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CN-121974931-A - Macrocyclic compounds and uses thereof

CN121974931ACN 121974931 ACN121974931 ACN 121974931ACN-121974931-A

Abstract

The present disclosure relates to macrocyclic compounds and uses thereof, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat diseases such as cancer.

Inventors

  • CUI JINGRONG

Assignees

  • 荣山医药股份有限公司

Dates

Publication Date
20260505
Application Date
20210708
Priority Date
20200710

Claims (10)

  1. 1. A compound of formula I or a pharmaceutically acceptable salt thereof, Wherein the method comprises the steps of A is a 5 to 10 membered heteroarylene or C 6 -C 10 arylene; each L is independently-C (R 3 )(R 4 )-、-C(O)-、-O-、-N(R 5 ) -, -S-, -S (O) -or-S (O) 2 -, the limitation is that, (L) n does not contain-O-; -O-S-or-O-N (R 5 ) -bond; x is N or C (R 6 ); X 1 is N or C (R 7 ); x 2 is N or C (R 8 ); X 3 is N or C (R 9 ); x 4 is N or C (R 10 ); y and Y 1 are each independently O or S; Y 2 is-O- -N (R 11 ) -or-S-; Z is 3 to 7 membered heterocycloalkylene, C 3 -C 6 cycloalkylene, C 6 -C 10 arylene, 5 to 10 membered heteroarylene, -C (R 12 )(R 13 )-、-C(O)-、-O-、-N(R 14 ) -, -S (O) -or-S (O) 2 -, wherein each hydrogen atom of 3 to 7 membered heterocycloalkylene, C 3 -C 6 cycloalkylene, C 6 -C 10 arylene and 5 to 10 membered heteroarylene is independently optionally substituted with deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e 、-CN or-NO 2 ; Z 1 is-NR 2 C(Y 1 )-、-C(Y 1 )NR 2 -、-O-、-N(R 2 ) -, -S-; -S (O) -or-S (O) 2 -, Each R 1 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl 、-OR a 、-OC(O)R a 、-OC(O)NR a R b 、-OS(O)R a 、-OS(O) 2 R a 、-SR a 、-S(O)R a 、-S(O) 2 R a 、-S(O)NR a R b 、-S(O) 2 NR a R b 、-OS(O)NR a R b 、-OS(O) 2 NR a R b 、-NR a R b 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b 、-NR a S(O)R b 、-NR a S(O) 2 R b 、-NR a S(O)NR a R b 、-NR a S(O) 2 NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-PR a R b 、-P(O)R a R b 、-P(O) 2 R a R b 、-P(O)NR a R b 、-P(O) 2 NR a R b 、-P(O)OR a 、-P(O) 2 OR a 、-CN, or-NO 2 , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl is independently optionally substituted with deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e 、-CN, or-NO 2 ; R 2 、R 5 、R 11 or R 14 are each independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl is independently optionally substituted with deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e' 、-CN, or-NO 2 ; Each R 3 、R 4 、R 12 and R 13 is independently H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, c 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl 、-OR c 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=N)NR c R d 、-OS(O)R c 、-OS(O) 2 R c 、-OS(O)NR c R d 、-OS(O) 2 NR c R d 、-SR c 、-S(O)R c 、-S(O) 2 R c 、-S(O)NR c R d 、-S(O) 2 NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=N)NR c R d 、-NR c S(O)R d 、-NR c S(O) 2 R d 、-NR c S(O)NR c R d 、-NR c S(O) 2 NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=N)NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O) 2 R c R d 、-P(O)NR c R d 、-P(O) 2 NR c R d 、-P(O)OR c 、-P(O) 2 OR c 、-CN、-NO 2 , or two of R 3 、R 4 、R 12 and R 13 together with the carbon or carbons to which they are attached form a C 3 -C 6 cycloalkyl or 4 to 6 membered heterocycloalkyl, wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, Each hydrogen atom in the 5-to 10-membered heteroaryl or 4-to 6-membered heterocycloalkyl is independently optionally substituted with deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e 、-CN or-NO 2 ; R 6 is H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or-CN; R 7 and R 8 are each independently a bond to Z, H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5-to 10-membered heteroaryl 、-OR a 、-OC(O)R a 、-OC(O)NR a R b 、-OS(O)R a 、-OS(O) 2 R a 、-SR a 、-S(O)R a 、-S(O) 2 R a 、-S(O)NR a R b 、-S(O) 2 NR a R b 、-OS(O)NR a R b 、-OS(O) 2 NR a R b 、-NR a R b 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b 、-NR a S(O)R b 、-NR a S(O) 2 R b 、-NR a S(O)NR a R b 、-NR a S(O) 2 NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-PR a R b 、-P(O)R a R b 、-P(O) 2 R a R b 、-P(O)NR a R b 、-P(O) 2 NR a R b 、-P(O)OR a 、-P(O) 2 OR a 、-CN or-NO 2 , wherein C 1 -C 6 alkyl, each hydrogen atom in a C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl is independently optionally substituted with deuterium, Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e 、-CN or-NO 2 , with the proviso that one of R 7 or R 8 is a bond to Z; R 9 and R 10 are each independently H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, c 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl 、-OR a 、-OC(O)R a 、-OC(O)NR a R b 、-OS(O)R a 、-OS(O) 2 R a 、-SR a 、-S(O)R a 、-S(O) 2 R a 、-S(O)NR a R b 、-S(O) 2 NR a R b 、-OS(O)NR a R b 、-OS(O) 2 NR a R b 、-NR a R b 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b 、-NR a S(O)R b 、-NR a S(O) 2 R b 、-NR a S(O)NR a R b 、-NR a S(O) 2 NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-PR a R b 、-P(O)R a R b 、-P(O) 2 R a R b 、-P(O)NR a R b 、-P(O) 2 NR a R b 、-P(O)OR a 、-P(O) 2 OR a 、-CN or-NO 2 , or R 8 and R 9 or R 9 and R 10 together with the carbon to which they are attached form C 4 -C 6 cycloalkyl, 4-to 7-membered heterocycloalkyl or C 6 -C 10 -aryl, wherein C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Each hydrogen atom in C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl or 4 to 7 membered heterocycloalkyl is independently optionally substituted with deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e 、-CN or-NO 2 ; Each R a 、R b 、R c 、R d 、R e and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, and 5to 10 membered heteroaryl; m is 0,1, 2, 3 or 4, and N is 2, 3, 4, 5, 6, 7 or 8.
  2. 2. The compound of claim 1, having formula IV Or a pharmaceutically acceptable salt thereof.
  3. 3. The compound of claim 1, having formula VI 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, wherein a is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinyl, pyrazinylene, pyrimidinylene, pyridazinylene or triazinylene.
  5. 5. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein a is a pyrrolylene group.
  6. 6. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein a is Or (b) Wherein R 1a is C 1 -C 6 alkyl, -C (O) R a 、-C(O)OR a 、-C(O)NR a R b , or-P (O) 2 OR a , wherein each hydrogen atom in the C 1 -C 6 alkyl group is independently optionally substituted with deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e 、-CN, or-NO 2 .
  7. 7. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein a is Or (b) 。
  8. 8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, each R 1 is-CN or C 1 -C 6 alkyl, wherein each hydrogen atom in the C 1 -C 6 alkyl is independently optionally substituted with deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl 、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NR e R f 、-P(O)OR e 、-P(O) 2 OR e 、-CN, or-NO 2 .
  9. 9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, each R 1 is-CN or methyl.
  10. 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, R 1a is methyl.

Description

Macrocyclic compounds and uses thereof The present application is a divisional application of the application patent application with the application date of 2021, 7, 8, the application number of 202180050126.8 and the application name of 'macrocyclic compound and its application'. Cross Reference to Related Applications The present application is hereby incorporated by reference in its entirety for all purposes in accordance with 35 U.S. c. ≡119 (e) claiming priority from U.S. provisional application serial No. 63/050,559 to 10/7/2020, U.S. provisional application serial No. 63/143,569 to 29/2021 and U.S. provisional application serial No. 63/217,950 to 2/2021. Technical Field The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat diseases such as cancer. Background Protein kinases are tightly regulated signaling proteins that coordinate activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G) et al, protein kinase complement of the human genome (The protein kinase complement of the human genome.), (Science), 2002, 298:1912-34). Deregulation of kinase activity has been associated with many diseases including cancer as well as cardiovascular diseases, degenerative diseases, immune diseases, infectious diseases, inflammatory diseases and metabolic diseases (lyviski a. (Levitzki, a.), (Protein kinase inhibitors as a therapeutic modality.), (review of chemical research (acc. Chem. Res.)), 2003, 36:462-469) as a protein kinase inhibitor for therapeutic modalities. The molecular basis leading to various diseases includes kinase gain-of-function and loss-of-function mutations, gene amplification and deletions, splice changes and translocations (Wilson LJ) et al, new prospects, opportunities and challenges in the development of the human protein kinase set (NEW PERSPECTIVES, op portunites, AND CHALLENGES IN Exploring the Human Protein kinome.), cancer research (CANCER RES). 2018, 78:15-29). The important role of kinases in cancer and other diseases makes them attractive targets for pharmaceutical inventions, 52 of which have been approved and 46 of which are used in cancer targeted therapies (Rosscosyl R Jr (Roskoski R Jr), FDA approved properties of small molecule protein kinase inhibitors: 2020, more recently (Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A2020 Update.), "pharmacological research (Pharmacol Res)," 2020, 152:104609). despite the great success of kinase inhibitors in cancer targeted therapies, the development of therapeutic resistance remains a challenge for small molecule kinase inhibitors. Acquired secondary mutations within the kinase domain during treatment typically result in therapeutic resistance to kinase inhibitors (Pottier C) et al, tyrosine kinase inhibitors in cancer: breakthrough and challenges of Targeted therapies (Tyrosine Kinase Inhibitors in Cancer: breakthrough AND CHALLENGES of Targeted therapy.), (Basel) (Cancers (Basel)), 2020, 12:731). Thus, there is a need for kinase inhibitors that not only address kinase oncogenic drivers, but also overcome the most common drug resistant mutations for better efficacy and longer disease control. Non-small cell lung cancer (NSCLC) is a major cause of cancer death worldwide (World Health organization—page of cancer information (CANCER FACT SHEET) 2017). Activating EGFR mutations have been reported in cases of adenocarcinoma of approximately 10% to 15% of white patients and 50% of Asian patients (Chen BA), house BG. (Hughes BG.), targeted therapies for non-small cell Lung cancer current standard and future prospect (Targeted therapy for non-small cell lung cancer: current standards and the promise of the future.), " Lung cancer transformation study (Transl Lung CANCER RES) 2015; 4:36-54. The two most common EGFR changes found in NSCLC tumors are the short in-frame deletion of exon 19 of the EGFR gene (del 19) and a single missense mutation in exon 21, L858R (Kang Duli k. (Konduri k.)) et al, EGFR was used as a novel therapeutic target in Lung Cancer (EGFR Fusions as Novel Therapeutic TARGETS IN Lung Cancer.), (Cancer Discovery) 2016, 6:601-11. The first generation reversible EGFR inhibitors erlotinib (erlotinib) and gefitinib (gefitinib) are superior to chemotherapy in advanced EGFR mutation positive (Del 19 or L858R) NSCLC patients and have been used as first line standard care in this case. However, over the course of treatment, most patients will develop resistance to gefitinib or erlotinib, with 50% to 70% of tumors developing the EGFR T790M goalkeeper mutation (tin quinist LV (Sequist LV) et al, genotype and histological evolution of lung cancer's acquired resistance to EGFR inhibitors (Genotypic and histological evolution of lung cancers acquiring resista