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US-20260124222-A1 - ISOTHIAZOLYLCARBOXAMIDE COMPOUNDS AND THEIR USE IN THERAPY

US20260124222A1US 20260124222 A1US20260124222 A1US 20260124222A1US-20260124222-A1

Abstract

The invention provides isothiazolylcarboxamide compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT 1), and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, or autoimmune disorder.

Inventors

  • Yingzhi Bi
  • Geraldine Cirillo Harriman
  • Kenneth G. Carson
  • Christian Josef Kuper
  • Sebastien Louis DEGORCE
  • Arwel LEWIS

Assignees

  • HOTSPOT THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20230912

Claims (20)

  1. 1 . A compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: A 1 is phenyl, a 6 membered heteroaryl containing 1 or 2 nitrogen atoms, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the phenyl, heteroaryl, and are substituted with m occurrences of R 5 and n occurrences of R 6 ; A 2 represents independently for each occurrence a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is substituted with y occurrences of R 7 ; R 1 is hydrogen or C 1-4 alkyl; R 2 is C 1-6 haloalkyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxyl, cyano, C 2-4 alkenyl, halogen, hydrogen, oxetanyl, tetrahydrofuranyl, or —N(R 12 )(R 13 ), wherein the oxetanyl and tetrahydrofuranyl are substituted with 0 or 1 hydroxyl groups; R 3 is one of the following: (a) phenyl, a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 3-10 membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the phenyl, heteroaryl, heterocyclyl, are substituted with t occurrences of R 4 ; or (b) C 2-6 alkyl, hydroxyl, or —N(R 9 )(R 10 ); R 4 represents independently for each occurrence halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 3-7 cycloalkyl, —C(O)R 11 , —C(O)N(R 9 )(R 10 ), cyano, —N(R 12 )(R 13 ), or —N(R 9 )C(O)R 11 ; R 5 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl and heterocyclyl are substituted with q occurrences of R 7 ; R 6 represents independently for each occurrence halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 3-7 cycloalkyl, cyano, —O—C 3-7 cycloalkyl, —N(R 9 )(R 10 ), —(C 0-4 alkylene)-C(O)R 8 , —C(O)N(R 9 )(R 10 ), or —N(R 9 )C(O)R 11 ; R 7 represents independently for each occurrence halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, or C 3-7 cycloalkyl; R 8 is —OH, —O—(C 1-6 alkyl), —O—C 3-7 cycloalkyl, or A 2 ; R 9 and R 10 are independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-4 hydroxyalkyl, or —(C 2-6 alkylene)-(C 1-6 alkoxyl), or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 groups independently selected from hydroxyl, halo, and C 1-6 alkyl; R 11 represents independently for each occurrence C 1-6 alkyl or (C 0-5 alkylene)-C 3-7 cycloalkyl; R 12 and R 13 are independently hydrogen, C 1-6 alkyl, or C 3-5 cycloalkyl, or R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; m is 0 or 1; and n, q, t, and y are independently 0, 1, or 2; provided that when R 2 is hydrogen and m is 1, then R 5 is 1,2,3-triazolyl substituted with q occurrences of R 7 .
  2. 2 . The compound of claim 1 , wherein the compound is a compound of Formula I.
  3. 3 . The compound of claim 1 or 2 , wherein R 2 is C 1-6 haloalkyl.
  4. 4 . The compound of claim 1 or 2 , wherein R 2 is —CF 3 .
  5. 5 . The compound of claim 1 or 2 , wherein R 2 is C 3-7 cycloalkyl.
  6. 6 . The compound of claim 1 or 2 , wherein R 2 is cyclopropyl.
  7. 7 . The compound of claim 1 or 2 , wherein R 2 is C 1-6 alkyl or C 2-4 alkenyl.
  8. 8 . The compound of claim 1 or 2 , wherein R 2 is halogen, C 1-6 alkoxyl, or cyano.
  9. 9 . The compound of any one of claims 1-8 , wherein the compound is a compound of Formula Ia or a pharmaceutically acceptable salt thereof:
  10. 10 . The compound of any one of claims 1-8 , wherein the compound is a compound of Formula Ib or Ic or a pharmaceutically acceptable salt thereof:
  11. 11 . The compound of any one of claims 1-10 , wherein A 1 is phenyl substituted with m occurrences of R 5 and n occurrences of R 6 .
  12. 12 . The compound of any one of claims 1-10 , wherein A 1 is a 6 membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with m occurrences of R 5 and n occurrences of R 6 .
  13. 13 . The compound of any one of claims 1-10 , wherein A 1 is pyridinyl substituted with m occurrences of R 5 and n occurrences of R 6 .
  14. 14 . The compound of any one of claims 1-10 , wherein A 1 is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heteroaryl is substituted with m occurrences of R 5 and n occurrences of R 6 .
  15. 15 . The compound of any one of claims 1-10 , wherein A 1 is or each of which is substituted with m occurrences of R 5 and n occurrences of R 6 .
  16. 16 . The compound of any one of claims 1-15 , wherein n is 1.
  17. 17 . The compound of any one of claims 1-15 , wherein n is 0.
  18. 18 . The compound of any one of claims 1-17 , wherein m is 1.
  19. 19 . The compound of any one of claims 1-8 , wherein the compound is a compound of Formula Id or a pharmaceutically acceptable salt thereof:
  20. 20 . The compound of any one of claims 1-8 , wherein the compound is a compound of Formula Ie or a pharmaceutically acceptable salt thereof:

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 63/405,676, filed Sep. 12, 2022, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION The invention provides isothiazolylcarboxamide compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, or autoimmune disorder. BACKGROUND Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects. Moreover, new therapies that achieve an anti-cancer effect through a different mechanism present an opportunity to treat cancers more effectively and/or to treat cancers that have become resistant to currently available medicines. Inflammatory disorders impact a substantial number of patients and often involve situations where the patient's biological response to a stimulus results in the immune system attacking the body's own cells or tissues. This can lead to abnormal inflammation and result in chronic pain, redness, swelling, stiffness, and/or damage to normal tissues. Current treatment options for these inflammatory disorders are not effective for all patients and/or can have substantial adverse side effects. Human mucosa-associated lymphoid tissue protein 1 (MALT1) is a key regulator of immune responses and is an immune modulatory target for the treatment of autoimmune and inflammatory diseases. In addition, research indicates that MALT1 inhibition impairs immune suppressive function of regulatory T cells in a tumor microenvironment, implicating MALT1 inhibitors for boosting anti-tumor immunity in the treatment of solid cancers. See, for example, Isabel Hamp et al. in Expert Opinion on Therapeutic Patents (2021) vol. 12, pages 1079-1096. The present invention addresses the foregoing needs and provides other related advantages. SUMMARY The invention provides isothiazolylcarboxamide compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, or autoimmune disorder. In particular, one aspect of the invention provides a collection of isothiazolylcarboxamide compounds, such as a compound represented by Formula I. or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of isothiazolylcarboxamide compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Another aspect of the invention provides a method of treating a disease or condition mediated by MALT1 in a subject. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I or I-1, or other compound in Section I, to a subject in need thereof to treat the disease or condition, as further described in the detailed description. Another aspect of the invention provides a method of inhibiting the activity of MALT1. The method comprises contacting a MALT1 with an effective amount of a compound described herein, such as a compound of Formula I or I-1, or other compound in Section I, to inhibit the activity of said MALT1, as further described in the detailed description. DETAILED DESCRIPTION The invention provides isothiazolylcarboxamide compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, or autoimmune disorder. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in Comprehensive Organic Synthesis (B. M. Trost & I. Fleming, eds., 1991-1992); Handbook of Experimental Immunology (D. M. Weir & C. C. Blackwell, eds.); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987, and periodic updates); and Current Protocols in Immunology” (J. E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety. Var