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JP-2026514378-A - Lactam-containing imidazopyridazine IL-17 inhibitor compound

JP2026514378AJP 2026514378 AJP2026514378 AJP 2026514378AJP-2026514378-A

Abstract

This application discloses compounds having the following formula (I), where R1a , R1b , R1c , R1d , R2a , R2b , R3 , R4 , n, and m are defined herein, or pharmaceutically acceptable salts thereof, as well as methods for producing and using the compounds disclosed herein for treating or improving syndromes, disorders, and/or diseases mediated by IL-17. [Chemical formula 1]

Inventors

  • ゴールドバーグ，スティーブン ディー．
  • ゴードン，ディーン
  • ハンナ，ルーク イー．
  • ロスコット，スティーブン エー．
  • マツヴィーツク，アナスタシア
  • メドゥーナ，スティーブン ピー．

Assignees

  • ヤンセン ファーマシューティカ エヌ．ベー．

Dates

Publication Date
20260511
Application Date
20240327
Priority Date
20230328

Claims (20)

  1. Formula I: A compound of or a pharmaceutically acceptable salt thereof During the ceremony, R1a and R1b are each independently H, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3)alkyl-O-C(1-3) alkyl, or -C( 1-3 ) alkyl-N(C (1-3) alkyl) 2 , where the -C (1-3) alkyl is unsubstituted or substituted with 1 to 6 R1aa groups, or R1a and R1b together with the carbon atoms to which they are bonded form a spiroC (3-5) cycloalkyl, or A spiroheterocylyl is formed by selecting from the following, where • indicates the carbon atom to which R1a and R1b are bonded, or R1a and R1c together form a C (1-2) alkylenyl bridge. R1c is H, halo, -OH, -C (1-3) alkyl, -C (1-3) alkyl-CN, -C (3-5) cycloalkyl, -C (1-3)alkyl-O-C(1-3) alkyl , or -C (1-3) alkyl-N(C (1-3) alkyl) 2 , where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R1aa groups. Each instance of R 1d is independently -OH, halo, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-N-(C (1-3) alkyl) 2 , where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R 1aa groups. Each instance of R 1aa is an independent halo. R2 is H, -OH, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3)alkyl, -C(1-3) alkyl -O-C (3-5) cycloalkyl, or a 4-6 membered heterocycline, wherein the -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, and -C (1-3) alkyl-O-C (3-5) cycloalkyl group are unsubstituted or substituted with 1-6 R2aa groups, or R2a and R1c together with the carbon atoms to which they are bonded to form a C (3-5) cycloalkyl or a 4-6 membered heterocycline. Each instance of R 2aa is independently a halo, -OH, or -CN. R2b is H or -C (1-3) alkyl, or R2a and R2b together with the carbon atoms to which they are bonded to form C=O. R3 is -C (1-10) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, -C (1-6) alkyl-O-C (3-5) cycloalkyl, -C (1-6) alkyl-O-C (3-5) cycloalkyl-C (1-3) alkyl, each of which is either unsubstituted or substituted with 1-6 halo atoms. R4 is a five-membered heteroaryl that is either unsubstituted or substituted with one or two R4a groups. R 4a is halo, -C (1-6) alkyl, -O-C (1-6) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, or -C (0-2) alkyl-C (3-6) cycloalkyl, wherein the -C (1-6) alkyl, the -O-C (1-6) alkyl, the -C (1-6) alkyl-O-C (1-6) alkyl, and the -C (0-2) alkyl-C (3-6) cycloalkyl are either unsubstituted or substituted with 1 to 6 substituents independently selected from halo, -CH3 , -CH2F , -CHF2 , and -CF3 . A compound or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and m is 0, 1, 2, 3, or 4.
  2. The compound has formula Ig-1: A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the formula.
  3. R1a and R1b are each independently H, -C (1-3) alkyl, or -C (3-5) cycloalkyl, where the -C (1-3) alkyl is unsubstituted or substituted with 1 to 6 R1aa groups, or R1a and R1b together with the carbon atoms to which they are bonded form a spiro-C (3-5) cycloalkyl, or A spiroheterocyl is formed by selecting from the formula, where ・ indicates the carbon atom to which R1a and R1b are bonded, or R1a and R1c together form a C (1-2) alkylenyl bridge. R1c is H, halo, -OH, -C (1-3) alkyl, -C (1-3) alkyl-CN, -C (1-3) alkyl-O-C (1-3)alkyl, or -C(1-3 ) alkyl-N(C (1-3) alkyl) 2 , where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R1aa groups. R 1d is independently a halo, a -C (1-3) alkyl, or a -C (3-5) cycloalkyl, where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R 1aa groups. Each instance of R 1aa is independently fluorine. R 2a is H, -OH, or -C (1-3) alkyl, where the -C (1-3) alkyl is unsubstituted or substituted with 1-6 R 2aa groups, or R 2a and R 1c together with the carbon atoms to which they are bonded to form a C (3-5) cycloalkyl or a 4-6 membered heterocycle. Each instance of R 2aa is independently fluorine, -OH, or -CN. R2b is H or -C (1-3) alkyl, or R2a and R2b together with the carbon atoms to which they are bonded to form C=O. R3 is -C (1-10) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, -C (1-6)alkyl-O-C(3-5) cycloalkyl, -C(1-6 ) alkyl-O-C (3-5) cycloalkyl-C (1-3) alkyl, or -C (3-6) cycloalkyl, each of which is either unsubstituted or substituted with 1-6 fluorine atoms. R4 is a five-membered heteroaryl that is either unsubstituted or substituted with one or two R4a groups. R 4a is a halo, -C (1-6) alkyl, -O-C (1-6) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, or -C (0-2) alkyl-C (3-6) cycloalkyl, wherein the -C (1-6)alkyl, the -O-C(1-6) alkyl , the -C (1-6) alkyl-O-C (1-6) alkyl, and the -C (0-2) alkyl-C (3-6) cycloalkyl are either unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3 , -CH2F , -CHF2 , and -CF3 . The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and m is 0, 1, 2, 3, or 4.
  4. R 1a is H, -C (1-3) alkyl, or -C (3-5) cycloalkyl, where the -C (1-3) alkyl is unsubstituted or substituted with 1-6 R 1aa groups, or R 1a and R 1c together form a C (1-2) alkylenyl bridge. R1b is H or -C (1-3) alkyl, where the -C (1-3)alkyl is unsubstituted or substituted with 1-6 R1aa groups, or R1a and R1b together with the carbon atoms to which they are bonded form a spiro-C(3-5 ) cycloalkyl , or A spiroheterocylyl is formed by selecting from the following, where ・ indicates the carbon atom to which R1a and R1b are bonded. R1c is H, halo, -OH, -C (1-3) alkyl, -C (1-3) alkyl-CN, -C (1-3) alkyl-O-C (1-3)alkyl, or -C(1-3 ) alkyl-N(C (1-3) alkyl) 2 , where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R1aa groups. Each instance of R 1d is independently a halo or a -C (1-3) alkyl group, wherein the -C (1-3) alkyl group is either unsubstituted or substituted with 1 to 6 R 1aa groups. Each instance of R 1aa is independently fluorine. R 2a is H, -OH, or -C (1-3) alkyl, where the -C (1-3) alkyl is unsubstituted or substituted with 1-6 R 2aa groups, or R 2a and R 1c together with the carbon atoms to which they are bonded to form a C (3-5) cycloalkyl or a 4-6 membered heterocycle. Each instance of R 2aa is independently either fluorine or -OH. R2b is H or -C (1-3) alkyl, or R2a and R2b together with the carbon atoms to which they are bonded to form C=O. R3 is a -C (1-10) alkyl or -C (3-6) cycloalkyl, each of which is either unsubstituted or substituted with 1-6 fluorine atoms. R4 is a five-membered heteroaryl that is either unsubstituted or substituted with one or two R4a groups. R 4a is -C (1-6) alkyl, -O-C (1-6) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, or -C (0-2) alkyl-C (3-6) cycloalkyl, A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and m is 0, 1, or 2.
  5. R 1a is H, -C (1-3) alkyl, or -C (3-5) cycloalkyl, where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R 1aa groups. R 1b is H or -C (1-3) alkyl, where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R 1aa groups. R1c is H, halo, -OH, -C (1-3) alkyl, -C (1-3) alkyl-CN, -C (1-3) alkyl-O-C (1-3)alkyl, or -C(1-3 ) alkyl-N(C (1-3) alkyl) 2 , where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R1aa groups. Each instance of R 1d is independently a halo or a -C (1-3) alkyl group, wherein the -C (1-3) alkyl group is either unsubstituted or substituted with 1 to 6 R 1aa groups. Each instance of R 1aa is independently fluorine. R 2a is H, -OH, or -C (1-3) alkyl, where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R 2aa groups. Each instance of R 2aa is independently fluorine. R2b is H or -C (1-3) alkyl, or R2a and R2b together with the carbon atoms to which they are bonded to form C=O. R3 is a -C (4-10) alkyl or cyclohexyl group, each of which is either unsubstituted or substituted with 1-6 fluorine atoms. R4 is a five-membered heteroaryl that is either unsubstituted or substituted with one or two R4a groups. R 4a is -C (1-6) alkyl, -O-C (1-6) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, or -C (3-6) cycloalkyl. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and m is 0, 1, or 2.
  6. R 1a is H or -C (1-3) alkyl, where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R 1aa groups. R 1b is H or -C (1-3) alkyl, where the -C (1-3) alkyl is either unsubstituted or substituted with 1 to 6 R 1aa groups. R1c is H, halo, -OH, -C (1-3) alkyl, -C (1-3) alkyl-CN, -C (1-3) alkyl-O-C (1-3)alkyl, or -C(1-3 ) alkyl-N(C (1-3) alkyl) 2 . Each instance of R 1d is independently a halo or a -C (1-3) alkyl group, wherein the -C (1-3) alkyl group is either unsubstituted or substituted with 1 to 6 R 1aa groups. Each instance of R 1aa is independently fluorine. R 2a is H, -OH, or -C (1-3) alkyl, R 2b is H or -C (1-3) alkyl, R3 is a -C (4-10) alkyl or cyclohexyl group, each of which is substituted with 1 to 6 fluorine atoms. R4 is a five-membered heteroaryl that is either unsubstituted or substituted with one or two R4a groups. R 4a is -C (1-6) alkyl, -O-C (1-6) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, or -C (3-6) cycloalkyl. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and m is 0, 1, or 2.
  7. R 1a is a -C (1-3) alkyl group, where the -C (1-3) alkyl group is either unsubstituted or substituted with 1-3 R 1aa groups. R 1b is H or -C (1-3) alkyl, where the -C (1-3) alkyl is either unsubstituted or substituted with 1-3 R 1aa groups. R1c is H, halo, -OH, -C (1-3) alkyl, -C (1-3) alkyl-CN, -C (1-3) alkyl-O-C (1-3)alkyl, or -C(1-3 ) alkyl-N(C (1-3) alkyl) 2 . Each instance of R 1aa is independently fluorine. R 2a is H or -OH, R 2b is H, R3 is a -C (4-8) alkyl group substituted with 1 to 3 fluorine atoms, or And, R 4 , And, R 4a is a -C (1-6) alkyl, -O-C (1-6) alkyl, or -C (3-6) cycloalkyl, A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein n is 1 and m is 0.
  8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 1.
  9. Formulas Ib-1 to Ib-7: A compound according to claim 8 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.
  10. Formulas Ib-1a to Ib-7a: A compound according to claim 8 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.
  11. Formula Ib-8: A compound according to claim 8 or a pharmaceutically acceptable salt thereof having the formula.
  12. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 2.
  13. Formulas Ic-1 to Ic-7: A compound according to claim 12 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of the following.
  14. Formulas Ic-1a to Ic-7a: A compound according to claim 12 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of the following.
  15. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 3.
  16. Formulas Id-1 to Id-2: A compound according to claim 15 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.
  17. Formulas Id-1a to Id-2a: A compound according to claim 15 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.
  18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 1a is H, -C (1-3) alkyl, or -C (3-5) cycloalkyl, and the -C (1-3) alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and R 1b is H or -C ( 1-3 ) alkyl, where the -C (1-3) alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms.
  19. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 1a is H, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , or cyclopropyl, and R 1b is H, -CH 3 , or -CF 3 .
  20. The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 1a is H or -C (1 to 3) alkyl, and the -C (1 to 3) alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms.

Description

(Reference to electronically submitted sequence listings) This application includes a sequence listing submitted electronically via EFS-Web as a sequence listing in ST. 26 XML format, with the filename "PRD4255WOPCT1-SeqListing.xml", created on March 12, 2024, and having a size of 3KB. The sequence listing submitted via EFS-Web is part of this specification and is incorporated herein by reference in its entirety. Interleukin-17 ("IL-17"), also known as IL-17A, and CTLA-8 are primarily produced by CD4+ Th17 cells, but are also produced by other immune cells such as CD8+ T cells, γδ T cells, NK cells, NKT cells, and innate lymphoid cells (ILCs). IL-17A exists as a homodimer (A/A) or as a heterodimer (A/F) with IL-17F, and signals are transmitted through binding to the dimer receptor complexes IL-17RA and IL-17RC. IL-17RA is expressed at particularly high levels and ubiquitously depending on hematopoietic cell type, while IL-17RC is preferentially expressed in non-hematopoietic cells (Gaffen, S. Structure and signaling in the IL-17 receptor family. Nat. Rev. Immunol. 2009, 9, 556-567). IL-17A/IL-17R signaling induces de novo gene transcription by triggering the NF-κB, C/EBP, and MAPK pathways via ACT1-TRAF6-TRAF4. This can also stabilize target mRNA transcription via the ACT1-TRAF2-TRAF5 complex (Amatya N. et al., Trends in Immunology, 2017, 38, 310-322). IL-17A stimulates the release of inflammatory mediators, including IL-6, IL-8, G-CSF, TNF-α, and IL-1β, which recruit lymphocytes to the injury or inflammation site, activate them, and maintain a pro-inflammatory state. As discussed below in this disclosure, preclinical and clinical data demonstrate the important pathological role of IL-17A in several autoimmune and inflammatory diseases. In summary, animal and human studies demonstrate that IL-17A plays a crucial role in the pathogenesis of the aforementioned diseases and/or conditions. The importance of targeting IL-17A is demonstrated by the transformative efficacy of injectable IL-17A neutralizing antibodies in patients. Despite the advances achieved with injectable IL-17A antagonist antibodies, the development of oral small molecule IL-17A inhibitors has long been urgently needed because they have the potential to broaden treatment options for many patients without the use of biologics. Furthermore, safe and effective small molecule IL-17A inhibitors can offer patients significant advantages over injectable IL-17A neutralizing antibodies, such as convenient dosing regimens and cost reductions, ultimately enabling effective long-term disease management. However, the development of oral small molecule therapies remains challenging. For example, none of the oral small molecule IL-17A inhibitors have yet progressed to late-stage clinical trials; as of September 28, 2021, only two (NCT04586920 and NCT04883333) have advanced to Phase I clinical trials. Furthermore, as of December 2021, one of these clinical trials (NCT04586920) was suspended for safety review. Therefore, new small molecule IL-17A regulators (e.g., inhibitors) are needed. Definitions The discussions of documents, operations, materials, devices, articles, etc., contained herein are for contextual purposes only. Such discussions do not imply that any or all of these things constitute prior art to any compound or method disclosed or claimed. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art in the field to which the disclosed patent pertains. Otherwise, any specific terms used herein have the meanings set forth herein. It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple reference subjects unless otherwise clearly indicated by the context. To assist readers of this application, this description is divided into various paragraphs or sections, or directed to various embodiments of this application. These divisions should not be considered to separate any paragraph or section or embodiment from another paragraph or section or embodiment. On the contrary, those skilled in the art will understand that this description has broad applications and encompasses all possible combinations of sections, paragraphs, and sentences. Any consideration of embodiments is intended to be illustrative only and is not intended to imply that the scope of this disclosure, including the claims, is limited to these embodiments. In relation to the methods of the present invention, the term "administering" means a method for therapeutically or preventively preventing, treating, or improving a syndrome, disorder, or disease described herein by using the compounds of this disclosure or pharmaceutically acceptable salts thereof, compositions thereof, or pharmaceuticals thereof. Such methods include administering therapeutically effective amounts of the compounds of this disclosure or pharmaceutically accep