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BR-112020021042-B1 - Bicyclic carboxamide compounds, pharmaceutical composition and uses thereof.

BR112020021042B1BR 112020021042 B1BR112020021042 B1BR 112020021042B1BR-112020021042-B1

Abstract

Compounds, compositions, and methods are provided for modulating the activity of EP2 and EP4 receptors and for the treatment, prevention, and improvement of one or more symptoms of diseases or disorders related to the activity of EP2 and EP4 receptors. In certain modalities, the compounds are antagonists of both EP2 and EP4 receptors.

Inventors

  • Yalda Bravo
  • AUSTIN CHIH-YU CHEN
  • Jinyue DING
  • Robert Gomez
  • Heather Lam
  • JOE FRED NAGAMIZO
  • RENATA MARCELLA OBALLA
  • DAVID ANDREW POWELL
  • Tao Sheng

Assignees

  • TEMPEST THERAPEUTICS, INC

Dates

Publication Date
20260317
Application Date
20190417
Priority Date
20180417

Claims (20)

  1. 1. Compound, characterized by having Formula(I), or a pharmaceutically acceptable salt thereof: wherein: X1 is N or CH; X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; wherein no more than two of X3, X4 and X5 are N; L1 is -(CRb2)t-; Ring A is aryl; each R1 is independently C2-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -OR8', wherein C2-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three R1; or two substituents of R1 on adjacent atoms of Ring A are taken together with the atom to which they are attached to form an aromatic or non-aromatic ring containing O2 heteroatoms selected from the group consisting of -O-, -NR10-, -S- and -S(O)2-, wherein the aromatic or non-aromatic ring is optionally deuterated and optionally substituted with one, two or three Ry; each R8' is independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, -OR8, -NR8R9, -CN, -C(O)R11, -C(O)NR8R9, -NR8C(O)R11, -NR8C(O)OR9, -NR10C(O)NR8R9, -OC(O)NR8R9, -S(O)2R11, -S(O)R11, -SR8, -S(O)2NR8R9, -S(O)NR8R9, -NR8S(O)R11, -NR8S(O)2R11 or -NR10S(O)2NR8R9; wherein the alkyl is optionally substituted with -OR8 or -NR8R9 and wherein the cycloalkyl and heterocyclyl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; each Rx is independently halogen, methyl, C1 haloalkyl or -CN; R2, R3, R4 and R5 are each independently hydrogen, alkyl, halogen, -OR8, -CN, cycloalkyl or haloalkyl; R6 is hydrogen, deuterium, alkyl or haloalkyl; R7 is hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkoxy, hydroxyl or haloalkyl; each R8 and each R9 are independently hydrogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; or R8 and R9, together with the atom or atoms to which they are attached, form a heterocycline optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; each R10 is independently hydrogen or alkyl; each R11 is independently alkyl, haloalkyl, cycloalkyl, heterocycline, aryl or heteroaryl, wherein cycloalkyl, heterocycline, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; 1. and Y2 are each independently a bond or -(CRa2)n-, since neither Y1 nor Y2 are a bond; Z1 and Z2 are each -CRa2-; L2 is -(CRc2)m-; G is -C(O)OR12, -C(O)NHOH, -SO3H, -SO2NH2, -SO2NHRd, -SO2NHC(O)Rd, -NHC(O)NHSO2Rd, -1H-tetrazolyl, -P(O)(OH)2, -1,2,4-oxadiazol-5(4H)-one, -tetrazol-5(4H)-one, or -C(O)NHSO2Rd; R12 is selected from hydrogen, C1-C6 alkyl, aryl, aralkyl, CH(R13)OC(=O)R14, CH(R13)OC(=O)OR14 and a a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group that has the following formula: wherein Re is C1-C6 alkyl; R13 is hydrogen or C1-C6 alkyl; R14 is C1-C6 alkyl or C3-C6 cycloalkyl; each Ra is independently hydrogen, deuterium, alkyl, halogen or haloalkyl; each Rb is independently hydrogen, deuterium, alkyl or haloalkyl, or two Rbs, together with the carbon atom to which they are attached, form cycloalkyl; each Rc is independently hydrogen or halogen; Rd is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl; m is 0, 1 or 2; each n is independently 1, 2 or 3; p is 1 or 2; q is 0, 1 or 2; et is 1, 2 or 3.
  2. 2. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, -OR8, -NR8R9, -CN, -C(O)R11, -C(O)NR8R9, -NR8C(O)R11, -NR8C(O)OR9, -NR10C(O)NR8R9, -OC(O)NR8R9, -S(O)2R11, -S(O)R11, -SR8, -S(O)2NR8R9, -NR8S(O)2R11, or -NR10S(O)2NR8R9 wherein alkyl is optionally substituted with -OR8 or -NR8R9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two or three selected groups from halogen, alkyl and haloalkyl; each R8 and each R9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; or R8 and R9, together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; each R10 is independently hydrogen or alkyl; each R11 is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; Each Rb is independently hydrogen or deuterium.
  3. 3. Compound according to claim 1 or 2, characterized in that it has Formula (II): or a pharmaceutically acceptable salt thereof.
  4. 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that: X3 is CR3; X4 is N or CR4; X5 is N or CR5; R3, R4 and R5 are each independently hydrogen, alkyl, halogen, -OR8, -CN, cycloalkyl or haloalkyl; each R8 is independently hydrogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl.
  5. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that X1 is CH.
  6. 6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that X1 is N.
  7. 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that one of R3, R4 or R5 is a halogen and the remainder of R3, R4 and R5, when present, are each hydrogen.
  8. 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that one of R3 or R4 is a halogen and the other of R3 and R4, when present, is hydrogen and R5 is hydrogen.
  9. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that: each R1 is independently cycloalkyl, heterocyclyl, aryl, heteroaryl or -OR8', wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently and optionally substituted with one, two or three Ry; each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, -OR8, -NR8R9, -CN, -C(O)R11, -C(O)NR8R9, -NR8C(O)R11, -NR8C(O)OR9, -NR10C(O)NR8R9, -OC(O)NR8R9, -S(O)2R11, -S(O)R11, -SR8, -S(O)2NR8R9, -S(O)NR8R9, -NR8S(O)R11, -NR8S(O)2R11 or -NR10S(O)2NR8R9; wherein alkyl is optionally substituted with -OR8 or -NR8R9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; each R8 and each R9 are independently hydrogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; R8 and R9, together with the atom or atoms to which they are attached, form a heterocycline optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl; each R10 is independently hydrogen or alkyl; each R11 is independently alkyl, haloalkyl, cycloalkyl, heterocycline, aryl, or heteroaryl, wherein cycloalkyl, heterocycline, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected independently from halogen, alkyl, and haloalkyl; and each R8' is independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycline, aryl, or heteroaryl, wherein cycloalkyl, heterocycline, aryl, and heteroaryl are each independently and optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl.
  10. 10. Compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that: each R1 is independently cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the heterocyclyl, aryl and heteroaryl are each independently and optionally substituted with one, two or three Ry; each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, -OR8, -NR8R9, -CN, -C(O)R11, -C(O)NR8R9, -NR8C(O)R11, -NR8C(O)OR9, -NR10C(O)NR8R9, -OC(O)NR8R9, -S(O)2R11, -S(O)R11, -SR8, -S(O)2NR8R9, -S(O)NR8R9, -NR8S(O)R11, -NR8S(O)2R11 or -NR10S(O)2NR8R9; wherein alkyl is optionally substituted with -OR8 or -NR8R9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; each R8 and each R9 are independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three groups selected from halogen, alkyl and haloalkyl; R8 and R9, together with the atom or atoms to which they are attached, form a heterocycline optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl; each R10 is independently hydrogen or alkyl; and each R11 is independently alkyl, haloalkyl, cycloalkyl, heterocycline, aryl, or heteroaryl, wherein cycloalkyl, heterocycline, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected independently from halogen, alkyl, and haloalkyl.
  11. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that p is 1 and R1 is aryl.
  12. 12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that p is 1, Ring A is phenyl and R1 is phenyl.
  13. 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, characterized in that R7 is hydrogen or deuterium.
  14. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, characterized in that q is 0 or 1.
  15. 15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized in that t is 1.
  16. 16. Compound according to claim 1, the compound being characterized in that it is selected from: , or a pharmaceutically acceptable salt thereof.
  17. 17. Compound according to claim 16, characterized in that the compound is: or a pharmaceutically acceptable salt thereof.
  18. 18. Compound, according to the claim, characterized by the fact that the compound is: or a pharmaceutically acceptable salt thereof.
  19. 19. Compound, according to the claim, characterized in that the compound is: or a pharmaceutically acceptable salt thereof.
  20. 20. Compound according to claim 16, characterized in that the compound is: or a pharmaceutically acceptable salt thereof.

Description

RELATED ORDERS [0001] This application claims the benefit of the Provisional Application in U.S. 62/659,068 filed April 17, 2018, and 62/746,843 filed October 17, 2018; the disclosures in the above applications are incorporated herein by reference in their entirety. TECHNICAL FIELD [0002] Compounds, compositions and methods are provided for modulating the activity of EP2 and EP4 receptors, and for the treatment, prevention and improvement of one or more symptoms of diseases or disorders mediated by the activity of EP2 and EP4 receptors. In certain embodiments, the compounds are antagonists of both EP2 and EP4 receptors. BACKGROUND [0003] Prostaglandin E2 (PGE2) is an endogenous bioactive lipid that, through its activation of transmembrane G protein-coupled receptors (GPCRs) EP1, EP2, EP3 and/or EP4, can elicit a wide range of context-dependent biological responses (Legler, D. F. et al., Int. J. Biochem. Cell Biol. 2010, 42, p. 198-201). In particular, although PGE2 strongly favors a pro-inflammatory immune response, the persistent and sustained activation of EP receptors in the tumor microenvironment by PGE2 (which is produced in significantly larger quantities by tumor cells (Ochs et al., J. Neurochem. 2016, 136, p.1142-1154; Zelenay, S. et al., Cell 2015, 162, p. 1257-1270)) would instead promote the accumulation and increase the activity of multiple immunosuppressive cells. These include type 2 tumor-associated microphages (TAMs) (Nakanishi Y et al., Carcinogenesis. 2011, 32, p. 1333-1339), Treg cells (Mahic, M. et al., J. Immunol. 2011, 177, p.246-254) and myeloid-derived suppressor cells (MDSCs) (Mao, et al., Clin. Cancer Res. 2014, 20, p. 40964106; Whiteside, T. L., Expert Opin. Bio. Th. 2010, 10, p.1019-1035). Furthermore, it has been reported that PGE2 induces immune tolerance by inhibiting the accumulation of antigen-presenting dendritic cells (DCs) in tumors, as well as by suppressing the activation of tumor-infiltrating DCs (Wang et al., Trends in Molecular Medicine 2016, 22, p. 1-3). All these PGE2-mediated repolarizations of immune cells would conspire to facilitate the escape of tumor cells from immune surveillance (Adams et al., Nat Rev DrugDiscov. 2015, 14, p. 603-622). Indeed, one of the major hallmarks of an immunosuppressive tumor microenvironment is the presence of a large number of MDSCs and TAMs, which, in turn, are significantly associated with poor overall survival in patients with gastric, ovarian, breast, bladder, hepatocellular carcinoma (HCC), head and neck, and other types of cancers (Qian et al., Cell. 2010, 141, p. 39-51; Gabitass et al., CancerImmunol. Immunother. 2011, 60, p. 1419-1430). [0004] Although the relative contributions of each of the EP receptor subtypes in mediating the large number of immunosuppressive effects of PGE2 have remained an area of active research (Kalinski, P. J Immunol. 2012, 188, p. 21-28), there is a general consensus that the EP4 receptor, which is highly expressed in myeloid cells, tumor cells, and T lymphocytes, plays an important role in enhancing several tumor survival pathways and in suppressing both innate and adaptive antitumor immune responses (Albu, D. I. et al., Oncoimmunology 2017, 6, e1338239, and references therein). It has recently been revealed that such a tumor survival pathway has EP4-mediated upregulation of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-deoxygenase (TDO) activity; through its stimulation by PGE2 secreted by tumors, in the tumor microenvironment (Ochs et al., J. Neurochem. 2016, 136, p. 1142-1154; Chen, J.-Y. et al., Breast Cancer Research, 2014, 16, p.410-424). Since tryptophan, the substrate of the enzymes IDO and TDO, is essential for the proliferation and activation of cytotoxic Teff cells and kynurenine; The product of the enzymes IDO and TDO is essential for the proliferation and activation of immunosuppressive Treg cells (Dounay, A. B. et al., J. Med. Chem. 2015, 58, p. 8762-8782). Inhibition of IDO and/or TDO activity represents a promising pathway for the treatment of various cancers (Jochems, et al., Oncotarget 2016, 7, p. 37762-37772). In fact, significantly increased overall response rates have been reported in patients with stage IIIB or IV advanced melanoma with epacadostate, a potent and selective IDO inhibitor from Incyte, when used in combination with pembrolizumab. Indeed, in light of these and other observations and studies, selective EP4 antagonists are being evaluated for the treatment of advanced cancer; both as a single agent and in combination with other anticancer therapies. [0005] It has been established that PGE2 stimulation of EP2 plays an important role in the regulation of maternal-fetal tolerance (Matsumoto et al., Biology of Reproduction 2001, 64, p. 1557-1565; Hizaki et al., Proc. Natl. Acad. Sci. U.S.A. 1999, 96, p. 10501-10506) and selective EP2 antagonists are currently under development for use as on-demand contraception (Lindenthal, B. et al., USA 9655887). More recent