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EP-4739310-A1 - ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1 (ENPP1) INHIBITOR COMBINATIONS AND USES THEREOF

EP4739310A1EP 4739310 A1EP4739310 A1EP 4739310A1EP-4739310-A1

Abstract

Described herein are methods of treating cancer using a small molecule Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) inhibitor and an additional agent.

Inventors

  • CHEN, XIAOJING
  • PU, Congying
  • LIU, JIN
  • ZHANG, Man
  • CHENG, XIN
  • LIU, Yingtao
  • QIN, Luoheng
  • REN, FENG
  • YU, Huaxing

Assignees

  • Insilico Medicine IP Limited

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject: (a) a compound of Formula (I) , or a pharmaceutically acceptable salt thereof: wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond, -NH-, or -O-; each R 1 is independently halogen, -CN, -NO 2 , -OH, -OR a , -OC (=O) R a , -OC (=O) OR b , -OC (=O) NR c R d , -SH, -SR a , -S (=O) R a , -S (=O) 2 R a , -S (=O) 2 NR c R d , -NR c R d , -NR b C (=O) NR c R d , -NR b C (=O) R a , -NR b C (=O) OR b , -NR b S (=O) 2 R a , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R 1 on the same atom are taken together to form an oxo; n is 0-6; R 2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; R 3 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; is a single bond or a double bond; wherein: when is a double bond, X is N or CR X and Y is N or CR Y ; when is a single bond, X is C (=O) and Y is NR Y1 or C (R Y2 ) 2 ; R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; R Y1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; each R Y2 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 4 is independently halogen, -CN, -NO 2 , -OH, -OR a , -OC (=O) R a , -OC (=O) OR b , -OC (=O) NR c R d , -SH, -SR a , -S (=O) R a , -S (=O) 2 R a , -S (=O) 2 NR c R d , -NR c R d , -NR b C (=O) NR c R d , -NR b C (=O) R a , -NR b C (=O) OR b , -NR b S (=O) 2 R a , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R 4 on the same atom are taken together to form an oxo; m is 0-4; R 5 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl (cycloalkyl) , C 1 -C 6 alkyl (heterocycloalkyl) , C 1 -C 6 alkyl (aryl) , or C 1 -C 6 alkyl (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R a are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl (cycloalkyl) , C 1 -C 6 alkyl (heterocycloalkyl) , C 1 -C 6 alkyl (aryl) , or C 1 -C 6 alkyl (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl (cycloalkyl) , C 1 -C 6 alkyl (heterocycloalkyl) , C 1 -C 6 alkyl (aryl) , or C 1 -C 6 alkyl (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH 3 , -S (=O) CH 3 , -S (=O) 2 CH 3 , -S (=O) 2 NH 2 , -S (=O) 2 NHCH 3 , -S (=O) 2 N (CH 3 ) 2 , -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , -C (=O) CH 3 , -C (=O) OH, -C (=O) OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R on the same atom form an oxo; and (b) an additional agent, wherein the combined amount of the compound of Formula (I) , or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.
  2. The method of claim 1, wherein the compound of Formula (I) is selected from Table 1.
  3. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject: (a) 5-fluoro-6- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridine-3-sulfonamide: or a pharmaceutically acceptable salt thereof; and (b) an additional agent.
  4. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject: (a) 5-fluoro-6- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridine-3-sulfonamide: or a pharmaceutically acceptable salt thereof; and (b) cisplatin.
  5. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject: (a) 5-fluoro-6- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridine-3-sulfonamide: or a pharmaceutically acceptable salt thereof; and (b) docetaxel.
  6. The method of any one of claims 3-5, wherein the combined amount of Compound 73 or the pharmaceutically acceptable salt thereof and the additional agent are therapeutically effective.
  7. The method of any one of claims 1-6, wherein the cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML) , glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC) , bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.
  8. The method of any one of claims 1-7, wherein the cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, cervical cancer, renal cell carcinoma, ovarian cancer, acute lymphoblastic leukemia (ALL) B-lineage, lymphoma, or T cell leukemia.
  9. The method of any one of claims 1-3 or 6-8, wherein the additional agent is a PARP inhibitor, a CHK1 inhibitor, a MDM2 inhibitor, a hypomethylating agent, an mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a BCL-2 inhibitor, a PRMT5 inhibitor, a PRMT1 inhibitor, an ATR inhibitor, a WEE1 inhibitor, an APE1 inhibitor, a topoisomerase inhibitor, a taxane, an immune checkpoint inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, a DNA synthesis inhibitor, an antimetabolite, an AURORA inhibitor, a microtubule stabilizer, a DNA cross-linker, a vinca alkaloid, an alkylating agent, a PRMT6 inhibitor, a PRMT7 inhibitor, a PRMT9 inhibitor, a KRAS inhibitor, an EGFR inhibitor, a VEGFR inhibitor, an aromatase inhibitor, a mitotic inhibitor, a radiopharmaceutical agent, a cytotoxic agent, or any combination thereof.
  10. The method of any one of claims 1-3 or 6-8, wherein the additional agent is a PARP inhibitor.
  11. The method of claim 8, wherein the PARP inhibitor is olaparib (AZD2281) , veliparib (ABT-888) , rucaparib, talazoparib (BMN 673) , AG-14361, INO-1001 (3-aminobenzamide) , A-966492, PJ34 HC1, niraparib, UPF 1069, ME0328, RK-287107, pamiparib (BGB-290) , NMS-P118, E7449, picolinamide, benzamide, NU1025, iniparib (B SI-201) , AZD2461, BGP-15 2HC1, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656, MN 64, or G007-LK, or a pharmaceutically acceptable salt thereof.
  12. The method of claim 11, wherein the PARP inhibitor is olaparib (AZD2281) , veliparib (ABT-888) , rucaparib, or talazoparib (BMN 673) , or a pharmaceutically acceptable salt thereof.
  13. The method of any one of claims 1-3 or 6-8, wherein the additional agent is a topoisomerase inhibitor.
  14. The method of claim 13, wherein the topoisomerase inhibitor is epipodopyyllotoxin, SN-38, ARC, NPC, camptothecin, topotecan, 9-nitrocamptothecin, exatecan, lurtotecan, lamellarin D9-aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa, cyclosphosphamide, amsacrine, etoposide, etoposide phosphate, teniposide, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, doxorubicin, or HU-331, or a pharmaceutically acceptable salt thereof.
  15. The method of any one of claims 1-3 or 6-8, wherein the additional agent is a taxane.
  16. The method of claim 15, wherein the taxane is docetaxel, paclitaxel, accatin III, 10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, chalcomenite, 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatin III, or 10-deacetyl chalcomenite, or a pharmaceutically acceptable salt thereof.
  17. The method of claim 16, wherein the taxane is docetaxel, or paclitaxel, or a pharmaceutically acceptable salt thereof.
  18. The method of any one of claims 1-3 or 6-8, wherein the additional agent is an immune checkpoint inhibitor.
  19. The method of claim 18, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, an anti-PD-1 antibody or a CTLA-4 antibody.
  20. The method of claim 19, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, sugemalimab, envafolimab, cosibelimab, or adebrelimab, or a pharmaceutically acceptable salt thereof.

Description

ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1 (ENPP1) INHIBITOR COMBINATIONS AND USES THEREOF CROSS-REFERENCE This patent application claims the benefit of International Application No. PCT/CN2023/106187, filed July 6, 2023; which is incorporated herein by reference in its entirety. BACKGROUND Ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) catalyzes the breakdown of extracellular adenosine triphosphate (ATP) into adenosine monophosphate (AMP) and pyrophosphate (PPi) -an important inhibitor of tissue calcification. In particular, ENPP1 degrades cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) , a secondary messenger molecule that mediates the upregulation of type I interferons and other inflammatory cytokines and chemokines by activating stimulator of interferon genes (STING) . Accordingly, there is a need for agents that inhibit the enzymatic activities of ENPP1 to treat diseases, disorders, and conditions associated with ENPP1 activity, such as cancer. SUMMARY Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject: (a) a compound of Formula (I) , or a pharmaceutically acceptable salt thereof: wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond, -NH-, or -O-; each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R1 on the same atom are taken together to form an oxo; n is 0-6; R2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; R3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; is a single bond or a double bond; wherein: whenis a double bond, X is N or CRX and Y is N or CRY; whenis a single bond, X is C (=O) and Y is NRY1 or C (RY2) 2; RX is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; RY1 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; each RY2 is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R4 on the same atom are taken together to form an oxo; m is 0-4; R5 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R6 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl (cycloalkyl) , C1-C6alkyl (heterocycloalkyl) , C1-C6alkyl (aryl) , or C1-C6alkyl (heteroaryl) ,  wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two Ra are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl,