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US-12624023-B2 - Sulfonylurea derivatives and uses thereof

US12624023B2US 12624023 B2US12624023 B2US 12624023B2US-12624023-B2

Abstract

The present disclosure relates to compounds of Formula (I) and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as inflammatory, autoinflammatory and autoimmune diseases and cancers.

Inventors

  • Mark G. Bock
  • David Harrison
  • Jane E. SCANLON

Assignees

  • NodThera Limited

Dates

Publication Date
20260512
Application Date
20200611

Claims (14)

  1. 1 . A compound selected from: Com- pound No. Structure 1 2 3 4 6 7 8 9 10 11 12 13 14 15 16 18 19 20 21 22 23 24 25 26 27 28 29 30 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 125 126 127 128 129 130 131 or a pharmaceutically acceptable salt thereof or a deuterium labeled compound thereof.
  2. 2 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  3. 3 . A method of inhibiting inflammasome activity, comprising contacting a cell with a compound of claim 1 or a pharmaceutically acceptable salt thereof.
  4. 4 . A method of treating or preventing an autoinflammatory disorder, autoimmune disorder, neurodegenerative disease, or cancer in a subject, comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
  5. 5 . The method of claim 4 , wherein the autoinflammatory disorder or an autoimmune disorder is selected from cryopyrin-associated auto-inflammatory syndrome (CAPS), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disease, and neuroinflammation occurring in protein misfolding diseases.
  6. 6 . The method of claim 4 , wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.
  7. 7 . The method of claim 4 , wherein the cancer is metastasizing cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small-cell lung carcinoma, head and neck squamous cell carcinoma or colorectal adenocarcinoma.
  8. 8 . The method, compound of claim 5 , wherein the CAPS is familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), or chronic infantile neurological cutaneous and articular (CINCA) syndrome/neonatal-onset multisystem inflammatory disease (NOMID).
  9. 9 . The method of claim 5 , wherein the dermatological disease is acne.
  10. 10 . The method of claim 5 , wherein the neuroinflammation occurring in protein misfolding diseases is a prion disease.
  11. 11 . A method of treating or preventing a neurodegenerative disease in a subject, comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
  12. 12 . The method of claim 11 , wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.
  13. 13 . A method of treating or preventing a cancer in a subject, comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
  14. 14 . The method of claim 13 , wherein the cancer is metastasizing cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small-cell lung carcinoma, head and neck squamous cell carcinoma, or colorectal adenocarcinoma.

Description

RELATED APPLICATION This application is a U.S. National Phase Application, filed under 35 U.S.C. § 371, of International Application No. PCT/EP2020/066185, filed on Jun. 11, 2020, which claims priority to, and the benefit of, U.S. provisional application No. 62/860,664, filed Jun. 12, 2019, the contents of which are hereby incorporated by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure relates to sulfonylurea derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may possess inflammasome inhibitory activity and are accordingly useful in methods of treatment of the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which inflammasome activity is implicated, such as inflammatory, autoinflammatory, autoimmune and oncological diseases. BACKGROUND Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of them is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system like dendritic cells. IL-1 is involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis (Seth L. al. Rev. Immunol. 2009. 27:621-68). In humans, 22 NLR proteins are divided into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple NLR family members are associated with inflammasome formation. Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability activate in response to endogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in gout patients are effective triggers of NLRP3 activation. Similarly, cholesterol crystals found in atherosclerotic patients can also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators led to IL-1 and IL-18 being implicated in a diverse range of pathophysiological indications including metabolic, physiologic, inflammatory, hematologic and immunologic disorders. The disclosure arises from a need to provide further compounds for the specific modulation of NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing compounds are desirable. SUMMARY In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted with one or more R1S;each R1S is independently C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), —O(C1-C6 haloalkyl), —(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl;R2 is —(CX2X2)n—R2S, wherein n is 0, 1, or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo;R2S is C1-C6 alkyl, C3-C16 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C16 cycloalkyl, or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, or oxo; andR3 is 5- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl optionally substituted with one or more R3S, wherein each R3S is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, or C3-C8 heterocycloalkyl wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl is optionally substituted with —O(C1-C6 alkyl), —N(C1-C6 alkyl)2, halo, or —CN. In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Schemes 1-6). In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediate