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EP-4736956-A2 - HETEROARYL AMIDE INHIBITORS OF CD38

EP4736956A2EP 4736956 A2EP4736956 A2EP 4736956A2EP-4736956-A2

Abstract

Disclosed are heteroaryl amide inhibitors of CD38 and methods of making and using the same in disease and disorder treatment.

Inventors

  • VOLKMANN, ROBERT A.
  • COE, JOTHAM W.
  • VERDIN, ERIC
  • PERRONE, Rosalba
  • NELSON, Frederick R.
  • Silva, Elena
  • FELSTEAD, Steve
  • JACKSON, Margaret

Assignees

  • Napa Therapeutics Limited
  • Buck Institute for Research on Aging

Dates

Publication Date
20260506
Application Date
20211008

Claims (15)

  1. A compound of Formula I or a pharmaceutically acceptable salt thereof wherein: -X-Y-Z- is =CR 1 -CR 2 =CR 3 - or =N-CR 2 =CR 3 -; R 1 is selected from the group consisting of H, halo, -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and perfluoro(C 1 -C 6 )alkoxy-; wherein (C 1 -C 6 )alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; R 2 is H, halo, -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, heterocycloalkyl-O-, aryl, aryl-O-, R 5 -(C(R 4 ) 2 ) n -O- or (R 6 ) 2 N-; wherein (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; R 3 is H, halo, (C 1 -C 3 )alkyl, -CF 3 , (C 1 -C 3 )alkoxy, -OCF 3 or (R 7 ) 2 N-; wherein R 7 is H or (C 1 -C 3 )alkyl; n is an integer from one to three; each R 4 is independently H or (C 1 -C 3 )alkyl; wherein (C 1 -C 3 )alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, - NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; R 5 is selected from the group consisting of (C 1 -C 3 )alkyl, perfluoro(C 1 -C 3 )alkyl, HO-(C 2 -C 4 )alkyl-, cycloalkyl, heterocycloalkyl, and aryl; wherein (C 1 -C 3 )alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; R 6 is independently H or (C 1 -C 3 )alkyl; wherein (C 1 -C 3 )alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; W is R 8 is H, -CH 3 or -CF 3 ; Het is a heterocycle of the formulae or each R 9 is independently selected from H, halo, (C 1 -C 6 )alkyl, -CF 3 , (C 1 -C 6 )alkoxy, -OCF 3 , - CN, (R 11 ) 2 N-, R 12 (O)(C=O)-, R 12 O((C 1 -C 3 )alkyl)-(NR 11 )-, R 13 -(C=O)-(NR 11 )- and (R 11 ) 2 N-(C=O)-; wherein (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are each optionally substituted by 1, 2, 3, 4, or 5 suitable substituents; each R 10 is independently selected from H, (C 1 -C 3 )alkyl, -CF 3 , -OCH 3 , -OCF 3 ,-CN, (R 11 ) 2 N-, R 12 (O)(C=O)-, R 12 O-((C 1 -C 3 )alkyl)-(NR 11 )-, R 13 -(C=O)-(NR 11 )-, and (R 11 ) 2 N-(C=O); R 11 is independently H or (C 1 -C 3 )alkyl; R 12 is H or (C 1 -C 3 )alkyl; and R 13 is (C 1 -C 3 )alkyl.
  2. A compound according to claim 1, wherein Het is a ring of the Formula ii
  3. A compound according to claim 1, wherein Het is a ring of the Formula vi
  4. A compound according to any of the previous claims, wherein: (i) R 8 is -CH 3 or -CF 3 ; and W is the compound of Formula (a) or (ii) R 8 is -CH 3 or -CF 3 ; and W is the compound of Formula (b) or (iii) R 8 is -CH 3 or -CF 3 ; and W is the compound of Formula (c) or (iv) R 8 is -CH 3 or -CF 3 ; and W is the compound of Formula (d) or (v) R 8 is -CH 3 or -CF 3 ; and W is the compound of Formula (e) or (vi) R 8 is -CH 3 or -CF 3 ; and W is the compound of Formula (f)
  5. A compound according to any preceding claim, wherein: (i) R 1 is selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -OCH 3 , and -OCF 3 ; and/or (ii) R 2 is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-, perfluoro(C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, aryl, R 5 -(C(R 4 ) 2 ) n -O- or (R 6 ) 2 N-; wherein (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl and aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; each R 4 is independently H or (C 1 -C 3 )alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; R 5 is selected from the group consisting of (C 1 -C 3 )alkyl, cycloalkyl, heterocycloalkyl, and aryl; wherein (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl and aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 , and -OCF 3 ; and R 6 is independently H or (C 1 -C 3 )alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 and -OCF 3 ; and/or (iii) R 3 is selected from the group consisting of H, halo, (C 1 -C 3 )alkyl, -CF 3 , -OCH 3 , -OCF 3 , and (R 7 ) 2 N-; and wherein R 7 is H or (C 1 -C 3 )alkyl.
  6. A compound according to any preceding claim, wherein R 1 is: (i) selected from the group consisting of H, F, -CH 3 , and -OCH 3 ; and/or (ii) is H.
  7. A compound according to any preceding claim, wherein: (i) R 2 is selected from the group consisting of H, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy-, perfluoro(C 1 -C 3 )alkyl, perfluoro(C 1 -C 3 )alkoxy-, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, R 5 -(C(R 4 ) 2 ) n -O- or (R 6 ) 2 N-; wherein (C 1 -C 3 )alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 , and -OCF 3 ; each R 4 is independently H or (C 1 -C 3 )alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH, 3, and -OCF 3 ; R 5 is selected from (C 1 -C 3 )alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, and 6- to 10-membered aryl; wherein (C 1 -C 3 )alkyl, 3- to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, and 6- to 10-membered aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 , and -OCF 3 ; and R 6 is independently H or (C 1 -C 3 )alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C 1 -C 3 )alkyl, -NH 2 , (C 1 -C 3 )alkyl-(NH)-, ((C 1 -C 3 )alkyl) 2 N-, -CF 3 , -OCH 3 , and -OCF 3 ; and/or (ii) R 2 is selected from the group consisting of methoxy-, cyclopropoxy- or R 5 -(C(R 4 ) 2 )-O-; and each R 4 is H; wherein R 5 is selected from C 1 -alkyl and tetrahydropyran, and wherein said C 1 -alkyl is substituted with -OCH 3 .
  8. A compound according to any preceding claim, wherein R 3 : (i) is selected from the group consisting of H, F, -CH 3 , -OCH 3 , and H 2 N-; and/or (ii) is H.
  9. A compound according to any preceding claim, wherein: (i) R 9 is selected from the group consisting of H, halo, (C 1 -C 3 )alkyl, -CF 3 , -OCH 3 , -OCF 3 , -CN, R 12 O((C 1 -C 3 )alkyl)-(NR 11 )-, -CO 2 R 12 , and (R 11 ) 2 N-(C=O)-; and each R 11 is independently selected from the group consisting of H, (C 1 -C 3 )alkyl; and R 12 is H or (C 1 -C 3 )alkyl; and/or. (ii) at least one R 9 is selected from the group consisting of F, (C 1 -C 3 )alkyl, -CF 3 , -OCH 3 , -OCF 3 , and - CN; and/or (iii) at least one R 9 is -CF 3 .
  10. A compound according to any preceding claim, wherein: (i) at least one R 10 is H; and/or (ii) in the compound of Formula I, R 10 is H.
  11. A compound according to any preceding claim, wherein R 8 is H.
  12. A compound according to claim 1, selected from the group consisting of 6-(1H-imidazol-1-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, 6-(1H-imidazol-1-yl)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, 2-(1H-imidazol-1-yl)-6-(2-methoxyethoxy)-N-(2-(trifluoromethyl) pyridin-4-yl)pyrimidine-4-carboxamide, 6-(1H-imidazol-1-yl)-4-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, 4-cyclopropoxy-6-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, 6-(1H-imidazol-1-yl)-N-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine, 6-cyclopropyl-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(1H-imidazol-1-yl)-4-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, 2-(3-methyl-4H-3l4-imidazol-4-yl)-6-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-2-yl)-6-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-5-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-hydroxy-2-methylpropoxy)-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, and a pharmaceutically acceptable salt thereof.
  13. A pharmaceutical formulation comprising: a compound of Formula I according to any preceding claim; and a pharmaceutically acceptable carrier.
  14. A compound according to any one of claims 1 to 12 for use in a method of treating a disease or disorder in a subject, optionally that benefits from modulation the level of NAD+ or related metabolite thereof, the method comprising administering to the subject a therapeutically effective amount of the compound.
  15. The compound for use according to claim 14, wherein: (i) the disease or disorder is or is related to nonalcoholic steatohepatitis, aging, senescence, immunometabolism, inflammation, infection, sepsis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, lupus erythematosus, Crohn disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, fibrosis, hepatic fibrosis, renal fibrosis, pulmonary fibrosis, cardiac fibrosis, cancer, multiple myeloma, neurodegeneration, infertility, loss of ovarian follicles, decreased oocyte quality and quantity, ovarian senescence, transient receptor potential melastatin 2 (TRPM2) regulation, calcium flux regulation, ischemia-reperfusion-injury, bipolar disoreder, Alzheimer, neuropathic pain, Parkinson, coronary arteries, obesity, type-2 diabetes, hepatotoxicity, digestive system, lung, or heart, kidney; or (ii) the disease or disorder is related to aging, for example: (a) wherein the age-related disease or disorder is or is related to a chronic age -related disease or disorder; or (b) wherein the disease or disorder is or is related to Senescence, ImmunoMetabolism, fibrotic, neurodegenerative, Multiple Myeloma, or Sepsis, optionally - wherein the disease or disorder is or is related to Multiple Myeloma, and the method further comprising administering an immuno-oncology drug to the subject; or - wherein the disease or disorder is or is related to a fibrotic disease or disorder of the lung, heart, or kidney, for example wherein the fibrotic disease is infection-induced fibrosis of the lung or virus-induced infection of the lung.

Description

RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 63/089,818 filed October 9, 2020, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present disclosure relates to biochemistry, and medicine. More specifically, this disclosure relates to novel compounds, processes for their preparation, and pharmaceutical formulations and methods of treating diseases by modulating the level of cellular NAD+ and related metabolites thereof through the inhibition of the CD38 enzyme. BACKGROUND Nicotinamide Adenine Dinucleotide (NAD+) is a biochemical that is found in all cells performing its critical role in oxidoreductase reactions. NAD+ and its related pyridine nucleotides NADH, nicotinamide adenine dinucleotide phosphate (NADP+), and NADPH are recognized as major redox carriers in all organisms. These pyridine dinucleotides regulate the cytosolic and mitochondrial redox state and are key participants monitoring the metabolic status of the cell (Houtkooper et al. (2010) Endo. Rev. 31(2):194-223); Koch-Nolte et al. (2009) Sci. Signal. 2(57); Houtkooper et al. (2012) J. Cell Biol.) 199(2):205-209). In addition to its role as a cofactor for oxidoreductases, NAD+ is also a substrate for various enzymes, where it is consumed in the process of donating its adenosine diphosphate (ADP) ribose to acceptor molecules or in the process of hydrolysis or cyclization. The enzymes that are the major consumers of NAD+ are the ADP ribosyl transferases (i.e., poly(ADP-ribose) polymerase (PARP) and ADP-ribosyltransferase (ART) family of enzymes), the sirtuins (Sirt1-7), and the ADP ribosyl cyclases/hydrolases (CD38/CD157). These enzymes are involved in pathways that regulate Ca2+ signalling, gene transcription, DNA repair, cell survival, energy metabolism, and oxidative stress. Thus, NAD+ and its phosphorylated relatives NADP and nicotine acid adenine dinucleotide phosphate (NAADP), both of which are derived from NAD+, also act as signalling molecules. NAD+ is also a component of the circadian cycle with daily oscillations that tie cellular metabolism to chromatin remodelling and gene transcription. It is known that exercise and caloric restriction elevate NAD+ levels while aging and obesity decrease cellular NAD+ levels. Cellular NAD+ is produced by either the de novo synthesis pathway from tryptophan or by the Preiss-Handler and/or the salvage synthesis pathways from precursors such as nicotinic acid (niacin), nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononuscleotide (NMN), which are imported into the cells. The modulation of cellular NAD+ levels can be achieved by blocking the consumption of NAD+ by inhibiting enzymes that consume NAD+. CD38 is one of such NAD+ consuming enzymes and reported to be the main cellular NAD+ consumer. Also known as ADP ribosyl cyclase, CD38 is a type II membrane-anchored enzyme. It efficiently catalyzes the breakdown of NAD+ to nicotinamide (NAM) and ADP ribose (ADPR) and hydrolyzes NAADP to ADPR phosphate (ADPRP). CD38 acts as a cyclase converting NAD+ to cyclic ADPR (cADPR). Finally, ADPR is also a breakdown product of cADPR hydrolysis mediated by CD38. ADP ribose (ADPR) and cyclic ADPR (cADPR) are metabolites of NAD+ generated by CD38-mediated hydrolysis or cyclization and they play a key role as intracellular Ca2+ mobilizing second messengers. cADPR is mainly involved stimulating Ca2+ release from the endoplasmic reticulum via ryanodine receptors, whereas ADPR activates the plasma membrane cation channel TRPM2 (Transient receptor potential melastatin 2) facilitating calcium entry into the cells. Aberrant TRPM2 activation has been shown to induce abnormal intracellular Ca2+ accumulation and cell death in a variety of cell types, including neurons, and is implicated in several neurological disorders. In particular, the activation of TRPM2 has been linked to diseases such as ischemia-reperfusion injury, bipolar disorder, Alzheimer's disease, neuropathic pain, and Parkinson's disease. Nicotinamide (NAM) is a precursor for NAD+ and is a key molecule involved in energy metabolism. NAM is converted into nicotinamide mononucleotide (NMN) by the enzyme nicotinamide phosphoribosyltransferase (NAMPT). Alternatively, NAM can be irreversibly methylated by Nicotinamide N-methyltransferase (NNMT) enzyme and excreted from the body. The methylated form of NAM (i.e., N1-methylnicotinamide (MNAM)) has been shown to be associate with coronary artery disease (CAD), obesity, type-2 diabetes, hepatotoxicity, Parkinson's disease, and cancers. Although NAM supplementation has shown positive effects, high levels of NAM can exert negative effects through multiple routes, including inhibition of PARPs and sirtuins and alteration of methyl metabolism. NAM supplementation has shown to cause a significant decrease of insulin sensitivity in human subjects, neurotoxicity and hepatotoxicity. Certain heteroaryl amides are known such as N-(3-ch