mL), the solution was cooled to 0 ° C, and HCl / 1,4-dioxane (4M, 3 mL) was then added. The reaction mixture was then stirred overnight at RT. After completion (LCMS), the reaction mixture was concentrated in vacuo to obtain the title compound. Yield: (540 mg, yellow solid). 1 H NMR (400MHz, DMSO-d6): δ 8.20-8.10 (m, 3H), 7.10 (d, J = 10.0Hz, 1H), 3.03-2.89 (m, 3H), 2.05-1.78 (m, 4H), 1.45-1.09 (m, 7H). LCMS: (Method A)207.2(M+H),Rt.0.48min

[0730] Step 3: 2-Chloropyrimidine-4-carbonyl chloride

[0731]

[0732] To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (251 mg, 1.58 mmol, CAS No. 149849-92-3) and a drop of DMF in DCM (5 mL) was added oxalyl chloride (0.40 mL, 4.74 mmol) at 0°C and the reaction mixture was stirred at the same temperature for 3 h. After completion (monitored by TLC), the reaction mixture was concentrated in vacuo to give the title compound, which was used immediately in the next step without any purification. Yield: 310 mg (black gummy solid).

[0733] Step 4: 2-Chloro-N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)pyrimidine-4-carboxamide

[0734]

[0735] To a stirred solution of 2-chloropyrimidine-4-carbonyl chloride (306 mg, 1.72 mmol) and TEA (1.24 mL, 8.64 mmol) in THF (7 mL) was added N-((1r, 4r)-4-aminocyclohexyl)ethanesulfonamide hydrochloride (535 mg, 2.59 mmol) at 0 ° C, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and quenched with water (50 mL). The resulting suspension was extracted with EtOAc (100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude residue was purified by Grace normal phase purification (100-200 mesh silica gel, eluent: 50%-80% EtOAc / petroleum ether) to give the title compound. Yield: 33% (199 mg, yellow solid). LCMS: (Method A) 347.0 (M+H), Rt.1.23 min.

[0736] Step 5: N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0737]

[0738] A stirred solution of 2-chloro-N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)pyrimidine-4-carboxamide (197 mg, 0.56 mmol) and 1H-imidazole (117 mg, 1.70 mmol) in DMF (3 mL) was purged with N2 gas for 5 min at RT. Potassium carbonate (235 mg, 1.70 mmol) and CuI (10.8 mg, 0.05 mmol) were then added at RT and the reaction mixture was heated at 120 °C overnight. Upon completion, the reaction mixture was filtered through celite and the celite bed was washed with 10% MeOH / DCM (50 mL). The combined filtrate was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC (Method B). The preparative fraction was concentrated under reduced pressure, the residue was diluted with 10% MeOH / DCM (20 mL) and washed with water (2×10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 5% (11.75 mg, off-white solid). 1 H NMR(400MHz, DMSO-d6):9.07(d,J=4.8Hz,1H),8.97-8.96(m,1H),8.87(d,J=8.4Hz ,1H),8.23-8.22(m,1H),7.91(d,J=4.8Hz,1H),7.19-7.18(m,1H),7.10(d,J=7.6Hz , 1H), 3.84-3.75 (m, 1H), 3.10-3.04 (m, 1H), 3.00 (q, J = 7.2 Hz, 2H), 1.97-1.94 (m, 2H), 1.86-1.83 (m, 2H), 1.64-1.55 (m, 2H), 1.43-1.33 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H). LCMS: (Method A) 379.0 (M+H), Rt. 0.46 min, HPLC: (Method A) Rt. 1.87 min.

[0739] Example 54: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxy-4-methylcyclohexyl)pyrimidine-4-carboxamide

[0740]

[0741] Step 1: (1r,4r)-4-(Benzhydrylamino)-1-methylcyclohexan-1-ol

[0742]

[0743] To a stirred solution of (1r, 4r)-4-amino-1-methylcyclohexan-1-ol (359 mg, 2.77 mmol, cas number-177908-37-1) in acetonitrile (10 mL) was added potassium carbonate (1.15 g, 8.33 mmol) and benzyl bromide (0.66 mL, 5.55 mmol) at RT, and the reaction mixture was heated at 75 ° C for 16 h. After completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with water (3×50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound. Yield: 61% (531 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.36-7.17 (m, 8H), 4.18 (s, 1H), 3.53 (s, 4H), 2.44-2.28 (m, 3H), 1.71-1.66 (m, 2H), 1.57-1.53 ​​(m, 2H), 1.49-1.36 (m, 2H), 1.27-1.17 (m, 2H), 1.10 (s, 3H). LCMS: (Method A) 296.2 (M-OH), Rt. 1.23 min.

[0744] Step 2: (1r,4r)-N,N-diphenylmethyl-4-methoxy-4-methylcyclohexan-1-amine

[0745]

[0746] To a stirred solution of (1r,4r)-4-(benzhydrylamino)-1-methylcyclohexan-1-ol (399 mg, 1.28 mmol) in THF (5 mL) was added sodium hydride (128 mg, 3.22 mmol, 60% suspension) followed by iodomethane (0.24 mL, 549 mg, 3.86 mmol) at 0°C under nitrogen atmosphere. After the addition was complete, the reaction mixture was allowed to warm to RT and stirred overnight at RT. After the reaction was complete, the reaction mixture was slowly poured into ice-cold water (50 mL) and the resulting suspension was extracted with EtOAc (50 mL). The organic layer was washed with water (2×50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting crude residue was purified by Grace normal phase purification (100-200 mesh silica gel, eluent: 20%-30% EtOAc / petroleum ether) to give the title compound. Yield: 93% (535 mg, colorless liquid). LCMS: (Method C) 324.2 (M+H), Rt. 1.48 min.

[0747] Step 3: (1r,4r)-4-methoxy-4-methylcyclohexan-1-amine

[0748]

[0749] To a stirred solution of (1r,4r)-N,N-dibenzhydryl-4-methoxy-4-methylcyclohexan-1-amine (705 mg, 2.17 mmol) in absolute ethanol (7 mL) was added 20% Pd(OH)2 / C (70 mg) at RT and the reaction mixture was stirred overnight at RT under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through a celite bed and the bed was washed with methanol (100 mL). The combined filtrates were concentrated in vacuo to give the title compound which was used in the next step without further purification. Yield: 323 mg (colorless liquid). LCMS: (Method C) 144.3 (M+H), Rt 0.24 min.

[0750] Step 4: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxy-4-methylcyclohexyl)pyrimidine-4-carboxamide

[0751]

[0752] To a stirred solution of 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (210 mg, 1.10 mmol) in DMF (5 mL) was added HATU (629 mg, 1.65 mmol) and DIPEA (0.50 mL, 2.76 mmol) at 0 ° C under a nitrogen atmosphere and the reaction mixture was stirred for 5 min at 0 ° C. (1r, 4r)-4-methoxy-4-methylcyclohexyl-1-amine (189 mg, 1.32 mmol) was subsequently added and the reaction mixture was stirred overnight at RT. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (30 mL) and then extracted with 10% MeOH / DCM (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting crude residue was purified by Grace reverse phase purification (method A). The preparative fraction was concentrated under reduced pressure, the residue was diluted with 10% MeOH / DCM (50 mL) and washed with 10% aqueous NaHCO3 (20 mL) followed by water (2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 52% (182.65 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): 9.07 (d, J = 5.2 Hz, 1H), 8.96-8.95 (m, 1H), 8.78 (d, J = 8.4 Hz, 1H), 8.22-8.21 (m, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.20-7.19 (m, 1H), 3.91-3.82 (m, 1H), 3.14 (s, 3H), 1.80-1.62 (m, 6H), 1.54-1.47 (m, 2H), 1.23 (s, 3H). LCMS: (Method C) 316.0 (M+H), Rt. 1.22 min. HPLC: (Method A) Rt. 2.08 min.

[0753] Example 55: N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0754]

[0755]

[0756] Step 1: 2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid

[0757]

[0758] A stirred solution of 2-chloropyrimidine-4-carboxylic acid (400 mg, 2.52 mmol) and 1H-imidazole (514 mg, 7.54 mmol) in DMF (4 mL) was purged with N2 gas for 5 min at RT. Potassium carbonate (1.046 g, 7.56 mmol) was then added at RT, followed by CuI (48.1 mg, 0.24 mmol) and the reaction mixture was heated to 120 ° C overnight. After completion (LCMS), the reaction mixture was filtered through diatomaceous earth, and the filter bed was washed with 10% MeOH / DCM (50 mL). The combined filtrate was concentrated in vacuo and the resulting crude residue was used in the next step without purification. Yield: 870 mg (yellow solid). LCMS: (Method A) 191.0 (M+H), Rt.0.21 min.

[0759] Step 2: N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0760]

[0761] To a stirred solution of 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (200 mg, 1.05 mmol) in DMF (3 mL) was added HATU (599 mg, 1.57 mmol) at 0 ° C under a nitrogen atmosphere, followed by DIPEA (0.9 mL, 5.25 mmol) and the reaction mixture was stirred at 0 ° C for 5 min. (1s, 4s)-4-amino-1-methylcyclohexan-1-ol (135.8 mg, 1.05 mmol, CAS: 177906-46-6) was subsequently added, and the reaction mixture was stirred at RT overnight. After completion (according to TLC, the starting material was consumed), the reaction mixture was diluted with water (30 mL) and extracted with 10% MeOH / DCM (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting crude product was purified by Grace reverse phase purification (method A). The preparative fraction was concentrated under reduced pressure, the residue was diluted with 10% MeOH / DCM (50 mL) and washed with 10% aqueous NaHCO3 (20 mL) followed by water (2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 30% (142 mg, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ9.05(d,J=5.2Hz,1H),9.01-9.00(m,1H),8.96(d,J=8.8Hz,1H),8.27-8.27(m,1H),7.91(d,J=4.8Hz,1H),7.17 -7.16(m,1H),4.17(s,1H),3.85-3.78(m,1H),2.08-1.88(m,2H),1.63-1.58(m,2H),1.54-1.51(m,2H),1.43-1.35(m,2H),1.14(s,3H). LCMS: (Method A) 302.1 (M+H), Rt.0.51min. HPLC: (Method A) Rt. 1.88 min.

[0762] Example 56: 6-Cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0763]

[0764] Step 1: Methyl 2-chloro-6-cyclopropylpyrimidine-4-carboxylate

[0765]

[0766] A stirred solution of 2,6-dichloropyrimidine-4-formic acid methyl ester (1.20 g, 5.79 mmol) and cyclopropylboronic acid (497 mg, 5.79 mmol) in THF (15 mL) was purged with nitrogen for 5 min at RT. K3PO4 (3.07 g, 14.49 mmol) and Pd (dppf) Cl2.DCM (473 mg, 0.57 mmol) were subsequently added at RT. The reaction mixture was heated at 70 ° C for 16 h. After completion, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc (500 mL). The filtrate was washed with saline solution (2 × 100 mL) and then with water (2 × 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude residue obtained was purified by Grace instrument using silica gel (100-200 mesh, 20-30% EtOAc / petroleum ether as eluent) to obtain the title compound. Yield: 52% (643 mg, yellow solid). 1 H NMR (400 MHz, DMSO-d6): δ8.04 (s, 1H), 3.91 (s, 3H), 2.40-2.36 (m, 1H), 1.24-1.20 (m, 2H), 1.13-1.11 (m, 2H), LCMS: (Method A) 213.1 (M+H), Rt 2.00 min, 1D NOE effect was observed between pyrimidine protons (8.04 ppm) and cyclopropyl CH (2.40-2.36 ppm), confirming the substitution at position 6.

[0767] Step 2: 6-Cyclopropyl-2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid

[0768]

[0769] At RT, a stirring solution of 2-chloro-6-cyclopropylpyrimidine-4-formic acid methyl ester (313mg, 1.47mmol) and 1H-imidazole (305mg, 4.41mmol) in DMF (5mL) was purged with nitrogen for 5min. K was subsequently added at RTCO (610mg, 4.41mmol), followed by CuI (28.03mg, 0.14mmol). The reaction mixture was heated at 120°C for 16h. After completion, the reaction mixture was filtered through diatomite, and the diatomite bed was washed with MeOH (100mL) and water (5mL). The combined filtrate was concentrated in vacuo. The crude residue was suspended in ether (20mL) and acidified with HCl / ether (20mL, 2M). The mixture was concentrated to obtain the title compound in the form of hydrochloride. Yield: crude material (535mg, yellow solid). LCMS: (Method A) 231.1 (M+H), Rt. 0.86 min.

[0770] Step 3: 6-cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide

[0771]

[0772] To a stirred solution of 6-cyclopropyl-2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (530 mg, 2.30 mmol) in DMF (17 mL) was added HATU (1.31 g, 3.45 mmol) and DIPEA (1.0 mL, 5.75 mmol) at 0 ° C under nitrogen atmosphere, followed by (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (498 mg, 2.87 mmol). The reaction mixture was stirred for 16 h at RT. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (20 mL) and then extracted with 10% MeOH / DCM (150 mL). The resulting organic solution was washed with 10% NaHCO3 solution (50 mL) followed by water (2×25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting crude product was purified by Grace instrument, reverse phase (Method A). The preparative fraction was concentrated under reduced pressure. The residue was diluted with 10% MeOH / DCM (50 mL) and washed with 10% NaHCO3 solution (15 mL) followed by water (2×10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and then lyophilized to give the title compound. Yield: 36% (321.12 mg, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ8.90-8.89(m,1H),8.75(d,J=8.4Hz,1H),8.17-8.16(m,1H),7.87(s,1H),7.143-7.137(m,1H),3.87-3.79(m,1H),3.57- 3.54(m,2H),3.45-3.42(m,2H),3.30-3.23(m,4H),2.41-2.37(m,1H),2. 06-2.03(m,2H),1.85-1.80(m,2H),1.58-1.50(m,2H),1.30-1.19(m,2H). LCMS: (Method C) 386.1 (M+H), Rt. 1.25 min. HPLC: (Method A) Rt. 2.61 min.

[0773] Example 57: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-vinylpicolinamide

[0774]

[0775] Step 1: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-vinylpicolinamide

[0776]

[0777] To a mixture of 4-bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.47 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborol (109.21 mg, 0.71 mmol) in a mixture of 1,4-dioxane-H2O (4.5 mL:0.5 mL) was added K2CO3 (163.12 mg, 1.18 mmol) and Pd(PPh3)2Cl2 (38.61 mg, 0.05 mmol) at RT and the mixture was purged with nitrogen for 5 min at RT. The reaction mixture was heated at 80°C for 16 h. After completion (TLC showed that the starting material was consumed), the reaction mixture was filtered through a celite bed and the celite bed was washed with DCM (20 mL). The solvent was evaporated in vacuo to give the crude compound, which was purified by column chromatography on a Biotage Isolera (100-200 mesh silica gel, eluted with 0-10% MeOH / DCM) and then further purified by preparative HPLC (Method A). The preparative fractions were concentrated to an aqueous phase, DCM was added, and then neutralized with a 10% aqueous NaHCO solution. The phases were separated. The organic phase was washed with water, brine, dried over anhydrous NaSO, and evaporated to give the title compound. Yield: 4.4% (8 mg, light brown solid). 1H NMR (400MHz, DMSO-d6): δ8.96 (s, 1H), 8.54 (d, J = 8.4Hz, 1H), 8.29-8.28 (m, 1H), 8.09 (d ,J=0.8Hz,1H),7.99(d,J=0.8Hz,1H),7.17(s,1H),6.95-6.87(m,1H),6.42-6.38(m,1H ), 5.73-5.70 (m, 1H), 3.89-3.80 (m, 1H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 2H), 3.29-3.24 (m, 4H), 2.06-2.03 (m, 2H), 1.85-1.83 (m, 2H), 1.62-1.56 (m, 2H), 1.31-1.22 (m, 2H). LCMS: (Method C) 371.2 (M+H), Rt. 1.22 min. HPLC: (Method A) Rt. 2.52 min.

[0778] Example 58: N-((1r,4r)-4-ethoxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0779]

[0780] Step 1: (1r,4r)-N,N-diphenylmethyl-4-ethoxycyclohexyl-1-amine

[0781]

[0782] To a stirred solution of (1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol (0.5 g, 1.69 mmol) in DMF (10 mL) was added sodium hydride (169 mg, 4.23 mmol) portionwise at 0°C. Ethyl iodide (0.27 mL, 3.38 mmol) was then added slowly at 0°C, and the reaction mixture was stirred overnight at RT. Upon completion (monitored by TLC), the reaction mixture was quenched with ice-cold water and the resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica column chromatography on a Biotage Isolera using 0-9% EtOAc / petroleum ether to give the title compound. Yield: 82% (0.45 g, colorless liquid). 1H NMR (300 MHz, DMSO-d6): 7.35-7.17 (m, 10H), 3.56 (s, 4H), 3.40 (q, J = 7.2 Hz, 2H), 3.15-3.10 (m, 1H), 2.43-2.35 (m, 1H), 2.01-1.97 (m, 2H), 1.83-1.79 (m, 2H), 1.46-1.34 (m, 2H), 1.05 (t, J = 6.9 Hz, 3H), 1.05-0.89 (m, 2H). LCMS: (Method A) 324.0 (M+H), Rt. 2.13 min.

[0783] Step 2: (1r,4r)-4-ethoxycyclohexan-1-amine

[0784]

[0785] To a stirred solution of (1r,4r)-N,N-dibenzhydryl-4-ethoxycyclohexan-1-amine (0.45 g, 1.39 mmol) in absolute ethanol (4 mL) was added Pd(OH)2 / carbon (45 mg, 20% by weight) at RT and the mixture was stirred under hydrogen atmosphere for 16 h at RT. After completion (monitored by TLC), the reaction mixture was filtered through a celite bed and the bed was washed with MeOH. The combined filtrates were evaporated in vacuo to give the title compound which was used in the next step without further purification. Yield: crude material (0.23 g, colorless liquid). LCMS: (Method C) 144.3 (M+H), 0.95 min.

[0786] Step 3: N-((1r,4r)-4-ethoxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0787]

[0788] To a stirred solution of 6-(thiazol-5-yl)-1H-indole-4-carboxylic acid (0.252 g, 1.32 mmol) in DMF (3 mL) was added HATU (1.26 g, 3.32 mmol) followed by DIPEA (0.57 mL, 3.31 mmol) at 0 °C under nitrogen atmosphere. (1r, 4r)-4-ethoxycyclohexan-1-amine (0.19 g, 1.32 mmol) was subsequently added at RT and the reaction mixture was stirred at RT for 16 h. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water and extracted with 10% MeOH / DCM. The organic layer was concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC (Method B) to give the title compound. Yield: 7% (25 mg, white solid). 1H NMR(400MHz, DMSO-d6):9.06(d,J=5.2Hz,1H),8.97(s,1H),8.85(d,J=8.8Hz,1H),8.23-8.22(m,1H),7.91(d,J=4.8Hz,1H),3.91-3.81(m,1H) ,3.48(q,J=6.8Hz,2H),3.26-3.21(m,1H),2.06-2.03(m,2H),1.86-1. 83(m,2H),1.62-1.53(m,2H),1.30-0.21(m,2H),1.11(t,J=6.8Hz,3H). LCMS: (Method D) 316.2 (M+H), Rt. 1.77 min, HPLC: (Method A) Rt. 2.14 min.

[0789] Example 59: Synthesis of 4-(difluoromethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0790]

[0791] Step 1: Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-vinylpyrimidine-4-carboxamide.

[0792]

[0793] To a briefly degassed solution of 6-bromo-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide (500 mg, 1.18 mmol) in a mixture of 1,4-dioxane / water (9:1, 10 mL) was added 2,4,6-trivinylboroxane-pyridine complex (470 mg, 1.77 mmol), CsF (530 mg, 3.54 mmol) at room temperature and the mixture was purged with N2(g). PdCl2(dppf).DCM complex (96 mg, 0.12 mmol) was then added and the reaction mixture was heated at 120°C for 5 h. The reaction was monitored by TLC and the starting material was consumed. The reaction mixture was concentrated, water (10 mL) was added and extracted with DCM (2×10 mL). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to give the title compound. Yield: 75% (330 mg, red-brown solid). 1H NMR (400MHz, DMSO-d6): δ8.97(s,1H),8.55(d,J=8.4Hz,1H),8.30(s,1H),8.10( s,1H),7.99(s,1H),7.17(s,1H),6.95-6.87(m,1H),6.43-6.38(m,1H),5.77-5.7 0 (m, 1H), 3.88-3.81 (m, 1H), 3.59-3.51 (m, 2H), 3.48-3.43 (m, 2H), 3.32-3.22 (m, 4H), 2.06-2.03 (m, 2H), 1.85-1.82 (m, 2H), 1.62-1.52 (m, 2H), 1.30-1.21 (m, 2H). LCMS: (Method C) 371.1 (M+H), Rt. 1.18 min.

[0794] Step 2: Synthesis of 4-formyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide.

[0795]

[0796] To a solution of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-vinylpyrimidine-4-carboxamide (330 mg, 0.89 mmol) in a mixture of 1,4-dioxane / water (3:1, 10 mL) was added OsO4 (2.5% in tert-butanol, 0.04 mL, 0.004 mmol), sodium periodate (1.14 g, 5.34 mmol) and 2,6-lutidine (143 mg, 1.33 mmol) at room temperature and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and the starting material was consumed. The reaction mixture was quenched by the addition of 10% aqueous Na2S2O3 solution (5 mL) and the slow addition of 10% NaHCO3 solution (5 mL). The reaction mixture was stirred for 10 min, DCM (10 mL) was added and the mixture was stirred for another 10 min. The layers were separated and the aqueous layer was extracted with 10% MeOH / DCM (2×10 mL). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude material was purified by flash column chromatography (silica gel, 230-400 mg) using eluent: 5%-7% MeOH / DCM to give the title compound. Yield: 45% (150 mg, yellow solid). LCMS: (Method D) 373.1 (M+H), Rt. 1.29 min.

[0797] Step 3: Synthesis of 4-(difluoromethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0798]

[0799] To a solution of 4-formyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (150 mg, 0.40 mmol) in DCM (4 mL) was slowly added dropwise DAST (0.106 mL, 0.8 mmol) at -78 °C, and the reaction mixture was warmed to 0 °C and stirred at 0 °C for 1 h. After consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice water (5 mL) and extracted with DCM (2 x 5 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 230-400 mg) using eluent: 5%-8% MeOH / DCM to give the title compound. Yield: 12% (20.1 mg, colorless gummy solid). 1 H NMR (400MHz, DMSO-d6): δ9.04-9.03(m,1H),8.67(d,J=8.8Hz,1H),8.37-8.36(m,1H),8.22(s,1H),8.08(s,1H),7.38-7.10(m,2H),3.88-3.81 (m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.29-3.23(m,4H),2.06 -2.03(m,2H),1.85-1.83(m,2H),1.64-1.53(m,2H),1.30-1.22(m,2H). LCMS: (Method A) 395.0 (M+H), Rt. 1.78min. HPLC: (Method A) Rt. 2.40 min.

[0800] Example 60: 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0801]

[0802] Step 1: (1s,4s)-4-(Benzhydrylamino)cyclohexan-1-ol

[0803]

[0804] To a stirred solution of (1s,4s)-4-aminocyclohexan-1-ol hydrochloride (1.0 g, 6.59 mmol) in ACN (15 mL) was added KCO (2.73 g, 19.78 mmol) and benzyl bromide (1.56 mL, 13.19 mmol) at RT, and the reaction mixture was heated at 70 ° C for 5 h. After completion (starting material was consumed according to TLC analysis), the reaction mixture was diluted with ice-cold water (100 mL) and extracted with MTBE (200 mL). The organic layer was washed with water (2×100 mL), brine solution (200 mL), dried over anhydrous NaSO, filtered and the filtrate was concentrated in vacuo. The crude residue was used in the next step without further purification. Yield: 76% (1.5 g, light yellow oil). 1 H NMR(400MHz, DMSO-d6):7.36-7.34(m,10H),4.26(d,J=3.6Hz1H),3.75-3.70(m,1H),3. 59(s,4H),2.41-2.35(m,1H),1.79-1.66(m,4H),1.55-1.51(m,2H),1.25-1.22(m,2H). LCMS: (Method C) 296.2 (M+H), Rt.1.24min.

[0805] Step 2: (1s,4s)-N,N-diphenylmethyl-4-(2-methoxyethoxy)cyclohexan-1-amine

[0806]

[0807] To a stirred solution of (1s,4s)-4-(benzhydrylamino)cyclohexan-1-ol (1.5 g, 5.07 mmol) in DMPU (10 mL) was added sodium hydride (0.50 g, 12.69 mmol) under continuous stirring at RT under nitrogen atmosphere (the mixture became exothermic). 1-Bromo-2-methoxyethane (1.76 g, 12.69 mmol) was then added over a period of 10 min at RT. During the addition of 1-bromo-2-methoxyethane, foam formation was observed. After completion of the addition, the reaction mixture was stirred at 50 °C for 5 h. After completion (monitored by TLC), the reaction mixture was cooled to RT and slowly poured into ice-cold water (50 mL) under continuous stirring. The suspension was extracted with MTBE (300 mL). The organic layer was washed with water (2×200 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a brown oil. The crude residue was dissolved in HCl / dioxane (10 mL, 4 M), stirred at RT for 10 min, and then concentrated. The resulting white solid was suspended in diethyl ether (20 mL), and the mixture was stirred for 10 min. The mixture was filtered, and the filter cake was washed with diethyl ether (20 mL) and dried. The resulting hydrochloride was dissolved in an aqueous NaOH solution (50 mL, 10% solution) and extracted with diethyl ether (100 mL). The combined organic layers were dried over Na2SO4, filtered, and then concentrated to give the title compound. Yield: 83% (1.5 g, light brown oil). LCMS: (Method C) 354.3 (M+H), Rt.1.39 min.

[0808] Step 3: (1s,4s)-4-(2-methoxyethoxy)cyclohexan-1-amine

[0809]

[0810] To a stirred solution of (1s,4s)-N,N-dibenzhydryl-4-(2-methoxyethoxy)cyclohexan-1-amine (1.5 g, 4.24 mmol) in absolute ethanol (10 mL) was added Pd(OH)2 / carbon (0.20 g, 20% by weight) at RT and the mixture was stirred under hydrogen atmosphere for 16 h at RT. After completion (monitored by TLC), the reaction mixture was filtered through a celite bed. The filtrate was evaporated in vacuo to give the title compound, which was used in the next step without further purification. Yield: 61% (0.45 g, colorless liquid). LCMS: (Method C) 174.2 (M+H), 0.41 min.

[0811] Step 4: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid

[0812]

[0813] A stirred solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (5.03 g, 26.95 mmol, cas number: 89581-58-8) and 1H-imidazole (5.50 g, 80.86 mmol) in DMF (75 mL) was degassed for 10 min at RT, followed by the addition of potassium carbonate (11.17 g, 80.86 mmol) and CuI (513 mg, 2.69 mmol). The reaction mixture was heated at 120 ° C for 16 h. After completion (monitored by LCMS), the reaction mixture was filtered through diatomaceous earth and the diatomaceous earth bed was washed with 10% MeOH / DCM (500 mL) and then with water (100 mL). The combined filtrate was concentrated under reduced pressure. The crude residue was suspended in 1,4-dioxane (30 mL) and acidified with HCl / 1,4-dioxane (50 mL, 4 M), and then concentrated in vacuo to give the title compound, which was used in the next reaction without further purification. Yield: crude material (11.1 g, yellow solid). LCMS: (Method C) 205.2 (M+H), Rt. 0.31 min, 54.40%, 205.1 (M+H), Rt. 0.38 min, 34.80%.

[0814] Step 5: 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0815]

[0816] To a stirred solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (93 mg, 0.45 mmol) in DMF (1 mL) was added HATU (259 mg, 0.68 mmol) and DIPEA (0.19 mL, 1.02 mmol) at 0°C under nitrogen atmosphere. After stirring at 0°C for 5 min, (1s, 4s)-4-(2-methoxyethoxy)cyclohexan-1-amine (79 mg, 0.45 mmol) was added and the reaction mixture was stirred at RT for 16 h. After completion (consumption of starting material according to TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer was washed with 10% NaHCO (20 mL), water (2×20 mL), brine solution (30 mL), dried over anhydrous NaSO, filtered and the filtrate concentrated in vacuo. The crude residue was purified by silica column chromatography on Biotageisolera using 1-2% MeOH / DCM and the title compound was obtained. Yield: 9% (14.30 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.84 (s, 1H), 7.15 (s, 1H), 3.94-3.82 (m, 1H), 3.54-3.47 (m, 5H), 3.28 (s, 3H), 2.63 (s, 3H), 1.92-1.75 (m, 4H), 1.57-1.46 (m, 4H). LCMS: (Method C) 360.2 (M+H), Rt. 1.34 min. HPLC: (Method A) Rt. 2.34 min.

[0817] Example 61: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxy-2-methylpropoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0818]

[0819] Step 1: 1-(((1r,4r)-4-(Benzhydrylamino)cyclohexyl)oxy)-2-methylpropan-2-ol

[0820]

[0821] To a stirred solution of (1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol (0.5 g, 1.69 mmol) in DMSO (5 mL) was added 2,2-dimethyloxirane (0.45 g, 6.23 mmol) and KOH (0.285 g, 5.08 mmol) at RT and the reaction mixture was heated to 60 ° C overnight in a sealed tube. An additional portion of 2,2-dimethyloxirane (0.45 g, 6.23 mmol) was added and the reaction mixture was heated to 60 ° C overnight. After completion (monitored by LCMS), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica column chromatography on Biotage Isolera using 0-12% EtOAc / petroleum ether to give the title compound. Yield: 59% (0.37 g, colorless liquid). LCMS: (Method C) 368.3 (M+H), Rt. 1.15 min.

[0822] Step 2: (1r,4r)-N,N-diphenylmethyl-4-(2-methoxy-2-methylpropoxy)cyclohexan-1-amine

[0823]

[0824] To a stirred solution of 1-(((1r,4r)-4-(benzhydrylamino)cyclohexyl)oxy)-2-methylpropan-2-ol (0.35 g, 0.95 mmol) in DMF (3.5 mL) was added sodium hydride (76 mg, 1.90 mmol, 60% suspension) at 0°C and the reaction mixture was stirred at 0°C for 0.5 h. MeI (0.15 mL, 2.36 mmol) was then added at 0°C and the reaction mixture was stirred at RT for 3 h. After completion (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4Cl solution. The mixture was diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The crude residue was purified by silica column chromatography on Biotage Isolera using 0-10% EtOAc / petroleum ether to give the title compound. Yield: 85% (0.31 g, colorless liquid). LCMS: (Method C) 382.2 (M+H), Rt. 1.42 min.

[0825] Step 3: (1r,4r)-4-(2-methoxy-2-methylpropoxy)cyclohexan-1-amine

[0826]

[0827] To a stirred solution of (1r,4r)-N,N-dibenzhydryl-4-(2-methoxy-2-methylpropoxy)cyclohexan-1-amine (0.3 g, 0.79 mmol) in absolute ethanol (3 mL) was added Pd(OH)2 / carbon (60 mg, 20% by weight) at RT and the mixture was stirred under hydrogen atmosphere for 24 h at RT. After completion (monitored by TLC and LCMS), the reaction mixture was filtered through a celite bed and the bed was washed with MeOH. The combined filtrates were evaporated in vacuo to give the title compound which was used in the next step without further purification. Yield: crude material (0.1 g, colorless liquid). LCMS: (Method A) 202.3 (M+H), 1.13 min.

[0828] Step 4: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxy-2-methylpropoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide

[0829]

[0830] To a stirred solution of sodium 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylate (100 mg, 0.44 mmol) in DMF (1 mL) at 0°C under nitrogen atmosphere was added HOBt (89.1 mg, 0.66 mmol), EDC.HCl (169 mg, 0.88 mmol) followed by DIPEA (0.08 mL, 0.44 mmol). After stirring at 0°C for 5 min, (1r,4r)-4-(2-methoxy-2-methylpropoxy)cyclohexan-1-amine (88.54 mg, 0.44 mmol) was added and the reaction mixture was stirred at RT for 16 h. After completion (consumption of starting material according to TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer was washed with 10% NaHCO (20 mL), water (2×20 mL), brine solution (30 mL), dried over anhydrous Na SO, filtered and the filtrate concentrated in vacuo. The crude product was purified by silica column chromatography on Biotage Isolera using 1-2% MeOH / DCM and then by preparative HPLC (Method B) to give the title compound. Yield: 23% (39.47 mg, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ8.95(s,1H),8.79(d,J=8.4Hz,1H),8.20-8.19(m,1H),7.83(s,1H),7.17-7.16(m,1H),3.89-3.80(m,1H),3.31(s, 2H),3.28-3.19(m,1H),3.12(s,3H),2.63(s,3H),2.06-2.03(m,2H), 1.86-1.83(m,2H),1.61-1.51(m,2H),1.31-1.24(m,2H),1.08(s,6H). LCMS: (Method A) 388.0 (M+H), Rt. 1.91min. HPLC: (Method A) Rt. 2.68 min.

[0831] Example 62: 6-(1H-imidazol-1-yl)-4-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0832]

[0833] Step 1: 4-Methoxy-2-(methoxycarbonyl)pyridine 1-oxide

[0834]

[0835] To a stirred solution of 4-methoxypicolinic acid methyl ester (1.0 g, 5.98 mmol) in EtOAc (20 mL) was added mCPBA (1.54 g, 8.97 mmol) and the reaction mixture was stirred at RT for 18 h. After completion, the reaction mixture was adjusted to about pH 7 with solid NaHCO, filtered and the filtrate was concentrated under reduced pressure. The obtained crude residue was purified by column chromatography (230-400 mesh silica gel, eluted with 10% MeOH / DCM) on Biotage Isolera to obtain the title compound. Yield: 36% (0.4 g, off-white colloid solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.20 (d, J = 9.6 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.15 (dd, J = 4.8, 9.6 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H). LCMS: (Method C) 184.1 (M+H), Rt. 0.27 min.

[0836] Step 2: Methyl 6-chloro-4-methoxypicolinate

[0837]

[0838] A stirred solution of 4-methoxy-2-(methoxycarbonyl)pyridine-1-oxide (0.4 g) in POCl (15 mL) was heated to 100 ° C overnight. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude residue was quenched with ice-cold water (20 mL), and the precipitated solid was filtered and dried in vacuo to give the title compound. Yield: 61% (0.27 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.58-7.54 (m, 1H), 7.41 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H). LCMS: (Method C) 202.0 (M+H), Rt. 1.66 min.

[0839] Step 3: 6-Chloro-4-methoxypicolinic acid

[0840]

[0841] To a stirred solution of 6-chloro-4-methoxypicolinic acid methyl ester (0.27 g, 1.33 mmol) in a mixture of THF (8 mL) and water (2 mL) was added NaOH (0.16 g, 4.01 mmol) at RT, and the reaction mixture was stirred overnight at RT. After completion (monitored by TLC), the reaction mixture was concentrated in vacuo and acidified to pH about 2.0 with 1.5 N HCl solution. The precipitated solid was filtered and dried in vacuo to obtain the title compound. Yield: 83% (0.21 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 13.54 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 3.93 (s, 3H). LCMS: (Method C) 188.1 (M+H), Rt. 0.89 min.

[0842] Step 4: 6-Chloro-4-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0843]

[0844] To a stirred solution of 6-chloro-4-methoxypicolinic acid (0.21 g, 1.12 mmol) in DMF (2 mL) was added DIPEA (0.6 mL, 3.36 mmol) and HATU (0.64 g, 1.68 mmol) at RT. After stirring for 5 min, a solution of (1r, 4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (0.252 g, 1.45 mmol) was added and the reaction mixture was stirred overnight at RT. After completion (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude residue was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluted with 55% EtOAc / petroleum ether) to give the title compound. Yield: 78% (0.3 g, light yellow gum). 1H NMR (400MHz, DMSO-d6): δ8.30(d,J=8.8Hz,1H),7.51-7.50(m,1H),7.31(d,J=2.4Hz,1H),3.94(s,3H),3.78-3.71(m,1H),3.55- 3.52(m,2H),3.43-3.41(m,2H),3.30-3.21(m,4H),2.01-1.98(m,2H),1.82-1.79(m,2H),1.52-1.48(m,2H),1.27-1.18(m,2H). LCMS: (Method C) 343.2 (M+H), Rt. 2.01min.

[0845] Step 5: 6-(1H-imidazol-1-yl)-4-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide

[0846]

[0847] A mixture of 6-chloro-4-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (0.15 g, 0.44 mmol), imidazole (89 mg, 1.31 mmol), L-proline (5 mg, 0.0437 mmol) and KCO (181 mg, 1.31 mmol) in DMSO (3 mL) was purged with N for 2 min at RT, followed by the addition of copper iodide (8 mg, 0.04 mmol). The reaction mixture was then heated at 90 °C in a sealed tube for 16 h. The presence of unreacted starting material was confirmed by TLC monitoring at this point. The reaction mixture was then heated to 120 °C for 5 h. Upon completion, the reaction mixture was diluted with EtOAc (10 mL) and filtered through a bed of celite. The filtrate was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC (Method C). The preparative fraction was concentrated under reduced pressure, and the residue was diluted with 10% MeOH / DCM (10 mL), washed with 10% aqueous NaHCO3 (4 mL), brine and water. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 8% (12.94 mg, off-white solid). 1H NMR (400MHz, DMSO-d6): δ8.94 (s, 1H), 8.53 (d, J = 8.8Hz, 1H), 8.27-8.26 (m, 1H),7.54(d,J=2.0Hz,1H),7.47(d,J=2.4Hz,1H),7.14(s,1H),3.99(s,3H), 3.89-3.81(m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.30-3.23(m,4H), 2.05-2.02(m,2H),1.84-1.81(m,2H),1.61-1.53(m,2H),1.30-1.20(m,2H). LCMS: (Method C) 375.0 (M+H), Rt. 1.47 min. HPLC: (Method A) Rt. 2.33 min.

[0848] Example 63: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide

[0849]

[0850] Step 1: (1r,4r)-N,N-diphenylmethyl-4-methoxycyclohexyl-1-amine

[0851]

[0852] To a stirred solution of ((1r,4r)-4-(benzhydrylamino)cyclohexan-1-ol (1.0 g, 3.38 mmol) in THF (20 mL) at 0°C under nitrogen atmosphere was added sodium hydride (0.195 g, 5.08 mmol, 60% in paraffin oil) (the mixture became exothermic). Iodomethane (0.42 mL, 6.77 mmol) was added dropwise at the same temperature (bubbling was observed). After completion of addition, the reaction mixture was allowed to warm to RT and stirred at RT for 10 h. After completion, the reaction mixture was slowly poured into ice water (20 mL) with continuous stirring. The suspension was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (25 mL), dried over anhydrous Na 2 SO 4 , filtered and the filtrate concentrated in vacuo to give the title compound. Product. Yield: 96% (1 g, light yellow liquid). 1H NMR (400 MHz, DMSO-d6): δ 7.35-7.28 (m, 8H), 7.22-7.18 (m, 2H), 3.57 (s, 4H), 3.19 (s, 3H), 3.07-3.01 (m, 1H), 2.43-2.36 (m, 1H), 2.03-2.00 (m, 2H), 1.84-1.81 (m, 2H), 1.46-1.37 (m, 2H), 0.98-0.86 (m, 2H). LCMS: (Method C) 310.2 (M+H), 1.53 min.

[0853] Step 2: (1r,4r)-4-methoxycyclohexan-1-amine

[0854]

[0855] To a stirred solution of (1r,4r)-N,N-dibenzhydryl-4-methoxycyclohexan-1-amine (1 g, 3.23 mmol) in absolute ethanol (20 mL) was added Pd(OH)2 / C (0.2 g, 20 wt.% loading) at RT and the reaction mixture was stirred overnight at RT under hydrogen atmosphere. After completion, the reaction mixture was filtered through a celite bed and the filtrate was concentrated in vacuo to give the title compound, which was used in the next step without further purification. Yield: 98% (0.41 g, light green liquid). 1 H NMR (400 MHz, DMSO-d6): δ 3.23 (s, 3H), 3.06-3.01 (m, 1H), 1.93-1.89 (m, 2H), 1.75-1.71 (m, 2H), 1.24-1.05 (m, 4H). LCMS: (Method A) 130.3 (M+H), 0.29 min.

[0856] Step 3: 2-Chloropyrimidine-4-carbonyl chloride

[0857]

[0858] To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (0.2 g, 1.26 mmol) and one drop of DMF in DCM (10 mL) was added oxalyl chloride (0.24 g, 1.89 mmol) at 0°C and the reaction mixture was stirred for 3 h at RT. After completion (monitored by TLC), the reaction mixture was dried in vacuo to give the title compound, which was used in the next step without any purification. Yield: 98% (0.2 g, light brown gum).

[0859] Step 4: 2-Chloro-N-((1r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide

[0860]

[0861] To a stirred solution of 2-chloropyrimidine-4-carbonyl chloride (0.2 g, 1.13 mmol) and TEA (0.47 mL, 3.39 mmol) in THF (10 mL) at 0 °C was added (1r, 4r)-4-methoxycyclohexan-1-amine (step-2) (0.219 g, 1.69 mmol) and the reaction mixture was stirred at RT overnight. After completion (monitored by TLC), the reaction mixture was quenched with saturated aqueous NaHCO3 solution (10 mL). The resulting suspension was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo to give the title compound. Yield: 82% (0.25 g, brown gummy liquid). LCMS: (Method C) 270.0 (M+H), Rt.1.85 min.

[0862] Step 5: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide

[0863]

[0864] A mixture of 2-chloro-N-((1r, 4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide (0.25 g, 0.93 mmol), imidazole (189 mg, 2.78 mmol) and KCO (0.384 g, 2.78 mmol) in DMF (5 mL) was purged with N (gas) for 2 min, followed by the addition of copper iodide (17 mg, 0.09 mmol). The reaction mixture was heated at 120 ° C overnight. After completion (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered through a diatomaceous earth bed. The filtrate was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC (method A). The preparative fraction was concentrated under reduced pressure, the residue was diluted with 10% MeOH / DCM (10 mL), and washed with 10% NaHCO aqueous solution (10 mL), followed by brine solution and water. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 18% (51.39 mg, light brown gummy solid). 1HNMR (400MHz, DMSO-d6): δ9.07(d,J=4.8Hz,1H),8.97(s,1H),8.85(d,J=8.4Hz,1H),8.24-8.23(m,1H),7.92(d,J=4.8Hz,1H),7.19-7.1 8(m,1H),3.89-3.82(m,1H),3.27(s,3H),3.18-3.11(m,1H),2.09-2.06(m,2H),1.87-1.84(m,2H),1.63-1.53(m,2H),1.29-1.22(m,2H). LCMS: (Method A) 302.1 (M+H), Rt.0.76min. HPLC: (Method A) Rt. 1.89 min.

[0865] Example 64: N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0866]

[0867] Step 1: 2-Chloropyrimidine-4-carbonyl chloride

[0868]

[0869] To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (0.2 g, 1.26 mmol) and one drop of DMF in DCM (10 mL) was added oxalyl chloride (0.24 g, 1.89 mmol) at 0°C and the reaction mixture was stirred for 3 h at RT. After completion (monitored by TLC), the reaction mixture was dried in vacuo to give the title compound, which was used in the next step without any purification. Yield: 98% (0.2 g, light brown gum).

[0870] Step 2: 2-Chloro-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide

[0871]

[0872] To a stirred solution of 2-chloropyrimidine-4-carbonyl chloride (0.2 g, 1.13 mmol) and TEA (0.47 mL, 3.39 mmol) in THF (10 mL) at 0 ° C. was added (1r, 4r)-4-amino-1-methylcyclohexan-1-ol (0.195 g, 1.35 mmol, CAS: 177908-37-1), and the reaction mixture was stirred at RT overnight. After completion (monitored by TLC), the reaction mixture was quenched with saturated aqueous NaHCO3 solution (10 mL). The resulting suspension was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound. Yield: 75% (0.23 g, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ9.00(d,J=2.0,6.8Hz,1H),8.69(d,J=11.6Hz,1H),8.00(dd,J=2 .0, 6.8Hz, 1H), 4.31 (d, J = 1.2Hz, 1H), 3.88-3.75 (m, 1H), 1.67-1.39 (m, 8H), 1.24 (s, 3H). LCMS: (Method C) 270.0 (M+H), Rt. 1.40min.

[0873] Step 3: N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide

[0874]

[0875] A mixture of 2-chloro-N-((1r, 4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide (0.23 g, 0.85 mmol), imidazole (174 mg, 2.56 mmol) and KCO (0.353 g, 2.56 mmol) in DMF (2 mL) was purged with N(gas) for 2 min at RT, followed by addition of copper iodide (16 mg, 0.085 mmol). The reaction mixture was heated at 120 °C overnight. After completion (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered through a diatomaceous earth bed. The filtrate was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC (method A). Preparative fractions were collected, concentrated under reduced pressure, and the crude residue was diluted with 10% MeOH / DCM (10 mL). The mixture was adjusted to neutral pH with solid NaHCO and stirred for 30 min. The mixture was filtered, and the filtrate was dried under reduced pressure and finally lyophilized to give the title compound. Yield: 34% (87.92 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 9.07 (d, J = 5.2 Hz, 1H), 8.96 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.22-8.21 (m, 1H), 7.91 (d, J = 5.2 Hz, 1H), 7.19 (s, 1H), 4.38 (s, 1H), 3.89-3.81 (m, 1H), 1.77-1.45 (m, 8H), 1.22 (s, 3H). LCMS: (Method B) 302.2 (M+H), Rt. 1.49 min. HPLC: (Method A) Rt. 1.52 min.

[0876] Example 65: 2-(1H-imidazol-1-yl)-N-((1r,3r)-3-(2-methoxyethoxy)cyclobutyl)pyrimidine-4-carboxamide

[0877]

[0878] Step 1: (1r,3r)-3-(Benzhydrylamino)cyclobutan-1-ol

[0879]

[0880] To a stirred solution of 3-aminocyclobutanol hydrochloride (1.0 g, 8.09 mmol) in acetonitrile (20 mL) was added potassium carbonate (4.46 g, 3.23 mmol) and benzyl bromide (2.83 g, 1.66 mmol) at RT. The reaction mixture was then heated at 75 ° C overnight. The precipitated solid was filtered, washed with EtOAc, and the filtrate was concentrated in vacuo. The resulting crude residue was triturated with petroleum ether and dried to give the title compound. Yield: 87% (1.9 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.34-7.20 (m, 10H), 4.84 (d, J = 6.4 Hz, 1H), 4.18-4.14 (m, 1H), 3.44 (s, 4H), 3.40-3.30 (m, 1H), 2.15-2.06 (m, 2H), 1.88-1.80 (m, 2H). LCMS: (Method A) 268.1 (M+H), Rt. 1.30 min.

[0881] Step 2: (1r,3r)-N,N-diphenylmethyl-3-(2-methoxyethoxy)cyclobutane-1-amine

[0882]

[0883] To a stirred solution of (1r,3r)-3-(benzhydrylamino)cyclobutan-1-ol (1.8 g, 9.73 mmol) in DMPU (20 mL) was added sodium hydride (0.64 g, 1.61 mmol, 60% in paraffin oil) at RT under nitrogen atmosphere. The mixture became exothermic and 1-bromo-2-methoxyethane (2.33 g, 1.68 mmol) was added over a period of 10 min. During this addition, foam formation was observed. After the addition was complete, the reaction mixture was stirred at 65 °C for 2 h. An additional amount of sodium hydride (0.13 g, 3.30 mmol, 60% in paraffin oil) was added under heating conditions, followed by 1-bromo-2-methoxyethane (0.46 g, 3.30 mmol). Furthermore, the reaction was continued at 67 °C for another 2 h. After the reaction was complete, the reaction mixture was cooled to RT and slowly poured into ice (5 g) with continuous stirring. The suspension was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×25 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in 1,4-dioxane (30 mL), to which 4N HCl / dioxane (20 mL) was added. The mixture was stirred for 20 min and concentrated in vacuo to give a solid, which was dissolved in H2O and basified with 1N NaOH aqueous solution. The suspension was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×25 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound. Yield: 91% (2 g, colorless liquid). 1 H NMR (400 MHz, DMSO-d6): δ 7.34-7.21 (m, 10H), 3.97-3.94 (m, 1H), 3.45 (s, 4H), 3.41-3.34 (m, 4H), 3.32-3.28 (m, 1H), 3.23 (s, 3H), 2.12-2.07 (m, 2H), 2.05-1.93 (m, 2H). LCMS: (Method C) 326.2 (M+H), Rt. 1.55 min.

[0884] Step 3: (1r,3r)-3-(2-methoxyethoxy)cyclobutane-1-amine

[0885]

[0886] To a stirred solution of (1r,3r)-3-(benzhydrylamino)cyclobutan-1-ol (2.0 g, 6.15 mmol) in absolute ethanol (20 mL) was added Pd(OH)2 / C (0.4 g, 20%) at RT and the mixture was stirred overnight at RT under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through a celite bed. The filtrate was concentrated in vacuo to give the title compound. It was used in the next step without further purification. Yield: 90% (0.8 g, colorless liquid). 1 H NMR (400 MHz, DMSO-d6): 4.05-4.04 (m, 1H), 3.45-3.33 (m, 4H), 3.24 (m, 3H), 3.23-3.18 (m, 1H), 2.09-2.02 (m, 2H), 1.87-1.81 (m, 2H); LCMS: (Method A) 146.2 (M+H), 0.40 min.

[0887] Step 4: 2-Chloropyrimidine-4-carbonyl chloride

[0888]

[0889] To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (0.2 g, 1.26 mmol) and DMF (catalytic amount) in DCM (10 mL) was added oxalyl chloride (0.24 g, 1.89 mmol) at 0°C. The reaction was allowed to slowly warm to RT and then stirred at RT for 3 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was dried in vacuo to give the title compound, which was immediately carried forward to the next step. Yield: 98% (0.2 g, light brown gum).

[0890] Step 5: 2-Chloro-N-((1r,3r)-3-(2-methoxyethoxy)cyclobutyl)pyrimidine-4-carboxamide

[0891]

[0892] To a stirred solution of 2-chloropyrimidine-4-carbonyl chloride (0.2 g, 1.13 mmol) and TEA (0.47 mL, 3.39 mmol) in THF (10 mL) at 0 °C, (1r,3r)-3-(2-methoxyethoxy)cyclobutane-1-amine (0.202 g, 1.39 mmol) was added in RM at the same temperature. The reaction was stirred for another 16 h at RT. The reaction mixture was monitored by TLC and quenched with saturated aqueous NaHCO3 solution (10 mL). The resulting suspension was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and the solvent evaporated in vacuo to give the title compound. Yield: 75% (0.18 g, off-white solid). 1 H NMR (400MHz, DMSO-d6): δ9.25(d,J=7.6Hz,1H),9.00(d,J=4.8Hz,1H),7.99(d,J=4.8Hz,1H),4.52-4.46(m,1H ), 4.15-4.10(m,1H),3.46-3.41(m,4H),3.34(s,3H),2.43-2.20(m,4H); LCMS: (Method A) 286.0(M+H), Rt.1.19min.

[0893] Step 6: 2-(1H-imidazol-1-yl)-N-((1r,3r)-3-(2-methoxyethoxy)cyclobutyl)pyrimidine-4-carboxamide

[0894]

[0895] A stirred solution of 2-chloro-N-((1r,3r)-3-(2-methoxyethoxy)cyclobutyl)pyrimidine-4-carboxamide (130 mg, 0.45 mmol) and 1H-imidazole (92.8 mg, 1.36 mmol) in DMF (4 mL) was purged with nitrogen for 5 min (RT) before potassium carbonate (188 mg, 1.36 mmol) was added followed by CuI (8.6 mg, 0.04 mmol). The reaction mixture was heated at 120 °C for 16 h. Upon completion, the reaction mixture was filtered through celite and the celite bed was washed with 10% MeOH / DCM (50 mL). The combined filtrate was concentrated in vacuo and the resulting crude material was purified by preparative HPLC (Method A). The preparative fraction was concentrated under reduced pressure, diluted with DCM (20 mL) and with NaHCO (15 mL) followed by washing with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and lyophilized to give the title compound. Yield: crude material (55 mg, yellow solid). 1H NMR (400 MHz, DMSO-d6): δ 9.25 (d, J = 7.6 Hz, 1H), 9.00 (d, J = 5.2 Hz, 1H), 8.98 (s, 1H), 8.26-8.24 (m, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.20-7.19 (m, 1H), 4.56-4.40 (m, 1H), 4.19-4.16 (m, 1H), 4.48-3.44 (m, 4H), 3.27 (s, 3H), 2.47-2.42 (m, 2H), 2.34-2.28 (m, 2H); LCMS: (Method A) 318.0 (M+H), Rt. 0.74 min. HPLC: (Method A) Rt. 1.794 min.

[0896] Example 66: Assay protocol for determining IC50 against human CD38:

[0897] CD38 (differentiation antigen of B lymphocytes) is a type II integral membrane protein. It is also known as ADP ribosyl cyclase and nicotinamide adenodinucleotide (NAD) glycerol hydrolase. Through its production of cyclic ADP ribose, CD38 regulates calcium ion-mediated signal transduction in various cells, including pancreatic cells. The major enzymatic activity of CD38 is the hydrolysis of NAD. CD38 is a predictive biomarker for acute B lymphoblastic leukemia.

[0898] The CD38 Inhibitor Screening Assay Kit (BPS Bioscience, catalog number: 79287) is designed to measure the glycerol hydrolase activity of CD38 for screening and profiling applications.

[0899] CD38 hydrolase buffer (4×) was thawed on ice, and 1×CD38 hydrolase buffer was prepared by diluting 4×CD38 hydrolase buffer with water. CD38 hydrolase was diluted to 0.5ng / ml with 1×CD38 hydrolase buffer (10ng / well). The master mixture was prepared by mixing equal volumes of water with CD38 hydrolase buffer (4×), and 10 μl of the mixture was added to all holes. After the master mixture was added, 10 μl of inhibitor and 20 μl of CD38 hydrolase were added to each hole. For the holes marked as blank, 10 μl and 20 μl of 1×CD38 hydrolase buffer were added to replace CD38 enzyme and inhibitor, respectively. The plate was covered and cultivated for 30 min at room temperature under slow shaking at 400 rpm. After 30 min cultivation, the plate was removed, and 10 μl of diluted ε-NAD substrate was added to all holes. The plates were incubated for 10 min, spun at 1200 rpm for 30 seconds to remove air bubbles, and read in a Tecan Spark using a fluorometer set to excite 300 nm and emit 410 nm. The blank reading was subtracted from all values. The IC50 of the test compounds was determined by using Graphpad Prism software v7.0.

[0900] Table 3

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

Claims

1. A compound represented by structural formula (IIIa), (IIIb) or (IIIc): or a pharmaceutically acceptable salt thereof, wherein: R 1 for: (i) optionally through one, two or three C 1-4 an alkyl-substituted 5-membered nitrogen-containing heteroaryl group; or (ii) -H, -NH2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C1-C4 haloalkylthio; or (iii) -C(=O)NH2, -COOH, C1-C4 hydroxyalkyl, C2-C4 alkenyl, -CN, C1-C4 alkylsulfone or C3-C4 cycloalkyl; R 2 is optionally ionized with one, two or three deuterium or C 1-4 Alkyl-substituted 5-membered nitrogen-containing heteroaryl; R d H, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, or optionally C 1-4 Alkoxy substituted C 1-4 Alkyl; and n is 1.

2. The compound according to claim 1, wherein the compound is represented by structural formula (IIIa): or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is represented by structural formula (IIIb): or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound is represented by structural formula (IIIc): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is represented by structural formula (IVa): or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound is represented by structural formula (IVb): or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is represented by structural formula (IVc): or a pharmaceutically acceptable salt thereof.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R d For optionally 1-4 Alkoxy substituted C 1-4 alkyl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R d For C 1-4 Alkoxy substituted C 1-4 alkyl.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R d It is -CH2CH2OCH3.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R d It is -H, -CH3 or -CH2CH2OCH3.

12. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 and 11, wherein R 1 is optionally treated with one, two or three C 1-4 Alkyl-substituted 5-membered nitrogen-containing heteroaryl.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole or oxadiazole, which is optionally substituted by one, two or three C 1-4 Alkyl substitution.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: Each optionally through one, two or three C 1-4 Alkyl substitution.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

16. A compound as claimed in any one of claims 1 to 7 and 11, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -H, -NH2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C1-C4 alkylthio.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 1 It is -H, -CH3, -CF3, -OCH3, -SCH3, -F, -Cl, -Br or -NH2.

18. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, 11 and 13 to 15, wherein R 2 is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole or oxadiazole, which is optionally substituted by one, two or three C 1-4 Alkyl substitution.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: and optionally through one, two or three C 1-4 Alkyl substitution.

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is -C(=O)NH2, -COOH, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkenyl, -CN, C1-C4 alkylsulfone, or C3-C4 cycloalkyl.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 1 It is -C(=O)NH2, -COOH, -CHF2, -CH2F, -CH(OH)CH3, -C(OH)(CH3)2, -CH2OH, -CH=CH2, -SO2Me, or cyclopropyl.

23. A compound as described in any one of claims 1, 21 and 22, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5-membered nitrogen-containing heteroaryl group substituted by one, two, or three deuterium groups.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 2 is imidazole substituted with one, two, or three deuteriums.

25. A compound as described in any one of claims 1, 21 and 22, or a pharmaceutically acceptable salt thereof, wherein R d C 1-4 Haloalkyl or C 1-4 Hydroxyalkyl.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R d It is -CHF2 or -CH2CH2OH.

27. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound is:

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

30. Use of a compound as claimed in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 29, in the preparation of a medicament for treating a disease or condition in a subject that benefits from an increase in NAD+.

31. The use of claim 30, wherein the disease or disorder is a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a metabolic disease, cancer, a vascular disease, a muscular eye disease or a kidney disease.

32. The use according to claim 31, wherein the vascular disease is an ocular vascular disease.

33. The use of claim 32, wherein the ocular vascular disease is selected from Stargardt's disease, retinopathy, macular degeneration, and glaucoma.

34. The use according to claim 33, wherein: (i) the retinopathy is hypertensive retinopathy or diabetic retinopathy; or (ii) The macular degeneration is age-related macular degeneration (AMD).

35. The use according to claim 31, wherein: The muscle structural disorder is selected from Bethlem myopathy, centralcore disease, congenital asymmetric fiber type, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline myopathy, limb-girdle MD, muscle sodium channel disorder, myotonic dystrophy, myotubular myopathy, nematode disease, oculopharyngeal MD, or stress urinary incontinence; The neuronal activation disorder is selected from the group consisting of amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, neuropathy, peripheral neuropathy, spinal muscular atrophy, tardive ulnar nerve palsy, and toxic myoneural disorder; The muscle fatigue disorder is selected from chronic fatigue syndrome, type I diabetes, type II diabetes, glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy; the muscle mass disorder is cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, myopathy gravis, inclusion body myositis, polymyositis, amyotrophy, sarcopenia, steroid myopathy, and systemic lupus erythematosus; The muscle mass disorder is selected from systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long chain acyl-CoA dehydrogenase deficiency, trifunctional enzyme deficiency, medium chain acyl-CoA dehydrogenase (MCAD) deficiency, short chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin responsive disorder of beta oxidation (RR-MADD); The metabolic disease is selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia, HLD noncholesterolemia, VLDL hyperproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, cerebrovascular disease, peripheral circulatory disease, syndrome X, obesity, type I diabetes, type II diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, heart failure, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), thrombosis, neurodegenerative diseases, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, psoriasis, acne, skin aging, hair diseases, inflammation, asthma, irritable bowel syndrome, and Crohn's disease; The cancer is selected from the group consisting of colon cancer, colorectal cancer, skin cancer, breast cancer, prostate cancer, ovarian cancer, and lung cancer; The vascular disease is selected from peripheral vascular insufficiency, intermittent claudication, and peripheral arterial disease (PAD); The muscular eye disease is selected from strabismus, progressive extraocular muscle palsy, esotropia, exotropia, refractive and accommodative abnormalities, hyperopia, myopia, astigmatism, anisotropia, presbyopia, and internal ophthalmoplegia; and The renal disease is selected from the group consisting of glomerulonephritis, glomerulosclerosis, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute renal failure, chronic renal failure, and Bartter's syndrome.

36. The use of claim 35, wherein: (i) the inflammation is dermatitis, arthritis, ulcerative colitis, or pancreatitis; or (ii) The peripheral arterial disease is peripheral arterial occlusive disease (PAOD).

37. Use as claimed in claim 30, wherein the disease or condition is selected from hereditary lipodystrophy, non-alcoholic fatty liver disease (NAFLD), renal ischemia / reperfusion injury (IRI), cardiac ischemia / reperfusion injury, Duchenne and Becker muscular dystrophy, type I diabetes, type II diabetes, obesity, and sarcopenia.

38. The use of claim 30, wherein the disease or condition is selected from Alpers's Disease, CPEO-chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF-myoclonic epilepsy with ragged red fibers, NARP-neurogenic muscle weakness, ataxia, and retinitis pigmentosa, Pearson Syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum A, Wallerian degeneration, and HIV-induced lipodystrophy.

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