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EP-4736882-A2 - TROPOMYOSIN RECEPTOR KINASE (TRK) DEGRADATION COMPOUNDS AND METHODS OF USE

EP4736882A2EP 4736882 A2EP4736882 A2EP 4736882A2EP-4736882-A2

Abstract

This disclosure relates to bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and to methods of use the bivalent compounds for the treatment of certain disease in a subject in need thereof. The disclosure also relates to 5 methods for identifying such bivalent compounds.

Inventors

  • LIU, JING
  • PLEWE, MICHAEL BRUNO
  • WANG, JIALIANG
  • HAN, Xiaoran
  • CHEN, LIQUN

Assignees

  • Cullgen (Shanghai), Inc.

Dates

Publication Date
20260506
Application Date
20190821

Claims (14)

  1. A bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt thereof, wherein the TRK ligand is conjugated to the degradation tag via a linker moiety, the TRK ligand comprises a moiety of Formula 1: wherein X is selected from CR'R", CO, O, S, SO, SO 2 , and NR', wherein R' and R" are independently selected from hydrogen, halogen, OH, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 3 -C 10 cycloalkoxy, and optionally substituted 3-10 membered heterocyclyl; or R' and R" together with the atom to which they are connected form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring; R is selected from optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1 , R 2 , and R 3 are independently selected from hydrogen, halogen, CN, NO 2 , OR 5 , SR 6 , NR 7 R 8 , COR 5 , CO 2 R 5 , C(O)NR 7 R 8 , SOR 5 , SO 2 R 5 , SO 2 NR 7 R 8 , NR 7 C(O)R 8 , NR 5 C(O)NR 7 R 8 , NR 7 SOR 8 , NR 7 SO 2 R 8 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 3 -C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl, wherein R 5 , R 6 , R 7 , and R 8 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, or R 7 and R 8 together with the atom to which they are connected form an optionally substituted 4-8 membered heterocyclyl ring; R 4 is connected to the linker moiety of the bivalent compound, and is selected from a bond, OR 9 , SR 9 , NR 10 R 11 , COR 9 , CO 2 R 9 , CONR 10 R 11 , SOR 9 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 10 COR 11 , NR 9 CONR 10 R 11 , NR 10 SOR 11 , NR 10 SO 2 R 11 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, aryl, and optionally substituted heteroaryl, wherein R 9 , R 10 , and R 11 are independently selected from null, a bond, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10 and R 11 together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring; and Ar is selected from aryl and heteroaryl group, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, NO 2 , OR 12 , SR 12 , NR 13 R 14 , COR 12 , CO 2 R 12 , CONR 13 R 14 , SOR 12 , SO 2 R 12 , SO 2 NR 13 R 14 , NR 13 COR 14 , NR 15 C(O)NR 13 R 14 , NR 13 SOR 14 , NR 13 SO 2 R 14 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 12 , R 13 , R 14 , and R 15 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 13 and R 14 together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring; wherein the degradation tag is a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C and 5D: wherein, V, W, and X are independently selected from CR 2 and N; Y is selected from CO and CH 2 ; Z is selected from null, CH 2 , CH=CH, C=C, NH and O; R 1 is selected from hydrogen, C 1 -C 5 alkyl and halogen; and R 2 is selected from hydrogen, halogen and C 1 -C 5 alkyl; wherein the linker moiety comprises a ring of Formula C1: wherein X' is CH, Y' is N, m is 1 and n is 1; and wherein the linker moiety is of Formula 9: wherein A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R ' -R " , R ' COR " , R ' CO 2 R " , R ' C(O)N(R 1 )R " , R ' C(S)N(R 1 )R " , R ' OR " , R ' OC(O)R " , R ' OC(O)OR " , R ' OCON(R 1 )R " , R ' SR " , R'SOR", R ' SO 2 R " , R ' SO 2 N(R 1 )R " , R ' N(R 1 )R " , R ' NR 1 COR " , R ' NR 1 C(O)OR " , R ' NR 1 CON(R 2 )R " , R ' NR 1 C(S)R " , R ' NR 1 S(O)R " , R ' NR 1 S(O) 2 R " , and R ' NR 1 S(O) 2 N(R 2 )R " , wherein R ' and R " are independently selected from null, optionally substituted R r -(C 1 -C 8 alkyl), or a moiety comprising of optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1 and R 2 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R ' and R " , R 1 and R 2 , R ' and R 1 , R ' and R 2 , R " and R 1 , R " and R 2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and m is 0 to 15.
  2. The bivalent compound of claim 1, wherein the degradation tag is a moiety selected from the group consisting of FORMULA 5B and FORMULA 5C.
  3. The bivalent compound of any one of claims 1 to 2, wherein X is selected from CH 2 , cyclopropylene, CHF, CF 2 , O, NH, NCH 3 , NCH 2 CH 3 , and N-isopropyl.
  4. The bivalent compound of any one of claims 1 to 3,wherein R is selected from optionally substituted phenyl and optionally substituted heteroaryl.
  5. The bivalent compound of any one of claims 1 to 4, wherein X is CH 2 ; and R is 3,5-difluorophenyl.
  6. The bivalent compound of any one of claims 1 to 5, wherein R 1 , R 2 , and R 3 are independently selected from hydrogen, F, Cl, and OH.
  7. The bivalent compound of any one of claims 1 to 6, wherein: wherein * indicates the connection to the linker moiety of the bivalent compound; and R a is selected from hydrogen, halogen, NR 13 R 14 , and NR 13 COR 14 , wherein R 13 and R 14 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, phenyl, and optionally substituted C 5 -C 6 heteroaryl, or R 13 and R 14 together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.
  8. The bivalent compound of claim 7, wherein R a is (tetrahydro-2H-pyran-4-yl)amino.
  9. A pharmaceutical composition comprising a bivalent compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  10. The pharmaceutical composition of claim 9, for use in a method of treating a tropomyosin receptor kinase (TRK)-mediated disease, the method comprising administering the pharmaceutical composition to a subject with a TRK-mediated disease.
  11. The pharmaceutical composition for use according to claim 10, wherein the TRK-mediated disease is cancer.
  12. The pharmaceutical composition for use according to claim 10, wherein the TRK-mediate disease is selected from the group consisting of non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, prostate cancer low-grade glioma, glioblastoma, Spitzoid cancer, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumors, pheochromocytoma, and Wilms' tumor.
  13. The pharmaceutical composition for use according to claim 10, wherein the TRK-mediated disease is acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmennorhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization.
  14. The pharmaceutical composition for use according to claim 10, wherein the TRK-mediate disease is chronic pain.

Description

BACKGROUND OF THE INVENTION This disclosure relates to bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and to methods of use of the bivalent compounds for the treatment of certain diseases in a subject in need thereof. The disclosure also relates to methods for identifying such bivalent compounds. SUMMARY OF THE INVENTION According to one aspect of the present disclosure, a bivalent compound disclosed herein comprises a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. In one embodiment, the TRK ligand is capable of binding to a TRK protein comprising TRK, a TRK mutant, TRK deletion, or a TRK fusion protein. In another embodiment, the TRK ligand is a TRK kinase inhibitor or a portion of TRK kinase inhibitor. In another embodiment, the TRK ligand is selected from the group consisting of altiratinib (DCC2701, DCC-270, DP-5164), sitravatinib (MGCD516), cabozantinib (XL-184, BMS-907351), dovitinib (TKI-258, CHIR-258), entrectinib (RXDX-101), milciclib (PHA-848125AC), belizatinib (TSR-011), GZ389988, pegcantratinib, AZD7451, larotrectinib (LOXO-101; ARRY-470), TPX-0005, LOXO-195, regorafenib, DS-6051b, F17752, PLX7486, AZD-6918, ASP7962, ONO-4474, PF-06273340, GNF-8625, and analogs thereof. In another embodiment, the degradation tag binds to an ubiquitin ligase, or is a hydrophobic group or a tag that leads to misfolding of the TRK protein. In another embodiment, the ubiquitin ligase is an E3 ligase. In another embodiment, the E3 ligase is selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, and an IAP ligase. In another embodiment, the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1-((-4.-4.5.5.5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, and analogs thereof. In another embodiment, the TRK ligand is conjugated to the degradation tag via a linker moiety. In another embodiment, the TRK ligand comprises a moiety of Formula 1 wherein X is selected from CR'R", CO, O, S, SO, SO2, and NR', wherein R' and R" are independently selected from hydrogen, halogen, OH, optionally substituted C1-C8 alkyl, optionally substituted C1-8 alkoxy, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkoxy, and optionally substituted 3-10 membered heterocyclyl: orR' and R" together with the atom to which they are connected form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;R is selected from optionally substituted C1-C8 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;R1, R2, and R3 are independently selected from hydrogen, halogen, CN, NO2, OR5, SR6, NR7R8, COR5, CO2R5, C(O)NR7R8, SOR5, SO2R5, SO2NR7R8, NR7C(O)R8, NR5C(O)NR7R8, NR7SOR8, NR7SO2R3, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl, wherein R5, R6, R7, and R8 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, orR7 and R8 together with the atom to which they are connected form an optionally substituted 4-8 membered heterocyclyl ring;R4 is connected to the linker moiety of the bivalent compound, and is selected from a bond, OR9, SR9, NR10R11, COR9, CO2R9, CONR10R11, SOR9, SO2R9, SO2NR10R11, NR10COR11, NR9CONR10R11, NR10SOR11, NR10SO2R11, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl, and optionally substituted heteroaryl, wherein R9, R10, and R11 are independently selected from null, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally sub