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JP-7854780-B2 - Compounds that are active against nuclear receptors

JP7854780B2JP 7854780 B2JP7854780 B2JP 7854780B2JP-7854780-B2

Inventors

  • サネ シュレーダー グラド
  • イアン サルバリー
  • アレクス ホー ゴリアエフ
  • トマス フランク
  • セーレン イェンスビュー ニルスン
  • ルイージ ピエロ スタシ

Assignees

  • ヌエヴォリューション・アクティーゼルスカブ

Dates

Publication Date
20260507
Application Date
20201218
Priority Date
20191220

Claims (20)

  1. Compounds according to formula (I) , its stereoisomer, or a pharmaceutically acceptable salt of the compound or stereoisomer (wherein Y1 , Y2 , and Y3 are independently -N- or -CR8- ; m is independently selected from 0, 1, and 2; R is selected from the group consisting of hydrogen, C1-6 alkyl, and C1-4 hydroxyalkyl; R0a and R0b are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl; R1a and R1b are independently selected from the group consisting of hydrogen, hydroxyl, halogen, amino, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl; R2 is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -C(=O) NH2 , -C(=O)OH, -C(=O)O- C1-4 alkyl, and substituted or unsubstituted heteroaryl; Ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl ; Each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl; and C1-4 hydroxyhaloalkyl; R 5 is either absent or is hydrogen or a C1-4 alkyl group; R 6 is selected from the group consisting of hydrogen, -CN, halogens, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 hydroxyhaloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and substituted or unsubstituted heteroaryl; R7 is selected from the group consisting of hydrogen, hydroxyl, -CN, halogen , C1-4 alkyl , C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; Each R 8 is independently selected from the group consisting of hydrogen, hydroxyl, -CN, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; and if R 7 is hydrogen and each present R 8 is hydrogen, then R 6 is always selected from the group consisting of -CN, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 hydroxyhaloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and substituted or unsubstituted heteroaryl; and if substituted, the heteroaryl is C1-4 alkyl, C1-4 hydroxyalkyl, C2-4 alkenyl, C2-4 alkynyl, hydroxy, C1-4 alkoxy, cyano, halogen, C1-4 haloalkyl, C1-4 haloalkoxy , and C (Substituted with 1 to 3 groups independently selected from the group consisting of 1 to 6 hydroxyhaloalkyl groups).
  2. The compound, stereoisomer, or salt according to claim 1, wherein R is hydrogen.
  3. The compound, stereoisomer, or salt according to claim 1 or 2 , wherein R 0a is selected from the group consisting of hydrogen, methyl, -CH₂OH , -CH₂CH₂OH , -CH₂F , and -CHF₂ ; and R 0b is selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl.
  4. A compound, stereoisomer, or salt according to any one of claims 1 to 3, wherein at least one of R1a , R1b , and R2 is not hydrogen.
  5. A compound, stereoisomer, or salt according to any one of claims 1 to 4, wherein R 1a is selected from the group consisting of hydroxyl, fluoro, and -CF3 ; and R 1b is selected from the group consisting of hydrogen, fluoro, and methyl.
  6. A compound, stereoisomer, or salt according to any one of claims 1 to 5, wherein R 1b is hydrogen.
  7. A compound, stereoisomer, or salt according to any one of claims 1 to 6 , wherein R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, methyl, ethyl , -CH₂OH , -CH₂CH₂OH , and -C(=O)O-C1-2alkyl groups.
  8. A compound, stereoisomer, or salt according to any one of claims 1 to 7 , wherein m is 0.
  9. A compound, stereoisomer, or salt according to any one of claims 1 to 7 , wherein each R3 is independently halogen or methyl, and m is 1 or 2.
  10. A compound, stereoisomer, or salt according to any one of claims 1 to 9 , wherein R5 is hydrogen.
  11. The compound, stereoisomer, or salt according to any one of claims 1 to 10, wherein R 6 is selected from the group consisting of hydrogen, halogen, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 hydroxyhaloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  12. A compound, stereoisomer, or salt according to any one of claims 1 to 11 , wherein R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -CF3 , -OCHF2 , -CHF2 , and -OCF3 .
  13. A compound, stereoisomer, or salt according to any one of claims 1 to 12 , wherein Y1 , Y2 , and Y3 are independently -CH-; or Y1 is -N- and Y2 and Y3 are independently -CH-; or Y2 is -N- and Y1 and Y3 are independently -CH-; or Y3 is -N- and Y1 and Y2 are independently -CH-; or Y3 is -CH- and Y1 and Y2 are independently -N-.
  14. A compound, stereoisomer, or salt according to any one of claims 1 to 12, wherein Y1 is -CH-, Y2 and Y3 are independently -CR8- , and each R8 is independently selected from the group consisting of hydrogen, methyl, fluoro, hydroxyl, and -CF3 .
  15. The compound, stereoisomer, or salt according to claim 14 , wherein each R8 is hydrogen.
  16. A compound, stereoisomer, or salt according to any one of claims 1 to 11 , wherein R 6 is hydrogen, at least one of Y 2 or Y 3 is -CR 8- , and R 8 is selected from the group consisting of -CN, hydroxyl, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.
  17. R is hydrogen; R0a and R0b are independently hydrogen or methyl; R 1a is selected from the group consisting of hydrogen, fluoro, and hydroxyl; R1b is hydrogen or fluoro; R2 is selected from the group consisting of hydrogen, fluoro, and hydroxyl; Ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl; m is selected from the group consisting of 0, 1, and 2; R3 is selected from the group consisting of hydrogen, fluoro, and methyl; R5 is either nonexistent or hydrogen; R 6 is selected from the group consisting of hydrogen, -CF3 , -OCF3 , and -Cl; R7 is hydrogen or fluoro; and Y1 , Y2 and Y3 are (1) to (5) below: (1) Y1 , Y2 , and Y3 are each -CH-; (2) Y1 is -CH-, Y2 is -CH-, and Y3 is -C(OH)-; (3) Y1 is -CH-, Y2 is -CH-, and Y3 is -N-; (4) Y1 is -CH-, Y2 is -C( CF3 )-, and Y3 is -CH-; and (5) Y1 is -CH-, Y2 is -N-, and Y3 is -CH- The compound, stereoisomer, or salt according to claim 1, which is any one of the following.
  18. 2-(4-(((5-fluoro-6-(3-(5-trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)-2-methylpropanamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-4-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(4-fluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane-2-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, A compound, stereoisomer, or salt according to claim 1, selected from the group consisting of 2-(3,3-difluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide and 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide.
  19. A compound, stereoisomer, or salt according to claim 1 having the structure of the compound, stereoisomer, or salt described in claim 1.
  20. A pharmaceutical composition for use in the treatment and/or prevention of inflammatory, metabolic, tumor, or autoimmune diseases, comprising a compound, stereoisomer, or salt according to any one of claims 1 to 19 .

Description

Cross-reference of related applications This application claims priority under § 119(e) of U.S. Provisional Patent Application No. 62/951,239, filed on 20 December 2019, which disclosure is incorporated herein by reference in its entirety. The embodiments and models described herein relate to compounds active against nuclear receptors, pharmaceutical compositions containing such compounds, and methods for treating inflammatory, metabolic, tumor, and autoimmune diseases or disorders using such compounds. Nuclear receptors are a family of transcription factors involved in regulating physiological functions such as cell differentiation, embryonic development, and organ physiology. Nuclear receptors have also been identified as important pathological regulators in diseases such as cancer, diabetes, and autoimmune disorders. Examples of nuclear receptors include nuclear retinoic acid receptor-associated orphan receptors (RORs). RORs contain four main domains: the N-terminal A/B domain, the DNA-binding domain, the hinge domain, and the ligand-binding domain. Ligand binding to the ligand-binding domain is thought to induce conformational changes in the downstream domains. Various isoforms exist, differing only in the N-terminal A/B domain (Non-Patent Literature 1). ROR consists of three members: ROR-alpha (RORα or RORa), ROR-beta (RORβ or RORb), and ROR-gamma (RORγ or RORc). RORα is expressed in many tissues, including cerebellar Purkinje cells, liver, thymus, skeletal muscle, skin, lungs, adipose tissue, and kidneys. RORα regulates neuronal development, bone metabolism, and arteriosclerosis (Non-Patent Literature 1). Furthermore, RORα plays a role in immune responses, including the expression of interleukin (IL) 17A in T helper (Th) 17 cells and the regulation of regulatory T (Treg) cell function (Non-Patent Literature 2; Non-Patent Literature 3). RORβ exhibits a restricted expression pattern limited to specific brain regions (cerebral cortex, thalamus, hypothalamus, and pineal gland) and the retina (Non-Patent Literature 1). RORβ is associated with epilepsy and, together with RORa, is also associated with bipolar disorder (Non-Patent Literature 4; Non-Patent Literature 5). RORγ exhibits a broad expression pattern and was the last of the three members to be discovered. To date, two distinct protein isoforms have been documented: RORγ1 and RORγ2 (RORγ2 is also known as RORγt). Generally, RORγ is used to describe RORγ1 and/or RORγt. RORγ1 is expressed in many tissues, primarily in the kidneys, liver, and skeletal muscle. In contrast, RORγt expression is limited to several cell types of the immune system as well as lymphoid organs such as the thymus and secondary lymphoid tissues (Non-Patent Literature 6; Non-Patent Literature 1). RORγt has been identified as an important regulator of Th17 cell differentiation and IL-17 production by γδ T cells, Th17 cells, T cell-toxic (Tc) 17 cells, and innate lymphoid cell type 3 (ILC3) cells (Non-Patent Literature 7). Th17 cells are a subset of T helper cells that preferentially produce cytokines IL-17A, IL-17F, IL-21, and IL-22 (Non-Patent Literature 2). T cells lacking RORγt cannot differentiate into Th17 cells even under Th17 polarization culture conditions, but overexpression of RORγt in naive CD4+ T cells was sufficient to promote the expression of Th17-related cytokines and chemokines (Non-Patent Literature 8; Non-Patent Literature 9). IL-23 is a critical checkpoint in the generation, maintenance, and activation of pathogenic Th17 cells. In response to IL-23 signaling, RORγt, in cooperation with a network of transcription factors (STAT3, IRF4, and BATF), initiates the complete differentiation program of Th17 cells (Non-Patent Literature 8). Th17 cells and the IL-17 immune response have been shown to be associated with the pathology of many human inflammatory and autoimmune disorders. Therapeutic strategies targeting the IL-23-IL-17 system have been developed for many autoimmune diseases, and some of these have already demonstrated clinical efficacy in certain conditions (Non-Patent Literature 10; Non-Patent Literature 11). Therefore, there is evidence that RORα, RORβ, and RORγ play a role in the pathogenesis of many diseases. It would be desirable to provide compounds that modulate the activity of RORα and/or RORγ for use in the treatment of inflammatory, metabolic, and autoimmune diseases. Patent Documents 1 and 2 describe compounds that modulate the activity or ROR gamma receptor. However, there remains a need for potent ROR gamma modulators with improved physicochemical properties. International Publication No. 2016020288 PamphletInternational Publication No. 2016020295U.S. Patent No. 7,931,909 Jetten, 2009, Nuclear Receptor SignalingCastro PLOS 2017Malhotra 2018Rudolf 2016Lai 2015Hirose 1994Gaffen 2014Gaffen 2014, Nat Rev ImmunolYang 2014, Trend Pharmacol SciPatel 2015Krueger 2018 Exp DermatolGreene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed. , John Wiley