CD38 inhibitors

Abstract

One aspect of the present invention is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables of Formula I are defined herein. The compounds of Formula I are CD38 inhibitors, which inhibit NAD + The compounds can be used to treat a disease or condition in a subject that would benefit from an increase in mitochondrial activity, or to treat a mitochondrial disease in a subject. TIFF2023521694000268.tif29128

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Indian Patent Application No. 202041015255, filed on April 7, 2020, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION This application relates to CD38 inhibitors and methods of use thereof, such as for regulating CD38 activity in a subject. [Background technology]

[0003] Background of the Invention Nicotinamide adenine dinucleotide (NAD + ) is a biochemical found in all cells and was first characterized over 100 years ago for its role in oxidoreductase reactions. + and its related pyridine nucleotides NADH and NADP + NADPH and NADPH are recognized as the major redox carriers in all living organisms. These pyridine dinucleotides regulate the redox state of the cytoplasm and mitochondria and are key participants in monitoring the metabolic state of the cell. + This is because NADH and NADH serve as hydride-accepting and -donating cofactors for metabolic enzymes involved in glycolysis, the TCA cycle, and the respiratory chain, thereby reallocating the reducing equivalents generated in these catabolic processes to the de novo synthesis of novel biomolecules (Houtkooper et al Endo Reviews (2010) 31:194-223 (Non-Patent Document 1); Koch-Nolte et al Science Signaling (2009) 2:mr1 (Non-Patent Document 2); Houtkooper and Auwerx J. Cell Biol (2012) 199:205-209 (Non-Patent Document 3); Berger et al Trends in Bioch Sci (2004) 29:111-18 (Non-Patent Document 4)).

[0004] In addition to its long-recognized role as a cofactor for oxidoreductases, recent studies have shown that NAD + It has also been demonstrated that NAD is a substrate for various enzymes. + NAD is consumed in the process of donating its ADP-ribose to an acceptor molecule. + The enzymes that are major consumers of Ca are ADP-ribosyltransferases (i.e., the PARP and ART enzyme families), sirtuins (Sirt1-7), and ADP-ribosyl cyclases / hydrolases (CD38 / CD157). ++ It is involved in pathways that regulate signal transduction, gene transcription, DNA repair, cell survival, energy metabolism, and oxidative stress. + and its phosphorylated analogues NADP and NAADP (both of which are NAD + NAD (derived from NAD) also acts as a signaling molecule. + NAD is also a key component of the circadian cycle with daily fluctuations that links cellular metabolism to chromatin remodeling and gene transcription. Exercise and calorie restriction can decrease NAD + While levels increase, cellular NAD levels decrease with age and obesity. + As cells try to maintain their energy status during times of stress, they release large amounts of NAD + In disease states that consume NAD + Restoring levels is likely to be medically beneficial (Tevy et al Trends in Endo and Metab (2013) 24:229-237 (Non-Patent Document 5); Pugh et al Aging Cell (2013) 12:672-681 (Non-Patent Document 6); Massudi et al PLoS ONE (2012) 7:e42357 (Non-Patent Document 7); Xu and Sauve (2010) Mech of Ageing and Development 131:287-298 (Non-Patent Document 8)).

[0005] cellular NAD +NAD+ is produced either from tryptophan by a de novo synthesis pathway or from precursors such as nicotinic acid (niacin) and nicotinamide (both of which are obtained from dietary sources) by a salvage synthesis pathway. A third method of regulating cellular NAD+ levels is to block NAD+ consumption by inhibiting NAD+-consuming enzymes.

[0006] CD38 is one such NAD+ consumer. CD38, also known as ADP-ribosyl cyclase, is a type II membrane-anchored enzyme. It efficiently catalyzes the degradation of NAD+ to nicotinamide and ADPR and hydrolyzes NAADP to ADPRP. CD38 can also act as a cyclase to convert NAD+ to cADPR, but its efficiency as a cyclase is 100-fold lower than its efficiency as a hydrolase. CD38 was originally characterized as a surface antigen on immune cells and is widely distributed throughout most tissues of the body. It is present on the cell membrane and on the membranes of intracellular organelles such as the nucleus and mitochondria. As expected from its function as an NAD+ glycohydrolase, CD38 KO mice exhibit elevated NAD+ levels compared to wild-type controls. Similarly, inhibitors of CD38 enzyme activity also regulate NAD+ tissue levels and may be useful in treating a variety of diseases in which CD38 is overexpressed or cellular NAD+ levels are suppressed or desynchronized (Malavasi et al (2008) 88:841-886 (Non-Patent Document 9)).

[0007] Compounds that inhibit CD38 and thereby increase NAD+ levels are useful for treating diseases or conditions that benefit from NAD+, including mitochondrial-related diseases or disorders. Diseases that can be treated by increasing NAD+ levels are disclosed in WO 2016 / 087975 (Patent Document 1) and WO 2017 / 079195 (Patent Document 2). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication Gazette No. 2016 / 087975 [Patent Document 2] International Publication Gazette No. 2017 / 079195 [Non-Patent Document]

[0009] [Non-Patent Document 1] Houtkooper et al Endo Reviews(2010)31:194-223 [Non-Patent Document 2] Koch-Nolte et al Science Signaling(2009)2:mr1 [Non-Patent Document 3] Houtkooper and Auwerx J.Cell Biol(2012)199:205-209 [Non-Patent Document 4] Berger et al Trends in Bioch Sci(2004)29:111-18 [Non-Patent Document 5] Tevy et al Trends in Endo and Metab(2013)24:229-237 [Non-Patent Document 6] Pugh et al Aging Cell(2013)12:672-681 [Non-Patent Document 7] Massudi et al PLoS ONE(2012)7:e42357 [Non-Patent Document 8] Xu and Sauve(2010)Mech of Ageing and Development 131:287-298 [Non-Patent Document 9] Malavasi et al(2008)88:841-886 [Summary of the Invention] [Means for Solving the Problems]

[0010] The present invention relates to a method for inhibiting CD38, thereby increasing cellular NAD. + Compounds and compositions are provided that increase the amount of CD38 inhibited by the IgG1 inhibitors. For example, the IC50 values ​​for CD38 inhibition provided in Example 66 are provided. 50 These results demonstrate that these compounds are potent inhibitors of CD38 and are also useful in treating mitochondrial-related diseases or disorders and cellular NAD + Methods of using the disclosed compounds and compositions to treat diseases that would benefit from increasing levels are also disclosed.

[0011] In one aspect, the present specification provides a compound of formula (I): The present invention provides a compound represented by TIFF0007792915000001.tif32128 or a pharmaceutically acceptable salt thereof.

[0012] In a first aspect, the variables represented in Formula (I) are defined as follows: X1 and X2 are independently CH or N, provided that X1 and X2 are not both CH; Cy may be substituted with an oxo group or may be substituted with one or two R x C optionally substituted with a group 3~7 cycloalkyl, where R x Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 hydroxyalkyl, -NHSO2C1-C4 alkyl, or SO2C1-C4 alkyl; 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, and 5-membered heteroaryl is selected from the group consisting of 1, 2, or 3 C 1~4 optionally substituted with an alkyl group; R 2 contains one, two or three deuterium or C 1~4 a 5-membered heteroaryl optionally substituted with an alkyl group; R d is H, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, or C 1~4 C optionally substituted with alkoxy 1~4 is alkyl; R a and R b is independently —H or C1-C4 alkyl; and n is 0 or 1.

[0013] In a second aspect, the variables represented in Formula (I) are defined as follows: X1 and X2 are independently CH or N, provided that X1 and X2 are not both CH; Cy may be substituted with an oxo group or may be substituted with one or two R x C optionally substituted with a group 3~7 cycloalkyl, where R x Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 hydroxyalkyl or SO2Me; 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, and the 5-membered heteroaryl is selected from the group consisting of 1, 2 or 3 C 1~4 optionally substituted with an alkyl group; R 2 One, two or three C's 1~4 a 5-membered heteroaryl optionally substituted with an alkyl group; R d is H or C 1~4 C optionally substituted with alkoxy 1~4 is alkyl; R a and R b is independently —H or C1-C4 alkyl; and n is 0 or 1.

[0014] Another aspect 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.

[0015] Another aspect of the present invention is NAD + A method of treating a disease or condition (or treating a mitochondrial disease) in a subject that would benefit from an increase in mitochondrial activity, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds.

[0016] Another aspect of the present invention is NAD + The present invention relates to the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds, for the preparation of a medicament for the treatment of a disease or condition (or for the treatment of a mitochondrial disease) in a subject that would benefit from an increase in mitochondrial activity.

[0017] Another aspect of the present invention is NAD +The present invention is directed to a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds, as disclosed herein, for use in treating a disease or condition (or treating a mitochondrial disease) in a subject that would benefit from an increase in mitochondrial activity. [The present invention 1001] Structural formula (I): TIFF0007792915000002.tif31128 or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are independently CH or N, provided that X 1 and X 2 shall not both be CH; Cy may be substituted with an oxo group or may be substituted with one or two R x C optionally substituted with a group 3~7 cycloalkyl, where R x Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -NHSO 2 C 1 ~C 4 Alkyl or SO 2 C 1 ~C 4 is alkyl; R 1 -H, -NR a R b , halo, -CN, -C(=O)NH 2 , -COOH, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 2 ~C 4 Alkenyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxyalkyl, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkyl sulfone, C 1 ~C 4 Alkoxyalkylthio, C 1 ~C 4 Haloalkylthio, C 1 ~C 4 Haloalkoxy, C 3 ~C 4 cycloalkyl, or a 5-membered heteroaryl, wherein the 5-membered heteroaryl has one, two or three C 1~4 optionally substituted with an alkyl group; R 2 contains one, two or three deuterium or C 1~4 a 5-membered heteroaryl optionally substituted with an alkyl group; R d is H, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, or C 1~4 C optionally substituted with alkoxy 1~4 is alkyl; R a and R b are independently -H or C 1 ~C 4 is alkyl; and n is 0 or 1; The compound or a pharmaceutically acceptable salt thereof. [The present invention 1002] X 1 and X 2 are independently CH or N, provided that X 1 and X 2 shall not both be CH; Cy may be substituted with an oxo group or may be substituted with one or two R x C optionally substituted with a group 3~7 cycloalkyl, where R x Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl or SO 2 Me; R 1 -H, -NR a R b , Halo, -CN, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxyalkyl, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkoxyalkylthio, C 1 ~C 4 Haloalkylthio, C 1 ~C 4 haloalkoxy or 5-membered heteroaryl, wherein the 5-membered heteroaryl has one, two or three C 1~4 optionally substituted with an alkyl group; R 2 But one, two or three C 1~4 a 5-membered heteroaryl optionally substituted with an alkyl group; R d But H or C 1~4 C optionally substituted with alkoxy 1~4 is alkyl; R a and R b are independently -H or C 1 ~C 4 is alkyl; and n is 0 or 1; The compound of the present invention or a pharmaceutically acceptable salt thereof. [The present invention 1003] Structural formula (IIa): TIFF0007792915000003.tif31128 The compound of the present invention 1002, represented by the following formula: or a pharmaceutically acceptable salt thereof. [The present invention 1004] Structural Formula (IIb): TIFF0007792915000004.tif33128 The compound of the present invention 1002, represented by the following formula: or a pharmaceutically acceptable salt thereof. [The present invention 1005] Structural formula (IIc): TIFF0007792915000005.tif31128 The compound of the present invention 1002, represented by the following formula: or a pharmaceutically acceptable salt thereof. [The present invention 1006] Structural formula (IIIa): TIFF0007792915000006.tif35128 or a pharmaceutically acceptable salt thereof. [The present invention 1007] Structural Formula (IIIb): TIFF0007792915000007.tif35128 or a pharmaceutically acceptable salt thereof. [The present invention 1008] Structural Formula (IIIc): TIFF0007792915000008.tif36128 or a pharmaceutically acceptable salt thereof. [The present invention 1009] Structural formula (IVa): TIFF0007792915000009.tif36128 or a pharmaceutically acceptable salt thereof. [The present invention 1010] Structural formula (IVb): TIFF0007792915000010.tif36128 or a pharmaceutically acceptable salt thereof. [The present invention 1011] Structural formula (IVc): TIFF0007792915000011.tif37128 or a pharmaceutically acceptable salt thereof. [The present invention 1012] The compound of any one of the present inventions 1002 to 1011, wherein n is 1, or a pharmaceutically acceptable salt thereof. [The present invention 1013] R d But C 1~4 C optionally substituted with alkoxy 1~4 The compound of any one of the present invention 1002 to 1012, or a pharmaceutically acceptable salt thereof, wherein R is alkyl. [The present invention 1014] R d But C 1~4 Alkoxy-substituted C 1~4 The compound of any one of the present invention 1002 to 1013, or a pharmaceutically acceptable salt thereof, wherein R is alkyl. [The present invention 1015] R d But -CH 2 CH 2 OCH 3 The compound of any one of the present inventions 1002 to 1014, or a pharmaceutically acceptable salt thereof, wherein [The present invention 1016] n is 0 or 1, and when n is 1, then R d -H, -CH 3 or -CH 2 CH 2 OCH 3 The compound of any one of the present inventions 1002 to 1011, or a pharmaceutically acceptable salt thereof, wherein [The present invention 1017] R 1 But one, two or three C 1~4 The compound of any one of 1002 to 1016 of the present invention, which is a 5-membered heteroaryl optionally substituted with an alkyl group, or a pharmaceutically acceptable salt thereof. [The present invention 1018] R 1 But one, two or three C 1~4 The compound of any one of the present inventions 1002 to 1017, which is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole or oxadiazole, optionally substituted by an alkyl group, or a pharmaceutically acceptable salt thereof. [The present invention 1019] R 1 but, One, two or three Cs 1~4 each optionally substituted with an alkyl group TIFF0007792915000012.tif21166 The compound of any one of the present inventions 1002 to 1018, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [The present invention 1020] R 1 but, TIFF0007792915000013.tif40153 The compound of any one of the present inventions 1002 to 1018, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [The present invention 1021] R 1 -H, -NR a R b , Halo, -CN, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxyalkyl, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkoxyalkylthio or C 1 ~C 4 The compound of any one of the present inventions 1002 to 1016, which is haloalkylthio, or a pharmaceutically acceptable salt thereof. [The present invention 1022] R 1 -H, -NH 2 , Haro, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1~C 4 Haloalkyl, C 1 ~C 4 Haloalkoxy or C 1 ~C 4 The compound of any one of the present inventions 1002 to 1016 and 1021, which is alkylthio, or a pharmaceutically acceptable salt thereof. [The present invention 1023] R 1 -H, -CH 3 , -CF 3 , -OCH 3 , -SCH 3 , -F, -Cl, -Br or NH 2 or a pharmaceutically acceptable salt thereof. [The present invention 1024] R 2 But one, two or three C 1~4 The compound of any one of the present inventions 1002 to 1023, which is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole or oxadiazole, optionally substituted by an alkyl group, or a pharmaceutically acceptable salt thereof. [The present invention 1025] R 2 but, TIFF0007792915000014.tif20165 and one, two or three C 1~4 The compound of any one of the present inventions 1002 to 1024, which may be substituted with an alkyl group, or a pharmaceutically acceptable salt thereof. [The present invention 1026] R 2 but, TIFF0007792915000015.tif40152 The compound of any one of the present inventions 1002 to 1024 selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [The present invention 1027] R 1 But -C(=O)NH 2 , -COOH, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 2 ~C 4 Alkenyl, -CN, C 1 ~C 4 Alkyl sulfone or C 3 ~C 4 1001. Any of the compounds of the present invention or a pharmaceutically acceptable salt thereof, wherein R is cycloalkyl. [The present invention 1028] R 1 But -C(=O)NH 2 , -COOH, -CHF 2 , -CH 2 F, -CH(OH)CH 3 , -C(OH)(CH 3) 2 , -CH 2 OH, -CH=CH 2 , -SO 2 The compound of the present invention 1001 or 1027, or a pharmaceutically acceptable salt thereof, wherein Me is cyclopropyl, or cyclopropyl. [The present invention 1029] R 2 is a 5-membered heteroaryl (e.g., imidazole) substituted with 1, 2, or 3 deuterium atoms, or a pharmaceutically acceptable salt thereof. [The present invention 1030] R d But C 1~4 Haloalkyl or C 1~4 The compound of the present invention, any one of compounds 1001 and 1027 to 1029, which is hydroxyalkyl, or a pharmaceutically acceptable salt thereof. [The present invention 1031] R d But -CHF 2 or CH 2 CH 2 OH, or a pharmaceutically acceptable salt thereof. [The present invention 1032] Cy-NHSO 2 (C 1 ~C 4 alkyl) (e.g., -NHSO 2

[0082] The compound of any one of the present invention 1001 and 1027 to 1031, or a pharmaceutically acceptable salt thereof, wherein the compound is cyclohexyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, [The present invention 1033] A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and any one of the compounds of the present invention 1002 to 1026 or a pharmaceutically acceptable salt thereof. [The present invention 1034] A method for treating a disease or condition in a subject that would benefit from an increase in NAD+, comprising administering to the subject an effective amount of any of the compounds of inventions 1002 to 1026 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of invention 1033. [This invention 1035] 1035. The method of claim 1034, wherein the disease or condition 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, an ocular muscle disease, or a renal disease. [The present invention 1036] The muscle structure disorder is selected from Bethlem myopathy, central core disease, congenital muscle fiber type disproportion, distal muscular dystrophy (MD), Duchenne and Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, muscle sodium channelopathy, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, or stress urinary incontinence; the neuronal activation disorder is selected from amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesions, peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy, and toxic neuromuscular disorders; the muscle fatigue disorder is selected from chronic fatigue syndrome, diabetes mellitus (type I or II), 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, critical illness myopathy, inclusion body myositis, polymyositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus; the beta-oxidation disorder is selected from systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, triglyceride deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin-responsive beta-oxidation disorder (RR-MADD); The metabolic disease may be hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL cholesterolemia, hyper-LDL cholesterolemia and / or non-HDL cholesterolemia, hyper-VLDL proteinemia, dyslipoproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, arteriosclerotic disease, cardiovascular disease, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, selected from: diabetes mellitus (type I or II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complications, 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, ectopic hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis; the cancer is selected from colon cancer, colorectal cancer, skin cancer, breast cancer, prostate cancer, ovarian cancer, and lung cancer; the vascular disease is selected from peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral arterial disease (PAD), peripheral arterial occlusive disease (PAOD), and peripheral obliterative arteriopathy; the ocular vascular disease is selected from age-related macular degeneration (AMD), Stargardt's disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma; the ocular muscle disorder is selected from strabismus, progressive external ophthalmoplegia, esotropia, exotropia, refractive and accommodative disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodative disorders, and internal ophthalmoplegia; and 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, chronic renal failure, diabetic nephropathy, and Bartter's syndrome. The method of the present invention 1035. [This invention 1037] 1034. The method of claim 1034, wherein said disease or condition is selected from hereditary 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. [The present invention 1038] 1034. The method of claim 1034, wherein the disease or condition is selected from Alpers disease, CPEO - chronic progressive external ophthalmoplegia, Kearns-Sayra syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF - myoclonic epilepsy and ragged-red fiber disease, NARP - neurogenic muscular weakness, ataxia, and retinitis pigmentosa, Pearson's syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne's syndrome, xeroderma pigmentosum group A, Wallerian degeneration, and HIV-induced lipodystrophy. [This invention 1039] A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and any one of the compounds of the present invention 1001 and 1027 to 1032 or a pharmaceutically acceptable salt thereof. [The present invention 1040] A method for treating a disease or condition in a subject that would benefit from an increase in NAD+, comprising administering to the subject an effective amount of any of compounds 1001 and 1027 to 1032 of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compound 1039 of the present invention. [The present invention 1041] 1040. The method of claim 1040, wherein said disease or condition 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, an ocular muscle disease, or a renal disease. [The present invention 1042] The muscle structure disorder is selected from Bethlem myopathy, central core disease, congenital muscle fiber type disproportion, distal muscular dystrophy (MD), Duchenne and Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, muscle sodium channelopathy, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, or stress urinary incontinence; the neuronal activation disorder is selected from amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesions, peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy, and toxic neuromuscular disorders; the muscle fatigue disorder is selected from chronic fatigue syndrome, diabetes mellitus (type I or II), 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, critical illness myopathy, inclusion body myositis, polymyositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus; the beta-oxidation disorder is selected from systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, triglyceride deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin-responsive beta-oxidation disorder (RR-MADD); The metabolic disease is selected from the group consisting of hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL cholesterolemia, hyper-LDL cholesterolemia and / or non-HDL cholesterolemia, hyper-VLDL proteinemia, dyslipoproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, arteriosclerotic diseases, cardiovascular diseases, cerebrovascular diseases, peripheral circulatory diseases, metabolic syndrome, syndrome X, obesity, diabetes mellitus (type I or II), and ), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complications, 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, ectopic hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis; the cancer is selected from colon cancer, colorectal cancer, skin cancer, breast cancer, prostate cancer, ovarian cancer, and lung cancer; the vascular disease is selected from peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral arterial disease (PAD), peripheral arterial occlusive disease (PAOD), and peripheral obliterative arteriopathy; the ocular vascular disease is selected from age-related macular degeneration (AMD), Stargardt's disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma; the ocular muscle disorder is selected from strabismus, progressive external ophthalmoplegia, esotropia, exotropia, refractive and accommodative disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodative disorders, and internal ophthalmoplegia; and 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, chronic renal failure, diabetic nephropathy, and Bartter's syndrome. The method of the present invention 1041. [This invention 1043] 1040. The method of claim 1040, wherein said disease or condition is selected from hereditary 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. [This invention 1044] 1040. The method of claim 1040, wherein the disease or condition is selected from Alpers disease, CPEO - chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF - myoclonic epilepsy and ragged-red fiber disease, NARP - neurogenic muscular weakness, ataxia, and retinitis pigmentosa, Pearson syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum group A, Wallerian degeneration, and HIV-induced lipodystrophy. [Brief explanation of the drawings]

[0018] [Figure 1] Figure 10 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 A. [Figure 2]FIG. 1 is a combined thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) graph of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide polymorph Form A. [Figure 3] Figure 1 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. [Figure 4] 1 is a combined thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) graph of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide polymorph Form B. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description The disclosed compounds are NAD + The CD38 inhibitors can be used to treat a disease or condition in a subject that would benefit from an increase in NAD or to treat a mitochondrial disease. Such diseases or disorders include muscle structure disorders, neuronal activation disorders, muscle fatigue disorders, muscle mass disorders, metabolic disorders, cancer, vascular diseases, ocular vascular diseases, ocular muscle diseases, or renal diseases. More specifically, NAD + Diseases or conditions (or mitochondrial diseases) that may benefit from increased NAD include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia / reperfusion injury (IRI), Duchenne and Becker muscular dystrophy, diabetes (type I or type II), obesity, and sarcopenia. +The "disease or condition in which a therapeutic benefit may be realized by increasing mitochondrial activity" or "mitochondrial-associated disease or disorder" is selected from Alpers disease, CPEO - chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes, MERRF - myoclonic epilepsy and ragged-red fiber disease, NARP - neurogenic muscular weakness, ataxia, retinitis pigmentosa, Pearson's syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne's syndrome, xeroderma pigmentosum group A, Wallerian degeneration, and HIV-induced lipodystrophy.

[0020] In a first aspect, the present invention is a compound represented by Formula I, or a pharmaceutically acceptable salt thereof. The variables of Formula I are described above as the first aspect of Formula I and the second aspect of Formula I.

[0021] In a second aspect, the present invention provides a compound of formula IIa, IIb, or IIc: TIFF0007792915000016.tif30159, or a pharmaceutically acceptable salt thereof. The variables of Formula IIa, Formula IIb and Formula IIc are as described above for Formula I (first and second aspects).

[0022] In a third aspect, the present invention provides a compound of formula IIIa, IIIb, or IIIc: TIFF0007792915000017.tif70139, or a pharmaceutically acceptable salt thereof. The variables of Formula IIIa, Formula IIIb and Formula IIIc are as described above for Formula I (first and second aspects).

[0023] In a fourth aspect, the present invention provides a compound of formula IVa, IVb, or IVc: TIFF0007792915000018.tif69139, or a pharmaceutically acceptable salt thereof. The variables of Formula IVa, Formula IVb and Formula IVc are as described above for Formula I (first and second aspects).

[0024] In a fifth aspect, the invention is a compound represented by Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, or Formula IVc, or a pharmaceutically acceptable salt thereof, wherein n is 1. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, and Formula IVc are as described above for Formula I (first and second aspects).

[0025] In a sixth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R d is C 1~4 C optionally substituted with alkoxy 1~4 The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, and Formula IVc are as described above for Formula I (first and second aspects) or in the fifth aspect.

[0026] In a seventh aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R d is C 1~4 Alkoxy-substituted C 1~4 alkyl; or R d is -CH2CH2OCH3. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb and Formula IVc are as described above for Formula I (first and second aspects) or in the fifth aspect.

[0027] In an eighth aspect, the present invention is a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, and when n is 1, then R d is -H, -CH, or -CHCHOCH. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, and Formula IVc are as described above for Formula I (first and second aspects).

[0028] In a ninth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 1 One, two or three C's 1~4 and 5-membered heteroaryl optionally substituted with an alkyl group. 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), or for the fifth, sixth, seventh, or eighth aspects.

[0029] In a tenth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 1 One, two or three C's 1~4 and imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, or oxadiazole, optionally substituted with an alkyl group. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, and Formula IVc are described above for Formula I (first and second aspects), or for the fifth, sixth, seventh, or eighth aspects.

[0030] In an eleventh aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, TIFF0007792915000019.tif16166, each of which contains one, two or three C 1~4 Alternatively, R 1 teeth, TIFF0007792915000020.tif39165. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb and Formula IVc are as described above for Formula I (first and second aspects) or for the fifth, sixth, seventh or eighth aspect.

[0031] In a twelfth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein 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 or C1-C4 haloalkylthio. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb and Formula IVc are described above for Formula I (first and second aspects) or for the fifth, sixth, seventh or eighth aspect.

[0032] In a thirteenth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 1is -H, -NH2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or C1-C4 alkylthio; or R 1 is -H, -CH3, -CF3, -OCH3, -SCH3, -F, -Cl, -Br or NH2; or R 1 is -CH3. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb and Formula IVc are described above for Formula I (first and second aspects) or for the fifth, sixth, seventh or eighth aspect.

[0033] In a fourteenth aspect, the present invention provides a compound represented by Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, or Formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 2 One, two or three C's 1~4 and imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, or oxadiazole, optionally substituted with an alkyl group. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, and Formula IVc are described above for Formula I (first and second aspects), or for the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspects.

[0034] In a fifteenth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 2 teeth, TIFF0007792915000021.tif16165, each of which is selected from the group consisting of one, two or three C 1~4 Alternatively, R 2 teeth, TIFF0007792915000022.tif39167. Or R 2 teeth, TIFF0007792915000023.tif14166. The remaining variables in Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb and Formula IVc are as described above for Formula I (first and second aspects) or for the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth aspects.

[0035] In a sixteenth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(═O)NH, —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 in the fifth, sixth, seventh, eighth, fourteenth, or fifteenth aspects.

[0036] In a seventeenth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(=O)NH, -COOH, -CHF, -CHF, -CH(OH)CH, -C(OH)(CH), -CHOH, -CH=CH, -SOMe, or cyclopropyl. The remaining variables are as described above for Formula I (first aspect) or in the fifth, sixth, seventh, eighth, fourteenth, fifteenth or sixteenth aspects.

[0037] In an eighteenth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein R2 is a 5-membered heteroaryl (e.g., imidazole) substituted with 1, 2, or 3 deuterium atoms. The remaining variables are described above for Formula I (first aspect) or in the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth aspects.

[0038] In a nineteenth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein: d is C 1~4 Haloalkyl or C 1~4 The remaining variables are as described above for Formula I (first aspect) or in the fifth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth or eighteenth aspects.

[0039] In a twentieth aspect, the present invention provides a compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa, formula IIIb, formula IIIc, formula IVa, formula IVb, or formula IVc, or a pharmaceutically acceptable salt thereof, wherein: d is —CHF or CHCHOH. The remaining variables are as described above for Formula I (first aspect) or in the fifth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth aspects.

[0040] In a twenty-first aspect, the invention is a compound represented by Formula I Formula IIa, Formula IIb, or Formula 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 in the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth aspect.

[0041] The present invention also encompasses the compounds shown in Table 3 and the compounds prepared in the Examples. Both pharmaceutically acceptable salts and neutral forms of these compounds are encompassed. In another aspect, the present invention relates to hydrates or solvates and / or crystalline polymorphs of the compounds of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof. In another aspect, the present invention relates to the anhydrous forms (i.e., not solvates or hydrates) of the compounds of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof. In another aspect, the present invention relates to the compounds of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, enriched with a radioactive or non-radioactive isotope at one or more positions. In another aspect, the present invention relates to a compound of Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa, Formula IIIb, Formula IIIc, Formula IVa, Formula IVb, or Formula IVc, or a pharmaceutically acceptable salt thereof, that is enriched with deuterium at one or more positions.

[0042] The present teachings encompass pharmaceutically acceptable salts of the compounds disclosed herein. Compounds of the present teachings that contain a basic group can form pharmaceutically acceptable salts 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). Compounds of the present teachings that contain an acidic group can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base 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).

[0043] 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 reaction, within the scope of sound medical judgment, and that is commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmacologically acceptable salts in J.Pharm.Sci.(1977)66:1-19.

[0044] The term "alkyl," used alone or as part of a larger moiety, such as "alkoxy," "haloalkyl," "haloalkoxy," "hydroxyalkyl," "alkoxyalkyl," "alkylthio," "alkoxyalkylthio," "haloalkylthio," etc., refers to a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has from 1 to 4 carbon atoms, i.e., a C1-C4 alkyl. As used herein, a "C1-C4 alkyl" group refers to a group having from 1 to 4 carbon atoms in a linear or branched arrangement, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0045] "Alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "C1-C4 alkoxy" includes methoxy, ethoxy, propoxy, butoxy, and isopropoxy.

[0046] The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy, optionally substituted with one or more halogen atoms. In some embodiments, "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy, optionally substituted with one or more fluorine atoms.

[0047] The terms "halogen" and "halo" mean fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

[0048] The term "hydroxyalkyl" means an alkyl substituted with one or more hydroxyl groups. For example, "C1-C4 hydroxyalkyl" includes, but is not limited to, hydroxyethyl and hydroxypropyl.

[0049] The term "alkoxyalkyl" refers to an alkyl substituted with an alkoxy group.

[0050] The term "alkylthio" refers to an alkyl group attached through a sulfur linking atom represented by -S-alkyl.

[0051] The term "alkoxyalkylthio" refers to an alkylthio substituted with an alkoxy group.

[0052] The term "haloalkylthio" means alkylthio substituted with one or more halogen atoms, for example one or more fluorine atoms.

[0053] "Cycloalkyl" refers to a saturated aliphatic monocyclic hydrocarbon group. Unless otherwise specified, cycloalkyl has 3 to 7 ring carbon atoms, alternatively 3 to 6 ring carbon atoms. For example, "C3-C6 cycloalkyl" refers to a group having 3 to 6 carbon atoms arranged in a monocyclic ring. C3-C6 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0054] The term "5-membered heteroaryl" refers to a monocyclic aromatic ring group having 5 ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen, or sulfur).

[0055] 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).

[0056] When a group is described as "substituted," there is a non-hydrogen substituent in place of a hydrogen substituent on a carbon, sulfur, or nitrogen of the group. Thus, for example, a substituted alkyl is an alkyl in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl group. For example, a monofluoroalkyl is an alkyl substituted with a fluoro substituent, and a difluoroalkyl is an alkyl substituted with two fluoro substituents. When there are two or more substitutions on a substituent, it should be recognized that each non-hydrogen substituent may be the same or different (unless otherwise specified).

[0057] When a group is described as being "optionally substituted," the substituent can be either (1) unsubstituted or (2) substituted.

[0058] When a group is described as being optionally substituted with up to a certain number of non-hydrogen substituents, the group can be either (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 being optionally substituted with up to three non-hydrogen substituents, then any cycloalkyl with fewer than three substitutable positions can only be substituted with as many non-hydrogen substituents as the cycloalkyl has substitutable positions.

[0059] 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, as well as racemates and mixtures thereof. "Geometric isomer" refers to isomers that differ in the orientation of substituents relative 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.

[0060] When a disclosed compound is named or depicted by structure without indication of stereochemistry, it is understood that the name or structure encompasses one of the possible stereoisomers or geometric isomers and not others, or encompasses mixtures of the encompassed stereoisomers or geometric isomers.

[0061] When a geometric isomer or stereoisomer is depicted by name or structure, it is to be understood that the named or depicted isomer is present to a greater extent than its corresponding isomer, i.e., the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% purity by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in a mixture by the total weight of all geometric isomers in the mixture.

[0062] A racemic mixture means 50% of one enantiomer and 50% of its corresponding enantiomer. When a compound with one chiral center is named or drawn without any indication of the stereochemistry of the chiral center, it is understood that the name or structure encompasses the compound in both possible enantiomeric forms (e.g., both enantiopure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or drawn without any indication of the stereochemistry of the chiral center, it is understood that the name or structure encompasses the compound in all possible diastereomeric forms (e.g., diastereomeric pure, diastereoenriched, and, in the case of one or more diastereomers, equimolar mixtures, e.g., racemic mixtures).

[0063] Enantiomeric mixtures can be resolved into their component enantiomers by well-known methods such as chiral-phase gas chromatography, chiral-phase 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 by well-known asymmetric synthetic methods from enantiopure intermediates, reagents, and catalysts.

[0064] When a compound is designated by a name or structure that designates a single enantiomer, unless otherwise specified, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiopure"). Optical purity is the weight of the named or depicted enantiomer in a mixture divided by the total weight of both enantiomers in the mixture.

[0065] When the stereochemistry of a disclosed compound is named or depicted by structure, and that named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further to be understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the stereoisomer encompassed by that name or structure in the mixture by the total weight of all stereoisomers in the mixture.

[0066] Methods for treating a mitochondrial-related disease or condition in a subject are disclosed. Also disclosed herein are methods for treating a mitochondrial-related disease or condition in a subject. + Increased levels of, e.g., in vivo NAD + levels (e.g., intracellular NAD + Levels of NAD in tissues or plasma + levels, and / or the organism's overall NAD + Also disclosed are methods of treating a disease or disorder that would benefit from an increase in the level of erythropoietin (erythropoietin) in a subject. Such methods can include administering to a subject an effective amount of one or more compounds or compositions provided herein.

[0067] Diseases and disorders that can be treated by the disclosed compounds and pharmaceutical compositions include diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular diseases, blood clotting disorders, inflammation, cancer, and / or flushing, etc.

[0068] In one aspect, the disease or disorder includes, but is not limited to, Alpers disease, CPEO - chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes, MERRF - myoclonic epilepsy and ragged-red fiber disease, NARP - neurogenic muscular weakness, ataxia, retinitis pigmentosa, Pearson's syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne's syndrome, xeroderma pigmentosum group A, Wallerian degeneration, and HIV-induced lipodystrophy.

[0069] In one embodiment, a mitochondrial-related disease or disorder or NAD + Diseases or disorders that would benefit from increased levels are muscle structure disorders, neuronal activation disorders, muscle fatigue disorders, muscle mass disorders, metabolic disorders, cancer, vascular diseases, ocular vascular diseases, ocular muscle diseases, or renal diseases.

[0070] The muscle structural disorder is selected from Bethlem myopathy, central core disease, congenital fiber type disproportion, distal muscular dystrophy (MD), Duchenne and Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, muscle sodium channelopathy, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, and stress urinary incontinence.

[0071] The neuronal activation disorder is selected from amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesions, peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy, and toxic neuromuscular disorders.

[0072] The muscle fatigue disorder is selected from chronic fatigue syndrome, diabetes mellitus (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 cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus.

[0073] The beta-oxidation disorder is selected from systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, triglyceride deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin-responsive beta-oxidation disorder (RR-MADD).

[0074] Metabolic diseases include hyperlipidemia, dyslipidemia, hypercholesterolemia (hyperchlolesterolemia), hypertriglyceridemia, hypo-HDL cholesterolemia, hyper-LDL cholesterolemia and / or non-HDL cholesterolemia, hyper-VLDL proteinemia, dyslipoproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, arteriosclerotic disease, cardiovascular disease, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, The disease is selected from diabetes (type I or II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complications, 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, ectopic hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis.

[0075] The vascular disease is selected from peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral arterial disease (PAD), peripheral arterial occlusive disease (PAOD), and peripheral obliterative arteriopathy.

[0076] The ocular vascular disease is selected from age-related macular degeneration (AMD), Stargardt's disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma.

[0077] The eye muscle disease is selected from strabismus, progressive external ophthalmoplegia, esotropia, exotropia, refractive and accommodative disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodative disorders, and internal ophthalmoplegia.

[0078] 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.

[0079] In another embodiment, a mitochondrial-associated disease or condition or NAD + Diseases or disorders that would benefit from increased levels are selected from hereditary lipodystrophies, 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.

[0080] In another embodiment, the compounds of the present invention and pharmaceutical compositions thereof may 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 cells or tissue may be an autograft, allograft, syngeneic graft, or xenograft. The cells or tissue may be treated with the compounds of the present invention and pharmaceutical compositions thereof before administration / transplantation into a subject, simultaneously with administration / transplantation, and / or after administration / transplantation. The cells or tissue may be treated before removal of the cells from the donor individual, ex vivo after removal of the cells or tissue from the donor individual, or after transplantation into a recipient. For example, the donor or recipient individual may be treated systemically with the CD38 inhibitor formulation or pharmaceutical composition of the present invention, or some cells / tissues may be treated locally with the compounds of the present invention and pharmaceutical compositions thereof. In certain embodiments, the cells or tissue (or the donor / recipient individual) may additionally be treated with another therapeutic agent useful for prolonging graft survival, such as, for example, an immunosuppressant, cytokine, or angiogenic factor.

[0081] In yet another embodiment, the compounds of the present invention and / or pharmaceutical compositions thereof can be used to treat skin conditions.Exemplary skin conditions that can be treated by the methods described herein include disorders or diseases associated with or caused by inflammation, sun damage, or natural aging.For example, the compositions are useful in treating contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, keratinization disorders (including eczema), epidermolysis bullosa (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 aspect, the compounds of the present invention and pharmaceutical compositions thereof may be used to promote healing in the treatment of wounds and / or burns, for example burns including first, second or third degree burns and / or thermal, chemical or electrical burns.

[0082] The compounds of the present invention and pharmaceutical compositions thereof can also be administered to a subject for the treatment of diseases associated with cell death, such as chronic diseases, 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 Creutzfeldt-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 ultraviolet light; lichen planus; skin atrophy; cataracts; and transplant rejection. Cell death can also be caused by surgery, drug therapy, chemical exposure, or radiation exposure.

[0083] The compounds of the present invention and pharmaceutical compositions thereof can also be administered to subjects suffering from acute diseases, such as organ or tissue damage, for example, subjects suffering from stroke or myocardial infarction or subjects suffering from spinal cord injury. The compounds of the present invention and pharmaceutical compositions thereof can also be used to repair alcoholic liver.

[0084] In another aspect, the present invention provides a method for treating cardiovascular disease by administering one or more of the compounds of the present invention and / or pharmaceutical compositions thereof to a subject in need thereof. Cardiovascular diseases that can be treated using the compounds of the present invention and their pharmaceutical compositions include cardiomyopathies 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 of major blood vessels (macrovascular disease), such as the aorta, coronary arteries, carotid arteries, cerebrovascular arteries, renal arteries, iliac arteries, femoral arteries, and popliteal arteries. Other vascular diseases that can be treated include platelet aggregation, retinal arterioles, glomerular arterioles, vasa nervorum, cardiac arterioles, and associated capillary beds in the eye, kidney, heart, and central and peripheral nervous system. The compounds of the present invention and their pharmaceutical compositions can also be used to increase HDL levels in an individual's plasma.

[0085] The compounds of the present invention and pharmaceutical compositions thereof may be administered to subjects who have recently received or are expected to receive a dose or dosage of radiation or toxin. In one embodiment, the dose or dosage of radiation or toxin is administered as part of an occupational or medical procedure, such as working at a nuclear power plant, flying an airplane, or administering a radioactive dye for X-rays, CAT scans, or medical imaging; in such an embodiment, the compounds are administered as a preventative measure. In another embodiment, exposure to radiation or toxin is unintentional, for example, as a result of an industrial accident involving radioactive or toxic materials, living in a location with natural radiation, an act of terrorism, or an act of war. In such cases, the compounds of the present invention and pharmaceutical compositions thereof are preferably administered as soon as possible after exposure to prevent apoptosis and the subsequent development of acute radiation syndrome.

[0086] In another aspect, the compounds of the present invention and pharmaceutical compositions thereof may be useful in the treatment of age-related disorders, such as cancer.

[0087] Exemplary cancers that can be treated using the compounds of the present invention and their pharmaceutical compositions include those of the brain and kidney; hormone-dependent cancers, including breast cancer, prostate cancer, colon cancer, colorectal cancer, skin cancer, lung cancer, testicular cancer, pancreatic cancer, and ovarian cancer; lymphoma and leukemia. Other diseases that can be treated include autoimmune diseases in which autoimmune cells should be eliminated, such as systemic lupus erythematosus, systemic sclerosis, and arthritis. 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.

[0088] In another aspect, the compounds of the present invention and pharmaceutical compositions thereof may be useful for disorders associated with accelerated aging, such as Hutchinson-Gilford progeria syndrome, Werner syndrome, telomere deficiency syndromes or telomeropathies, and dyskeratosis gongenita. 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, as well as diseases in which "inflammaging," or secreted factors from senescent cells, alter the balance between NAD synthesis and consumption.

[0089] In certain aspects, the compounds of the present invention and their pharmaceutical compositions can be used to treat patients suffering from neurodegenerative diseases and traumatic or mechanical injuries 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 disease (ophthalmic neuritis), chemotherapy-induced neuropathy (e.g., due to vincristine, paclitaxel, or bortezomib), diabetes-induced neuropathy, and Friedreich's ataxia. The compounds of the present invention and their pharmaceutical compositions can be used to treat these disorders and other disorders as described below.

[0090] In an exemplary embodiment, the compounds of the invention and pharmaceutical compositions thereof may be used to treat multiple sclerosis (MS), including relapsing MS and monosymptomatic MS, and other demyelinating conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), or conditions associated therewith.

[0091] In yet another aspect, the compounds of the present invention and pharmaceutical compositions thereof may be used to treat neurological trauma, including trauma due to disease, injury (including surgical intervention), or environmental trauma (e.g., neurotoxins, alcoholism, etc.).

[0092] The compounds of the present invention and their pharmaceutical compositions may also be useful in 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 spinal cord—peripheral nerves—are damaged. Peripheral neuropathy may also be referred to as peripheral neuritis, or, if multiple nerves are affected, polyneuropathy or polyneuritis. PNS disorders may be the result of, for example, leprosy, diabetes, Guillain-Barré syndrome, etc.

[0093] Other PNS disorders treatable with the compounds of the present invention and their pharmaceutical compositions include brachial plexus neuropathy (diseases of the cervical and first thoracic spinal nerve roots, nerve trunks, nerve bundles, and peripheral nerve components of the brachial plexus). Clinical symptoms include localized pain, paresthesias, muscle weakness, and decreased sensation in the upper extremities. These disorders may be associated with trauma, including birth injuries; thoracic outlet syndrome; neoplasms, neuritis, radiation therapy; and other conditions (see Adams et al., Principles of Neurology, 6th ed., pp. 1351-1352). Also included is diabetic neuropathy (peripheral, autonomic, and cranial nerve disorders associated with diabetes). These conditions are usually caused by diabetic microvascular injury affecting the small blood vessels (vasa nervorum) that supply the nerves. Relatively common conditions that may be associated with diabetic neuropathy include third cranial nerve palsy; mononeuropathy; multiple mononeuropathy; diabetic amyotrophy; painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy (see Adams et al., Principles of Neurology, 6th ed., p. 1325). PNS disorders also include mononeuropathy (isolated involvement of a single peripheral nerve or disease or trauma disproportionate to evidence of diffuse peripheral nerve dysfunction). Multiple mononeuropathy refers to conditions characterized by multiple isolated nerve injuries. Mononeuropathy can result from a wide variety of causes, including ischemia; trauma; compression; connective tissue disease; cumulative trauma; and other conditions.Also included are neuralgia (severe or aching pain occurring along the course or distribution of a peripheral or cranial nerve); peripheral nervous system neoplasms (neoplasms arising from peripheral nerve tissue, including neurofibromas; schwannomas; granular cell tumors; and malignant peripheral nerve sheath tumors; see DeVita Jr et al., Cancer: Principles and Practice of Oncology, 5th ed., p. 750-1); and nerve compression syndromes (mechanical compression of a nerve or nerve root by intrinsic or extrinsic causes, which can result in blockage of nerve impulse conduction due to, for example, myelin sheath dysfunction or axonal loss; nerve and nerve sheath injury can be caused by ischemia; inflammation; or direct mechanical influence); and neuritis (a collective term referring to inflammation of a peripheral or cranial nerve). Clinical symptoms can include pain; paresthesia; paresis; or hyperesthesia; and polyneuropathy (disease of multiple peripheral nerves). These 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 or proximal), by the predominantly affected nerve component (e.g., demyelinating or axonal), by etiology, or by mode of inheritance.

[0094] The compounds of the present invention and pharmaceutical compositions thereof can also be used to treat blood clotting disorders (or hemostatic disorders). As used interchangeably herein, the terms "hemostasis," "blood coagulation," and "clotting" refer to the control of bleeding, including the physiological properties of vasoconstriction and clotting.

[0095] The present invention also provides anticoagulant and antithrombotic therapies aimed at inhibiting blood clot formation to treat blood clotting disorders such as myocardial infarction, stroke, limb loss due to peripheral arterial disease or pulmonary embolism.

[0096] As used interchangeably herein, "modulating or modulating hemostasis" and "modulating or modulating hemostasis" include inducing (e.g., stimulating or increasing) hemostasis, as well as inhibiting (e.g., reducing or decreasing) hemostasis.

[0097] 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 a hypercoagulable state. Examples of thrombotic disorders include, but are not limited to, thromboembolism, deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, miscarriage, thrombophilia associated with antithrombin III deficiency, protein C deficiency, protein S deficiency, activated protein C resistance, dysfibrinogenemia, fibrinolytic disorders, homocystinuria, pregnancy, inflammatory disorders, myeloproliferative disorders, arteriosclerosis, angina, e.g., unstable angina, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, cancer metastasis, sickle cell disease, glomerulonephritis, and drug-induced thrombocytopenia (including, e.g., heparin-induced thrombocytopenia).

[0098] In addition, the compounds of the present invention and pharmaceutical compositions thereof may be administered during or after a procedure such as therapeutic clot lysis or angioplasty or surgery to reduce thrombotic events or to reduce reocclusion.

[0099] The compounds of the present invention and pharmaceutical compositions thereof may also be used to treat or reduce weight gain or obesity in a subject. For example, the compounds of the present invention and pharmaceutical compositions thereof may be used to treat genetic obesity, diet-induced obesity, hormone-related obesity, obesity associated with medication, reduce the weight of a subject, or reduce weight gain in a subject. A subject in need of such treatment may be an obese subject, a subject at risk of becoming obese, an overweight subject, or a subject at risk of becoming overweight. A subject at risk of becoming obese or overweight can be identified, for example, based on family history, genetics, diet, activity level, medication, or various combinations thereof.

[0100] In yet another embodiment, 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, including, for example, elevated 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 respiratory disorders, certain cancers (e.g., endometrial, breast, prostate, and colon cancer), pregnancy complications, poor female reproductive health (e.g., menstrual irregularities, infertility, irregular ovulation), bladder control disorders (e.g., stress urinary incontinence), uric acid nephrolithiasis, and psychological disorders (e.g., depression, eating disorders, distorted body image, and low self-esteem). Stunkard AJ, Wadden TA. (Editors) Obesity: theory and therapy, Second Edition. New York: Raven Press, 1993. Finally, AIDS patients may develop lipodystrophy or insulin resistance in response to combination AIDS therapy. In another embodiment, the compounds of the present invention and pharmaceutical compositions thereof may be used to inhibit adipogenesis or adipocyte differentiation, whether in vitro or in vivo. In particular, high levels of circulating insulin and / or insulin-like growth factor (IGF) 1 prevent the mobilization of preadipocytes, which differentiate into adipocytes. Such methods may be used to treat obesity.

[0101] In other embodiments, the compounds of the present invention and pharmaceutical compositions thereof may be used to reduce appetite and / or increase satiety, thereby causing weight loss or avoiding weight gain. A subject in need of such treatment may be an overweight, obese subject, or a subject at risk of becoming overweight or obese. The method may include administering a dose, for example, in the form of a pill, to a subject daily, or every other day, or once a week. The dose may be an "appetite-reducing dose."

[0102] In other embodiments, the compounds of the present invention and pharmaceutical compositions thereof may be used to treat subjects who have cachexia or may be at risk of developing cachexia. The method may further include monitoring the disease state in the subject. The method of promoting appetite and / or weight gain may include, for example, determining the subject's BMI before identifying the subject as needing a reduction in fat or lipid metabolism, for example, by weighing the subject. The method may also include monitoring the subject, for example, during and / or after administration of the compounds of the present invention and pharmaceutical compositions thereof. Administration may include one or more doses, for example, delivered as a bolus 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.

[0103] In another aspect, the compounds of the present invention and pharmaceutical compositions thereof may be administered to reduce drug-induced weight gain. For example, the compounds of the present invention and pharmaceutical compositions thereof may be administered as a combination therapy with drug treatments that may stimulate appetite or that may cause weight gain, particularly weight gain due to factors other than water retention.

[0104] Examples of medications that may cause weight gain include, for example, diabetes medications, including, for example, sulfonylureas (such as glipizide and glyburide), thiazolidinediones (such as pioglitazone and rosiglitazone), meglitinides, nateglinide, repaglinide, sulfonylureas, and insulin; antidepressants, including, for example, tricyclic antidepressants (such as amitriptyline and imipramine), irreversible monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), bupropion, paroxetine, and mirtazapine; 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 may be administered as part of a smoking cessation program to reduce weight gain or to reduce existing weight gain.

[0105] In another aspect, the compounds of the present invention and pharmaceutical compositions thereof may be used to treat metabolic disorders such as insulin resistance, pre-diabetic conditions, type II diabetes, and / or complications thereof.

[0106] Administration of the compounds of the present invention and pharmaceutical compositions thereof can increase insulin sensitivity and / or decrease insulin levels in a subject. A subject in need of such treatment can have insulin resistance or other precursors to type II diabetes, have type II diabetes, or be at risk of developing any of these conditions. For example, a subject can have insulin resistance, e.g., high circulating insulin levels and / or associated conditions, such as hyperlipidemia, dyslipidemia, hypercholesterolemia, impaired glucose tolerance, high blood glucose levels, other manifestations of Syndrome X, hypertension, atherosclerosis, and lipodystrophy.

[0107] The compounds of the present invention and pharmaceutical compositions thereof can 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, spondouloarthropathy, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin-dependent diabetes mellitus or juvenile-onset diabetes), menstrual pain, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastrointestinal tract infections, and the like. Inflammatory skin conditions include, for example, eczema, atopic dermatitis, 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, burns (i.e., sunburn), necrotizing enterocolitis, granulocyte transfusion-associated syndrome, and / or Sjogren's syndrome. Exemplary inflammatory skin conditions include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriasis, and dermatoses with an acute inflammatory component.

[0108] In another aspect, the compounds of the present invention and pharmaceutical compositions thereof may be used to treat allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD). The compounds may be used to treat chronic hepatitis infections, including hepatitis B and hepatitis C.

[0109] Additionally, the compounds of the present invention and pharmaceutical compositions thereof may be used to treat autoimmune diseases and / or inflammation associated with autoimmune diseases, such as organ and tissue autoimmune diseases (e.g., Raynaud's syndrome), scleroderma, myasthenia gravis, transplant rejection, endotoxic shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosus, Addison's disease, polyglandular autoimmune disease (also known as polyglandular autoimmune syndrome), and Graves' disease.

[0110] The compounds of the present invention and pharmaceutical compositions thereof may also be used to reduce the incidence or severity of flushing and / or hot flashes, which are symptoms of certain disorders. In one embodiment, the compounds of the present invention and pharmaceutical compositions thereof may be used to reduce the flushing side effect of vasodilators or antilipidemic agents (including cholesterol-lowering agents and antilipidemic agents).

[0111] In another exemplary embodiment, the method relates to the use of the compound of the present invention and its pharmaceutical composition for reducing the flushing side effect of antidepressant or antipsychotic drug.For example, the compound of the present invention and its pharmaceutical composition can be used in conjunction with serotonin reuptake inhibitor, 5HT2 receptor antagonist, anticonvulsant, norepinephrine reuptake inhibitor, α-adrenergic receptor antagonist, NK-3 antagonist, NK-1 receptor antagonist, PDE4 inhibitor, neuropeptide Y5 receptor antagonist, D4 receptor antagonist, 5HT1A receptor antagonist, 5HT1D receptor antagonist, CRF antagonist, monoamine oxidase inhibitor or hypnotic sedative (administered separately or together).

[0112] In certain embodiments, the compounds of the present invention and pharmaceutical compositions thereof may be used as part of a serotonin reuptake inhibitor (SRI) treatment to reduce flushing. 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 pharmaceutical compositions thereof may also be used as part of a treatment with sedative-hypnotics, such as those selected from the group consisting of benzodiazepines (such as alprazolam, chlordiazepoxide, clonazepam, clorazepate, clobazam, diazepam, halazepam, lorazepam, oxazepam, and prazepam), zolpidem, and barbiturates. In yet another embodiment, the compounds of the present invention and pharmaceutical compositions thereof may be used as part of a treatment with 5-HT1A receptor partial agonists, such as those selected from the group consisting of buspirone, flesinoxan, gepirone, and ipsapirone. The compounds of the present invention and pharmaceutical compositions thereof may also be used as part of a treatment with norepinephrine reuptake inhibitors, such as those selected from tertiary amine tricyclic antidepressants and secondary amine tricyclic antidepressants. Exemplary tertiary amine tricyclic antidepressants include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine. Exemplary secondary amine tricyclic antidepressants include amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline. In certain embodiments, the compounds of the present invention and pharmaceutical compositions thereof may be used as part of a monoamine oxidase inhibitor treatment, such as one selected from the group consisting of isocarboxazid, phenelzine, tranylcypromine, selegiline, and moclobemide.

[0113] In yet another exemplary embodiment, the compounds of the present invention and pharmaceutical compositions thereof may be used to reduce the flushing side effects of chemotherapy agents such as cyclophosphamide and tamoxifen. Similarly, the compounds can be used to reduce the cardiotoxicity associated with anti-neoplastic agents, including anthracyclines, taxanes, and in therapies that target hEGFR2 / HER2, such as trastuzumab.

[0114] In another aspect, the compounds of the present invention and pharmaceutical compositions thereof may be used to reduce the flushing side effect of calcium channel blockers, such as amlodipine.

[0115] In another embodiment, the compounds of the present invention and pharmaceutical compositions thereof may be used to reduce the flushing side effects of antibiotics. For example, the compounds of the present invention and pharmaceutical compositions thereof may 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.

[0116] When administered with another therapeutic agent, the disclosed compounds may be administered simultaneously in the same pharmaceutical formulation or in separate pharmaceutical formulations. Alternatively, when administered with another therapeutic agent, the disclosed compounds may be administered at separate times depending on the administration requirements of the second therapeutic agent.

[0117] Pharmaceutical compositions are disclosed that include one or more compounds provided herein (e.g., a compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, or IVc), and optionally at least one additional substance, such as an excipient, a known therapeutic agent other than those disclosed herein, and combinations thereof. In some embodiments, the disclosed compounds can be used in combination with other agents known to have beneficial activity targeting the diseases or disorders listed above. For example, the disclosed compounds can be administered alone or in combination with one or more compounds selected from the group consisting of PPAR δ agonists, AMPK activators, PARP inhibitors, SIRT activating compounds, nicotinamide N-methyltransferase (NNMT) inhibitors, niacin, nicotinamide, or nicotinamide riboside and its derivatives, and acetyl-CoA carboxylase inhibitors, and pharmaceutically acceptable salts of these compounds.

[0118] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. For administration techniques that can be utilized with the agents and methods described herein, see, e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0119] 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, etc.), agricultural animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0120] The exact amount of a compound administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the disease or condition, as well as on characteristics of the subject, such as general health, age, sex, weight, and drug tolerance. One of ordinary skill in the art will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, for example, when administered in combination with an anti-cancer agent, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by one of ordinary skill in the art based on the condition of the subject, the type of condition(s) being treated, and the amount of the compound of the invention used, for example, by following dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).

[0121] The term "effective amount" means an amount that, upon administration to a subject, produces a beneficial or desired result, including a clinical result, e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount may be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day; and in another example, alternatively, 10 mg to 1 gram per day).

[0122] The specific mode of administration and dosage regimen will be selected by the attending clinician, taking into account the specifics of the case (e.g., the subject, the disease, the disease state occurring, the specific treatment, and whether the treatment is prophylactic). Treatment may involve daily or frequent daily or less-than-daily (such as weekly or monthly) doses over a period of several days to several months, or even years. However, one of ordinary skill in the art will readily recognize appropriate and / or equivalent doses for treating mitochondrial-related diseases using the disclosed compounds, given the dosages of approved compositions as guidance.

[0123] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. In some embodiments, 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.

[0124] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the formulation and / or administration to and / or absorption by a subject of an active agent, and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if necessary, mixed with auxiliary substances that do not adversely react with or interfere with the activity of the compounds provided herein, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for adversely affecting osmotic pressure, buffers, coloring agents, and / or aromatic substances. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds. [Example]

[0125] Abbreviation Ac Acetyl ACN Acetonitrile aq aqueous solution Boc tert-butyloxycarbonyl Boc anhydride di-tert-butyl dicarbonate Bn Benzyl CuI Copper iodide DCM dichloromethane DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO Dimethyl Sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EDC 3-(3-dimethylaminopropyl)-l-ethylcarbodiimide Et Ethyl EtOAc ethyl acetate FWHM Full width at half maximum h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt 1-hydroxybenzotriazole HPLC High Performance Liquid Chromatography K2CO3 Potassium Carbonate LCMS Liquid Chromatography Mass Spectrometry M concentration expressed in mol / L Me methyl MeOH Methanol MEK Methyl ethyl ketone MIBK Methyl isobutyl ketone MTBE Methyl tert-butyl ether Na2SO4 Sodium Sulfate NaOH Sodium hydroxide Ph Phenyl Preparative HPLC Preparative high performance liquid chromatography Rel.Int. Relative Intensity RT room temperature TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography 1 H NMR(DMSO-d6) in DMSO-d6 1 H NMR peak δ (ppm) s singlet (spectrum) d doublet (spectrum) t triplet (spectrum) q quartet (spectrum) dd doublet doublet (spectrum) br Broad peak (spectrum) m multiplet (spectrum) mg milligram mM millimolar nM nanomolar o 2Th 2θ angle, i.e. the angle between transmitted and reflected light.

[0126] General information: LCMS analysis conditions: Instrument name: Agilent Technologies 1290 infinity 11. Method A: Method: A - 0.1% TFA in H2O, B - 0.1% TFA in ACN; Flow rate: 2.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 μm). Method B: Method: A - 10 mM NH4HCO3 in H2O, B - ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 μm). Method C: Method: A-0.1% HCOOH in H2O, B-0.1% FA in ACN; Flow rate: 1.5 mL / min; Column: ZORBAX XDB C-18 (50 x 4.6 mm, 3.5 μm). Method D: Method: A - 10 mM ammonium acetate in H2O, B - ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 μm).

[0127] HPLC analysis conditions: Instrument name: Agilent 1260 Infinity II. Method A: Method: A - 0.1% TFA in H2O, B - 0.1% TFA in ACN; Flow rate: 2.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 μm). Method B: Method: A - 10 mM NH4HCO3 in H2O, B - ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 μm).

[0128] Preparative HPLC purification conditions: Method A: A - 0.1% TFA in H2O, B - MeOH or ACN; Column: Sunfire C8 (19 x 250 mm, 5 μm) or Sunfire C18 (30 x 250 mm, 10 μm). Method B: A - 10 mM NH4HCO3 in H2O, B - MeOH or ACN, Column: Sunfire C8 (19 x 250 mm, 5 μm) or Sunfire C18 (30 x 250 mm, 10 μm). Method C: A - 0.1% formic acid in H2O, B - MeOH or ACN, Column: Sunfire C8 (19 x 250 mm, 5 μm) or Sunfire C18 (30 x 250 mm, 10 μm).

[0129] X-ray powder diffraction (XRPD) Powder X-ray diffraction data were collected under ambient conditions on a Bruker D2 PHASER diffractometer equipped with a 300 W low-power X-ray generator. Powder patterns were collected at 30 kV and 10 mA with a zero-background sample holder, taking 0.15 s per step for a total of 1837 steps, and 0.02° 2θ per step. A Cu(Kα) X-ray tube was used, with a Kα2 / Kα1 intensity ratio of 0.50 (1.54439 Å / 1.5406 Å).

[0130] Thermogravimetric analysis (TGA) Thermogravimetric data were collected on a TA Discovery series TGA. A few milligrams of material were heated from room temperature to 300°C at a heating rate of 10°C per minute under nitrogen protection.

[0131] Differential scanning calorimetry (DSC) Differential scanning calorimetry was performed on a TA Discovery series DSC using approximately a few milligrams of material in Tzero aluminum pans with Tzero hermetic lids. Samples were analyzed using a heating rate of 10°C per minute under a nitrogen flow of 25 mL per minute.

[0132] 7.2.4 Polarized Light Microscopy (PLM) Micrographs were taken using an Olympus BX53M polarizing microscope at room temperature.

[0133] Example 1: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(1H-imidazol-1-yl)isonicotinamide TIFF0007792915000024.tif98165Step 1: 2,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide TIFF0007792915000025.tif25128 To a stirred solution of 2,6-dichloroisonicotinic acid (0.5 g, 2.61 mmol) in DMF (5 mL) at room temperature, HATU (1.69 g, 4.45 mmol) and DIPEA (1.07 mL, 7.85 mmol) were added. After stirring for 5 minutes at room temperature, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (589 mg, 3.40 mmol) was added at room temperature, and the reaction mixture was stirred overnight at room temperature. 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). 1H 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.

[0134] Step 2: 2-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide A stirred suspension 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 K2CO3 (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 Na2SO4, and the solvent was evaporated in vacuo. The crude residue was purified by flash chromatography on a Biotage Iaolera (230-400 mesh silica gel, eluting with 10-50% EtOAc in PET ether) to give the title compound. Yield: 29% (0.1 g, yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.63(d,J=8.0 Hz,1H),8.56(s,1H),8.09(s,1H),7.98(d,J=1.2 Hz,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),3.31-3.2 5(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.1.25 min.

[0135] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(1H-imidazol-1-yl)isonicotinamide To a stirred solution of 2-chloro-6-(1H-imidazol-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), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (73 mg, 0.34 mmol) and K2CO3 (0.11 g, 0.79 mmol) were added at room temperature, and the mixture was purged with nitrogen gas at room temperature for 5 minutes. Pd(dppf)Cl2.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 Celite, and the filtrate was concentrated under vacuum. The obtained crude material was purified by flash chromatography on Biotage Isolera to obtain the title compound. Yield: 47% (53 mg, pale yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.26(s,1H),8.78(s,1H),8.64(br s,1H),8.60(d,J=7.6 Hz,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,2 1.64 min. HPLC: (Method A) Rt. 2.34 min.

[0136] Example 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)isonicotinamide 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-dioxaborolan-2-yl)thiazole (533 mg, 2.52 mmol) in a mixture of dioxane (5 mL) and water (0.5 mL) was deoxygenated by purging with nitrogen gas for 5 min. KCO (558 mg, 4.04 mmol), CuI (19.23 mg, 0.10 mmol), followed by Pd(dppf)Cl.DCM (82.4 mg, 0.10 mmol) were then added, and the resulting mixture was heated at 115 °C for 16 h. After completion, the reaction mixture was filtered through a pad of Celite, washed with 10% MeOH in DCM (100 mL), dried over anhydrous NaSO, filtered, and concentrated under vacuum to obtain the crude product. The crude residue obtained 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 in DCM (10 mL) and washed with 10% NaHCO solution (50 mL) and water (2 x 50 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to obtain the title compound. Yield: 59% (264.64 mg, off-white solid); 1 HNMR(400 MHz,DMSO-d6):δ 9.22(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.

[0137] Example 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)isonicotinamide TIFF0007792915000029.tif131149Step 1: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)isonicotinamide 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-dioxaborolan-2-yl)-1H-pyrazole (414 mg, 1.99 mmol) in a mixture of dioxane (10 mL) and water (1 mL) was deoxygenated by purging with nitrogen gas for 5 min. KCO (786 mg, 5.69 mmol) and Pd(dppf)Cl.DCM (232 mg, 0.28 mmol) were then added, and the resulting mixture was heated at 90 °C for 16 h. After completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (100 mL). The filtrate was washed with water (2 x 50 mL), dried over anhydrous NaSO, filtered, and concentrated under vacuum. The crude residue obtained was then purified by Grace normal phase chromatography (100-200 mesh silica gel, eluent: 2%-5% MeOH in DCM) to give the title compound. Yield: 54.5% (610 mg, brown gummy solid). 1HNMR(400 MHz,DMSO-d6):δ 8.54(d,J=7.6 Hz,1H),8.39(s,1H),8.04(d,J=0.4 Hz,1H),7.93(d,J=1.2 Hz,1H),7.57(d,J=0.8 Hz,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.

[0138] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)isonicotinamide TIFF0007792915000031.tif501281,4 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-dioxaborolan-2-yl)thiazole (413 mg, 1.95 mmol) in dioxane (5 mL) and water (0.5 mL) was deoxygenated by purging with nitrogen gas for 5 minutes. Next, K2CO3 (448 mg, 3.25 mmol), CuI (24.7 mg, 0.13 mmol), followed by Pd(dppf)Cl2.DCM (106 mg, 0.13 mmol) were added and heated at 110 °C for 16 h. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (100 mL). The filtrate was washed with water (2 × 50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum 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 in DCM (50 mL) and 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(400 MHz,DMSO-d6):δ 9.19(s,1H),8.67(d,J=0.8 Hz,1H),8.51(d,J=7.6 Hz,1H),8.38(s,1H),8.08(d,J=0.4 Hz,1H),8.00(d,J=1.6 Hz,1H),7.90(d,J=1.2 Hz,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.

[0139] Example 4: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(trifluoromethyl)isonicotinamide TIFF0007792915000032.tif68169Step 1: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)isonicotinamide 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 room temperature. After stirring for 5 min, a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (230.1 mg, 1.33 mmol) in DMF (0.5 mL) was added at the same temperature. The reaction was further stirred overnight at room temperature. 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 layers were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and the solvent was evaporated under vacuum. The resulting crude product was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel, eluted with 10-50% EtOAc in pet ether) to give the title compound. Yield: 32% (109 mg, white solid). 1 HNMR(300 MHz,DMSO-d6):δ 8.79(d,J=7.2 Hz,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.

[0140] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(trifluoromethyl)isonicotinamide A mixture of 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)isonicotinamide (100 mg, 0.263 mmol), 5-(tributylstannyl)thiazole (147.63 mg, 0.394 mmol) in DMA (3 mL), Pd(dppf)Cl.DCM (21.47 mg, 0.0263 mmol) was added at room temperature after purging with nitrogen gas for 5 minutes. 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 under vacuum to give the crude compound, which was purified by preparative HPLC (Method A). The aqueous fraction was concentrated, and DCM was added and neutralized with 10% aqueous NaHCO. The phases were separated. The organic phase was washed with water, brine, dried over anhydrous NaSO, 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,2) H),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.

[0141] Example 5: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)pyrimidine-4-carboxamide TIFF0007792915000035.tif115151Step 1: Methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate To a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (2.0 g, 96.62 mmol) in THF (25 mL) was added aqueous NaSMe (676 mg, 96.62 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After completion (monitored by TLC), the reaction mixture was diluted with water (100 mL), and the resulting suspension was extracted with diethyl ether (2 × 150 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous NaSO, and the solvent was evaporated under vacuum 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.

[0142] Step 2: 2,6-di(thiazol-5-yl)pyrimidine-4-carboxylic acid and 6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid 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), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (729 mg, 3.45 mmol) and potassium carbonate (0.95 g, 6.90 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen gas for 5 minutes. 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 in DCM and filtered through Celite. The filtrate was concentrated in vacuo to give the mixture of 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.

[0143] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)pyrimidine-4-carboxamide 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) at room temperature, 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)cyclohexan-1-amine (553 mg, 3.20 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was monitored by TLC. Upon 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 under vacuum. The crude residue obtained was purified by preparative HPLC (Method A). The fractions received from preparative HPLC were made weakly basic using aqueous NaHCO3 and concentrated under reduced pressure to remove acetonitrile. The aqueous layer of the residue was extracted with 5% methanol in DCM (2 x 100 mL). The combined organic layers were washed with water (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. Finally, the residue was 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.

[0144] Example 6: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxamide TIFF0007792915000039.tif117166Step 1: Methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate To a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g, 9.66 mmol) in THF (25 mL), aqueous NaSMe (676 mg, 9.66 mmol) was added at room temperature and stirred at the same temperature for 3 hours. The reaction mixture was monitored by TLC and quenched with water (100 mL). The resulting suspension was extracted with diethyl 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 was evaporated under vacuum 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.

[0145] Step 2: 2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylate methyl 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 minutes, after which 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.72 g, 27.52 mmol), copper(1) thiophene-2-carboxylate (5.24 g, 27.52 mmol), and Pd(PPh) (1.56 g, 1.37 mmol) were added at room temperature. The reaction was then stirred at 85 °C for 6 hours. The reaction mass was diluted with 5% methanol in DCM (150 mL) and filtered through a bed of Celite. 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 in DCM) to give the title compound. Yield: 35% (1.2 g, yellow solid). 1 1.53 minutes.

[0146] Step 3: 6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid To a stirred solution of methyl 2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylate (1.0 g, 3.95 mmol) in 1,4-dioxane (10 mL) and water (2 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (1.08 g, 5.14 mmol), CuI (75 mg, 0.39 mmol), and potassium carbonate (1.63 g, 11.87 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen gas for 5 minutes. Pd(dppf)Cl.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 minutes, and filtered. The filtrate was acidified using aqueous HCl (1.5 M) and the resulting solid was filtered and washed with water to give the title compound. Yield: 23% (0.28 g, brown solid). 1 H NMR(400MHz,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.

[0147] Step 4: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxamide 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), DIPEA (202 mg, 1.56 mmol), and (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (118 mg, 0.68 mmol) at room temperature, and the reaction mixture was stirred overnight at room temperature. 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), dried over anhydrous NaSO, and concentrated in vacuo. The crude residue obtained was purified by flash chromatography on a Biotage Isolera (230-400 mesh silica gel, eluent: 0-5% methanol in DCM) to give the title compound. Yield: 32% (73 mg, yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.30(d,J=0.4 Hz,1H),9.08(d,J=0.8 Hz,1H),8.70(s,1H),8.6(d,J=8.8 Hz,1H),8.3(d,J=0.4 Hz,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 minutes.

[0148] Example 7: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxamide TIFF0007792915000044.tif110147Step 1: Methyl 2-chloro-6-(methylthio)pyrimidine-4-carboxylate To a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g, 96.62 mmol) in THF (25 mL) was added aqueous NaSMe (676 mg, 96.62 mmol) at room temperature and stirred at the same temperature for 3 hours. 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 NaSO, and the solvent was evaporated under vacuum to give the title compound. Yield: 66% (1.4 g, yellow solid). 1 H NMR (400 MHz, 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.

[0149] Step 2: 6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid 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), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (729 mg, 3.45 mmol), CuI (43 mg, 0.23 mmol), and K2CO3 (0.95 g, 6.90 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen gas for 5 minutes. 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 in DCM and filtered through Celite. The combined filtrates were concentrated in vacuo and the resulting crude material was used directly in the subsequent step. Yield: 96% (0.56 g, black solid, crude). LCMS: (Method C) 353.9 [M+H], Rt. 1.44 min.

[0150] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxamide 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)cyclohexane-1-amine (553 mg, 3.20 mmol), and the reaction mixture was stirred at room temperature 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 NaSO, and the solvent was evaporated in vacuo. The crude product obtained was purified by preparative HPLC (Method A). The fractions received from preparative HPLC were made weakly basic using aqueous NaHCO3, and the ACN was removed on a rotary evaporator under reduced pressure. The aqueous layer was extracted with 5% methanol in DCM (2 x 100 mL). The combined organic layers were washed with water (2 x 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.

[0151] Example 8: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)picolinamide TIFF0007792915000048.tif107164Step 1: 4,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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)cyclohexan-1-amine (3.24 g, 18.75 mmol) in DMF (5.0 mL) was added at the same temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC. After completion of the reaction, 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 NaSO, and the solvent was evaporated under vacuum to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet ether) to give the title compound Yield: 77% (4.2 g, yellow solid). 1 HNMR 300 MHz,DMSO-d6):δ 8.46(d,J=8.1 Hz,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.

[0152] Step 2: 4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide 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 of ethanol and water (1.0 mL) in a sealed tube, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (364.9 mg, 1.729 mmol), CuI (27.37 mg, 0.144 mmol), potassium carbonate (497.1 mg, 3.602 mmol), and Pd(dppf)Cl.DCM (58.83 mg, 0.0724 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen gas for 5 minutes. The reaction mixture was heated at 95°C for 16 hours. After completion of the reaction, it was filtered through Celite and washed with DCM (20 mL). The solvent was evaporated under vacuum to give the crude compound. The obtained crude product was purified by column chromatography on Biotage isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM) to give the title compound. Yield: 55.5% (290 mg, light brown solid). 1 HNMR(400 MHz,DMSO-d6):δ 9.26(s,1H),8.87(s,1H),8.37(d,J=1.6 Hz,1H),8.30(d,J=8.4 Hz,1H),7.91(d,J=1.6 Hz,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.1.912 min.

[0153] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)picolinamide 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-dioxaborolan-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) 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 completion of the reaction, it was filtered through Celite and washed with DCM (20 mL). The filtrate was evaporated under vacuum to give the crude product, which was purified by preparative HPLC (Method A). The collected fractions were 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: 45% (141.7 mg, off-white solid). 1 HNMR(400 MHz,DMSO-d6):δ 9.22(s,1H),8.84(s,1H),8.60(s,1H),8.33(d,J=1.2 Hz,1H),8.26(s,1H),8.20(d,J=8.4 Hz,1H),8.06(d,J=1.6 Hz,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.

[0154] Example 9: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide TIFF0007792915000052.tif77163Step 1: 6-Bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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) under a nitrogen atmosphere at 0 °C, and the resulting mixture was stirred for 15 min. After 15 min, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (533 mg, 3.08 mmol) was added and stirred at room temperature 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 NaSO, filtered, and concentrated in vacuo to give the title compound. Yield: 69.9% (510 mg, brown gummy solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.32(d,J=10.80 Hz,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),3.53-3.50(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)360.0[M+H],Rt.1.94 min.

[0155] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide TIFF0007792915000054.tif361281,4 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-dioxaborolan-2-yl)thiazole (186 mg, 0.88 mmol) in dioxane (3 mL) and water (0.5 mL) was deoxygenated by purging with nitrogen gas for 10 min. K2CO3 (162 mg, 1.17 mmol) was then added, followed by CuI (11.1 mg, 0.058 mmol) and Pd(dppf)Cl2.DCM (47.3 mg, 0.058 mmol), and the resulting mixture was heated at 110 °C for 16 h. The mixture was heated for 1 hour. After completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a crude residue. The crude product obtained was then purified by Grace reverse-phase chromatography (Method A), and the collected fractions were concentrated under reduced pressure. The product obtained was redissolved in 10% MeOH in DCM (50 mL) and washed with 10% NaOH solution (20 mL), followed by water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further dried using lyophilization to obtain the title compound. Yield: 66.12% (140.5 mg, white solid); 1 HNMR(400 MHz,DMSO-d6):δ 9.22(s,1H),8.79(s,1H),8.23(d,J=8.4 Hz,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),3.45-3.40(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.

[0156] Example 10: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide TIFF0007792915000055.tif110163Step 1: 4,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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)cyclohexane-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC. After completion of the reaction, 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 NaSO, and the solvent was evaporated under vacuum to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet 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),3.20(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.

[0157] Step 2: 4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide 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) in a sealed tube, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (145.93 mg, 0.691 mmol), CuI (10.95 mg, 0.0576 mmol), potassium carbonate (159.0 mg, 1.15 mmol), and Pd(dppf)Cl.DCM (23.53 mg, 0.028 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen gas for 5 minutes. The reaction mixture was then heated at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered through Celite and washed with DCM (20 mL). The solvent was evaporated under vacuum to give the crude compound. The crude product obtained was purified by column chromatography on Biotage isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM) to give the title compound. Yield: 35.2% (80 mg, light brown solid). 1 HNMR(400 MHz,DMSO-d6):δ 9.26(s,1H),8.87(s,1H),8.37(d,J=2.0 Hz,1H),8.29(d,J=8.4 Hz,1H),7.91(d,J=1.6 Hz,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.2.584 min.

[0158] Step 3: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide 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) was placed in a sealed tube and purged with N2 for 5 minutes. The reaction mixture was heated at 125 °C for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered through Celite and washed with DCM (10 mL). The filtrate was evaporated in vacuo to give the crude product, which was purified by preparative HPLC (Method A). The collected fractions were concentrated, diluted with DCM, and neutralized with 10% aqueous NaHCO. The organic phase was washed with water, brine, dried over anhydrous NaSO, and evaporated to give the title compound. Yield: 19.7% (17.02 mg, off-white solid). 1 HNMR(400 MHz,DMSO-d6):δ 9.25(s,1H),8.92(d,J=0.4 Hz,1H),8.75(s,1H),8.47(d,J=2.4 Hz,1H),8.30(d,J=8.4 Hz,1H),8.19(d,J=1.6 Hz,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.

[0159] Example 11: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000059.tif36128Step 1: 6-(1H-imidazol-1-yl)picolinic acid A solution of methyl 6-bromopicolinate (502 mg, 2.32 mmol) and 1H-imidazole (474 ​​mg, 6.97 mmol) in DMF (5 mL) was deoxygenated by purging with nitrogen gas for 5 minutes. After 5 minutes, K2CO3 (801 mg, 5.80 mmol) was added, followed by CuI (44.2 mg, 0.23 mmol), and heated at 140 °C for 16 hours. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with EtOAc (200 mL) and water (50 mL). The aqueous layer was acidified using 1.5 N HCl and evaporated under vacuum. The mixture was then washed with EtOAc (200 mL) and water (50 mL). The aqueous layer was acidified using 1.5 N HCl and evaporated under vacuum. This crude product was used for the next step without any purification. Yield: 44.5% (210 mg, white solid); LCMS: (Method B) 190.1 [M+H], Rt. 0.56 min.

[0160] Step 2: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 6-(1H-imidazol-1-yl)picolinic acid (102 mg, 0.53 mmol) in DMF (7 mL) was added HATU (307 mg, 0.80 mmol) followed by DIPEA (0.37 mL, 2.02 mmol) under a nitrogen atmosphere at 0 °C and stirred for 5 min. Then, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (146 mg, 0.80 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. Upon completion, water (50 mL) was added to the reaction mixture and extracted with EtOAc (100 mL) (solvent excess for a 100 mg scale). The organic layer was washed with water (2 × 25 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue obtained 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 in DCM (50 mL) and washed with 10% aqueous NaHCO (20 mL) followed by water (2 x 25 mL). (Some insoluble particles were observed in the organic layer, which were dissolved in excess water.) The organic layer was dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and further dried by lyophilization to give the title compound. Yield: 56.7% (105.39 mg, off-white solid); 1 HNMR(400 MHz,DMSO-d6):δ 8.95(s,1H),8.56(d,J=8.8 Hz,1H),8.26(s,1H),8.15(d,J=7.6 Hz,1H),8.00(d,J=8.0 Hz,1H),7.16(s,1H),3.86-3.80(m,1H),3.57-3.55(m,2H),3.55-3.54(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.

[0161] Example 12: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)picolinamide TIFF0007792915000062.tif125170Step 1: 4,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.8 mmol, CAS number 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)cyclohexan-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC. After completion of the reaction, 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 NaSO, and the solvent was evaporated under vacuum to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet 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),3.20(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.

[0162] 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 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) was taken in a sealed tube and purged with N2 for 5 minutes. The reaction mixture was heated at 90 °C for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, it 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 purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM). Yield 80% (610.1 mg, gummy solid). 1 HNMR(400 MHz,DMSO-d6):δ 8.71(s,1H),8.45(d,J=8.4 Hz,1H),8.27(d,J=2.8 Hz,1H),8.19(d,J=2.0 Hz,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,2) H),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.

[0163] Step 3: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)picolinamide TIFF0007792915000065.tif54128 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 in 4.5 mL dioxane and 0.5 mL water in sealed tubes A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (184.88 mg, 0.888 mmol), K2CO3 (255.5 mg, 1.851 mmol), and Pd(dppf)Cl2.DCM (30.24 mg, 0.0370 mmol) was purged with N2 for 5 minutes. The reaction mixture was heated at 97 °C for 16 hours. 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 the crude product, which was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in 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. 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). 1HNMR(400 MHz,DMSO-d6):δ 8.97(s,1H),8.60(s,1H),8.52(d,J=8.4 Hz,1H),8.31-8.30(m,1H),8.27(s,1H),8.14(,J=1.2 Hz,1H),8.07(d,J=1.2 Hz,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.

[0164] Example 13: 6-(1H-imidazol-1-yl)-4-(1-isopropyl-1H-pyrazol-4-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000066.tif103152Step 1: 6-Bromo-4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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)cyclohexane-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 room temperature. 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 NaSO, and the solvent was evaporated under vacuum. The crude residue was purified by column chromatography on a Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc in pet ether) to give the title compound. Yield: 43% (2.1 g, yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.44(d,J=8.4 Hz,1H),8.14(d,J=1.6 Hz,1H),8.00(d,J=2.0 Hz,1H),3.78-3.71(m,1H),3.55-3.52(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.2.20 min.

[0165] Step 2: 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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), and copper iodide (9.7 mg, 0.0510 mmol) in DMF (15 mL) was taken in a sealed tube and purged with N2 for 5 minutes. The reaction mixture was heated at 90 °C for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, it was filtered through Celite and washed with DCM (10 mL). The filtrate was evaporated in vacuo to give the crude product, which was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM). Yield 65% (125.1 mg, gummy solid). 1 HNMR(400 MHz,DMSO-d6):δ 8.99(s,1H),8.63(d,J=8.4 Hz,1H),8.30(d,J=1.6 Hz,1H),8.26(d,J=1.6 Hz,1H),7.92(d,J=2.0 Hz,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),2.06-2.0 3(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.

[0166] Step 3: 6-(1H-imidazol-1-yl)-4-(1-isopropyl-1H-pyrazol-4-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide A mixture of 4-chloro-6-(1H-imidazol-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-dioxaborolan-2-yl)-1H-pyrazole (89.9 mg, 0.3809 mmol), NaHCO (80.01 mg, 0.9523 mmol), and Pd(PPh) (36.66 mg, 0.03177 mmol) in 2.0 mL DMF and 0.1 mL water was placed in a sealed tube and purged with nitrogen gas for 5 minutes. The reaction mixture was heated at 100 °C for 16 hours. After completion of the reaction, it was filtered through Celite and washed with DCM (10 mL). The solvent was evaporated under vacuum to give the crude compound. The obtained crude product was purified by column chromatography on a Biotage isolera (230-400 mesh silica gel eluted with 0-10% MeOH in 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% aqueous NaHCO3 solution. The organic phase was washed with water, brine, and water, dried over anhydrous sodium sulfate, and lyophilized to give the title compound. Yield: 28% (40 mg, off-white solid). 1 HNMR(400 MHz,DMSO-d6):δ 8.97(s,1H),8.71(s,1H),8.52(d,J=8.4 Hz,1H),8.31-8.30(m,1H),8.28(s,1H),8.15(d,J=1.2 Hz,1H),8.11(d,J=1.2 Hz,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.1.47min, HPLC: (Method A) Rt.2.80min.

[0167] Example 14: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)picolinamide To a stirred suspension of 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (90 mg, 0.24 mmol) in DMF (3.0 mL) and water (1 drop) at room temperature, 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 mg, 0.28 mmol) and NaHCO (59 mg, 0.71 mmol) were added, and the mixture was purged with N (gas) for 5 minutes. Pd(PPh) (27.4 mg, 0.02 mmol) was then added at room temperature, and the reaction mixture was heated at 100 °C in a sealed tube for 16 hours. 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 under vacuum, and the resulting crude material was purified by preparative HPLC (Method A). The preparative fractions were concentrated under vacuum. DCM was added to the residue, and neutralized with 10% aqueous NaHCO3 solution. 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 H NMR(400 MHz,DMSO-d6):δ 8.98(s,1H),8.58(d,J=8.8 Hz,1H),8.31-8.30(m,1H),7.81-7.79(m,2H),7.17-7.16(m,1H),3.89-3.83(m ,1H),3.76(s,3H),3.57-3.55(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.

[0168] Example 15: 4-amino-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000071.tif112167Step 1: 4,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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)cyclohexan-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction was further stirred overnight at room temperature. 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 NaSO, and the solvent was evaporated in vacuo to give the crude compound, which was purified by column chromatography Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet 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.

[0169] Step 2: 6-chloro-4-((2,4-dimethoxybenzyl)amino)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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 with (2,4-dimethoxyphenyl)methanamine (794.1 mg, 4.75 mmol) and DIPEA (1.50 mL, 8.646 mmol) and purged with N for 5 minutes. 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 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and the solvent was evaporated in vacuo to give the crude compound, which was purified by column chromatography Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet ether) to give the title compound. Yield: 65% (1.30 g, yellow solid). 1 HNMR(300 MHz,DMSO-d6):δ 8.00(d,J=8.4 Hz,1H),7.57-7.56(m,1H),7.21(s,1H),7.10(d,J=8.1 Hz,1H),6.58(s,2H),6.48(d,J=8.4 Hz,1H),4.21(d,J=5.4 Hz,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.

[0170] Step 3: 4-amino-6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide. 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 mmol) at 0° C. and room temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to 0° C. and ice-cold water was added slowly, followed by neutralization with saturated Na2CO3 solution. The solid formed during neutralization was filtered, washed with water, hexane, and dried to give the title compound. Yield: 96% (860 mg, off-white solid). 1 HNMR(300 MHz,DMSO-d6):δ 7.99(d,J=8.4 Hz,1H),7.18(d,J=2.1 Hz,1H),6.71(s,2H),6.58(d,J=2.1 Hz,1H),3.81-3.75(m,1H),3.52-3.51(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.1.74 min.

[0171] Step 4: 4-amino-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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), K2CO3 (253.2 mg, 1.834 mmol), and copper iodide (11.6 mg, 0.0611 mmol) in DMF (4 mL) was purged with N2 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 collected fractions were concentrated to remove ACN, and the resulting fractions were neutralized with 10% aqueous NaHCO3 and extracted with DCM. The organic phase was washed with water, brine, dried over anhydrous Na2SO4, and evaporated to give the title compound. Yield 13% (30.1 mg, off-white solid). 1 HNMR(400 MHz,DMSO-d6):δ 8.71(s,1H),8.31(d,J=8.8 Hz,1H),7.94(s,1H),7.19(d,J=1.6 Hz,1H),7.09(s,1H),6.79(d,J=1.6 Hz,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.

[0172] Example 16: 4,6-Di(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000076.tif84165Step 1: 4,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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)cyclohexane-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC. Upon 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 NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on a Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet ether) to give the title compound. Yield: 49% (1.35 g, yellow solid). 1 H NMR(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),3.31-3.25(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.2.27 min.

[0173] Step 2: 4,6-di(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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 K2CO3 (59.65 mg, 0.43 mmol) in DMF (2 mL) in a sealed tube was purged with N2 for 5 minutes. Copper iodide (5.4 mg, 0.03 mmol) was then added, the tube was sealed, and the reaction mixture was heated at 125 °C overnight. The reaction was monitored by LCMS. Upon completion, the reaction mixture was filtered through Celite, and the Celite bed was washed with DCM (10 mL). The filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC (Method A). The collected fractions were concentrated, diluted with DCM, and neutralized with 10% aqueous NaHCO. 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). 1 H NMR(400 MHz,DMSO-d6):δ 9.03(s,1H),8.75(s,1H),8.64(d,J=8.8 Hz,1H),8.36-8.35(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.

[0174] Example 17: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide TIFF0007792915000079.tif97165Step 1: 4,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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)cyclohexane-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC. After completion of the reaction, 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 NaSO, and the solvent was evaporated under vacuum to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet 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),3.20(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.

[0175] 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 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) was taken in a sealed tube and purged with N2 for 5 minutes. The reaction mixture was heated at 90 °C for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, it 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 purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM). Yield 80% (610.1 mg, gummy solid). 1 HNMR(400 MHz,DMSO-d6):δ 8.71(s,1H),8.45(d,J=8.4 Hz,1H),8.27(d,J=2.8 Hz,1H),8.19(d,J=2.0 Hz,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,2) H),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.

[0176] Step 3: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide TIFF0007792915000082.tif36128 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 mL) in 9.0 mL ethanol and 1.0 mL water in a sealed tube at room temperature. A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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, and DCM (64.81 mg, 0.0793 mmol) was added, and nitrogen gas was purged into the reaction mixture for 5 minutes. The reaction mixture was then heated at 100 °C for 16 hours. After completion of the reaction, it was filtered through Celite and washed with DCM (20 mL). The solvent was evaporated under vacuum to give the crude compound. The resulting crude product was purified by column chromatography on a Biotage isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM) to give the title compound, which was further purified by preparative HPLC (method HCOOH). The fractions of the minor isomer 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: 3.2% (21 mg, off-white solid). 1HNMR(400 MHz,DMSO-d6):δ 9.33(d,J=0.4 Hz,1H),9.03(s,1H),8.84(d,J=0.4 Hz,1H),8.61(d,J=8.8 Hz,1H),8.38-8.37(m,1H),8.31(d,J=1.6 Hz,1H),8.09(d,J=1.2 Hz,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.

[0177] Example 18: 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-picolinamide 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), and copper iodide (9.7 mg, 0.0510 mmol) in DMF (15 mL) was taken in a sealed tube and purged with N2 for 5 minutes. The reaction mixture was heated at 90 °C for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, it was filtered through Celite and washed with DCM (10 mL). The filtrate was evaporated in vacuo to give the crude product, which was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM). Yield 65% (125.1 mg, gummy solid). 1HNMR(400 MHz,DMSO-d6):δ 8.99(s,1H),8.63(d,J=8.4 Hz,1H),8.30(d,J=1.6 Hz,1H),8.26(d,J=1.6 Hz,1H),7.92(d,J=2.0 Hz,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),2.06-2.0 3(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.

[0178] Example 19: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide TIFF0007792915000084.tif99166Step 1: Methyl 4-(trifluoromethyl)picolinate To a stirred solution of 4-(trifluoromethyl)picolinic acid (1 g, 5.23 mmol) in MeOH (10 mL) at 280 °C, thionyl chloride (1.15 mL, 15.69 mmol) was slowly added over 5 minutes 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 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, and the solvent was evaporated under vacuum to give the title compound. Yield: 75% (0.8 g, pale 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.

[0179] Step 2: 2-(Methoxycarbonyl)-4-(trifluoromethyl)pyridine 1-oxide To a stirred solution of methyl 4-(trifluoromethyl)picolinate (0.6 g, 2.92 mmol) in DCM (20 mL), urea peroxide (0.55 g, 5.84 mmol) and TFAA (1.22 g, 5.84 mmol) were added and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO 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 NaSO, filtered, and evaporated to dryness to give the title compound. Yield: 94% (0.61 g, pale 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.

[0180] Step 3: 6-chloro-4-(trifluoromethyl)picolinate methyl ester TIFF0007792915000087.tif26128 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 crude product obtained was redissolved 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.

[0181] Step 4: 6-chloro-4-(trifluoromethyl)picolinic acid To a solution of methyl 6-chloro-4-(trifluoromethyl)picolinate (0.6 g, 2.51 mmol) in THF (12 mL) and water (4 mL), NaOH (0.301 g, 7.53 mmol) was added at room temperature and stirred at the same temperature overnight. The reaction mixture was evaporated in vacuo, 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 layer was washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, 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.

[0182] Step 5: 6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide 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 room temperature. After stirring for 5 min, a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (0.461 g, 2.66 mmol) was added at the same temperature. The reaction was further stirred overnight at room temperature. 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 layers were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and the solvent was evaporated in vacuo. The resulting crude product was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 16-20% EtOAc in pet 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.

[0183] Step 6: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide 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 K2CO3 (217 mg, 1.57 mmol) in DMF (4 mL) was purged with N2 for 2 minutes, and then the reaction mixture was heated at 120 °C in a sealed tube overnight. The reaction mixture was diluted with EtOAc (10 mL) and filtered through a bed of Celite. 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 NaSO, filtered, dried under reduced pressure, and lyophilized to give the product. Yield: 44% (95.53 mg, white gummy solid). 1 HNMR(400 MHz,DMSO-d6):δ 9.09-9.09(m,1H),8.73(d,J=8.4 Hz,1H),8.45(s,1H),8.43-8.42(m,1H),8.12(d,J=0.4 Hz,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.

[0184] Example 20: 4-Fluoro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000091.tif77166Step 1: 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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 minutes, and then the reaction mixture was heated at 65 °C in a sealed tube for 48 hours. The reaction was monitored by LCMS, and after completion of the reaction, 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 purified by column chromatography Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM) in 35% yield (210 mg, gummy solid). 1 HNMR(300 MHz,DMSO-d6):δ 8.99(s,1H),8.63(d,J=8.7 Hz,1H),8.29(d,J=4.5 Hz,1H),8.26(d,J=1.5 Hz,1H),7.92(d,J=1.5 Hz,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),2.06-2.0 3(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.

[0185] Step 2: 4-fluoro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000093.tif35128 A mixture of 4-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.529 mmol) in DMSO (4.0 mL), cesium fluoride (200.91 mg, 1.322 mmol) was added at room temperature, and nitrogen gas was purged into the reaction mixture for 5 minutes. The reaction mixture was then heated at 100° C. in a sealed tube for 3 hours. 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 NaSO, and the solvent was evaporated under vacuum to give the crude compound, which was purified by preparative HPLC (Method C). The collected fractions were concentrated to remove ACN, and the resulting aqueous layer was neutralized with 10% NaHCO. It was then extracted with DCM (25 mL), and the DCM layer was washed with water, brine, dried over anhydrous NaSO, and evaporated to give the title compound. Yield: 21% (41.1 mg, off-white solid). 1 HNMR(400 MHz,DMSO-d6):δ 8.99(s,1H),8.63(d,J=8.8 Hz,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.

[0186] Example 21: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide TIFF0007792915000094.tif79162Step 1: 2-Bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide To a stirred solution of 2-bromoisonicotinic acid (510 mg, 2.52 mmol) in DMF (5 mL) at 280 °C under a nitrogen atmosphere, HATU (1.43 g, 3.78 mmol) was added, followed by DIPEA (1.16 mL, 6.30 mmol) and stirred for 5 min. After 5 min, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (656 mg, 3.78 mmol) was added and stirred at room temperature 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 × 25 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound. Yield: 48.2% (435 mg, yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.59(d,J=7.60 Hz,1H),8.53(d,J=5.20 Hz,1H),7.99(s,1H),7.78(dd,J=6.40,1.2 Hz,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.1.86 min.

[0187] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide 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 by purging with nitrogen gas for 5 minutes. After 5 minutes, K2CO3 (151 mg, 1.10 mmol) was added at room temperature, followed by CuI (10.4 mg, 0.05 mmol), and the resulting mixture was heated at 140 °C for 16 hours. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (50 mL). The combined filtrates were evaporated under vacuum to give the crude product, and the crude residue was purified by Grace normal phase chromatography (eluent: 2% to 3% MeOH in DCM). The collected fractions were concentrated under reduced pressure, then redissolved in 10% MeOH in DCM (50 mL) and washed with 10% aqueous NaHCO (20 mL) followed by water (2 x 20 mL). The organic layer was dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and further dried by lyophilization to give the title compound. Yield: 11.3% (20.89 mg, white solid); 1 HNMR(400MHz,DMSO-d6):8.61(d,J=5.2 Hz,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.

[0188] Example 22: 2,6-di(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide 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 with nitrogen gas for 5 minutes. KCO (143 mg, 1.03 mmol) and CuI (3.9 mg, 0.02 mmol) were then added, and the reaction mixture was heated at 130° C. for 16 hours. After completion, the reaction mixture was filtered through a Celite pad and washed with 10% MeOH in DCM (50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under vacuum. 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 in DCM (50 mL), washed with 10% aqueous NaHCO (20 mL), water (20 mL), and dried over anhydrous NaSO. The solvent was evaporated under reduced pressure and lyophilized to give the title compound. Yield: 62.8% (53.57 mg, off-white solid); 1 HNMR(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,2 H),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.

[0189] Example 23: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)isonicotinamide 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-dioxaborolan-2-yl)-1H-pyrazole (177 mg, 0.85 mmol) in a mixture of dioxane (5 mL) and water (0.5 mL) was deoxygenated by purging with nitrogen gas for 5 min. KCO (195 mg, 1.41 mmol) and Pd(dppf)Cl.DCM (46.3 mg, 0.05 mmol) were then added, and the resulting reaction mixture was heated at 100 °C for 16 h. After completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue obtained was purified by Grace reverse-phase chromatography (Method A) and further purified by preparative HPLC using Method A. The collected fractions were concentrated under reduced pressure, and the obtained product was redissolved in 10% MeOH in DCM (50 mL) and washed with 10% aqueous NaHCO3 (20 mL), followed by water (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: 12.3% (29.80 mg, off-white solid); 1HNMR(400 MHz,DMSO-d6):δ 8.69(s,1H),8.50(d,J=8.0 Hz,2H),8.17(d,J=0.8 Hz,1H),8.09(t,J=1.6 Hz,1H),7.87(d,J=1.2 Hz,1H),7.80(d,J=0.8 Hz,1H),7.16(t,J=1.2 Hz,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.

[0190] Example 24: 2-(1-ethyl-1H-pyrazol-4-yl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide 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-dioxaborolan-2-yl)-1H-pyrazole (99.38 mg, 0.44 mmol) in dioxane (2 mL) and water (0.13 mL) was purged with nitrogen gas for 5 min. After 5 min, KCO (102.8 mg, 0.74 mmol) and PdCl(dppf).DCM (24.3 mg, 0.02 mmol) were added, and the resulting mixture was heated at 100 °C for 16 h. After completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. 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 in DCM (50 mL) and washed with 10% aqueous NaHCO3 (20 mL), followed by water (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: 24% (31.5 mg, off-white solid); 1 HNMR(400 MHz,DMSO-d6):δ 8.90(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=7.2 Hz,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.

[0191] Example 25: 2-(1H-imidazol-1-yl)-6-(1-isopropyl-1H-pyrazol-4-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide 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-dioxaborolan-2-yl)-1H-pyrazole (95.3 mg, 0.40 mmol) in a mixture of dioxane (2 mL) and water (0.2 mL) was deoxygenated by purging with nitrogen gas for 5 min. Then, KCO (92.87 mg, 0.67 mmol) and Pd(dppf)Cl.DCM (21.96 mg, 0.02 mmol) were added, and the reaction mixture was heated at 100 °C for 16 h. After completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue, which 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 in DCM (50 mL). This layer was washed with 10% NaHCO3 solution (20 mL), water (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and further dried by lyophilization to give the title compound. Yield: 42.5% (51.88 mg, pale yellow solid); 1HNMR(400 MHz,DMSO-d6):δ 8.73-8.72(m,1H),8.59(s,1H),8.50(d,J=7.6 Hz,1H),8.18(d,J=0.4 Hz,1H),8.11-8.10(m,1H),7.90(d,J=0.8 Hz,1H),7.80(d,J=1.2 Hz,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.

[0192] Example 26: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-3-yl)isonicotinamide TIFF0007792915000101.tif100169Step 1: 2-chloro-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide To a stirred solution of 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide (950 mg, 2.73 mmol) and 1H-imidazole (558 mg, 8.20 mmol) in DMF (100 mL) was degassed for 10 minutes, followed by potassium carbonate (1.13 g, 8.20 mmol) at room temperature, followed by additional CuI (51.9 mg, 0.27 mmol). The reaction mixture was heated at 100° C. for 16 hours. Upon completion, the reaction mixture was filtered through Celite and washed with 5% MeOH in DCM (200 mL). The combined organic layers were washed with 10% NaHCO solution (50 mL), followed by water (2×50 mL). The combined organic layers were evaporated in vacuo and the crude material was purified by grace chromatography on silica gel (100-200 mesh, 2%-3% MeOH in DCM) to give the title compound. Yield: 40% (410 mg, brown solid). LCMS: (Method C) 378.9 [M+H], Rt 1.26 min.

[0193] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-3-yl)isonicotinamide 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-dioxaborolan-2-yl)-1H-pyrazole (80 mg, 0.39 mmol) in a mixture of 1,4 dioxane (2.5 mL) and water (0.25 mL), KCO (110 mg, 0.78 mmol) was added followed by an additional Pd(dppf)Cl.DCM (20 mg, 0.02 mmol) at room temperature after purging nitrogen gas through the reaction mixture for 5 minutes. The reaction mixture was heated at 100 °C for 16 hours. After completion, the reaction mixture was filtered through Celite and washed with 10% MeOH in DCM (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue obtained was purified by preparative HPLC (Method A). The collected fractions were concentrated under reduced pressure, diluted with 10% MeOH / DCM (50 mL), and washed with 10% NaHCO3 solution (20 mL), followed by water (2 x 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(400 MHz,DMSO-d6):δ 9.20((s,1H),8.73(d,J=7.6 Hz,1H),8.30(s,1H),8.25(d,J=1.2 Hz,1H),8.06(d,J=1.2 Hz,1H),7.90(d,J=2.0 Hz,1H),7.50(s,1H),7.10(d,J=2.4 Hz,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.

[0194] Example 27: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxamide TIFF0007792915000104.tif116164Step 1: 2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylate methyl ester 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 gas for 15 minutes, then copper(1) thiophene-2-carboxylate (1) (1.75 g, 9.17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g, 9.17 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.53 g, 0.46 mmol) were added at room temperature and heated at 85 °C for 6 hours. The reaction mixture was diluted with 5% methanol in DCM and filtered through Celite. The combined filtrates were concentrated in vacuo, and the resulting crude material was purified by flash chromatography on a Biotage Isolera to provide 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.

[0195] Step 2: 2-(1H-imidazol-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid A reaction mixture of methyl 2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylate (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 bed of Celite. The filtrate was concentrated to give the crude title compound, which was used directly in the next step. 1 HNMR(400MHz,DMSO-d6):δ 12.1(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.

[0196] Step 3: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxamide To a stirred solution of 2-(1H-imidazol-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 room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with 5% methanol in DCM (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated in vacuo. The crude residue obtained was purified by preparative HPLC (Method A). The fractions received from preparative HPLC were made weakly basic using aqueous NaHCO3, and the ACN was removed on a rotary evaporator under reduced pressure. The aqueous layer was extracted with 5% methanol in DCM (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give the title compound. Yield: 23% (10 mg, off-white solid). 1 HNMR(400 MHz,DMSO-d6):δ 9.04(s,1H),8.83(s,1H),8.76(d,J=8.80 Hz,1H),8.43(s,1H),8.3(s,1H),8.1(s,1H),7.2(s,1H),3.9(s,3H),3.80-0.00(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.

[0197] Example 28: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide TIFF0007792915000108.tif108148Step 1: 2-Chloropyrimidine-4-carbonyl chloride TIFF0007792915000109.tif25128To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (1 g, 6.3 mmol) and 2 drops of DMF in DCM (20 ml) was added oxalyl chloride (1.20 g, 9.46 mmol) at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was dried under vacuum to give the desired product. Yield: 98% (1 g, light brown gum).

[0198] Step 2: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide 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 80 °C, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (0.977 g, 5.65 mmol) was added at the same temperature and stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO 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 NaSO, 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.

[0199] Step 3: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide 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 K2CO3 (1.97 g, 14.34 mmol) in DMF (20 mL) was purged with N2 for 5 minutes, and then the reaction mixture was heated at 120 °C in a sealed tube overnight. The reaction mixture was diluted with DCM and filtered through a bed of Celite. The filtrate was evaporated under vacuum, 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 NaSO, filtered, dried under reduced pressure, and lyophilized to give the product. Yield: 38% (635.57 mg, pale yellow gummy solid). 1 HNMR(400 MHz,DMSO-d6:δ 9.06(d,J=4.8 Hz,1H),8.97(s,1H),8.85(d,J=8.8 Hz,1H),8.23(s,1H),7.91(d,J=5.2 Hz,1H),7.19(s,1H),7.33(d,J=8.4 Hz,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.

[0200] Example 29: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide TIFF0007792915000112.tif76164Step 1: 6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide To a stirred solution of 6-chloro-4-methylpicolinic acid (511 mg, 2.97 mmol) in DMF (5 mL) at 280 °C under a nitrogen atmosphere, EDC.HCl (856 mg, 4.46 mmol), HOBt (603 mg, 4.46 mmol), followed by DIPEA (1.37 mL, 7.44 mmol) were added, and the resulting mixture was stirred for 5 min. After 5 min, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (774 mg, 4.46 mmol) was added and stirred at room temperature for 16 h. Upon completion, the reaction mixture was quenched with ice-cold water (25 mL), extracted with EtOAc (50 mL), washed with water (2 × 20 mL), and dried over anhydrous NaSO. The solvent was evaporated under reduced pressure to give the title compound. Yield: 77.05% (750 mg, brown solid); 1 H NMR(400 MHz,DMSO-d6):δ 11.99(s,1H),8.18(d,J=7.6 Hz,1H),7.61(d,J=8.0 Hz,1H),7.54(d,J=16.4 Hz,1H),6.91(s,1H),3.75-3.70(m,1H),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.2.10 min.

[0201] Step 2: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide 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 with 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, washed with DCM (50 mL), and the filtrate was evaporated under vacuum 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 in DCM (50 mL), washed with 10% aqueous NaHCO (20 mL), water (2×20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. Yield: 33.5% (77.29 mg, off-white solid); 1 HNMR(400 MHz,DMSO-d6):δ 8.91(s,1H),8.52(d,J=8.8 Hz,1H),8.22(t,J=1.2 Hz,1H),7.88(s,1H),7.82(s,1H),7.15(s,1H),3.84-3.79(m,1H),3.5 7-3.50(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.

[0202] Example 30: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide TIFF0007792915000115.tif126164Step 1: 4,6-Dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4,6-dichloropicolinic acid (1.5 g, 7.8 mmol, CAS number 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)cyclohexan-1-amine (1.48 g, 8.59 mmol) in DMF (2.5 mL) was added at the same temperature. The reaction was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC. After completion of the reaction, 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 NaSO, and the solvent was evaporated under vacuum to give the crude compound, which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet 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),3.20(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.

[0203] 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 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) was taken in a sealed tube and purged with N2 for 5 minutes. The reaction mixture was heated at 95 °C for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, it was filtered through Celite and washed with DCM (10 mL). The filtrate was evaporated in vacuo to give the crude product, which was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM) to give the title compound. The yield with 55 was 71% (310.1 mg, off-white solid). 1 HNMR(400 MHz,DMSO-d6):δ 8.61(d,J=8.0 Hz,1H),8.44(d,J=8.0 Hz,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.

[0204] Step 3: 4-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide TIFF0007792915000118.tif38128 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, A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (184.88 mg, 0.888 mmol, CAS number 761446-44-0), K2CO3 (255.5 mg, 1.851 mmol), Pd(dppf)Cl2, and DCM (30.24 mg, 0.0370 mmol) was purged with N2 for 5 minutes. The reaction mixture was heated at 97 °C for 16 hours. 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 under vacuum to give the crude product, which was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM) to give the title compound, which was further purified by preparative HPLC (Method A). The preparative fractions were concentrated, dissolved in 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: 15% (48.1 mg, off-white solid). 1HNMR(400 MHz,DMSO-d6):δ 8.72(s,1H),8.60(s,1H), 8.48(d,J=8.4 Hz,1H),8.36(d,J=0.4 Hz,1H),8.16(d,J=2.0 Hz,1H),8.13(s,1H),8.04(d,J=2.0 Hz,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.

[0205] Example 31: N-((1r,4r)-4-hydroxycyclohexyl)-6-(1H-imidazol-1-yl)picolinamide TIFF0007792915000119.tif113151Step 1: 6-(1H-imidazol-1-yl)picolinate methyl ester A solution of methyl 6-bromopicolinate (1.23 g, 5.69 mmol, CAS number 26218-75-7) and 1H-imidazole (1.16 g, 17.08 mmol) in DMF (20 mL) was deoxygenated by purging with nitrogen gas for 10 minutes. After 10 minutes, K2CO3 (1.96 g, 14.23 mmol) and CuI (108 mg, 0.56 mmol) were added, and the resulting mixture was heated at 120 °C for 16 hours. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with 10% MeOH in DCM (200 mL). The combined filtrates were concentrated in vacuo to give the crude product, which was then purified by Grace chromatography using silica gel (100-200 mesh, 70-100% EtOAc in petroleum ether) to give the title compound. Yield: 81.2% (940 mg, pale yellow solid). LCMS: (Method B) 204.1 [M+H], Rt. 1.44 min. 1HNMR(400 MHz,DMSO-d6):δ 8.57(t,J=1.20 Hz,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).

[0206] Step 2: 6-(1H-imidazol-1-yl)picolinic acid TIFF0007792915000121.tif341286-(1H-imidazol-1-yl)methyl picolinate (937 mg, 4.61 mmol) was dissolved in THF (5 mL) and MeOH (5 mL), then 3N aqueous NaOH (5 mL) was added at room temperature, and the resulting mixture was stirred for 16 hours. After completion, the solvent was evaporated in vacuo, and the residue was acidified with 4M HCl in 1,4 dioxane and then concentrated in vacuo to give the title compound. Yield: crude (950 mg, yellow solid). LCMS: (Method C) 190.2 [M+H], Rt. 0.19 min. 1 HNMR (400 MHz, DMSO-d6): δ 9.39(s,1H),8.33-8.28(m,2H),8.22(d,J=8.0 Hz,1H),8.11(d,J=7.6 Hz,1H),7.55(s,1H).

[0207] Step 3: N-((1r,4r)-4-hydroxycyclohexyl)-6-(1H-imidazol-1-yl)picolinamide To a stirred solution of 6-(1H-imidazol-1-yl)picolinic acid (110 mg, 0.58 mmol) in DMF (3 mL) was added HATU (331 mg, 0.87 mmol) followed by DIPEA (0.26 mL, 1.45 mmol) under a nitrogen atmosphere at 0° C., 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 room temperature for 16 h. Upon completion, the reaction mixture was concentrated to give the crude product, which was then purified by Grace reverse-phase chromatography (Method B). The collected fractions were concentrated under reduced pressure, and the resulting product was redissolved in 10% MeOH in DCM (20 mL) and washed with 10% aqueous NaHCO (10 mL) followed by water (10 mL). The organic layer was dried over anhydrous NaSO, 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(400 MHz,DMSO-d6):δ 8.94(t,J=0.8 Hz,1H),8.53(d,J=8.8 Hz,1H),8.26(t,J=1.6 Hz,1H),8.16(t,J=8.0 Hz,1H),8.01-7.94(m,2H),7.20(t,J=1.2 Hz,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.

[0208] Example 32: N-cyclohexyl-6-(1H-imidazol-1-yl)picolinamide To a stirred solution of 6-(1H-imidazol-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) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. After 10 min, cyclohexanamine (57.7 mg, 0.87 mmol) was added and stirred at room temperature 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 NaSO, 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 (50 mL) in DCM, washed with 10% aqueous NaHCO (20 mL), water (20 mL), dried over anhydrous NaSO, 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):δ 8.95(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.

[0209] Example 33: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)picolinamide TIFF0007792915000124.tif113159Step 1: (1r,4r)-N,N-Dibenzyl-4-methoxycyclohexan-1-amine To a stirred solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (710 mg, 2.40 mmol) in THF (10 mL) was added sodium hydride (240 mg, 6.00 mmol) under a nitrogen atmosphere at 0 °C. After 10 min, methyl iodide (0.37 mL, 6.00 mmol) was added, and the resulting reaction mixture was stirred at room temperature 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 NaSO, filtered, and concentrated in vacuo to give the crude compound. The resulting crude residue was purified by Grace normal phase chromatography (100–200 mesh silica gel, eluent: 5%–10% EtOAc in petroleum ether) to give the title compound. Yield: 70% (520 mg, colorless liquid; LCMS: (Method C) 310.2 [M+H], Rt. 1.38 min.

[0210] Step 2: (1r,4r)-4-Methoxycyclohexan-1-amine TIFF0007792915000126.tif18128 To a stirred solution of (1r,4r)-N,N-dibenzyl-4-methoxycyclohexan-1-amine (510 mg, 1.64 mmol) in absolute ethanol (10 mL) at room temperature, 20% Pd(OH)2 / C (50 mg) was added, and the mixture was stirred overnight under hydrogen at room temperature. 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 under vacuum to give the title compound. This product was taken on to the next step without further purification. Yield: 100%. Yield is 215 mg (310 mg, yellow liquid). Crude product (310 mg, yellow liquid). LCMS: (Method A) 130.3 [M+H], Rt 0.52 min.

[0211] Step 3: 6-(1H-imidazol-1-yl)picolinic acid 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), KCO (863 mg, 6.24 mmol) was added, followed by CuI (39.6 mg, 0.20 mmol), and the resulting reaction mixture was heated at 140 °C for 16 h. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with DCM (50 mL) and water (25 mL). The aqueous layer from the filtrate was separated, acidified using 1.5 N HCl, and then concentrated under reduced pressure to give the title compound as the hydrochloride salt. Yield: 100% (395 mg, pale blue solid); LCMS: (Method C) 190.0 [M+H], Rt. 0.18 min.

[0212] Step 4: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)picolinamide To a stirred solution of 6-(1H-imidazol-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 room temperature 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 NaSO, 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. The product was redissolved in 10% MeOH in DCM (20 mL), washed with 10% NaHCO solution (10 mL), dried over water (10 mL) and anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. Yield: 76% (145 mg, off-white solid); 1HNMR(400 MHz,DMSO-d6):δ 8.95(s,1H),8.57(d,J=8.4 Hz,1H),8.26-8.25(m,1H),8.18-8.14(m,1H),8.01-7.90(m,2H),7.16(t,J=1.2 Hz,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.

[0213] Example 34: N-((1r,4r)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide TIFF0007792915000129.tif117153Step 1: 2-Chloropyrimidine-4-carbonyl chloride TIFF0007792915000130.tif2612 To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (300 mg, 1.89 mmol) and 1 drop of DMF in DCM (10 mL) at 80 °C was added oxalyl chloride (359 mg, 2.84 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to give the title compound as a crude material, which was used in the next step without any purification. Yield: 95% (320 mg, light brown gum).

[0214] Step 2: 2-chloro-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide 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 280 °C, (1r,4r)-4-aminocyclohexan-1-ol (249 mg, 2.17 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated aqueous NaHCO (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 NaSO, 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.

[0215] Step 3: N-((1r,4r)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide 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 K2CO3 (405 mg, 2.94 mmol) in DMF (3 mL) was purged with N2 for 2 minutes, and the reaction mixture was heated at 140 °C in a sealed tube overnight. After completion (the reaction was monitored by TLC), the reaction mixture was diluted with DCM. The resulting mixture was filtered through a bed of Celite, the filtrate was concentrated under vacuum, 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 in DCM (10 mL) and neutralized with 10% aqueous NaHCO (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(400 MHz,DMSO-d6):δ 9.06(d,J=4.8 Hz,1H),8.97-8.96(m,1H),8.84(d,J=8.4 Hz,1H),8.24-8.23(m,1H),7.91(d,J=4.8 Hz,1H),7.19-7.18(m,1H),4.63(d,J=4.4 Hz,1H),3.83-3.80(m,1H),3.49-3.42(m,1H),1.91-1.88(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 minutes.

[0216] Example 35: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide TIFF0007792915000133.tif87165Step 1: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid To a stirred solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (52 mg, 0.30 mmol, CAS number 89581-58-8) (2 mL) and 1H-imidazole (62 mg, 0.90 mmol) in DMF was added KCO (124 mg, 0.90 mmol), followed by CuI (5.78 mg, 0.03 mmol), and the resulting mixture was heated at 120 °C for 16 h. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with methanol (20 mL) and water (10 mL). All layers were concentrated under reduced pressure to give the crude product. The crude compound was redissolved in 1,4 dioxane and acidified with 4 M HCl in 1,4 dioxane (3 mL). The solvent was then evaporated under reduced pressure to give the title compound as the hydrochloride salt. Yield: crude product (75 mg, yellow solid). LCMS: (Method D) 205.1 [M+H], Rt. 0.52 min.

[0217] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide 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) under a nitrogen atmosphere at 0° C. Then, (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (90 mg, 0.52 mmol) was added and the mixture was stirred at room temperature for 16 h. After completion, water (30 mL) was added to the reaction mixture, which was extracted with 10% MeOH in DCM (50 mL), washed with water (3 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated under vacuum to obtain 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 in DCM (35 mL), washed with 10% NaHCO solution (15 mL), water (2 × 20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to obtain the title compound. Yield: 25% (31.36 mg, light brown solid); 1 HNMR(400 MHz,DMSO-d6):δ 8.94(t,J=1.2 Hz,1H),8.79(d,J=8.8 Hz,1H),8.20(t,J=1.2 Hz,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.

[0218] The final product was characterized by powder X-ray diffraction, thermogravimetric analysis, and differential scanning calorimetry (DSC). Characterization results indicated that the product was a crystalline form, herein designated polymorph Form A, which was further identified as an anhydrate. The X-ray diffraction pattern is shown in Figure 1. The X-ray diffraction peaks are listed in Table 1 below.

[0219] [Table 1]

[0220] The results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) are shown in Figure 2. The TGA (top curve, left axis) shows minimal weight loss before decomposition, and the DSC (bottom curve, right axis) shows a single sharp melting peak at 136.4°C (onset) before decomposition, indicating that this material is an anhydrate.

[0221] Polymorph Form A could also be obtained by dissolving approximately 15 mg of the compound in 0.4–3.0 mL of methanol, ethanol, acetone, THF, 1,4-dioxane, ACN, DMF, or DMSO until a clear solution was obtained. The solution was magnetically stirred, followed by the stepwise addition of 0.2–0.5 mL of water as an antisolvent until a precipitate appeared or until a total volume of antisolvent reached 15.0 mL. Alternatively, clear solutions were obtained in isopropyl alcohol, acetone, MIBK, EtOAc, THF, DCM, MTBE, or toluene; and n-heptane was used as the antisolvent. Alternatively, clear solutions were obtained in ethanol, MEK, isopropanol, CPME, 2-MeTHF, trichloromethane, and anisole (3:1), with n-hexane as the antisolvent. XRPD revealed that polymorph Form A was obtained in all cases.

[0222] Polymorph Form A could also be obtained by dissolving approximately 15 mg of starting material in 0.6–2.0 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 for further steps. The visually clear solution was then covered with Parafilm® with 4–8 pinholes and allowed to evaporate at room temperature. XRPD revealed that polymorph Form A was obtained in all cases.

[0223] The second polymorphic crystalline form, designated herein as Polymorph Form B, was prepared by adding the compound to a toluene / n-heptane system as an inverse antisolvent at room temperature. The X-ray diffraction pattern is shown in Figure 3. The X-ray diffraction peaks are shown in Table 2 below.

[0224] [Table 2]

[0225] In Figure 4, polymorph Form B exhibits negligible weight loss before decomposition by TGA (top curve, left axis) and shows two endothermic peaks at 123.8°C and 137.9°C (onset) and an exothermic peak at 125.6°C (onset) by DSC (bottom curve, right axis), both data indicating that polymorph Form B is an anhydrate.

[0226] Example 36: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide TIFF0007792915000138.tif79164 Step 1: 2-(1H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylic acid 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. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with methanol (50 mL) and water (10 mL). All layers were concentrated under reduced pressure to give the crude product. The crude product was redissolved in 1,4-dioxane (2 mL), and 4 M HCl in 1,4-dioxane (5 mL) was added. The solvent was evaporated to give the title compound as the hydrochloride salt. Yield: crude product (75 mg, yellow solid). LCMS: (Method D) 259.0 [M+H], Rt. 1.30 min.

[0227] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide 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) at 280 °C, EDC.HCl (79 mg, 0.41 mmol), HOBt (55 mg, 0.41 mmol), followed by DIPEA (0.12 mL, 0.68 mmol) were added under a nitrogen atmosphere. Then, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (57 mg, 0.33 mmol) was added and the mixture was stirred for 16 h. After completion, water (30 mL) was added to the reaction mixture, which was extracted with 10% MeOH in DCM (50 mL), washed with water (3 × 30 mL), dried over anhydrous NaSO, and concentrated under vacuum to obtain a 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 in DCM (35 mL), washed with 10% NaHCO solution (15 mL), water (2 × 20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to obtain 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.

[0228] Example 37: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylthio)picolinamide TIFF0007792915000141.tif121169Step 1: 4-Bromo-6-fluoropicolinate methyl ester To a stirred solution of methyl 4-bromopicolinate (2.7 g, 12.5 mmol) in acetonitrile (30 mL), AgF (5.46 g, 37.5 mmol) was added all at once and stirred at the same room temperature for 16 h. The reaction progress was monitored by TLC and quenched with 10% aqueous NaHCO (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 NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on a Biotage Isolera (100–200 mesh silica gel, eluted with 0–10% EtOAc in PET ether) to give 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.

[0229] Step 2: 4-bromo-6-(1H-imidazol-1-yl)picolinate methyl ester To a stirred solution of methyl 4-bromo-6-fluoropicolinate (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 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 NaSO, and the solvent was evaporated under vacuum. The crude residue was purified by column chromatography on a Biotage Isolera (100–200 mesh silica gel, eluted with 0–10% MeOH in DCM) to give the title compound. Yield: 54% (550.1 mg, solid). 1H NMR (400 MHz, DMSO-d6): δ 8.60-8.59(m,1H),8.49(d,J=1.6 Hz,1H),8.14(d,J=1.6 Hz,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. 0.70 min.

[0230] Step 3: 4-Bromo-6-(1H-imidazol-1-yl)picolinic acid To a stirred solution of methyl 4-bromo-6-(1H-imidazol-1-yl)picolinate (540 mg, 1.91 mmol) in MeOH (3 mL), THF (3 mL), and water (2 mL) was added NaOH (229.7 mg, 5.74 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 4 hours. The reaction progress was monitored by TLC, and complete consumption of the starting material was observed. The reaction mixture was concentrated in vacuo, and the residue was acidified with 3N HCl solution (20 mL). The resulting solid was collected by filtration and dried to give the title compound. Yield: 66% (340.1 mg, solid). 1 H NMR(400 MHz,DMSO-d6):δ 13.70(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. 0.24 min.

[0231] Step 4: 4-Bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4-bromo-6-(1H-imidazol-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 room temperature. After stirring for 5 min, a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (255.6 mg, 1.477 mmol) in DMF (0.5 mL) was added at the same temperature. The reaction was further stirred at room temperature for 16 h. 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 NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on a Biotage Isolera (100-200 mesh silica gel, eluted with 0-60% EtOAc in pet ether) to give the title compound in 53% yield (280 mg, yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.99(s,1H),8.62(d,J=8.7 Hz,1H),8.39(d,J=1.5 Hz,1H),8.31(d,J=1.2 Hz,1H),8.04(d,J=1.2 Hz,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.

[0232] Step 5: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylthio)picolinamide To a stirred solution of 4-bromo-6-(1H-imidazol-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 NaSO, and the solvent was evaporated under vacuum. The crude residue was purified by preparative HPLC (Method A). The aqueous phase was concentrated, DCM was added, and the mixture was neutralized with 10% aqueous NaHCO3. 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(400 MHz,DMSO-d6):δ 8.95(s,1H),8.54(d,J=8.0 Hz,1H),8.29-8.28(m,1H),7.77(d,J=1.6 Hz,1H),7.73(d,J=1.2 Hz,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.

[0233] Example 38: 4-(1-hydroxyethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000147.tif112166Step 1: Methyl 4-bromopicolinate To a stirred solution of 4-bromopicolinic acid (10 g, 49.50 mmol) in DMF (80 mL), K2CO3 (20.49 g, 148.51 mmol) was added all at once, and the reaction mixture was stirred at room temperature for 10 min. Then, MeI (42.17 g, 297.0 mmol) was added slowly, and the reaction mixture was stirred at room temperature in a sealed tube for 30 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water (150 mL). The resulting suspension was extracted with EtOAc (3 x 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 column chromatography on a Biotage Isolera (100-200 mesh silica gel, eluting with 0-20% EtOAc in pet ether) to give 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.

[0234] Step 2: 4-bromo-6-fluoropicolinate methyl ester To a stirred solution of methyl 4-bromopicolinate (3.3 g, 15.27 mmol) in acetonitrile (40 mL), AgF (6.68 g, 45.83 mmol) was added all at once, and the reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with 10% aqueous NaHCO (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 NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on a Biotage Isolera (100–200 mesh silica gel, eluting with 0–10% EtOAc in PET ether) to give the title compound. Yield: 34% (1.23 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) 233.9 (M+H), Rt. 1.81 min.

[0235] Step 3: 4-bromo-6-(1H-imidazol-1-yl)picolinate methyl ester To a stirred solution of methyl 4-bromo-6-fluoropicolinate (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. Upon completion, the reaction mixture was diluted 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 NaSO, and the solvent was evaporated under vacuum. The crude residue was purified by column chromatography on a Biotage Isolera (100–200 mesh silica gel, eluted with 0–10% MeOH in DCM) to give the title compound. Yield 74% (1.6 g, solid). 1H NMR(400 MHz,DMSO-d6):δ 8.60-8.59(m,1H),8.49(d,J=1.2 Hz,1H),8.14(d,J=1.6 Hz, 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. 0.54 min.

[0236] Step 4: 4-Bromo-6-(1H-imidazol-1-yl)picolinic acid To a stirred solution of methyl 4-bromo-6-(1H-imidazol-1-yl)picolinate (1.56 g, 5.53 mmol) in MeOH (9 mL), THF (9 mL), and water (6 mL) was added NaOH (664 mg, 16.59 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was monitored by TLC, and the starting material was consumed. The reaction mixture was concentrated in vacuo and acidified with 3N aqueous HCl (20 mL). The resulting solid was collected by filtration and dried to give the title compound. Yield: 94% (1.39 g, solid). 1 H NMR(300 MHz,DMSO-d6):δ 9.94(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. 1.02 min.

[0237] Step 5: 4-Bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4-bromo-6-(1H-imidazol-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 room temperature. After stirring for 5 min, a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (1.3 g, 7.55 mmol) in DMF (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC and, upon completion, diluted with water (25 mL). The resulting suspension was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on a Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet ether) to give the title compound. Yield: 52% (1.2 g, yellow solid). 1 H NMR(300 MHz,DMSO-d6):δ 8.98(s,1H),8.62(d,J=8.7 Hz,1H),8.39(d,J=1.5 Hz,1H),8.31-8.30(m,1H),8.04(d,J=1.5 Hz,1H),7.17(s,1H),3.84-3.80(m,1H),3.56-3.50(m,2H),3.44-3.41(m,2H),3.23(s,4H),2.05-2.0 3(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.1.21 min.

[0238] Step 6: 4-acetyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-ethoxyethoxy)cyclohexyl)picolinamide A mixture of 4-bromo-6-(1H-imidazol-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 room temperature was purged with nitrogen gas for 5 minutes. Pd(PPh3)2Cl2 (28.9 mg, 0.04 mmol) was then added, and the reaction mixture was heated at 90 °C for 16 hours. The reaction was monitored by TLC, and complete conversion of the starting material was observed. The reaction mixture was filtered through a bed of Celite and washed with DCM (20 mL). The solvent was evaporated in vacuo and the crude residue was purified by column chromatography on a Biotage Isolera (100-200 mesh silica gel eluted with 0-10% MeOH in DCM) to give the title compound. Yield: 87% (320 mg, yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.05(d,J=0.8 Hz,1H),8.63(d,J=8.8 Hz,1H),8.40-8.39(m,1H),8.34(d,J=1.2 Hz,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),2.7 4(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.

[0239] Step 7: 4-(1-hydroxyethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4-acetyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (110 mg, 0.28 mmol) in MeOH (5 mL) at 0 °C was slowly added NaBH (16.20 mg, 0.43 mmol). After the addition was complete, the reaction mixture was stirred at room temperature 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) and stirred for 5 min. Then DCM (10 mL) was added, and the mixture was stirred at room temperature 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 NaSO, concentrated in vacuo, and the crude residue was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel eluted with 0-10% MeOH in DCM as a gradient) to give the title compound. Yield: 38% (42.0 mg, gummy solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.93(s,1H),8.53(d,J =7.6 Hz,1H),8.25-8.24(m,1H),7.99(s,1H),7.90(s,1H ),7.15(s,1H),5.64(d,J =4.4 Hz,1H),4.89-4.87(m,1H),3.85-3.83(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.

[0240] Example 39: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylsulfonyl)picolinamide To a stirred solution of 4-bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (150 mg, 0.35 mmol) in DMSO (3 mL), sodium methanesulfinate (54.25 mg, 0.53 mmol), CuI (6.73 mg, 0.03 mmol), and sodium L-prophosphate (9.73 mg, 0.07 mmol) were added, 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 (3×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under vacuum to give the crude compound, which was purified by preparative HPLC (Method A). The aqueous fraction was concentrated, and DCM was added and neutralized with 10% aqueous NaHCO. The phases were separated. The organic phase was washed with water, brine, dried over anhydrous NaSO, and concentrated to give the title compound. Yield: 27% (41.5 mg, white solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.08-9.07(m,1H),8.73(d,J=8.8 Hz,1H),8.46(d,J=1.2 Hz,1H),8.41-8.40(m,1H),8.29(d,J=1.2 Hz,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),2.0 7-2.04(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.

[0241] Example 40: 4-(2-hydroxypropan-2-yl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4-acetyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (200 mg, 0.52 mmol) in dry THF (5 mL) was added MeMgBr (0.51 mL, 1.55 mmol, 3 M solution in THF) dropwise over 5 min at -40 °C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to 0 °C, saturated aqueous NH4Cl (5 mL) was added slowly, 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 NaSO, and the solvent was evaporated in vacuo to give the crude product, which was purified by column chromatography on a Biotage Isolera (230-400 mesh silica gel gradient eluted with 0-10% MeOH in DCM) to give the title compound. Yield: 27% (56 mg, off-white solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.95(s,1H),8.53(d,J =8.8 Hz,1H),8.28-8.27(m,1H),8.10(d,J=1.2 Hz,1H),7.92(d,J=1.2 Hz,1H),7.16-7.15(m,1H),5.52(s,1H),3.86-3.77(m,1H),3.57-3.54(m,2H),3.45-3.42(m,2H),3.30-3.24(m,4H),2.0 5-2.03(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.

[0242] Example 41: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide TIFF0007792915000157.tif118164Step 1: (1r,4r)-N,N-Dibenzyl-4-(difluoromethoxy)cyclohexan-1-amine To a stirred solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (2.03 g, 6.87 mmol) in ACN (100 mL) was added CuI (261 mg, 1.37 mmol) at room temperature. 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 hour. After 1 hour, TLC showed unreacted (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol. An additional 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 an additional 1 hour. Upon completion, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was slowly diluted with water (30 mL), 10% aqueous NaHCO3 (30 mL), and EtOAc (100 mL) while continuing to stir. The suspension was filtered through a bed of Celite. The layers of the filtrate were separated. The combined organic layers were washed with brine solution (30 mL), followed by water (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude residue obtained was purified by Grace normal phase purification using silica gel (100-200 mesh, 2-5% EtOAc / pet ether) to give the title compound. Yield: 51% (1.21 g, white solid). 1 H NMR(400 MHz,DMSO-d6):δ 7.35-7.18(m,10H),6.67(t,J=76.8 Hz,1H),4.01-3.94(m,1H),3.57(s,4H),2.51-2.40(m,1H),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. 2.74 min.

[0243] Step 2: (1r,4r)-4-(difluoromethoxy)cyclohexan-1-amine To a stirred solution of (1r,4r)-N,N-dibenzyl-4-(difluoromethoxy)cyclohexan-1-amine (610 mg, 1.76 mmol) in absolute ethanol (6 mL), Pd(OH)2 / C (60 mg, 20%) was added at room temperature, and the mixture was stirred under hydrogen (bladder reaction) at room temperature for 16 h. After completion, the reaction mixture was filtered through a bed of Celite, and the bed was washed with MeOH (50 mL). The filtrate was evaporated under vacuum, 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.

[0244] Step 3: 2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid A stirred solution of methyl 2-chloropyrimidine-4-carboxylate (510 mg, 2.95 mmol) and 1H-imidazole (612 mg, 8.86 mmol) in DMF (5 mL) was degassed at room temperature for 5 minutes, after which potassium carbonate (1.22 g, 8.86 mmol) was added, followed by CuI (56.2 mg, 0.29 mmol). The reaction mixture was heated at 120 °C for 16 hours. Upon completion, the reaction mixture was filtered through Celite, and the Celite bed was washed with 10% MeOH in DCM (20 mL), followed by MeOH (20 mL). The combined filtrates were concentrated under reduced pressure. The crude residue was dissolved in 1,4-dioxane (10 mL), acidified with HCl in 1,4-dioxane (4 M, 5 mL), and then concentrated in vacuo to provide the title compound as the hydrochloride salt. Yield: 98% (550 mg, yellow solid). LCMS: (Method C) 191.1 (M+H), Rt. 0.43 min.

[0245] Step 4: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide To a stirred solution of 2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid (195 mg, 1.02 mmol) in DMF (10 mL) at 280 °C, EDC.HCl (294 mg, 1.53 mmol), HOBt (207 mg, 1.53 mmol), and DIPEA (0.47 mL, 2.56 mmol) were added under a nitrogen atmosphere. (1r,4r)-4-(difluoromethoxy)cyclohexane-1-amine (203 mg, 1.23 mmol) was then added, and the reaction mixture was stirred at room temperature for 16 h. After completion (starting material consumed by TLC), the reaction mixture was diluted with water (20 mL) and then extracted with 10% MeOH in 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 under vacuum. 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.

[0246] Example 42: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide TIFF0007792915000162.tif104160Step 1: (1r,4r)-4-(difluoromethoxy)cyclohexan-1-amine To a stirred solution of (1r,4r)-N,N-dibenzyl-4-(difluoromethoxy)cyclohexan-1-amine (610 mg, 1.76 mmol) in absolute ethanol (6 mL), Pd(OH)2 / C (61 mg, 20%) was added at room temperature, and the mixture was stirred under hydrogen (bladder reaction) at room temperature for 16 h. Upon completion, the reaction mixture was filtered through a bed of Celite, and the bed was washed with MeOH (100 mL). The combined filtrate was concentrated in vacuo, and the residue was co-distilled with toluene (2 × 50 mL) to give the title compound. Yield: crude (310 mg, colorless liquid). LCMS: (Method A) 166.2 (M+H), Rt. 1.16 min.

[0247] Step 2: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid 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 minutes at room temperature, after which potassium carbonate (466 mg, 3.37 mmol) was added, followed by CuI (21.4 mg, 0.11 mmol) at room temperature. The reaction mixture was heated at 120° C. for 16 hours. Upon completion, the reaction mixture was filtered through Celite, and the bed was washed with methanol (20 mL) and water (10 mL). The combined filtrates were concentrated in vacuo. The crude residue was dissolved in 1,4-dioxane (5 mL) and then acidified with HCl in 1,4-dioxane (5 mL, 4 M). The mixture was concentrated in vacuo to provide the title compound as the hydrochloride salt. Yield: crude (220 mg, yellow solid). LCMS: (Method C) 205.1 (M+H), Rt. 0.40 min.

[0248] Step 3: N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide To a stirred solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (210 mg, 1.02 mmol) in DMF (3 mL) at 280 °C under a nitrogen atmosphere, HATU (585 mg, 1.54 mmol) and DIPEA (0.47 mL, 2.57 mmol) were added. (1r,4r)-4-(difluoromethoxy)cyclohexane-1-amine (203 mg, 1.23 mmol) was then added, and the reaction mixture was stirred at room temperature for 16 h. After completion (starting material was consumed by TLC), the reaction mixture was diluted with water (30 mL) and then extracted with 10% MeOH in DCM (50 mL). The resulting organic solution was washed with water (3 × 30 mL). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The obtained crude product was purified by reverse-phase purification. The collected fraction was concentrated under reduced pressure, and 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, pale 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.

[0249] Example 43: 4-cyano-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000166.tif117165Step 1: 4-Bromo-6-fluoropicolinate methyl ester To a stirred solution of methyl 4-bromopicolinate (10.0 g, 46.29 mmol) in acetonitrile (90 mL), AgF (20.0 g, 138.88 mmol) was added all at once, and the reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC and quenched with 10% aqueous NaHCO (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 NaSO, 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 in PET ether) to give the title compound. Yield: 38% (4.13 g, white solid). 1 1.61 min.

[0250] Step 2: 4-bromo-6-(1H-imidazol-1-yl)picolinate methyl ester To a stirred solution of methyl 4-bromo-6-fluoropicolinate (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. Upon 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 NaSO, and the solvent was evaporated under vacuum. The crude residue was purified by column chromatography on a Biotage Isolera (100–200 mesh silica gel, eluted with 0–10% MeOH in DCM) to give the title compound. Yield: 55% (2.76 g, yellow solid). 1H NMR(400 MHz,DMSO-d6):δ 8.60-8.59(m,1H),8.49(d,J=1.6 Hz,1H),8.14(d,J=1.6 Hz, 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. 1.88 min.

[0251] Step 3: 4-Bromo-6-(1H-imidazol-1-yl)picolinic acid To a stirred solution of methyl 4-bromo-6-(1H-imidazol-1-yl)picolinate (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) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. 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, 3N). 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.

[0252] Step 4: 4-Bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4-bromo-6-(1H-imidazol-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 room temperature. After stirring for 5 min, a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (2.2 g, 12.87 mmol) in DMF (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 16 h. 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 NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on a Biotage Isolera (100-200 mesh silica gel eluted with 0-60% EtOAc in pet ether) to give the title compound. Yield: 66% (2.4 g, yellow solid). 1 H NMR(300 MHz,DMSO-d6):δ 8.99(s,1H),8.62(d,J=8.7 Hz,1H),8.39(d,J=1.5 Hz,1H),8.31-8.30(m,1H),8.04(d,J=1.5 Hz,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),2.05-2 .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.1.01 min.

[0253] Step 5: 4-cyano-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a mixture of 4-bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (150 mg, 0.35 mmol), Zn(CN) (63.0 mg, 0.53 mmol) in DMF (3 mL) was added Pd(PPh) (41.0 mg, 0.035 mmol) at room temperature, and the reaction mixture was purged with nitrogen gas for 5 minutes. The reaction mixture was heated at 80 °C for 24 hours. After completion (the reaction was monitored by LCMS), the reaction mixture was filtered through a bed of Celite, and the bed was washed with DCM (20 mL). The combined filtrates were concentrated in vacuo to give the crude compound, which was purified by preparative HPLC (Method A). The preparative fractions were concentrated. The residual aqueous phase was added with DCM and neutralized with 10% aqueous NaHCO. The organic layer was washed with water, brine, dried over anhydrous NaSO, and concentrated in vacuo to give the title compound. Yield: 44% (60 mg, off-white solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.01(s,1H),8.69(d,J=8.4 Hz,1H),8.59(d,J=1.2 Hz,1H),8.33-8.31(m,1H),8.24(d,J=1.2 Hz,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),2.06-2 .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.

[0254] Example 44: N-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide TIFF0007792915000172.tif122163Step 1: 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethan-1-ol To a stirred solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (2.10 g, 7.10 mmol) in DMPU (20 mL) at 280 °C, 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 room temperature for 16 h. After 16 h, TLC showed unreacted (1r,4r)-4-(dibenzylamino)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 room temperature for 16 h. The reaction mixture was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was quenched by adding water (2.5 mL) and concentrated H2SO4 (2.5 mL), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with 10% aqueous NaHCO3 (50 mL) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine solution (50 mL) followed by water (2 × 50 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude residue obtained was purified by Grace normal phase silica gel (100-200 mesh, 20-30% EtOAc / pet ether) to give the title compound. Yield: 50% (1.22 g, white solid). 1 H NMR(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 minutes.

[0255] Step 2: 2-(((1r,4r)-4-aminocyclohexyl)oxy)ethan-1-ol TIFF0007792915000174.tif18128 To a stirred solution of 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethan-1-ol (1.21 g, 3.56 mmol) in absolute ethanol (50 mL) at room temperature, Pd(OH)2 / C (150 mg, 20 wt%) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After completion, the reaction mixture was filtered through a bed of Celite, and the Celite 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: crude (612 mg, colorless liquid). LCMS: (Method A), 160.2 (M+H), Rt. 0.58 min, 59.16% (ELSD), and Rt. 0.51 min.

[0256] Step 3: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid TIFF0007792915000175.tif33128 To a stirred solution of ethyl 2-(1H-imidazol-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) at room temperature, NaOH (184 mg, 4.61 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion (starting material consumed by TLC), 1,4-dioxane was concentrated under vacuum. Water (15 mL) was added to the residue, 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.

[0257] Step 4: N-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide To a stirred solution of sodium 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylate (205 mg, 0.90 mmol) in DMF (3 mL) at room temperature, 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) were added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 16 h. After completion (starting material was consumed by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The resulting organic solution was washed with 10% aqueous NaHCO3 (10 mL) and water (2 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The resulting crude residue was purified by preparative HPLC. The fraction was concentrated under reduced pressure, diluted with DCM (20 mL), and washed with brine solution (10 mL), followed by water (2 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. Yield: 41% (121.1 mg, off-white solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.94-8.93(m,1H),8.78(d,J=8.4 Hz,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.1.54 min. HPLC: (Method A) Rt. 1.83 min.

[0258] Example 45: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide. TIFF0007792915000177.tif74159 To a mixture of 2-(1H-imidazol-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 10% conversion. The reaction mixture was concentrated in vacuo, and the resulting 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 aqueous fraction was concentrated, and DCM was added, followed by neutralization 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: 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.

[0259] Example 46: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide TIFF0007792915000178.tif55167Step 1: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide To a stirred solution of 2-chloro-6-methylisonicotinic acid (210 mg, 1.22 mmol) in DMF (3 mL) at 280 °C under a nitrogen atmosphere, EDC.HCl (351.9 mg, 1.83 mmol), HOBt (248 mg, 1.83 mmol), followed by DIPEA (0.53 mL, 3.05 mmol) were added, and the reaction mixture was stirred at 0 °C for 5 min. Next, (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (212 mg, 1.22 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. After completion (starting material was consumed by TLC), the reaction mixture was diluted with water (30 mL) and then extracted with EtOAc (50 mL). The resulting organic solution was washed with 10% aqueous NaHCO (15 mL) followed by 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 silica gel chromatography (100-200 mesh, 50%-70% EtOAc / pet ether) to give the title compound. Yield: 37% (151 mg, yellow solid). LCMS: (Method A) 327.0 (M+H), Rt 2.09 min.

[0260] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide 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 gas for 5 minutes. KCO (183 mg, 1.33 mmol) was added at room temperature, followed by CuI (8.4 mg, 0.04 mmol), and the reaction mixture was heated at 120 °C for 16 hours. Upon completion, the reaction mixture was filtered through Celite and washed with 5% MeOH in DCM (50 mL). The combined organic layers were washed with 10% aqueous NaHCO (20 mL) and water (2 × 15 mL), then concentrated in vacuo. The resulting crude residue was purified by preparative HPLC. The collected fractions were concentrated under reduced pressure, and the residue was diluted with DCM (20 mL) and washed with 10% aqueous NaHCO (10 mL) and water (10 mL). The organic layer was dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 28% (45.48 mg, off-white solid). 1 H 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),3.3 0-3.24(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.

[0261] Example 47: 6-cyano-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide TIFF0007792915000181.tif103163 Step 1: 2-(1H-Imidazol-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylic acid. To a stirred solution of methyl 2-(1H-imidazol-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 room temperature for 30 minutes. 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 directly in the next step. Yield 52% (0.4 g, light brown solid). LCMS: (Method C) 390.1 (M+H), Rt. 0.93 min.

[0262] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4,6-dicarboxamide. To a stirred solution of 2-(1H-imidazol-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) was slowly added (COCl) (0.12 mL, 1.33 mmol) at 0 °C, and the reaction mixture was slowly warmed to room temperature and stirred at room temperature 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 vol) at 0 °C, and the reaction mixture was stirred at room temperature 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 was evaporated in vacuo to give the crude compound, which was used directly in the next step. Yield: 100% (0.4 g, brown solid). LCMS: (Method C) 389.1 (M+1), Rt. 1.08 min.

[0263] Step 3: 6-cyano-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide To a mixture of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4,6-dicarboxamide (400 mg, 1.03 mmol) in DCM (4.0 mL) at 28-20 °C, TEA (0.28 mL, 2.06 mmol) was slowly added, followed by TFAA (0.18 mL, 1.32 mmol). After the addition was complete, the reaction mixture was stirred at room temperature 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 at room temperature for 10 min, the layers were separated, and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with 10% aqueous NaHCO (10.0 mL), brine (10.0 mL), water (10.0 mL), dried over anhydrous NaSO, and the solvent was evaporated under vacuum. The crude residue obtained was purified by preparative HPLC (neutral method, ACN-water) to give the title compound. Yield: 29% (110 mg, off-white solid). 1 H 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.

[0264] Example 48: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4,6-dicarboxamide. To a mixture of 2-(1H-imidazol-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylic acid (50 mg, 0.13 mmol) in DCM (1.0 mL) at 590 °C, (COCl) (0.02 mL, 0.19 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 1 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 (1.0 mL, 0.5 M) at room temperature, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under vacuum. The crude residue was purified by preparative HPLC to give the title compound. Yield: 40% (20.0 mg, off-white solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.23-9.22(m,1H),8.90(d,J=8.8 Hz,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),3.89-3.81(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.

[0265] Example 49: 6-(hydroxymethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide. To a suspension of methyl 2-(1H-imidazol-1-yl)-6-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)pyrimidine-4-carboxylate (0.8 g, 1.98 mmol) in MeOH (16 mL) at 40 °C, NaBH (98 mg, 2.57 mmol) was slowly added, 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 room temperature 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 NaSO, and the solvent was evaporated under vacuum. The crude residue obtained was purified by preparative HPLC to give the title compound. Yield: 54% (400 mg, off-white solid). 1 H NMR (400 MHz,DMSO-d6):δ 8.95(s,1H),8.83(d,J=8.4 Hz,1H),8.20(s,1H),8.00(s,1H),7.17(s,1H),5.90-5.87(m,1H),4.68(d,J=5.6 Hz,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.

[0266] Example 50: 2-(1H-imidazol-1-yl-d3)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide TIFF0007792915000187.tif132159Step 1: Ethyl 2-(1H-imidazol-1-yl-d3)-6-methylpyrimidine-4-carboxylate Commercially available 1H-imidazole-d4 (500 mg, 6.944 mmol) was treated with 10% DIPEA in EtOH (4 × 8 mL), and the mixture was concentrated in vacuo. The residue was co-evaporated with ACN (4 × 8 mL) to give 1H-imidazole-d3 (500 mg), which was used directly in the subsequent reaction.

[0267] To a stirred solution of 1H-imidazole-d3 (500 mg, 6.94 mmol) and ethyl 6-methyl-2-(methylsulfonyl)pyrimidine-4-carboxylate (1.86 g, 7.64 mmol) in ACN (10 mL) at room temperature, DIPEA (3.0 mL, 17.36 mmol) was added, and the reaction mixture was heated at 60° C. for 14 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL) and brine solution (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under vacuum. The resulting crude residue was triturated with petroleum ether to give the title compound. Yield: 78% (1.28 g, 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). (H NMR indicated the presence of traces of the D2 analog.) LCMS: (Method C) 236.1 (M+H), Rt 0.93 min.

[0268] Step 2: Ethyl 2-(1H-imidazol-1-yl-d3)-6-methylpyrimidine-4-carboxylate TIFF0007792915000189.tif37128 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 DO (12 mL) and 1,4-dioxane (4.0 mL), and the mixture was heated at 80 °C for 16 hours. The reaction mixture was concentrated in vacuo, and the resulting solid was dissolved in EtOAc (10 mL). The organic layer was dried over anhydrous NaSO and filtered, and the filtrate was concentrated in vacuo to give the compound. Yield: 88% (1.06 g, brown solid). 1 H 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.

[0269] Step 3: Sodium 2-(1H-imidazol-1-yl-d3)-6-methylpyrimidine-4-carboxylate To a stirred solution of ethyl 2-(1H-imidazol-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) at room temperature, NaOH (196.59 mg, 4.91 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After completion (starting material consumed by TLC), 1,4-dioxane was evaporated under vacuum. 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 (H NMR indicated the presence of trace amounts of the D2 analogue). 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.

[0270] Step 4: 2-(1H-imidazol-1-yl-d3)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide 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) at room temperature, 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)cyclohexane-1-amine (830 mg, 4.80 mmol) were added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 16 h. After completion (starting material was consumed by 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 NaSO, filtered, and the filtrate was 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 in pet 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,3 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%).

[0271] Example 51: 6-(Fluoromethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide A mixture of 6-(hydroxymethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide (150 mg, 0.40 mmol) in DCM (1.5 mL) was slowly added at −78 °C with DAST (161 mg, 1.00 mmol), followed by triethylamine trihydrofluoride (161.0 mg, 1.00 mmol). 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% aqueous NaHCO (5 mL), and the reaction mixture was stirred at room temperature for 10 min. DCM (20.0 mL) was then 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 NaSO, and the solvent was evaporated in vacuo. The crude residue was purified by flash column chromatography on a Biotage Isolera (230-400 mesh silica gel, eluting with 0-10% MeOH in DCM as a gradient) to give the title compound. Yield: 14% (20.61 mg, pale yellow solid). 1H NMR (400 MHz,DMSO-d6):δ 8.97(s,1H),8.88(d,J=8.8 Hz,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.1.76 min. HPLC: (Method A) Rt.2.22 min.

[0272] Example 52: 6-(Difluoromethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide TIFF0007792915000193.tif61164 Step 1: 6-Formyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide. 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) at 280 °C, Dess-Martin periodinane (610.0 mg, 1.44 mmol) was added slowly. 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 slow addition of 10% aqueous NaSO (15 mL) and 10% NaHCO (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 x 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, pale yellow solid). LCMS: (Method C) 374.0 (M+H), Rt. 1.06 min.

[0273] Step 2: 6-(Difluoromethyl)-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide 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) at −78 °C, DAST (485.62 mg, 3.01 mmol) was slowly added, 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 (5 mL). The mixture was stirred at room temperature for 10 min, 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 x 15 mL). The combined organic phases were washed with water, followed by brine, dried over anhydrous Na2SO4, and the solvent was evaporated under vacuum. The crude residue obtained was purified by preparative HPLC (Method A). The preparative fraction was concentrated to the 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 under vacuum 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.

[0274] Example 53: N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide TIFF0007792915000196.tif103170Step 1: tert-Butyl ((1r,4r)-4-(ethylsulfonamido)cyclohexyl)carbamate To a stirred solution of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (0.5 g, 2.33 mmol, CAS number 177906-48-8) in DCM (10 mL) at 280 °C, triethylamine (472 mg, 4.66 mmol) was added, followed by ethanesulfonyl chloride (449 mg, 3.49 mmol), and the reaction mixture was stirred at room temperature overnight. 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 NaSO and concentrated under vacuum to give the title compound. Yield: 735 mg (white solid). 1 H NMR(400 MHz,DMSO-d6):δ 7.00(d,J=10.0 Hz,1H),6.72(d,J=10.0 Hz,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.2.00 min.

[0275] Step 2: N-((1r,4r)-4-aminocyclohexyl)ethanesulfonamide hydrochloride To a stirred solution of tert-butyl ((1r,4r)-4-(ethylsulfonamido)cyclohexyl)carbamate (335 mg, 1.09 mmol) in DCM (20 mL) under a nitrogen atmosphere was added TFA (0.41 mL, 5.46 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours, after which no reaction was observed by crude LCMS analysis. 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 then HCl in 1,4-dioxane (4 M, 3 mL) was added. The reaction mixture was then stirred at room temperature overnight. After completion (LCMS), the reaction mixture was concentrated in vacuo to provide the title compound. Yield: (540 mg, yellow solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.20-8.10(m,3H),7.10(d,J=10.0 Hz,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.0.48 min.

[0276] Step 3: 2-chloropyrimidine-4-carbonyl chloride To a stirred solution of 2-chloropyrimidine-4-carboxylic acid (251 mg, 1.58 mmol, cascode no. 149849-92-3) and 1 drop of DMF in DCM (5 mL) at 280 °C, oxalyl chloride (0.40 mL, 4.74 mmol) was added, 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).

[0277] Step 4: 2-chloro-N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)pyrimidine-4-carboxamide TIFF0007792915000200.tif271 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) at 280 °C was added N-((1r,4r)-4-aminocyclohexyl)ethanesulfonamide hydrochloride (535 mg, 2.59 mmol), and the reaction mixture was stirred at room temperature 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 NaSO and concentrated in vacuo. The crude residue obtained was purified by Grace normal phase purification (100-200 mesh silica gel, eluent: 50%-80% EtOAc in petroleum ether) to give the title compound. Yield: 33% (199 mg, yellow solid). LCMS: (Method A) 347.0 (M+H), Rt. 1.23 min.

[0278] Step 5: N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide 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 N gas at room temperature for 5 minutes. Potassium carbonate (235 mg, 1.70 mmol) and CuI (10.8 mg, 0.05 mmol) were then added at room temperature, 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 in DCM (50 mL). The combined filtrates were concentrated in vacuo, and the resulting crude residue was purified by preparative HPLC (Method B). The fractions were concentrated under reduced pressure, and the residue was diluted with 10% MeOH in DCM (20 mL) and washed with water (2 x 10 mL). The organic layer was dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 5% (11.75 mg, off-white solid). 1H NMR(400 MHz,DMSO-d6):9.07(d,J=4.8 Hz,1H),8.97-8.96(m,1H),8.87(d,J=8.4 Hz,1H),8.23-8.22(m,1H),7.91(d,J=4.8 Hz,1H),7.19-7.18(m,1H),7.10(d,J=7.6 Hz,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.

[0279] Example 54: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxy-4-methylcyclohexyl)pyrimidine-4-carboxamide TIFF0007792915000202.tif111170Step 1: (1r,4r)-4-(dibenzylamino)-1-methylcyclohexan-1-ol To a stirred solution of (1r,4r)-4-amino-1-methylcyclohexan-1-ol (359 mg, 2.77 mmol, cascode no. 177908-37-1) in acetonitrile (10 mL), potassium carbonate (1.15 g, 8.33 mmol) and benzyl bromide (0.66 mL, 5.55 mmol) were added at room temperature, 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 NaSO, filtered, and the filtrate was concentrated in vacuo to give the title compound. Yield: 61% (531 mg, white solid). 1H NMR(400MHz,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.

[0280] Step 2: (1r,4r)-N,N-Dibenzyl-4-methoxy-4-methylcyclohexan-1-amine To a stirred solution of (1r,4r)-4-(dibenzylamino)-1-methylcyclohexan-1-ol (399 mg, 1.28 mmol) in THF (5 mL) at 280 °C under a nitrogen atmosphere, sodium hydride (128 mg, 3.22 mmol, 60% suspension) was added, followed by methyl iodide (0.24 mL, 549 mg, 3.86 mmol). After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight at room temperature. After completion of the reaction, 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 NaSO, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by Grace normal phase purification (100-200 mesh silica gel, eluent: 20%-30% EtOAc in petroleum ether) to give the title compound. Yield: 93% (535 mg, colorless liquid). LCMS: (Method C) 324.2 (M+H), Rt. 1.48 min.

[0281] Step 3: (1r,4r)-4-Methoxy-4-methylcyclohexan-1-amine TIFF0007792915000205.tif18128 To a stirred solution of (1r,4r)-N,N-dibenzyl-4-methoxy-4-methylcyclohexan-1-amine (705 mg, 2.17 mmol) in absolute ethanol (7 mL) at room temperature, 20% Pd(OH)2 / C (70 mg) was added, and the reaction mixture was stirred overnight under a hydrogen atmosphere at room temperature. After completion of the reaction, the reaction mixture was filtered through a bed of Celite, 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.

[0282] Step 4: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxy-4-methylcyclohexyl)pyrimidine-4-carboxamide To a stirred solution of 2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid (210 mg, 1.10 mmol) in DMF (5 mL) at 280 °C under a nitrogen atmosphere, HATU (629 mg, 1.65 mmol) and DIPEA (0.50 mL, 2.76 mmol) were added, and the reaction mixture was stirred at 0 °C for 5 min. Next, (1r,4r)-4-methoxy-4-methylcyclohexan-1-amine (189 mg, 1.32 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After completion (starting material was consumed by TLC), the reaction mixture was diluted with water (30 mL) and then extracted with 10% MeOH in 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, and the residue was diluted with 10% MeOH in DCM (50 mL) and washed with 10% aqueous NaHCO (20 mL) followed by water (2 x 20 mL). The organic layer was dried over anhydrous NaSO, 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.

[0283] Example 55: N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide TIFF0007792915000207.tif84165Step 1: 2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid 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 N gas for 5 minutes at room temperature. Potassium carbonate (1.046 g, 7.56 mmol) was then added, followed by CuI (48.1 mg, 0.24 mmol) at room temperature, and the reaction mixture was heated to 120 °C overnight. After completion (LCMS), the reaction mixture was filtered through Celite and the filtrate bed was washed with 10% MeOH in DCM (50 mL). The combined filtrate was concentrated in vacuo, and the crude residue obtained was carried on to the next step without purification. Yield: 870 mg (yellow solid). LCMS: (Method A) 191.0 (M+H), Rt. 0.21 min.

[0284] Step 2: N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide To a stirred solution of 2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid (200 mg, 1.05 mmol) in DMF (3 mL) at 280 °C under a nitrogen atmosphere, HATU (599 mg, 1.57 mmol) was added, followed by DIPEA (0.9 mL, 5.25 mmol). The reaction mixture was stirred at 0 °C for 5 min. Next, (1s,4s)-4-amino-1-methylcyclohexan-1-ol (135.8 mg, 1.05 mmol, CAS: 177906-46-6) was added, and the reaction mixture was stirred at room temperature overnight. After completion (starting material consumed by TLC), the reaction mixture was diluted with water (30 mL) and extracted with 10% MeOH in DCM (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude product obtained 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 in DCM (50 mL) and washed with 10% aqueous NaHCO (20 mL) followed by water (2 x 20 mL). The organic layer was dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and finally lyophilized to give the title compound. Yield: 30% (142 mg, off-white solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.05(d,J=5.2 Hz,1H),9.01-9.00(m,1H),8.96(d,J=8.8 Hz,1H),8.27-8.27(m,1H),7.91(d,J=4.8 Hz,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.0.51 min. HPLC: (Method A) Rt. 1.88 min.

[0285] Example 56: 6-Cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide TIFF0007792915000210.tif115167Step 1: 2-chloro-6-cyclopropylpyrimidine-4-carboxylate methyl A stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (1.20 g, 5.79 mmol) and cyclopropylboronic acid (497 mg, 5.79 mmol) in THF (15 mL) was purged with nitrogen gas for 5 minutes at room temperature. KPO (3.07 g, 14.49 mmol) and Pd(dppf)Cl.DCM (473 mg, 0.57 mmol) were then added at room temperature. The reaction mixture was heated at 70 °C for 16 hours. Upon completion, the reaction mixture was filtered through Celite and washed with EtOAc (500 mL). The filtrate was washed with brine solution (2 × 100 mL) followed by water (2 × 100 mL). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by Grace apparatus using silica gel (100-200 mesh, 20-30% EtOAc / pet ether as eluent) to give the title compound. Yield: 52% (643 mg, yellow solid). 1 H NMR (400 MHz, DMSO-d): δ 8.04 (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. A 1D NOE effect was observed between the pyrimidine protons (8.04 ppm) and the cyclopropyl CH (2.40-2.36 ppm), confirming substitution at position 6.

[0286] Step 2: 6-Cyclopropyl-2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid A stirred solution of methyl 2-chloro-6-cyclopropylpyrimidine-4-carboxylate (313 mg, 1.47 mmol) and 1H-imidazole (305 mg, 4.41 mmol) in DMF (5 mL) was purged with nitrogen gas for 5 minutes at room temperature. KCO (610 mg, 4.41 mmol) was then added, followed by CuI (28.03 mg, 0.14 mmol) at room temperature. The reaction mixture was heated at 120 °C for 16 hours. Upon completion, the reaction mixture was filtered through Celite, and the Celite bed was washed with MeOH (100 mL) and water (5 mL). The combined filtrate was concentrated in vacuo. The crude residue was suspended in diethyl ether (20 mL) and acidified with HCl in diethyl ether (20 mL, 2 M). The mixture was concentrated to give the title compound as the hydrochloride salt. Yield: crude (535 mg, yellow solid). LCMS: (Method A) 231.1 (M+H), Rt. 0.86 min.

[0287] Step 3: 6-cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide To a stirred mixture of 6-cyclopropyl-2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid (530 mg, 2.30 mmol) in DMF (17 mL) at 280 °C under a nitrogen atmosphere, HATU (1.31 g, 3.45 mmol) and DIPEA (1.0 mL, 5.75 mmol) were added, followed by (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (498 mg, 2.87 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon completion (starting material consumed by TLC), the reaction mixture was diluted with water (20 mL) and then extracted with 10% MeOH in DCM (150 mL). The resulting organic solution was washed with 10% NaHCO solution (50 mL) followed by water (2 × 25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product obtained 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 x 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(400 MHz,DMSO-d6):δ 8.90-8.89(m,1H),8.75(d,J=8.4 Hz,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,4) 1.25 min. HPLC: (Method A) Rt. 2.61 min.

[0288] Example 57: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-vinylpicolinamide TIFF0007792915000214.tif93165Step 1: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-vinylpicolinamide 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-dioxaborolane (109.21 mg, 0.71 mmol), KCO (163.12 mg, 1.18 mmol), and Pd(PPh)Cl (38.61 mg, 0.05 mmol) in 1,4-dioxane-HO (4.5 mL:0.5 mL) was added at room temperature, and the mixture was purged with nitrogen gas at room temperature for 5 minutes. The reaction mixture was heated at 80 °C for 16 hours. After completion (TLC showed that the starting material had been consumed), the reaction mixture was filtered through a bed of Celite, and the Celite bed was washed with DCM (20 mL). The solvent was evaporated under vacuum 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 in DCM), followed by further purification by preparative HPLC (Method A). The preparative fractions were concentrated to the aqueous phase, and DCM was added, followed by neutralization with 10% aqueous NaHCO3. The phases were separated. The organic phase was washed with water, brine, dried over anhydrous Na2SO4, and evaporated to give the title compound. Yield: 4.4% (8 mg, light brown solid). 1H NMR(400 MHz,DMSO-d6):δ 8.96(s,1H),8.54(d,J=8.4 Hz,1H),8.29-8.28(m,1H),8.09(d,J=0.8 Hz,1H),7.99(d,J=0.8 Hz,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.

[0289] Example 58: N-((1r,4r)-4-ethoxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide TIFF0007792915000216.tif35128Step 1: (1r,4r)-N,N-Dibenzyl-4-ethoxycyclohexan-1-amine To a stirred solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (0.5 g, 1.69 mmol) in DMF (10 mL) at 280 °C, sodium hydride (169 mg, 4.23 mmol) was added portionwise. Ethyl iodide (0.27 mL, 3.38 mmol) was then added slowly at 0 °C, and the reaction mixture was stirred at room temperature overnight. After 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 NaSO, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by silica column chromatography on a Biotage Isolera using 0–9% EtOAc in 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.

[0290] Step 2: (1r,4r)-4-ethoxycyclohexan-1-amine TIFF0007792915000218.tif27128 To a stirred solution of (1r,4r)-N,N-dibenzyl-4-ethoxycyclohexan-1-amine (0.45 g, 1.39 mmol) in absolute ethanol (4 mL) at room temperature, Pd(OH)2 on carbon (45 mg, 20% by weight) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was filtered through a bed of Celite, 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 (0.23 g, colorless liquid). LCMS: (Method C) 144.3 (M+H), 0.95 min.

[0291] Step 3: N-((1r,4r)-4-ethoxycyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide To a stirred solution of 6-(thiazol-5-yl)-1H-indole-4-carboxylic acid (0.252 g, 1.32 mmol) in DMF (3 mL) at 280 °C under a nitrogen atmosphere, HATU (1.26 g, 3.32 mmol) was added, followed by DIPEA (0.57 mL, 3.31 mmol). (1r,4r)-4-ethoxycyclohexane-1-amine (0.19 g, 1.32 mmol) was then added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion (starting material consumed by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The resulting 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). 1 H NMR(400 MHz,DMSO-d6):9.06(d,J=5.2 Hz,1H),8.97(s,1H),8.85(d,J=8.8 Hz,1H),8.23-8.22(m,1H),7.91(d,J=4.8 Hz,1H),3.91-3.81(m,1H),3.48(q,J=6.8 Hz,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=6.8 Hz,3H).LCMS: (Method D) 316.2 (M+H), Rt. 1.77 min, HPLC: (Method A) Rt. 2.14 min.

[0292] Example 59: Synthesis of 4-(difluoromethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide TIFF0007792915000220.tif121163 Step 1: Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-vinylpyridine-4-carboxamide. To a slightly 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) at room temperature, 2,4,6-trivinylboroxine-pyridine complex (470 mg, 1.77 mmol) and CsF (530 mg, 3.54 mmol) were added, and the mixture was purged with N2 (gas) for 5 minutes. PdCl2(dppf).DCM complex (96 mg, 0.12 mmol) was then added, and the reaction mixture was heated at 120 °C for 5 hours. The reaction was monitored by TLC; the starting material was consumed. The reaction mixture was concentrated, water (10 mL) was added, and extracted with DCM (2 x 10 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and the solvent was evaporated under vacuum to give the title compound. Yield: 75% (330 mg, reddish-brown solid). 1 H NMR(400 MHz,DMSO-d6):δ 8.97(s,1H),8.55(d,J=8.4 Hz,1H),8.30(s,1H),8.10(s,1H),7.99(s,1H),7.17(s,1H),6.95-6.87(m,1 H),6.43-6.38(m,1H),5.77-5.70(m,1H),3.88-3.81(m,1H),3.59-3.51(m,2 H),3.48-3.43(m,2H),3.32-3.22(m,4H),2.06-2.03(m,2H),1.85-1.82(m,2 H),1.62-1.52(m,2H),1.30-1.21(m,2H).LCMS:(Method C) 371.1(M+H), Rt.1.18 min.

[0293] Step 2: Synthesis of 4-formyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide. To a solution of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-vinylpyridine-4-carboxamide (330 mg, 0.89 mmol) in a mixture of 1,4-dioxane / water (3:1, 10 mL) at room temperature, OsO (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) were added, 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 slow addition of 10% aqueous NaSO (5 mL) and 10% NaHCO 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 NaSO, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel, 230–400 mg) using 5%–7% MeOH / DCM as the eluent to give the title compound. Yield: 45% (150 mg, yellow solid). LCMS: (Method D) 373.1 (M+H), Rt. 1.29 min.

[0294] Step 3: Synthesis of 4-(difluoromethyl)-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide 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) at −78° C., DAST (0.106 mL, 0.8 mmol) was slowly added dropwise, and the reaction mixture was warmed to 0° C. and stirred at 0° C. for 1 h. After the starting material was consumed (monitored by TLC), the reaction mixture was quenched with ice-water (5 mL) and extracted with DCM (2×5 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and the solvent was evaporated under vacuum. The crude residue was purified by flash column chromatography (silica gel, 230-400 mg) using 5%-8% MeOH / DCM as eluent to give the title compound in 12% yield (20.1 mg, colorless gummy solid). 1 H NMR(400 MHz,DMSO-d6):δ 9.04-9.03(m,1H),8.67(d,J=8.8 Hz,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.1.78 min. HPLC: (Method A) Rt.2.40 min.

[0295] Example 60: 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide TIFF0007792915000224.tif35128Step 1: (1s,4s)-4-(dibenzylamino)cyclohexan-1-ol To a stirred solution of (1s,4s)-4-aminocyclohexan-1-ol hydrochloride (1.0 g, 6.59 mmol) in ACN (15 mL) at room temperature, K2CO3 (2.73 g, 19.78 mmol) and benzyl bromide (1.56 mL, 13.19 mmol) were added, 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 resulting organic layer was washed with water (2 × 100 mL), brine solution (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude residue obtained was used in the next step without further purification. Yield: 76% (1.5 g, pale yellow oil). 1 H NMR(400 MHz,DMSO-d6):7.36-7.34(m,10H),4.26(d,J=3.6 Hz 1H),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.1.24 min.

[0296] Step 2: (1s,4s)-N,N-Dibenzyl-4-(2-methoxyethoxy)cyclohexan-1-amine To a stirred solution of (1s,4s)-4-(dibenzylamino)cyclohexan-1-ol (1.5 g, 5.07 mmol) in DMPU (10 mL) at room temperature, sodium hydride (0.50 g, 12.69 mmol) was added under a nitrogen atmosphere with continued stirring (the mixture became exothermic). 1-Bromo-2-methoxyethane (1.76 g, 12.69 mmol) was then added over 10 minutes at room temperature. Effervescence was observed during the addition of 1-bromo-2-methoxyethane. After the addition was complete, the reaction mixture was stirred at 50 °C for 5 hours. Upon completion (monitored by TLC), the reaction mixture was cooled to room temperature and slowly poured into ice-cold water (50 mL) with continued stirring. The suspension was extracted with MTBE (300 mL). The organic layer was washed with water (2 x 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 in dioxane (10 mL, 4 M), stirred at room temperature for 10 minutes, and then concentrated. The resulting white solid was suspended in diethyl ether (20 mL), and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with diethyl ether (20 mL) and dried. The resulting hydrochloride salt was dissolved in aqueous NaOH (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.

[0297] Step 3: (1s,4s)-4-(2-methoxyethoxy)cyclohexan-1-amine TIFF0007792915000227.tif18128 To a stirred solution of (1s,4s)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexane-1-amine (1.5 g, 4.24 mmol) in absolute ethanol (10 mL) at room temperature, Pd(OH)2 on carbon (0.20 g, 20% by weight) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was filtered through a bed of Celite. 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.

[0298] Step 4: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid A stirred solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (5.03 g, 26.95 mmol, cascode number 89581-58-8) and 1H-imidazole (5.50 g, 80.86 mmol) in DMF (75 mL) was degassed at room temperature for 10 minutes, after which potassium carbonate (11.17 g, 80.86 mmol) was added, followed by CuI (513 mg, 2.69 mmol). The reaction mixture was heated at 120 °C for 16 hours. After completion (monitored by LCMS), the reaction mixture was filtered through Celite, and the Celite bed was washed with 10% MeOH in DCM (500 mL) followed by water (100 mL). The combined filtrates were concentrated under reduced pressure. The crude residue was suspended in 1,4-dioxane (30 mL), acidified with HCl in 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 (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%.

[0299] Step 5: 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide To a stirred solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (93 mg, 0.45 mmol) in DMF (1 mL) at 280 °C under a nitrogen atmosphere, HATU (259 mg, 0.68 mmol) and DIPEA (0.19 mL, 1.02 mmol) were added. After stirring at 0 °C for 5 min, (1s,4s)-4-(2-methoxyethoxy)cyclohexane-1-amine (79 mg, 0.45 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. After completion (starting material was consumed by 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 was concentrated in vacuo. The crude residue was purified by silica column chromatography on a Biotage Isolera using 1-2% MeOH in DCM to give the title compound. Yield: 9% (14.30 mg, off-white solid). 1 H 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.

[0300] Example 61: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxy-2-methylpropoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide TIFF0007792915000230.tif122159Step 1: 1-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)-2-methylpropan-2-ol TIFF0007792915000231.tif30128 To a stirred solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (0.5 g, 1.69 mmol) in DMSO (5 mL) at room temperature, 2,2-dimethyldioxirane (0.45 g, 6.23 mmol) and KOH (0.285 g, 5.08 mmol) were added, and the reaction mixture was heated to 60 °C overnight in a sealed tube. An additional portion of 2,2-dimethyldioxirane (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 NaSO, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica column chromatography on a Biotage Isolera using 0-12% EtOAc in 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.

[0301] Step 2: (1r,4r)-N,N-Dibenzyl-4-(2-methoxy-2-methylpropoxy)cyclohexan-1-amine To a stirred solution of 1-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)-2-methylpropan-2-ol (0.35 g, 0.95 mmol) in DMF (3.5 mL) at 280 °C, sodium hydride (76 mg, 1.90 mmol, 60% suspension) was added, 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 room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH Cl solution. The mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous Na SO , filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica column chromatography on a Biotage Isolera using 0-10% EtOAc in 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.

[0302] Step 3: (1r,4r)-4-(2-methoxy-2-methylpropoxy)cyclohexan-1-amine TIFF0007792915000233.tif28128 To a stirred solution of (1r,4r)-N,N-dibenzyl-4-(2-methoxy-2-methylpropoxy)cyclohexan-1-amine (0.3 g, 0.79 mmol) in absolute ethanol (3 mL) at room temperature, Pd(OH)...

Claims

1. Structural Formula (IIIa), (IIIb), or (IIIc): 、 ,or or a pharmaceutically acceptable salt thereof, wherein: R １ teeth, (i) One, two or three Cs １～４ a 5-membered nitrogen-containing heteroaryl optionally substituted with an alkyl group; (ii) -H, -NH ２ , Haro, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ haloalkoxy, or C １ ~C ４ alkylthio; or (iii) -C(=O)NH ２ , -COOH, C １ ~C ４ Hydroxyalkyl, C ２ ~C ４ Alkenyl, -CN, C １ ~C ４ Alkyl sulfone, or C ３ ~C ４ cycloalkyl and R ２ is one, two or three deuterium or C １～４ a 5-membered nitrogen-containing heteroaryl optionally substituted with an alkyl group; R ｄ is C １～４ Haloalkyl, C １～４ Hydroxyalkyl, or C １～４ C optionally substituted with alkoxy １～４ is alkyl; and n is 1; The compound or a pharmaceutically acceptable salt thereof.

2. Structural formula (IIIa):

2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

3. Structural Formula (IIIb):

2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

4. Structural Formula (IIIc):

2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

5. Structural formula (IVa):

2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

6. Structural formula (IVb):

2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

7. Structural formula (IVc):

2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

8. R ｄ But C １～４ C optionally substituted with alkoxy １～４ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

9. R ｄ But C １～４ C substituted with alkoxy １～４ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

10. R ｄ But -CH ２ CH ２ OCH ３ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

11. R ｄ But -CH ３ or -CH ２ CH ２ OCH ３ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

12. R １ But one, two or three C １～４ The compound according to any one of claims 1 to 11, which is a 5-membered nitrogen-containing heteroaryl optionally substituted with an alkyl group, or a pharmaceutically acceptable salt thereof.

13. R １ But one, two or three C １～４ The compound according to any one of claims 1 to 11, which is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, or oxadiazole, each of which may be substituted by an alkyl group, or a pharmaceutically acceptable salt thereof.

14. R １ but, One, two or three Cs １～４ each optionally substituted with an alkyl group; The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

15. R １ but, The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

16. R １ But -H, -NH ２ , Haro, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ haloalkoxy or C １ ~C ４ The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is alkylthio.

17. R １ But -H, -CH ３ , -CF ３ , -OCH ３ , -SCH ３ , —F, —Cl, —Br or NH ２ 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

18. R ２ But one, two or three C １～４ The compound according to any one of claims 1 to 17, which is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, or oxadiazole, each of which may be substituted by an alkyl group, or a pharmaceutically acceptable salt thereof.

19. R ２ but, and one, two or three C １～４ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, which may be substituted with an alkyl group.

20. R ２ but, The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

21. R １ is -C(=O)NH ２ , -COOH, C １ ~C ４ Haloalkyl, C １ ~C ４ Hydroxyalkyl, C ２ ~C ４ Alkenyl, -CN, C １ ~C ４ Alkyl sulfone, or C ３ ~C ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

22. R １ is -C(=O)NH ２ , -COOH, -CHF ２ , -CH ２ F, -CH(OH)CH ３ , -C(OH)(CH ３ ) ２ , -CH ２ OH, -CH=CH ２ , -SO ２ 22. The compound of any one of claims 1 and 21, or a pharmaceutically acceptable salt thereof, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27

23. R ２ 23. The compound of any one of claims 1, 21, and 22, or a pharmaceutically acceptable salt thereof, wherein is a five-membered nitrogen-containing heteroaryl substituted with one, two, or three deuterium atoms.

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

25. R ｄ But C １～４ Haloalkyl or C １～４ 25. The compound of any one of claims 1 and 21 to 24, or a pharmaceutically acceptable salt thereof, which is hydroxyalkyl.

26. R ｄ But -CHF ２ or CH ２ CH ２ 26. The compound of any one of claims 1 and 21 to 25, or a pharmaceutically acceptable salt thereof, wherein R is OH.

27. below: or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which 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. 29. A pharmaceutical composition for use in treating a disease or condition in a subject that would benefit from increased NAD+, comprising a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

31. 31. The pharmaceutical composition of claim 30, wherein the disease or condition 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, an ocular muscle disease, or a renal disease.

32. the muscle structure disorder is selected from Bethlem myopathy, central core disease, congenital muscle fiber type disproportion, distal muscular dystrophy (MD), Duchenne and Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, muscle sodium channelopathy, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, or stress urinary incontinence; the neuronal activation disorder is selected from amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesions, peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy, and toxic neuromuscular disorders; the muscle fatigue disorder is selected from chronic fatigue syndrome, diabetes mellitus (type I or II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy; the muscle mass disorder is selected from cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, polymyositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus; 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, triploidy enzyme deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin-responsive beta-oxidation disorder (RR-MADD); The metabolic disease is selected from the group consisting of hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL cholesterolemia, hyper-LDL cholesterolemia and / or non-HDL cholesterolemia, hyper-VLDL proteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis, arteriosclerotic diseases, cardiovascular diseases, cerebrovascular diseases, peripheral circulatory diseases, metabolic syndrome, syndrome X, obesity, and the like. selected from: diabetes mellitus (type I or II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complications, 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, ectopic hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis; the cancer is selected from colon cancer, colorectal cancer, skin cancer, breast cancer, prostate cancer, ovarian cancer, and lung cancer; the vascular disease is selected from peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral arterial disease (PAD), peripheral arterial occlusive disease (PAOD), and peripheral obliterative arteriopathy; the ocular vascular disease is selected from age-related macular degeneration (AMD), Stargardt's disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma; the ocular muscle disease is selected from strabismus, progressive external ophthalmoplegia, esotropia, exotropia, refractive and accommodative disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodative disorders, and internal ophthalmoplegia; and 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, chronic renal failure, diabetic nephropathy, and Bartter's syndrome.

32. The pharmaceutical composition of claim 31.

33. 31. The pharmaceutical composition of claim 30, wherein the disease or condition is selected from hereditary 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.

34. 31. The pharmaceutical composition of claim 30, wherein the disease or condition is selected from Alpers disease, CPEO - chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF - myoclonic epilepsy and ragged-red fiber disease, NARP - neurogenic muscular weakness, ataxia, and retinitis pigmentosa, Pearson syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum group A, Wallerian degeneration, and HIV-induced lipodystrophy.

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