Combinations treatments of diacylglycerol kinase (DGK) alpha inhibitors and other therapies

Abstract

Described herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject (a) a DGK [alpha] inhibitor or a pharmaceutically acceptable salt thereof; and (b) a further active agent, in particular an immune checkpoint inhibitor.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480068512.3 (22) Application Date 2024.09.03 (66) Domestic Priority Data PCT / CN2023 / 116718 2023.09.04 CN (85) PCT International Application Entering National Phase Date 2026.04.24 (86) PCT International Application Application Data PCT / CN2024 / 116517 2024.09.03 (87) PCT International Application Publication Data WO2025 / 051110 EN 2025.03.13 (71) Applicant: Insil Intelligent Technology Intellectual Property Limited Address: 26 / F, Tower 3, Exchange Square, 8 Connaught Place, Central, Hong Kong (72) Inventors: Sun Deheng, Lu Hongfu, Yu Huaxing, Zhang Man, Ding Xiao, Ren Feng (74) Patent Agency: Beijing Zhongzi Law Firm 11247 Patent Attorneys: Jia Shicong, Huang Gesheng (51) Int.Cl. A61K 31 / 4985 (2006.01) A61K 31 / 553 (2006.01) A61K 31 / 4353 (2006.01) A61K 39 / 00 (2006.01) A61P 35 / 00 (2006.01) (54) Invention Title: Combination Therapy of Diacylglycerol Kinase (DGK) α Inhibitor with Other Therapies (57) Abstract: This article describes a method for treating cancer in an individual in need, comprising administering (a) DGK α to said individual. (a) Inhibitors or their pharmaceutically acceptable salts; and (b) additional active agents, particularly immune checkpoint inhibitors. Claims 9 pages, Description 84 pages, CN 122094689 A 2026.05.26 CN 1 22 09 46 89 A 1. A method of treating cancer in an individual in need, the method comprising administering to the individual: (a) a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof: Formula (I), Formula (II), wherein: ring A is phenyl or a 6-membered heteroaryl; each R1 is independently a halogen, -CN, -NO2, -OH, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O) ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxylAlkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more of the claims 1 / 9 page 2 CN 122094689 AR; n is an integer from 0 to 4; R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CRU; RU is hydrogen, halogen, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 Hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R; each R3 is independently a 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)2R a, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more Rs; or two R3s on the same atom together form an oxo group; or two R3s on adjacent carbons together form an alkenyl group; or two R3s on the same or different carbons together form a cycloalkyl or heterocycloalkyl group, each of which is optionally substituted by one or more Rs; m is an integer from 0 to 8; T is N or CRT; RT is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R4 is independently a halogen, -CN, -NO2, -OH, -OR a, -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)2R a, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; p is an integer from 0 to 4; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; or two Ra together with the atoms to which they are attached form a heterocycloalkyl, which is optionally substituted by one or more R; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Claims 2 / 9, page 3, CN 122094689 A Alternatively, two Rb together with the atoms to which they are attached form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by one or more Rs; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; or Rc and Rd together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted by one or more R; andEach R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group; R1a' is a halogen, -CN, -NO2, -OH, -OR a', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc'Rd', -SH, -SRa', - S(=O)Ra', -S(=O)2Ra', -S(=O)2NRc'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2Ra', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; W' is N or CR1b'; Each R1b' is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc' Rd', -SH, -SRa', -S(=O)Ra', -S(=O)2Ra', -S(=O)2NR c'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2Ra', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R'; R2' is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;U' is N or CRU'; RU' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R's; cycloB' is a heterocycloalkyl; each R3' is independently halogen, -CN, -NO2, -OH, -ORa', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc'Rd', - SH, -SRa', -S(=O)Ra', -S(=O)2Ra', -S(=O)2NRc'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2Ra', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; Claims 3 / 9, page 4, CN 122094689 A: or two R3' on the same atom together form an oxo group; or two R3' on the same or different carbons together form a cycloalkyl or heterocycloalkyl group, each optionally substituted by one or more R's; m' is an integer from 0 to 6; X' is N or CRX'; RX' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally and independently substituted by one or more R's; Y' represents N or CRY'; RY' represents hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', or C1-C6 alkane.The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally and independently substituted by one or more R's; Z' is N or CRZ'. RZ' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R'; R5' is hydrogen, halogen, -CN, -NO2, -OH, -ORa', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc'Rd', -SH, -SRa', -S(=O)Ra', -S(=O)2R a', -S(=O)2NR c'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2R a', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; R4' is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by one or more R4a'; each R4a' is independently halogen, -CN, -NO2, -OH, -OR a', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc' Rd', -SH, -SRa', -S(=O)Ra', -S(=O)2Ra', -S(=O)2NR c'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2Ra', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; or two R4a' on the same atom together form an oxo group; Each Ra' is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R's; or two Ra's together with the atoms to which they are attached form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by one or more R's. Each Rb' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently and optionally substituted by one or more R's; or two Rb's together with the atoms to which they are attached form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R's; Rc' and Rd' are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1- C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R'; or Rc' and Rd' together with the atoms to which they are attached form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R'; andEach R' is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two R's on the same atom form an oxo group; and (b) an additional active agent, wherein the combination of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof with the additional active agent is therapeutically effective for treating cancer. 2. The method of claim 1, wherein the compound of formula (I) or formula (II) is selected from Table 1, Table 2, or Table 3. 3. The method of claim 1 or 2, wherein the cancer is primary leukemia, hematologic malignancy, 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's lymphoma, or mesothelioma. 4. The method of any one of claims 1-3, wherein the cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, B-cell acute lymphoblastic leukemia (ALL), lymphoma, or T-cell leukemia. 5. The method of any one of claims 1-4, wherein the additional active agent is a PARP inhibitor, CHK1 inhibitor, MDM2 inhibitor, demethylating agent, mTOR inhibitor, ATM inhibitor, CDK4 / 6 inhibitor, BCL-2 inhibitor, PRMT5 inhibitor, PRMT1 inhibitor, ATR inhibitor, WEE1 inhibitor, APE1 inhibitor, topoisomerase inhibitor, taxane, immune checkpoint inhibitor, CDK7 inhibitor, CDK9 inhibitor, DNA synthesis inhibitor, antimetabolite, AURORA inhibitor, microtubule stabilizer, DNA cross-linking agent, vinca alkaloid, alkylating agent, PRMT6 inhibitor, PRMT7 inhibitor, PRMT9 inhibitor, KRAS inhibitor, EGFR inhibitor, VEGFR inhibitor, MEK inhibitor, SHP2 inhibitor, PI3K inhibitor, AKT inhibitor, BRAF inhibitor, aromatase inhibitor, mitotic inhibitor, radiopharmaceutical, cytotoxic agent, or any combination thereof. 6. The method of any one of claims 1-5, wherein the additional active agent is an immune checkpoint inhibitor. Claims, pages 5 / 9, CN 122094689 A7. The method of any one of claims 1-5, wherein the immune checkpoint inhibitor is PD-1, PD-L1, PD-2, PD-L2, IDO-1, IDO-2, CTNNB1 (β-catenin), SIRPα, VISTA, RNASE H2, DNase II, CLEVER-1 / Stabilin-1, LIGHT, HVEM, CTLA-4, LAG-3, TIGIT, galactoglobulin-9, KIR, GITR, TIM-1, TIM-3, TIM-4, CEACAM1, OX40, OX40L, CD27, CD40 / CD40L, CD48, CD70, CD80, CD86, CD112, CD137 (4-1BB), CD155, CD160, CD200, CD226, CD244 (2B4), CD272 (BTLA), B7-H2, B7-H3, B7-H4, B7-H6, A2aR, CD73, NKG2A, CCR2, ICOS, A2bR, HHLA2, ILT-2, ILT-4, gp49B, PIR-B, HLA-G, ILT-2 / 4, MDR1, arginase 1, iNOs, IL-10, TGF-β, pGE2, STAT3, VEGF, KSP, HER2, Ras, EZH2, NIPP1, PP1, TAK1, or PLK1 inhibitors or antagonists. 8. The method of claim 7, wherein the immune checkpoint inhibitor is an antagonist of IDO-1, IDO-2, A2aR, CD73, or CCR2, or a pharmaceutically acceptable salt thereof. 9. The method of claim 8, wherein the IDO-1 antagonist is LY3381916, icardostat, linrostat, BMT-297376, palmatine, PF-06840003, or a pharmaceutically acceptable salt thereof. 10. The method of claim 8, wherein the IDO-2 antagonist is IDO2-IN-1, GNF-PF-3777, or a pharmaceutically acceptable salt thereof. 11. The method of claim 8, wherein the A2aR antagonist is cefranal, imadendron, ictredinam, NIR178, enotinam, CS3005, PBF-999, or INCB106385, or a pharmaceutically acceptable salt thereof. 12. The method of claim 8, wherein the CD73 antagonist is quimritarashtra, AB680, methADP, OP-5244, MRS4620, PSB-12379, or BK50164, or a pharmaceutically acceptable salt thereof. 13. The method of claim 8, wherein the CCR2 antagonist is JNJ-41443532, CCR2-RA-[R], PF-4136309, or BMS CCR2.22. RS 504393, MK-0812, AZD2423, PF-0463481, BMS-813160, BMS-753426, RS102895, JNJ-27141491, sinevirol, BX471, INCB 3284 or INCB 3344, or pharmaceutically acceptable salts thereof. 14. The method of claim 7, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, an anti-A2aR antibody, an anti-CD73 antibody, an anti-NKG2A antibody, an anti-CCR2 antibody, an anti-HVEM antibody, an anti-KIR antibody, an anti-OX40 antibody, an anti-IgG antibody, an anti-IDO-1 antibody, an anti-IDO-2 antibody, an anti-CEACAM1 antibody, an anti-BTLA antibody, an anti-OX40L antibody, an anti-TIM-3 antibody, an anti-GAL9 antibody, an anti-VISTA antibody, an anti-TIGIT antibody, or a variant thereof or a bioanalyst thereof. 15. The method of claim 14, wherein the anti-PD-L1 antibody is AUNP12, JS003, CS-1001, BMS-936559, atezolizumab, avelumab, betifestolimumab, durvalumab, garevelumab, octolimumab, sugemalimab, tetralimumab, envorimab, cochilimumab, adebenonemab, socarzolimumab, or a variant thereof or a biosimilar thereof. 16. The method of claim 14, wherein the anti-PD-1 antibody is AMP-224, AMP-514, 14C12H1L1, BAT-1306, AK103, AK104, AK105, SG001, nivolumab, nofazilimumab, pembrolizumab, fenolinumab, genozumab, spartazumab, slulilimumab, dostalimumab, cimiprimab, toripalimab, camrelizumab, tislelilimumab, penamprolium, pimivalimab, refulimumab, sintilimumab, cepalimumab, or a variant thereof or a biosimilar thereof. 17. The method of claim 14, wherein the anti-CTLA-4 antibody is botecilimumab, ipilimumab, zefulimumab, or trimemumab or a variant thereof or a biosimilar thereof. 18. The method of claim 14, wherein the anti-LAG-3 antibody is retalitumab, fumarazimab, mipro, tanlimumab, malazelimumab, ellalimumab, Sym022, GSK2831781, INCAGN02385, TSR-033, or a variant thereof or a biosimilar thereof.19. The method of claim 14, wherein the anti-TIGIT antibody is tireliumab, dovanalimab, vimbrolizumab, ateribimab, tangipilimab, M6223, osperimab, or EOS884448, or a variant thereof or a biosimilar thereof. 20. The method of claim 14, wherein the anti-TIM-3 antibody is sabatolimab, sozebimab, cobbimab, Sym023, R07121661, LY3321367, ICAGN02390, or BMS-986258, or a variant thereof or a biosimilar thereof. 21. The method of claim 14, wherein the anti-B7-H3 antibody is enotozumab, octotumab, vorbretatumab, mirtautumab, B7-H3 TriKE, 131I-octotumab, DS-7300a, or 177Lu-DTPA-octotumab, or a variant thereof or a biosimilar thereof. 22. The method of claim 14, wherein the anti-B7-H4 antibody is esvorimab, FPA150, or a variant thereof or a biosimilar thereof. 23. The method of claim 14, wherein the anti-CD73 antibody is olelenumab, moparibumab, euradiumab, MEDI9447, AK119, HLX23, IPH5301, Sym042, IBI325, PT199, JAB-BX102, NZV930, INCA00186, or BMS-986179, or a variant thereof or a biosimilar thereof. 24. The method of claim 14, wherein the anti-NKG2A antibody is monalizumab, or a variant thereof or a biosimilar thereof. 25. The method of claim 14, wherein the anti-CCR2 antibody is lozalizumab, or a variant thereof or a biosimilar thereof. 26. The method of claim 6, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, AMP-224, PF-06801591, MEDI0680, PDR001, REGN2810, SHR-12-1, TSR-042, CA-170, atezolizumab, durvalumab, KN035, BMS-936559, ipilimumab, trimemumab, avelumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR-022, or a variant thereof or a biosimilar thereof. 27. The method of claim 26, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, ipilimumab, trimemumab, avelumab, or a variant thereof or a biosimilar thereof.28. The method of claim 26, wherein the immune checkpoint inhibitor is nivolumab or a variant thereof or a biosimilar thereof. 29. The method of claim 26, wherein the immune checkpoint inhibitor is pembrolizumab or a variant thereof or a biosimilar thereof. 30. The method of claim 26, wherein the immune checkpoint inhibitor is pildizumab or a variant thereof or a biosimilar thereof. 31. The method of claim 26, wherein the immune checkpoint inhibitor is atezolizumab or a variant thereof or a biosimilar thereof. 32. The method of claim 26, wherein the immune checkpoint inhibitor is ipilimumab or a variant thereof or a biosimilar thereof. 33. The method of claim 26, wherein the immune checkpoint inhibitor is trimemumab or a variant thereof or a biosimilar thereof. 34. The method of claim 26, wherein the immune checkpoint inhibitor is avelumab or a variant thereof or a biosimilar thereof. 35. Use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the medicament is formulated for administration in combination with a further active agent. 36. Use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in combination with a further active agent in the preparation of a medicament for treating cancer. 37. Use of compound 23 or compound 13A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the medicament is formulated for administration in combination with a further active agent: Compound 23; Compound 13A. 38. Use of compound 23 or compound 13A or a pharmaceutically acceptable salt thereof in combination with a further active agent in the preparation of a medicament for treating cancer: Compound 23; Compound 13A. 39. The use according to claim 37 or 38, wherein the further active agent is an immune checkpoint inhibitor. 40. The use of claim 39, wherein the additional active agent is nivolumab, pembrolizumab, pildizumab, atezolizumab, ipilimumab, trimemumab, avelumab, or a variant thereof or a biosimilar thereof. Claims 9 / 9 pages 10 CN 122094689 A Combination therapy of diacylglycerol kinase (DGK) α inhibitors with other therapies

[0001] Cross-reference

[0002] This patent application claims priority to International Application No. PCT / CN2023 / 1116718, filed on September 4, 2023, the entire contents of which are incorporated herein by reference. Background Art

[0003] Diacylglycerol kinase (DGK) represents the catalytic phosphorylation of membrane lipid sn-1,2-diacylglycerol (DAG) to formPhosphatidic acid (PA) is an enzyme family. In T cells, DAG is formed downstream of the T cell receptor (TCR) after activation of the γ1 isoform of phospholipase C (PLCyl) and cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into DAG and another second messenger, inositol 1,4,5-triphosphate (IP3). IP3 is important in promoting calcium release from the endoplasmic reticulum, and DAG interacts with other proteins important in TCR signaling, such as protein kinase CO and Ras-activated protein RasGRPI. Although three isoforms of DGK (DGKα, DGKδ, and DGKζ) are known to exist in T cells, only DGKα and DGKζ are considered to play important roles in promoting DAG metabolism downstream of the TCR.

[0004] Supporting evidence includes DGKα or DGKζ gene knockout mouse models, which exhibit a hyperresponsive T cell phenotype and enhanced antitumor immune activity (Riese M.J. et al., Journal of Biological Chemistry, (2011)7:5254-5265; Zha Y et al., Nature Immunology, (2006)12:1343; Olenchock BA et al., (2006)11:1174-81). Furthermore, overexpression of DGKα leading to suppression of T cell function has been observed in tumor-infiltrating lymphocytes isolated from human renal cell carcinoma patients (Prinz, PU et al., J Immunology (2012)12:5990-6000). Therefore, DGKα and DGKζ are considered targets for cancer immunotherapy (Riese M.J. et al., Front Cell DevBiol. (2016) 4:108; Chen, S.S. et al., Front Cell Dev Biol. (2016) 4:130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95:549-563; Noessner, E., Front Cell Dev Biol. (2017) 5:16; Krishna, S. et al., Front Immunology (2013) 4:178; Jing, W. et al., Cancer Research (2017) 77:5676-5686). There remains a need for compounds that can be used as inhibitors of one or both of DGKα and DGKζ, especially compounds selective for other diacylglycerol kinases, protein kinases, and / or other lipid kinases. There is still a need for methods that can safely and effectively restore T cell activation, lower the antigen threshold, enhance anti-tumor function, and / orCompounds that overcome the inhibitory effects of one or more endogenous immune checkpoints (e.g., PD-1, PD-L1, and CTLA-4) would be an important complement to the treatment of patients with proliferative disorders (e.g., cancer) and viral infections.

[0005] Summary of the Invention

[0006] This disclosure provides a method of treating cancer in an individual in need, the method comprising administering to the individual: (a) a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof: [Specification 1 / 84 page 11 CN 122094689 A] Formula (I), as described herein, Formula (II), as described herein, and (b) a further active agent, wherein the combined amount of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof with the further active agent is therapeutically effective for treating cancer.

[0007] On the other hand, this disclosure provides the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the medicament is formulated for administration in combination with a further active agent.

[0008] On the other hand, this disclosure provides the use of compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof with additional active agents in the preparation of medicaments for treating cancer.

[0009] On the other hand, this disclosure provides the use of compound 23 or compound 13A or pharmaceutically acceptable salts thereof with the preparation of medicaments for treating cancer, wherein the medicament is formulated for administration in combination with additional active agents: Specification 2 / 84 page 12 CN 122094689 A Compound 23; Compound 13A.

[0010] On the other hand, this disclosure provides the use of compound 23 or compound 13A or pharmaceutically acceptable salts thereof with additional active agents in the preparation of medicaments for treating cancer.

[0011] Incorporated by Reference

[0012] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference.

[0013] Detailed Description

[0014] Definitions

[0015] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, the word “comprising” and variations thereof, such as “including,” should be interpreted throughout the specification and the following claims in an open, inclusive sense, i.e., “including but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0016] References to “some embodiments” or “implementation” in this specification mean that a particular feature, structure, or characteristic associated with that embodiment is included in at least one embodiment. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing throughout this specification do not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any suitable manner in one or more embodiments. Additionally, as used in this specification and the appended claims, the singular forms “an,” “a,” and “the” include plural references unless otherwise expressly stated. It should also be noted that the term “or” is generally used in a meaning including “and / or” unless otherwise expressly stated.

[0017] Unless otherwise stated, the following terms as used herein have the following meanings: “Oxygenated” means =O.

[0018] “Carboxyl” means -COOH.

[0019] “Cyano” means -CN.

[0020] “Amino”, whether used as part of another term or independently, refers to the group -NRaRb, wherein Ra and Rb are independently selected from the following groups: hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclic or other suitable organic groups, and each of which may optionally be substituted.

[0021] “Hydroxy” or “hydroxyl”, whether used as part of another term or independently, refers to -OH.

[0022] “Alkyl”, whether used as part of another term or independently, refers to a straight-chain or branched saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this document, numerical ranges such as "C1-C6 alkyl" or "C1-6 alkyl" mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term "alkyl" without a specified numerical range. In some practical...In some embodiments, the alkyl group is C1-10 alkyl. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl. Unless otherwise expressly stated in this specification, the alkyl group may optionally be substituted, for example, substituted by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted by one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted by one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted by a halogen.

[0023] Whether used as part of another term or independently, “alkenyl” refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in the cis or trans configuration of the relevant double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as “C2-C6 alkenyl” or “C2-6 alkenyl” mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term “alkenyl” without a specified numerical range. Unless otherwise expressly stated in this specification, the alkenyl group may optionally be substituted, for example, by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted by one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted by a halogen.

[0024] "Alkyne" whether used as part of another term or independently refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, […].Limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 ynyl" or "C2-6 ynyl" mean that the ynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term "ynyl" without a specified numerical range. Unless otherwise expressly stated in this specification, the ynyl group may optionally be substituted, for example, by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the ynyl group is optionally substituted by one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0025] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly stated in this specification, alkylene may be optionally substituted, for example, with oxo, halogen, amino, nitrile, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with a halogen.

[0026] "Alkoxy" whether used as part of another term or independently refers to a group of the formula -ORa, wherein Ra is an alkyl group as defined. Whenever it appears herein, numerical ranges such as “C1-C6 alkoxy” or “C1-6 alkoxy” mean that the alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term “alkoxy” without a specified numerical range. In some embodiments, the alkoxy group is C1-10 alkoxy. In some embodiments, the alkoxy group is C1-6 alkoxy. In some embodiments, the alkoxy group is C1-5 alkoxy. In some embodiments, the alkoxy group is C1-4 alkoxy. In some embodiments, the alkyl group is C1-3 alkoxy. In some embodiments, the alkyl group is C1-2 alkoxy. In some embodiments, the alkyl group is methoxy. Unless otherwise expressly stated in this specification, the alkoxy group may optionally be substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, or haloalkane.The alkoxy group is substituted with alkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0027] "Aryl" whether used as part of another term or independently refers to a group derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic or polycyclic (including but not limited to bicyclic, tricyclic, or tetracyclic) ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded by aromatic ring atoms), bridged, or spirocyclic systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems such as anthracene, naphthylene, phenanthrylene, anthracene, azurite, benzene, phenanthrene, fluorene, as-indacene, s-indacene, indene, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and benzo[9,10]triphenylene. Unless otherwise expressly stated in this specification, aryl groups may optionally be substituted, for example, by one or more substituents such as halogens, amino groups, nitrile groups, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups. In some embodiments, the aryl group is optionally substituted with one or more substituents, such as halogens, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with one or more substituents, such as halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen.

[0028] "Cycloalkyl" whether used as part of another term or independently refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused rings (when fused with an aryl or heteroaryl ring, the cycloalkyl group is bonded by non-aromatic ring atoms), spirocyclic, or bridging ring systems. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups includeHowever, it is not limited to cycloalkyl groups having 3 to 15 carbon atoms (C3-C15 fully saturated cycloalkyl groups or C3-C15 cycloalkenyl groups), cycloalkyl groups having 3 to 10 carbon atoms (C3-C10 fully saturated cycloalkyl groups or C3-C10 cycloalkenyl groups), cycloalkyl groups having 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyl groups or C3-C8 cycloalkenyl groups), cycloalkyl groups having 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyl groups or C3-C6 cycloalkenyl groups), cycloalkyl groups having 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyl groups or C3-C5 cycloalkenyl groups), or cycloalkyl groups having 3 to 4 carbon atoms (C3-C4 fully saturated cycloalkyl groups or C3-C4 cycloalkenyl groups). In some embodiments, the cycloalkyl group is a 3 to 10-membered fully saturated cycloalkyl group or a 3 to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3 to 6-membered fully saturated cycloalkyl group or a 3 to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered fully saturated cycloalkyl group or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in this specification, cycloalkyl groups are optionally substituted, for example, by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted by a halogen.

[0029] "Halogen" or "halogen" means bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0030] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0031] "Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0032] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0033] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl, as described on page 6 / 84 of the specification (CN 122094689 A). In some embodiments, the aminoalkyl group is aminomethyl.

[0034] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof), wherein the heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, heteroalkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[0035] Whether used as part of another term or independently, “heterocyclic alkyl” refers to a 3- to 24-membered moiety or complete alkyl group.A fully saturated cycloalkyl group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl group is fully saturated. In some embodiments, the heterocyclic alkyl group comprises 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group comprises 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl group comprises 1 to 3 nitrogen atoms. In some embodiments, the heterocyclic alkyl group comprises 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl group comprises 1 nitrogen atom. In some embodiments, the heterocyclic alkyl group comprises 1 nitrogen atom and 1 oxygen atom. Unless otherwise expressly stated in this specification, the heterocyclic alkyl group can be a monocyclic or polycyclic (including but not limited to bicyclic, tricyclic, or tetracyclic) ring system, and may include fused rings (when fused with aryl or heteroaryl rings, the heterocyclic alkyl group is bonded by non-aromatic ring atoms), spirocyclic, or bridging ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, heterocyclic alkyl groups having 2 to 15 carbon atoms (C2-C15 fully saturated heterocyclic alkyl groups or C2-C15 heterocyclic alkenyl groups) and heterocyclic alkyl groups having 2 to 10 carbon atoms (C2-C10 fully saturated heterocyclic alkyl groups or C2-C10 heterocyclic alkenyl groups). Heterocyclic alkyl groups having 2 to 8 carbon atoms (C2-C8 fully saturated heterocyclic alkyl groups or C2-C8 heterocyclic alkenyl groups), heterocyclic alkyl groups having 2 to 7 carbon atoms (C2-C7 fully saturated heterocyclic alkyl groups or C2-C7 heterocyclic alkenyl groups), heterocyclic alkyl groups having 2 to 6 carbon atoms (C2-C6 fully saturated heterocyclic alkyl groups or C2-C6 heterocyclic alkenyl groups), heterocyclic alkyl groups having 2 to 5 carbon atoms (C2-C5 fully saturated heterocyclic alkyl groups or C2-C5 heterocyclic alkenyl groups), or heterocyclic alkyl groups having 2 to 4 carbon atoms (C2-C4 fully saturated heterocyclic alkyl groups or C2-C4 heterocyclic alkenyl groups). Examples of such heterocyclic alkyl groups include, but are not limited to, aziridine propane, aziridine butane, oxadiazine, dioxapentane, thienyl[1,3]dithiohexane, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, and others. Isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidyl, 2-oxopiperylyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylyl, pyrazolylyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, trithiacyclohexyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl and 2-oxo-1,3-dioxacyclopenten-4-ylThe term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl, the number of carbon atoms in the heterocyclic alkyl is different from the total number of atoms (including heteroatoms) constituting the heterocyclic alkyl (i.e., the skeleton atoms of the heterocyclic alkyl ring). In some embodiments, the heterocyclic alkyl is a 3- to 8-membered fully saturated heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 3- to 7-membered fully saturated heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 3- to 6-membered fully saturated heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 4- to 6-membered fully saturated heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 5- to 6-membered fully saturated heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 3- to 8-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl is a 3- to 7-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise expressly stated in this specification, the heterocyclic alkyl group may optionally be substituted as described below, for example, substituted by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the heterocyclic alkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted by one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0036] “Heteroaryl”, whether used as part of another term or independently, refers to a 5- to 14-membered ring group comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group comprises 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 nitrogen atom. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is fused through the aromatic ring atoms).The heteroaryl group is either bonded, bridged, or spirocyclic; and the nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azazyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, 1,4-benzodioxylalkyl, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl, benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazole, indolyl, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indolazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyridine, oxazolyl, oxacyclopropane, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purineyl, Pyrroleyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl (i.e., thienyl). Unless otherwise expressly stated in this specification, heteroaryl groups may optionally be substituted, for example, by one or more substituents, such as halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, heteroaryl groups are optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents, such as halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0037] The term "partially saturated" refers to a group containing at least one double or triple bond and is intended to cover groups having multiple unsaturated sites. (Specification 8 / 84 pages 18 CN 122094689 A)The ring is a dot, but is not intended to include an aromatic (i.e., fully unsaturated) moiety.

[0038] The terms “optional” or “optionally” indicate that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of said event or condition. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially impractical and / or synthetically infeasible substitution or substitution pattern. Therefore, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons.

[0039] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0040] "Effective amount" or "therapeutic effective amount" refers to the amount of compound administered to a mammalian individual in a single dose or a portion of a series of doses that is effective in producing the desired therapeutic effect.

[0041] As used herein, the term "treatment" includes relieving, reducing, or improving at least one symptom of a disease or condition, preventing other symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, relieving the condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0042] As used herein, “DGK-related disease or disorder” or “DGK-mediated disease or disorder” means any disease or other harmful condition for which DGK or its mutants are known or suspected to play a role.

[0043] As used herein, “DGKα-related disease or disorder” or “DGKα-mediated disease or disorder” means any disease or other harmful condition for which DGKα or its mutants are known or suspected to play a role.

[0044] As used herein, “DGKζ-related disease or disorder” or “DGKζ-mediated disease or disorder” means any disease or other harmful condition for which DGKζ or its mutants are known or suspected to play a role.

[0045] Compound (I)

[0046] This document discloses compounds of formula (I) or pharmaceutically acceptable salts thereof used as DGKα inhibitors: Specification 9 / 84 pages 19 CN 122094689 A Formula (I), wherein: ring A is phenyl or a 6-membered heteroaryl; each R1 is independently a 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)2R a, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; n is 0-4; R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; U is N or CRU; RU is hydrogen, halogen, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R; each R3 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)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, arylOr heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally and independently substituted by one or more Rs; or two R3s on the same atom together form an oxo group; or two R3s on adjacent carbons together form an alkenyl group; or two R3s on the same or different carbons together form a cycloalkyl or heterocycloalkyl group, each optionally substituted by one or more Rs; m is 0-8; T is N or CRT; RT is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; each R4 is independently a 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; p is 0-4; Each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; or two Ra together with the atoms to which they are attached form a heterocycloalkyl, said heterocycloalkyl being optionally substituted by one or more R; each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1- C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene,Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R; or two Rb together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted by one or more R; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Alternatively, Rc and Rd together with the atoms to which they are attached form a heterocyclic alkyl group, which may optionally be substituted by one or more Rs; and each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group.

[0047] In some embodiments of the compound of formula (I), ring A is phenyl. In some embodiments of the compound of formula (I), ring A is a 6-membered heteroaryl. In some embodiments of the compound of formula (I), ring A is pyridyl.

[0048] In some embodiments of the compound of formula (I), the compound has a formula selected from the following: (Ia), (Ib), (Ic), (Id), (Ie), (Ig ...

[0049] In some embodiments of the compound of formula (Ib), n' is 1 or 2; each R1 is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl or -O-C1-C6 aminoalkyl; R2 is C1-C6 alkyl.The compound (Ib) is composed of: a radical (R1); T is CH; U is N or CH; p is 1 or 2; and each R4 is independently a halogen or C1-C6 alkyl. In some embodiments of the compound (Ib), p is 1. In some embodiments of the compound (Ib), p is 2. In some embodiments, R4 is a halogen, such as F. In some embodiments, R4 is a C1-C6 alkyl. In some embodiments of the compound (Ib), R4 is a C1-C3 alkyl. In some embodiments of the compound (Ib), R4 is methyl. In some embodiments, R2 is a C1-C3 alkyl. In some embodiments of the compound (Ib), R2 is methyl. In some embodiments of the compound (Ib), U is N. In some embodiments, U is CH. In some embodiments of the compound (Ib), each R1 is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (Ib), each R1 is independently -CN or -O-heterocyclic alkyl. In some embodiments of the compound of formula (Ib), each R1 is independently -CN or -O-C1-C6 haloalkyl. In some embodiments of the compound of formula (Ib), each R1 is independently -CN or -O-C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (Ib), each R1 is independently -CN or -O-C1-C3 hydroxyalkyl. In some embodiments of the compound of formula (Ib), each R1 is independently -CN or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (Ib), each R1 is independently -CN or -O-CH2CH2OH. In some embodiments of the compound of formula (Ib), at least one R1 is CN. In some embodiments of the compound of formula (Ib), n' is 1. In some embodiments of the compound of formula (Ib), n' is 2.

[0050] In some embodiments of the compound of formula (If), each R1a and R1b is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl; R2 is C1-C6 alkyl; T is CH; U is N or CH; p is 1 or 2; and each R4 is independently halogen or C1-C6 alkyl. In some embodiments of the compound of formula (If), p is 1. In some embodiments of the compound of formula (If), p is 2. In some embodiments of the compound of formula (If), R4 is halogen, such as F. In some embodiments of the compound of formula (If), R4 is C1-C6 alkyl. In some embodiments of the compound of formula (If), R4 is C1-C3 alkyl. In some embodiments of the compound of formula (If), R4 is methyl.In some embodiments of the (If) compound, R2 is a C1-C3 alkyl group. In some embodiments of the (If) compound, R2 is a methyl group. In some embodiments of the (If) compound, U is N. In some embodiments of the (If) compound, U is CH. Specification 15 / 84 pages 25 CN 122094689 A In some embodiments of the (If) compound, each R1a and R1b is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the (If) compound, each R1a and R1b is independently -CN or -O-heterocyclic alkyl. In some embodiments of the (If) compound, each R1a and R1b is independently -CN or -O-C1-C6 haloalkyl. In some embodiments of the (If) compound, each R1a and R1b is independently -CN or -O-C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (If), each R1a and R1b is independently -CN or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (If), R1a is -O-C1-C6 hydroxyalkyl, and R1b is CN. In some embodiments of the compound of formula (If), R1a is -O-C1-C3 hydroxyalkyl, and R1b is CN. In some embodiments of the compound of formula (If), R1a is -O-CH2CH2OH, and R1b is CN.

[0051] In some embodiments of the compound of formula (Ig), each R1a and R1b is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl; R2 is C1-C6 alkyl; T is CH; U is N or CH; and R4 is halogen or C1-C6 alkyl. In some embodiments of the compound of formula (Ig), R4 is a halogen, such as F. In some embodiments of the compound of formula (Ig), R4 is a C1-C6 alkyl. In some embodiments of the compound of formula (Ig), R4 is a C1-C3 alkyl. In some embodiments of the compound of formula (Ig), R4 is methyl. In some embodiments of the compound of formula (Ig), R2 is a C1-C3 alkyl. In some embodiments of the compound of formula (Ig), R2 is methyl. In some embodiments of the compound of formula (Ig), U is N. In some embodiments of the compound of formula (Ig), U is CH. In some embodiments of the compound of formula (Ig), each R1a and R1b is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 haloalkyl, or -O-C1-C6 hydroxyl.Alkyl or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (Ig), each R1a and R1b is independently -CN or -O-heterocyclic alkyl. In some embodiments of the compound of formula (Ig), each R1a and R1b is independently -CN or -O-C1-C6 haloalkyl. In some embodiments of the compound of formula (Ig), each R1a and R1b is independently -CN or -O-C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (Ig), each R1a and R1b is independently -CN or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (Ig), R1a is -O-C1-C6 hydroxyalkyl, and R1b is CN. In some embodiments of the compound of formula (Ig), R1a is -O-C1-C3 hydroxyalkyl, and R1b is CN. In some embodiments of the compound of formula (Ig), R1a is -O-CH2CH2OH, and R1b is CN.

[0052] In some embodiments of the compound of formula (If) or (Ig), R1a is a halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (If) or (Ig), R1a is a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (If) or (Ig), R1a is a halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (If) or (Ig), R1a is a halogen or -CN. In some embodiments of the compound of formula (If) or (Ig), R1a is a halogen. In some embodiments of the compound of formula (If) or (Ig), R1a is fluorine or chlorine. In some embodiments of the compound of formula (If) or (Ig), R1a is -CN. In some embodiments of the compound of formula (If) or (Ig), R1a is independently a halogen, -CN, -ORa, or -NRcRd. In some embodiments of the compound of formula (If) or (Ig), R1a is -CN or -ORa. In some embodiments of the compound of formula (If) or (Ig), R1a is -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (If) or (Ig), R1a is -CN, -O-heterocyclic alkyl, -O-Cl-C3 alkyl, -O-C1-C3 haloalkyl, -O-C1-C3 hydroxyalkyl, or -O-C1-C3 aminoalkyl. In some embodiments of the compound of formula (If) or (Ig), R1a is independently -CN or -NRcRd. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5- or 6-membered ring. In some embodiments of the compound of formula (If) or (Ig), -ORa is or In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 alkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 haloalkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 aminoalkyl.

[0053] In some embodiments of the compound of formula (If) or (Ig), R1b is a halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (If) or (Ig), R1b is a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (If) or (Ig), R1b is a halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (If) or (Ig), R1b is a halogen. In some embodiments of the compound of formula (If) or (Ig), R1b is fluorine or chlorine. In some embodiments of the compound of formula (If) or (Ig), R1b is -CN. In some embodiments of the compound of formula (If) or (Ig), R1b is independently a halogen, -CN, -ORa, or -NRcRd. In some embodiments of the compound of formula (If) or (Ig), R1b is -CN or -ORa. In some embodiments of compounds of formula (If) or (Ig)In the formulation, R1b is -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (If) or (Ig), R1b is -CN, -O-heterocyclic alkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, -O-C1-C3 hydroxyalkyl, or -O-C1-C3 aminoalkyl. In some embodiments of the compound of formula (If) or (Ig), R1b is independently -CN or -NRcRd. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5- or 6-membered ring. In some embodiments of the compound of formula (If) or (Ig), -ORa is or. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 alkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 haloalkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (If) or (Ig), -ORa is -O-C1-C6 aminoalkyl.

[0054] In some embodiments of the compound of formula (I) or (Ia), n is 0, 1, 2, 3, or 4. In some embodiments of the compound of formula (I) or (Ia), n is 0-2. In some embodiments of compounds of formula (I) or (Ia), n is 0 or 1. In some embodiments of compounds of formula (I) or (Ia), n is 2. In some embodiments of compounds of formula (I) or (Ia), n is 1. In some embodiments of compounds of formula (I) or (Ia), n is 0.

[0055] In some embodiments of compounds of formula (Ib)-(Ie), n' is 0, 1, 2, or 3. In some embodiments of compounds of formula (Ib)-(Ie), n' is 0-2. In some embodiments of compounds of formula (Ib)-(Ie), n' is 0 or 1. In some embodiments of compounds of formula (Ib)-(Ie), n' is 2. In some embodiments of compounds of formula (Ib)-(Ie), n' is 1. In some embodiments of compounds of formula (Ib)-(Ie), n' is 0.

[0056] In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently a halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently a halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently a halogen or -CN. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently a halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is fluorine or chlorine. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is -CN. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently a halogen, -CN, -ORa, or -NRcRd. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently -CN or -ORa. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently -CN, -O-heterocyclic alkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, -O-C1-C3 hydroxyalkyl, or -O-C1-C3 aminoalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R1 is independently -CN or -NRcRd. In some embodiments of compounds of formula (I) or (Ia)-(Ig), -ORa is -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ig), -ORa is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5- or 6-membered ring. In some embodiments of compounds of formula (I) or (Ia)-(Ig), -ORa is orIn some embodiments of the compounds of formula (I) or (Ia)-(Ig), -ORa is -O-C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), -ORa is -O-C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), -ORa is -O-C1-C6 hydroxyalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), -ORa is -O-C1-C6 aminoalkyl. In some embodiments, each R1 is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments, each R1 is independently -CN or -O-heterocyclic alkyl. In some embodiments, each R1 is independently -CN or -O-C1-C6 haloalkyl. In some embodiments, each R1 is independently -CN or -O-C1-C6 hydroxyalkyl. In some embodiments, each R1 is independently -CN or -O-C1-C3 hydroxyalkyl. In some embodiments, each R1 is independently -CN or -O-CH2CH2OH. In some embodiments, each R1 is independently -CN or -O-C1-C6 aminoalkyl. In some embodiments, at least one R1 is -CN.

[0057] In some embodiments of the compounds of formula (I) or (Ia)-(Ig), R2 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), R2 is C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), R2 is C1-C3 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), R2 is methyl.

[0058] In some embodiments of the compounds of formula (I) or (Ia)-(Ig), U is N. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), U is CRU.

[0059] In some embodiments of the compounds of formula (I) or (Ia)-(Ig), RU is hydrogen, halogen, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), RU is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), RU is hydrogen.

[0060] In some embodiments of the compound of formula (I), is or.

[0061] In some embodiments of the compound of formula (I), is or .

[0062] In some embodiments of the compound of formula (I), is or .

[0063] In some embodiments of the compound of formula (I), is or .

[0064] In some embodiments of the compound of formula (I), is. In some embodiments of the compound of formula (I), is. In some embodiments of the compound of formula (I), is. In some embodiments of the compound of formula (I), is. In some embodiments of the compound of formula (I), is. In some embodiments of the compound of formula (I), is. In some embodiments of the compound of formula (I), is.

[0065] In some embodiments of compounds of formula (I) or (Ia)-(Ie), each R3 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ie), each R3 is independently a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ie), each R3 is independently a C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ie), two R3s on the same or different carbons together form a cycloalkyl or heterocycloalkyl group, each optionally substituted by one or more Rs. In some embodiments of compounds of formula (I) or (Ia)-(Ie), two R3s on different carbons together form a cycloalkyl group, which is optionally substituted by one or more Rs.

[0066] In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 0-4. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 0-3. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 0-2. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 0. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 1. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 2. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 3. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 4. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 3. In some embodiments of compounds of formula (I) or (Ia)-(Ie), m is 5-8.

[0067] In some embodiments of the compounds of formula (I) or (Ia)-(Ig), T is N. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), T is CRT.

[0068] In some embodiments of the compounds of formula (I) or (Ia)-(Ig), RT is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), RT is hydrogen.

[0069] In some embodiments of the compounds of formula (I) or (Ia)-(Ie), it is specified on page 21 / 84 of CN 122094689 A.

[0070] In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R4 is independently a halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R4 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R4 is independently a halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R4 is independently a halogen or a C1-C6 alkyl group. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R4 is independently a C1-C6 alkyl group. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), each R4 is a methyl group. In some embodiments of the compounds of formula (I) or (Ia)-(Ig), R4 is F.

[0071] In some embodiments of the compounds of formula (I) or (Ia)-(If), p is 0-2. In some embodiments of the compounds of formula (I) or (Ia)-(If), p is 1 or 2. In some embodiments of the compounds of formula (I) or (Ia)-(If), p is 0. In some embodiments of the compounds of formula (I) or (Ia)-(If), p is 1. In some embodiments of the compounds of formula (I) or (Ia)-(If), p is 2.

[0072] In some embodiments of compounds of formula (I) or (Ia)-(If), is.

[0073] This document discloses compounds of formula (I-1) or pharmaceutically acceptable salts thereof as DGKα inhibitors: Specification 22 / 84 pages 32 CN 122094689 A Formula (I-1), wherein: ring A is phenyl or a 6-membered heteroaryl;Each R1 is independently a halogen, -CN, -NO2, -OH, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl. C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R; n is 0-4; R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CRU; RU is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R; ring B is bicyclic; each R3 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2R a, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; or two R3s on the same atom together form an oxo group; m is 0-8; 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)2R a、-S(=O)2NR cRd、-NRcRd、-NRbC(=O)NRcRd、-NRbC(=O)Ra、- NRbC(=O)ORb、-NRbS(=O)2R a、-C(=O)Ra、-C(=O)ORb、-C(=O)NRcRd、C1-C6 alkyl、C1-C6 haloalkyl、 C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; p is 0-4; Each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; or two Ra together with the atoms to which they are attached form a heterocycloalkyl, said heterocycloalkyl being optionally substituted by one or more R; each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1- C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; or two Rb together with the atoms to which they are attached form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl group,Alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are independently and optionally substituted by one or more Rs; or Rc and Rd together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted by one or more Rs; and each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group.

[0074] In some embodiments of the compound of formula (I-1), ring A is phenyl. In some embodiments of the compound of formula (I-1), ring A is a 6-membered heteroaryl. In some embodiments of the compound of formula (I-1), ring A is pyridyl.

[0075] In some embodiments of the compound of formula (I-1), the compound has a formula selected from the following: (Specification 24 / 84 page 34 CN 122094689 A) Formula (I-1a), Formula (I-1b), Formula (I-1c), (Specification 25 / 84 page 35 CN 122094689 A) Formula (I-1d), Formula (I-1e), Formula (I-1f); (Specification 26 / 84 page 36 CN 122094689 A) where n' is an integer from 0 to 3, and each R1a and R1b is independently selected from R1.

[0076] In some embodiments of compounds of formula (I-1) or (I-1a), n is 0, 1, 2, 3, or 4. In some embodiments of compounds of formula (I-1) or (I-1a), n is 0-2. In some embodiments of compounds of formula (I-1) or (I-1a), n is 0 or 1. In some embodiments of compounds of formula (I-1) or (I-1a), n is 2. In some embodiments of compounds of formula (I-1) or (I-1a), n is 1. In some embodiments of compounds of formula (I-1) or (I-1a), n is 0. In some embodiments of compounds of formula (I-1b)-(I-1e), n' is an integer from 0 to 2. In some embodiments of compounds of formula (I-1b)-(I-1e), n' is 0 or 1. In some embodiments of compounds of formula (I-1b)-(I-1e), n' is 2. In some embodiments of the compound of formula (I-1b)-(I-1e), n' is 1. In some embodiments of the compound of formula (I-1b)-(I-1e), n' is 0.

[0077] In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently a halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently a halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently a halogen or -CN. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently a halogen. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is fluorine or chlorine. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is -CN. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently a halogen, -CN, -ORa, or -NRcRd. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently -CN or -ORa. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R1 is independently -CN or -NRcRd. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), -ORa is -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), -ORa is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5- or 6-membered ring. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), -ORa is or . In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), -ORa is -O-C1-C6 alkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), -ORa is -O-C1-C6 haloalkyl.C1-C6 hydroxyalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), -ORa is -O-C1-C6 aminoalkyl. In some embodiments, each R1 is independently -CN, -O-heterocyclic alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments, each R1 is independently -CN or -O-heterocyclic alkyl. In some embodiments, each R1 is independently -CN or -O-C1-C6 haloalkyl. In some embodiments, each R1 is independently -CN or -O-C1-C6 hydroxyalkyl. In some embodiments, each R1 is independently -CN or -O-C1-C6 aminoalkyl. In some embodiments, at least one R1 is -CN.

[0078] In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), R2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), R2 is C1-C6 alkyl.

[0079] In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), U is N. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), U is CRU. Specification 27 / 84 pages 37 CN 122094689 A

[0080] In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), RU is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), RU is hydrogen, halogen, -CN, -C(=O)NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), RU is hydrogen, -CN, or -C(=O)NRcRd. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), RU is hydrogen or -CN. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), RU is -CN.

[0081] In some embodiments of the compound of formula (I-1), is or.

[0082] In some embodiments of the compound of formula (I-1), is or.

[0083] In some embodiments of the compound of formula (I-1), is or.Yes or.

[0084] In some embodiments of the compound of formula (I-1), yes or.

[0085] In some embodiments of the compound of formula (I-1), yes. In some embodiments of the compound of formula (I-1), yes. In some embodiments of the compound of formula (I-1), on page 29 / 84 of the specification CN 122094689 A, yes. In some embodiments of the compound of formula (I-1), yes. In some embodiments of the compound of formula (I-1), yes.

[0086] In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), ring B is a bicyclic heterocyclic alkyl. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), ring B is a bicyclic 6- to 10-membered heterocyclic alkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), ring B is a bicyclic 6- to 10-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), ring B is a bicyclic 6- to 10-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from N and O. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), ring B is a bridging bicyclic ring. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), ring B is 3,8-diazabicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octane. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), ring B is...

[0087] In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R3 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R3 is independently a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R3 is independently a C1-C6 alkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R3 is independently a methyl or ethyl compound.

[0088] In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), m is 0-4. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), m is 0-3. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f)In some embodiments, m is 0-2. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), m is 2. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), m is 1. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), m is 2. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), m is 3. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), m is 4. In some embodiments of the compound of formula (I-1) or (I-1a)-(I-1f), m is 5-8.

[0089] In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R4 is independently a halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R4 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R4 is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R4 is independently a halogen or a C1-C6 alkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R4 is independently a C1-C6 alkyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), each R4 is methyl. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), R4 is F.

[0090] In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), p is 0-2. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), p is 1 or 2. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), p is 2. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), p is 1. In some embodiments of compounds of formula (I-1) or (I-1a)-(I-1f), p is 0.

[0091] In formula (I-1) or (I-1a)-(I-1f ...1 f) In some embodiments of the compound, is.

[0092] In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein (pages 31 / 84, CN 122094689 A), each Ra is independently C1-C6 alkyl.

[0093] In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyl.Alkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each Rb is hydrogen. In some embodiments of the compounds disclosed herein, each Rb is independently C1-C6 alkyl.

[0094] In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is hydrogen. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently a C1-C6 alkyl group.

[0095] In some embodiments of the compounds disclosed herein, Rc and Rd together with the atoms to which they are attached form a heterocyclic alkyl group, which is optionally substituted by one or more Rs.

[0096] In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, or C1-C6 alkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -OH, or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen.

[0097] In some embodiments of the compounds disclosed herein, one or more of the R, R1, R2, R3, R4, RU, RT, Ra, Rb, Rc, and Rd groups contain a percentage of deuterium higher than the natural abundance of deuterium.

[0098] In some embodiments of the compounds disclosed herein, one or more 1H of one or more of the following groups is replaced by one or more deuterium groups: R, R1, R2, R3, R4, RU, RT, Ra, Rb, Rc, and Rd.

[0099] In some embodiments of the compounds disclosed herein, the deuterium abundance in each of R, R1, R2, R3, R4, RU, RT, Ra, Rb, Rc, and Rd is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0100] In some embodiments of the compounds disclosed herein, one or more 1H atoms of ring A or ring B are substituted with one or more deuterium atoms.

[0101] Any combination of groups of various variables described above is considered herein. Throughout the specification, groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0102] In some embodiments, the compounds of formula (I) disclosed herein are one of the compounds in Table 1.

[0103] Table 1 Specification 33 / 84 pages 43 CN 122094689 A Specification 34 / 84 pages 44 CN 122094689 A Specification 35 / 84 pages 45 CN 122094689 A

[0104] Compounds of Formula (II)

[0105] This document discloses compounds of Formula (II) or pharmaceutically acceptable salts thereof used as DGKα inhibitors: Specification 36 / 84 pages 46 CN 122094689 A Formula (II), wherein: R1a' is a halogen, -CN, -NO2, -OH, -OR a', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc'Rd', -SH, -SRa', -S(=O)Ra', -S(=O)2Ra', -S(=O)2NR c'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2Ra', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; W' is N or CR1b'; each R1b' is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a',‑OC(=O)Ra',‑OC(=O)ORb',‑OC(= O)NRc'Rd',‑SH,‑SRa',‑S(=O)Ra',‑S(=O)2R a',‑S(=O)2NR c'Rd',‑NRc'Rd',‑NRb'C(=O)NRc'Rd',‑ NRb'C(=O)Ra', ‑NRb'C(=O)ORb', ‑NRb'S(=O)2R a', ‑C(=O)Ra', ‑C(=O)ORb', ‑C(=O)NRc'Rd', C1‑C6 alkaneThe alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally and independently substituted by one or more R's; R2' is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U' is N or CRU'; RU' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R'; ring B' is a heterocycloalkyl; each R3' is independently a halogen, -CN, -NO2, -OH, -OR a', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc' Rd', -SH, -SRa', -S(=O)Ra', -S(=O)2Ra', -S(=O)2NR c'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O) O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2Ra', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; Specification 37 / 84 pages 47 CN 122094689 A or two R3' on the same atom together form an oxo group; or two R3' on the same or different carbons together form a cycloalkyl or heterocycloalkyl group, each optionally substituted by one or more R'; m' is an integer from 0 to 6; X' represents N or CRX'; RX' represents hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', Cl-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R'; Y' is N or CRY'; RY' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R'; Z' is N or CRZ'; RZ' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R'; R5' is hydrogen, halogen, -CN, -NO2, -OH, -OR a', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc'Rd', -SH, -SRa', -S(=O)Ra', -S(=O)2R a', -S(=O)2NR c'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O) Ra', -NRb'C(=O)ORb', -NRb'S(=O)2R a', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; R4' is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted by one or more R4a';Each R4a' is independently a halogen, -CN, -NO2, -OH, -OR a', -OC(=O)Ra', -OC(=O)ORb', -OC(=O)NRc'Rd', -SH, -SRa', -S(=O)Ra', -S(=O)2Ra', -S(=O)2NR c'Rd', -NRc'Rd', -NRb'C(=O)NRc'Rd', -NRb'C(=O)Ra', -NRb'C(=O)ORb', -NRb'S(=O)2Ra', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more R'; or two R4a' on the same atom together form an oxo group; each Ra' is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 Alkylene (heterocyclic alkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are independently and optionally substituted by one or more R's; or two Ra's together with the atoms to which they are attached form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally substituted by one or more R's; each Rb' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1- C6 alkylene (heterocyclic alkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R's; or two Rb's together with the atoms to which they are attached form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally substituted by one or more R's; Rc' and Rd' are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, or C1-C6 alkylene (cycloalkyl)The alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally and independently substituted by one or more R's; or Rc' and Rd' together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted by one or more R's; and each R' is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl or C3-C6 cycloalkyl; or two R's on the same atom forming an oxo group.

[0106] In some embodiments of the compound of formula (II), R1a' is a halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (II), R1a' is a halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (II), R1a' is a halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (II), R1a' is independently a halogen, -CN, -ORa', or -NRc'Rd'. In some embodiments of the compound of formula (II), R1a' is -CN or -ORa'. In some embodiments of the compound of formula (II), R1a' is -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (II), R1a' is -CN, -O-heterocyclic alkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, -O-C1-C3 hydroxyalkyl, or -O-C1-C3 aminoalkyl. In some embodiments of the compound of formula (II), R1a' is independently -CN or -NRc'Rd'. In some embodiments of the compound of formula (II), -ORa' is -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (II), -ORa' is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5- or 6-membered ring. In some embodiments of the compound of formula (II), -ORa' is or. In some embodiments of the compound of formula (II), -ORa' is -O-C1-C6 alkyl. In some embodiments of the compound of formula (II), -ORa' is -O-C1-C6 haloalkyl. In some embodiments of the compound of formula (II), -ORa' is -O-C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (II), -ORa' is -O-C1-C3 hydroxyalkyl. In some embodiments of the compound of formula (II), -ORa' is -O-CH2CH2OH. In some embodiments of the compound of formula (II), -ORa' is -O-C1-C6 aminoalkyl. Specification 39 / 84 pages 49 CN 122094689 A

[0107] In some embodiments of the compound of formula (II), R1a' is -ORa', -NRc'Rd', or heterocyclic alkyl. In some embodiments of the compound of formula (II), R1a' is -ORa'. In some embodiments of the compound of formula (II), R1a' is -O-heterocyclic alkyl, -O-C1-C6 hydroxyalkyl, -NH-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (II), R1a' is -O-heterocyclic alkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of the compound of formula (II), R1a' is -O-heterocyclic alkyl. In some embodiments of the compound of formula (II), R1a' is -O-5-6-membered heterocyclic alkyl. In some embodiments of the compound of formula (II), R1a' is -O-C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (II), R1a' is -O-C1-C3 hydroxyalkyl. In some embodiments of the compound of formula (II), R1a' is -O-CH2CH2OH. In some embodiments of the compound of formula (II), R1a' is -O-C1-C6 aminoalkyl.

[0108] In some embodiments of the compound of formula (II), W is N. In some embodiments of the compound of formula (II), W is CR1b'.

[0109] In some embodiments of the compound of formula (II), each R1b' is independently hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heteroalkyl.Cycloalkyl. In some embodiments of the compound of formula (II), each R1b' is independently hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compound of formula (II), each R1b' is independently hydrogen, halogen, or -CN. In some embodiments of the compound of formula (II), each R1b' is independently hydrogen or halogen. In some embodiments of the compound of formula (II), each R1b' is independently hydrogen or -CN.

[0110] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt thereof, the compound has a formula selected from: formula (IIa), formula (IIb), or formula (IIc). Specification 40 / 84 pages 50 CN 122094689 A

[0111] In some embodiments of compounds of formula (IIa), (IIb) or (IIc), R1a' is a halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (IIa), (IIb) or (IIc), R1a' is a halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is a halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is independently a halogen, -CN, -ORa', or -NRc'Rd'. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -CN or -ORa'. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -CN, -O-heterocyclic alkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, -O-C1-C3 hydroxyalkyl, or -O-C1-C3 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is independently -CN or -NRc'Rd'. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5- or 6-membered ring. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is or. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 alkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 haloalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 hydroxyalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 aminoalkyl.

[0112] In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -ORa', -NRc'Rd', or heterocyclic alkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -ORa'. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-heterocyclic alkyl, -O-C1-C6 hydroxyalkyl, -NH-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-heterocyclic alkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-heterocyclic alkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C6 hydroxyalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C3 hydroxyalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-CH2CH2OH. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C6 aminoalkyl.

[0113] In some embodiments of compounds of formula (IIa), (IIb) or (IIc), R1b' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is hydrogen, halogen, or -CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is a halogen or -CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is hydrogen or -CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is -CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is hydrogen or a halogen. Specification 41 / 84 pages 51 CN 122094689 A In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is a halogen. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is Cl.

[0114] In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is a halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is a halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is a halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (IIa), R1b' is a halogen or -CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is a halogen. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is fluorine or...Chlorine. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is -CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is independently a halogen, -CN, -ORa', or -NRc'Rd'. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is -CN or -ORa'. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is -CN, -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is -CN, -O-heterocyclic alkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, -O-C1-C3 hydroxyalkyl, or -O-C1-C3 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1b' is independently -CN or -NRc'Rd'. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-heterocyclic alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 hydroxyalkyl, or -O-C1-C6 aminoalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5- or 6-membered ring. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is or. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 alkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 haloalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 hydroxyalkyl. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), -ORa' is -O-C1-C6 aminoalkyl.

[0115] In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C6 hydroxyalkyl and R1b' is CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C3 hydroxyalkyl and R1b' is CN. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-CH2CH2OH and R1b' is CN.

[0116] In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C6 hydroxyalkyl and R1b' is a halogen. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C3 hydroxyalkyl and R1b' is a halogen. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-CH2CH2OH and R1b' is a halogen.

[0117] In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C6 hydroxyalkyl and R1b' is chlorine. In some embodiments of compounds of formula (IIa), (IIb), or (IIc), R1a' is -O-C1-C3 hydroxyalkyl and R1b' is chlorine. In some embodiments of compounds of formula (IIa), (IIb) or (IIc), R1a' is -O-CH2CH2OH and R1b' is chlorine.

[0118] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R's.

[0119] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R's.

[0120] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is hydrogen, halogen, -ORa', -NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally and independently substituted by one or more R's.

[0121] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is hydrogen, -ORa', C1-C6 alkyl,, 3-6 membered cycloalkyl or 5-6 membered heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally and independently substituted by one or more R'.

[0122] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is hydrogen.

[0123] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is -ORa'. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is -O-C1-C6 alkyl, wherein the alkyl is optionally substituted. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is -O-C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R5' is -O-cycloalkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R5' is -O-cycloalkyl, wherein the cycloalkyl is a 3-6 membered ring and optionally substituted with one or more R's. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R5' is -O-heterocyclic alkyl, wherein the heterocyclic alkyl is a 5-6 membered ring and optionally substituted with one or more R's.

[0124] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R5' is C1-C6 alkyl.

[0125] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R5' is...

[0126] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R5' is a 3-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is optionally and independently substituted by one or more R's.

[0127] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R2' is hydrogen or a C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R2' is a C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R2' is a C1-C3 alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R2' is methyl.

[0128] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), U' is N. In formula (II),In some embodiments of compounds of formula (IIa), (IIb), or (IIc), U' is CRU'. Specification 43 / 84 pages 53 CN 122094689 A

[0129] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), RU' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), RU' is hydrogen, halogen, -CN, -C(=O)NRc'Rd', C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), RU' is hydrogen, -CN, or -C(=O)NRc'Rd'. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), RU' is hydrogen or -CN. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), RU' is -CN. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), RU' is hydrogen.

[0130] In some embodiments of compounds of formula (II), (IIa), or (IIb), either 44 / 84 pages of the specification 54 CN 122094689 A or .

[0131] In some embodiments of compounds of formula (II), (IIa), or (IIb), either or .

[0132] In some embodiments of compounds of formula (II), (IIa), or (IIb), or specification 45 / 84 page 55 CN 122094689 A, yes or no.

[0133] In some embodiments of compounds of formula (II), (IIa), or (IIb), yes or no. Specification 46 / 84 page 56 CN 122094689 A

[0134] In some embodiments of compounds of formula (II), (IIa), or (IIb), yes or no. In some embodiments of compounds of formula (II), (IIa), or (IIb), yes or no. In some embodiments of compounds of formula (II), (IIa), or (IIb), yes or no. In some embodiments of compounds of formula (II), (IIa), or (IIb), or specification 47 / 84 page 57 CN122094689 A is. In some embodiments of compounds of formula (II), (IIa) or (IIb), or. In some embodiments of compounds of formula (II), (IIa) or (IIb), or.

[0135] In some embodiments of compounds of formula (II) or (IIa), ring B' is a 6- to 8-membered heterocyclic alkyl. In some embodiments of compounds of formula (II) or (IIa), ring B' is a 6- to 8-membered heterocyclic alkyl; comprising 1 to 3 heteroatoms selected from O, N and S. In some embodiments of compounds of formula (II) or (IIa), ring B' is a 6- to 8-membered heterocyclic alkyl; comprising 1 to 3 heteroatoms selected from O and N.

[0136] In some embodiments of compounds of formula (II) or (IIa), ring B' is a 6- to 7-membered heterocyclic alkyl. In some embodiments of the compound of formula (II) or (IIa), ring B' is a 6- to 7-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from O, N, and S. In some embodiments of the compound of formula (II) or (IIa), ring B' is a 6- to 7-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from O and N.

[0137] In some embodiments of the compound of formula (II) or (IIa), ring B' is a 6-membered heterocyclic alkyl group. In some embodiments of the compound of formula (II) or (IIa), ring B' is a 6-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from O, N, and S. In some embodiments of the compound of formula (II) or (IIa), ring B' is a 6-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from O and N.

[0138] In some embodiments of the compound of formula (II) or (IIa), ring B' is a 7-membered heterocyclic alkyl group. In some embodiments of compounds of formula (II) or (IIa), ring B' is a 7-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from O, N, and S. In some embodiments of compounds of formula (II) or (IIa), is or . In some embodiments of compounds of formula (II) or (IIa), is .

[0140] In some embodiments of compounds of formula (II) or (IIa), each R3' is independently a halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl.The compounds are C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II) or (IIa), each R3' is independently a halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II) or (IIa), each R3' is independently a C1-C6 alkyl or C1-C6 haloalkyl.

[0141] In some embodiments of compounds of formula (II) or (IIa), m' is 0-6. In some embodiments of compounds of formula (II) or (IIa), m' is 0-5. In some embodiments of compounds of formula (II) or (IIa), m' is 0-4. In some embodiments of compounds of formula (II) or (IIa), m' is 0-3. In some embodiments of compounds of formula (II) or (IIa), m' is 0-2. In some embodiments of compounds of formula (II) or (IIa), m' is 0 or 1. In some embodiments of compounds of formula (II) or (IIa), m' is 1-6. In some embodiments of compounds of formula (II) or (IIa), m' is 1-5. In some embodiments of compounds of formula (II) or (IIa), m' is 1-4. In some embodiments of compounds of formula (II) or (IIa), m' is 1-3. In some embodiments of compounds of formula (II) or (IIa), m' is 1 or 2. In some embodiments of compounds of formula (II) or (IIa), m' is 0. In some embodiments of compounds of formula (II) or (IIa), m' is 1. In some embodiments of compounds of formula (II) or (IIa), m' is 2. In some embodiments of compounds of formula (II) or (IIa), m' is 3. In some embodiments of compounds of formula (II) or (IIa), m' is 4. In some embodiments of compounds of formula (II) or (IIa), m' is 5. In some embodiments of compounds of formula (II) or (IIa), m' is 6. In some embodiments of compounds of formula (II) or (IIa), m' is 7. In some embodiments of compounds of formula (II) or (IIa), m' is 5-8. Specification 49 / 84 pages 59 CN 122094689 A

[0142] In some embodiments of compounds of formula (II) or (IIa), is.

[0143] In some embodiments of compounds of formula (II), (IIa) or (IIb), X' is N. In some embodiments of compounds of formula (II), (IIa) or (IIb), X' is CRX'.

[0144] In some embodiments of compounds of formula (II), (IIa) or (IIb), RX' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RX' is hydrogen, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RX' is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RX' is hydrogen.

[0145] In some embodiments of compounds of formula (II), (IIa), or (IIb), Y' is N. In some embodiments of compounds of formula (II), (IIa), or (IIb), Y' is CRY'.

[0146] In some embodiments of compounds of formula (II), (IIa), or (IIb), RY' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RY' is hydrogen, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RY' is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RY' is hydrogen.

[0147] In some embodiments of compounds of formula (II), (IIa), or (IIb), Z' is N. In some embodiments of compounds of formula (II), (IIa), or (IIb), Z' is CRZ'.

[0148] In some embodiments of compounds of formula (II), (IIa), or (IIb), RZ' is hydrogen, halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RZ' is hydrogen, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RZ' is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), or (IIb), RZ' is hydrogen.

[0149] In some embodiments of compounds of formula (II) or (IIa), specification 50 / 84 pages 60 CN 122094689 A isIn some embodiments of compounds of formula (II) or (IIa), is . In some embodiments of compounds of formula (II) or (IIa), is . In some embodiments of compounds of formula (II) or (IIa), is .

[0150] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R4' is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R4a'. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R4' is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more R4a'. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R4' is a 3-6 membered cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more R4a'. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R4' is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each optionally substituted by one or more R4a'. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R4' is cyclopropyl, said cyclopropyl being optionally substituted by one or more R4a'. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R4' is [missing information]. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R4' is [missing information]. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R4' is hydrogen. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), R4' is hydrogen or a C1-C6 alkyl group.

[0151] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), R4' is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R4a'.

[0152] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each R4a' is independently a halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl, C1-C6 haloalkane.The alkyl group, C1-C6 hydroxyalkyl group, C1-C6 aminoalkyl group, C1-C6 heteroalkyl group, cycloalkyl group, or heterocycloalkyl group; wherein each alkyl group, alkylene group, cycloalkyl group, and heterocycloalkyl group is optionally and independently substituted by one or more R'.

[0153] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R4a' is independently a halogen, -CN, -OH, -ORa', -NRc'Rd', -C(=O)Ra', -C(=O)ORb', -C(=O)NRc'Rd', C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 hydroxyalkyl group, C1-C6 aminoalkyl group, C1-C6 heteroalkyl group, 3- to 6-membered cycloalkyl group, or 5- to 6-membered heterocycloalkyl group; wherein each alkyl group, cycloalkyl group, and heterocycloalkyl group is optionally and independently substituted by one or more R'.

[0154] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R4a' is independently a halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, or C1-C6 haloalkyl; wherein each alkyl group is optionally and independently substituted by one or more R's. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R4a' is independently a halogen, -CN, -OH, -ORa', -NRc'Rd', C1-C6 alkyl, or C1-C6 haloalkyl.

[0155] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R4a' is independently a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R4a' is independently a C1-C6 haloalkyl group. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R4a' is independently a C1-C3 haloalkyl group. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R4a' is independently CF3.

[0156] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each Ra' is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally composed of one or more of the following:Multiple R' substitutions. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Ra' is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted by one or more R's. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Ra' is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Ra' is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclic alkyl.

[0157] In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Rb' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R's. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Rb' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted by one or more R's. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), as described on pages 52 / 84 of CN 122094689 A, each Rb' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each Rb' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Rb' is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each Rb' is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each Rb' is hydrogen. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each Rb' is independently C1-C6 alkyl.

[0158] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each Rc' and Rd' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Rc' and Rd' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally independently substituted by one or more R's. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Rc' and Rd' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Rc' and Rd' is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, or heterocyclic alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Rc' and Rd' is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each Rc'Rc' and Rd' are independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each Rc' and Rd' is hydrogen. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each Rc' and Rd' is independently C1-C6 alkyl.

[0159] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), Rc' and Rd' together with the atoms to which they are attached form a heterocyclic alkyl group, which is optionally substituted with one or more R.

[0160] In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each R' is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl or C3-C6 cycloalkyl; or two R's on the same atom form an oxo group. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R' is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two R's on the same atom form an oxo group. In some embodiments of compounds of formula (II), (IIa), (IIb), or (IIc), each R' is independently a halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; or two R's on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R' is independently a halogen, -CN, -OH, or C1-C6 alkyl; or two R's on the same atom form an oxo group. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each R' is independently a halogen, -OH, or C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each R' is independently a halogen or C1-C6 alkyl. In some embodiments of compounds of formula (II), (IIa), (IIb) or (IIc), each R' is independently a halogen. Specification 53 / 84 pages 63 CN 122094689 A

[0161] In some embodiments of the compounds disclosed herein, R', R1', R2', R3', R4', R4a', R5', RX', RY', RZ',One or more of the Ra', Rb', Rc', and Rd' groups contain a percentage of deuterium higher than the natural abundance of deuterium.

[0162] In some embodiments of the compounds disclosed herein, one or more 1H of one or more of the following groups is replaced by one or more deuterium: R', R1', R2', R3', R4', R4a', R5', RX', RY', RZ', Ra', Rb', Rc', and Rd'.

[0163] In some embodiments of the compounds disclosed herein, the deuterium abundance in each of R', R1', R2', R3', R4', R4a', R5', RX', RY', RZ', Ra', Rb', Rc', and Rd' is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0164] In some embodiments of the compounds disclosed herein, one or more 1H atoms of ring A or ring B are substituted with one or more deuterium atoms.

[0165] Any combination of groups of various variables described above is considered herein. Throughout the specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0166] In some embodiments, the compounds of formula (I) disclosed herein are one of the compounds in Table 2.

[0167] Table 2 Specification 54 / 84 pages 64 CN 122094689 A Specification 55 / 84 pages 65 CN 122094689 A Specification 56 / 84 pages 66 CN 122094689 A Specification 57 / 84 pages 67 CN 122094689 A

[0168] In some embodiments, the compounds of formula (II) disclosed herein are one of the compounds in Table 3.

[0169] Table 3 Specification 58 / 84 pages 68 CN 122094689 A Specification 59 / 84 pages 69 CN 122094689 A

[0170] Other forms of the compounds disclosed herein

[0171] Isomers / stereoisomers

[0172] In some embodiments, the compounds described herein are present as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (cis, syn, zusammen(Z)), trans (trans, anti, engegen(E)) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center is present in an R configuration or an S configuration. The compounds described herein include all diastereomers, enantiomers and epimers and their corresponding mixtures.In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compounds described herein with an optically active resolving agent to form a pair of diastereomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and these differences are utilized for separation. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered together with the resolving agent by any practical method that does not cause racemization.

[0173] Isotope-enriched compounds

[0174] Unless otherwise stated, the compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope having the same atomic number but a different atomic mass or mass number than that predominantly found in nature. All isotopic variants of the compounds disclosed herein, whether or not radioactive, are covered within the scope of this disclosure. For example, hydrogen has three naturally occurring isotopes, denoted as 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium may provide some therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds for studying in vivo drug elimination and metabolic pathways.

[0175] For example, the compounds described herein may be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes selected from deuterium (2H), tritium (3H), iodine-125 (125I), or carbon-14 (14C). In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0176] In some embodiments, the compound is deuterated at at least one position. In some embodiments, the 1H atom of the compound disclosed herein is partially or wholly replaced by a 2H atom. Specification 60 / 84 pages 70 CN 122094689 A

[0177] Methods for synthesizing deuterated compounds are known in the art and include, by way of non-limiting example only, the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997 and the following synthetic methods. For example, deuterium-substituted compounds can be synthesized using various methods, such as those described in the following literature: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2), 9-32.

[0178] Deuterated starting materials are readily available and are used in the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A wide variety of deuterium-containing reagents and building blocks are available from chemical suppliers, such as Aldrich Chemical Co.

[0179] Pharmaceutically Acceptable Salts

[0180] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0181] In some embodiments, the compounds described herein have acidic or basic groups and are therefore capable of reacting with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodimentsIn this context, these salts are prepared in situ during the final separation and purification of the compounds disclosed herein, or by reacting the purified compound in its free form with a suitable acid or base alone and separating the resulting salt.

[0182] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic, organic acids, or inorganic bases, including acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-diacidates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptates, glycerophosphates, glycolates, hemisulfates, heptanates, hexyne-1 6-Diosyl salt, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0183] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts, which are formed by reacting the free base form of the compounds with: pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, amylopectin. (See page 61 / 84 of the specification, 71 CN 122094689 A) Acids, arylsulfonic acids, methanesulfonic acids, ethanesulfonic acids, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acidAcids, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, although not pharmaceutically acceptable on their own, are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein, and their pharmaceutically acceptable acid addition salts.

[0184] In some embodiments, the compounds comprising free acid groups described herein react with a suitable base, such as a pharmaceutically acceptable hydroxide of a metal cation, a carbonate, a bicarbonate, a sulfate, ammonia, or a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include bases or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, etc.

[0185] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternized products of any basic nitrogen-containing group they contain. In some embodiments, such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0186] Tautomers

[0187] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert through hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In bond arrangements where tautomerization is possible, there will be a chemical equilibrium of tautomers. All tautomer forms of the compounds disclosed herein are considered. The exact proportions of tautomers depend on a variety of factors, including temperature, solvent, and pH.

[0188] Compound 23

[0189] Compound 23 is 3-(2-hydroxyethoxy)-5-methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthidine-2-carboxynitrile:

[0190] Compound 23 is a diacylglycerol kinase α (DGKα) inhibitor. In some embodiments, compound 23 is present in the form of a free base. In some embodiments, compound 23 is present in the form of its pharmaceutically acceptable salt.

[0191] Compound 13A

[0192] Compound 13A is 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazolidin-1(5H)-yl)quinazolin-2(1H)-one: Specification 62 / 84 pages 72 CN 122094689 A.

[0193] Compound 13A is diacylglycerol kinase α(DGKα) inhibitor. In some embodiments, compound 13A is present in the form of a free base. In some embodiments, compound 13A is present in the form of a pharmaceutically acceptable salt.

[0194] Method / Combination

[0195] This document discloses a method for treating cancer in an individual in need, the method comprising administering to the individual: (a) a DGKα inhibitor or a pharmaceutically acceptable salt thereof; and (b) an additional active agent, wherein the combined amount of said DGKα inhibitor or a pharmaceutically acceptable salt thereof and said additional active agent is therapeutically effective for treating said cancer.

[0196] This document discloses a method of treating cancer in an individual in need, the method comprising administering to the individual: (a) a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof; formula (I), as described herein; formula (II), as described herein; and (b) an additional active agent, 63 / 84 pages, 73 CN 122094689 A, wherein the combination amount of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof with the additional active agent is therapeutically effective for treating cancer.

[0197] In some embodiments, the compound of formula (I) or (II) is selected from Table 1, Table 2, or Table 3.

[0198] This document also discloses a method of treating cancer in an individual in need, the method comprising administering to the individual: (a) compound 23 or compound 13A, or a pharmaceutically acceptable salt thereof; and (b) an additional active agent, wherein the combination amount of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof with the additional active agent is therapeutically effective for treating cancer.

[0199] This document also discloses a method of treating cancer in an individual in need, the method comprising administering to the individual: (a) compound 23 or compound 13A or a pharmaceutically acceptable salt thereof; and (b) an immune checkpoint inhibitor, wherein the combined amount of said compound 23 or compound 13A or a pharmaceutically acceptable salt thereof with the immune checkpoint inhibitor is therapeutically effective for treating the cancer.

[0200] In some embodiments, the cancer is primary leukemia, hematologic malignancy, 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.

[0201] In some embodiments, the cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, B-cell acute lymphoblastic leukemia (ALL), lymphoma, or T-cell leukemia.

[0202] In some embodiments, additional active agents are PARP inhibitors, CHK1 inhibitors, MDM2 inhibitors, hypomethylating agents, mTOR inhibitors, ATM inhibitors, CDK4 / 6 inhibitors, BCL-2 inhibitors, PRMT5 inhibitors, PRMT1 inhibitors, ATR inhibitors, WEE1 inhibitors, APE1 inhibitors, topoisomerase inhibitors, taxanes, immune checkpoint inhibitors, CDK7 inhibitors, CDK9 inhibitors, DNA synthesis inhibitors, antimetabolites, AURORA inhibitors, microtubule stabilizers, DNA cross-linking agents, vinca alkaloids, alkylating agents, PRMT6 inhibitors, PRMT7 inhibitors, PRMT9 inhibitors, KRAS inhibitors, EGFR inhibitors, VEGFR inhibitors, MEK inhibitors, SHP2 inhibitors, PI3K inhibitors, AKT inhibitors, BRAF inhibitors, aromatase inhibitors, mitotic inhibitors, radiopharmaceuticals, cytotoxic agents, or any combination thereof. In some embodiments, additional active agents are immune checkpoint inhibitors.

[0203] In some embodiments, the immune checkpoint inhibitors are PD-1, PD-L1, PD-2, PD-L2, IDO-1, IDO-2, CTNNB1 (β-catenin), SIRPα, VISTA, RNASE H2, DNase II, CLEVER-1 / Stabilin-1, LIGHT, HVEM, CTLA-4, LAG-3, TIGIT, galactoglobin-9, KIR, GITR, TIM-1, TIM-3, TIM-4, CEACAM1, OX40, OX40L, CD27, CD40 / CD40L, CD48, CD70, CD80, CD86, CD112, CD137 (4-1BB), CD155, CD160, CD200, CD226, CD244 (2B4), CD272 (BTLA), B7-H2, B7-H3, B7-H4, B7-H6, A2aR, CD73, NKG2A, CCR2, ICOS, A2bR, HHLA2, ILT-2, ILT-4, gp49B, PIR-B, HLA-G, ILT-2 / 4, MDR1, arginase 1, iNOs, IL-10, TGF-β, pGE2, STAT3, VEGF, KSP, HER2, Ras, EZH2, NIPP1, PP1, TAK1, or PLK1 inhibitors or antagonists.

[0204] In some embodiments, the immune checkpoint inhibitor is an antagonist of IDO-1, IDO-2, A2aR, CD73, or CCR2, or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the IDO-1 antagonist is LY3381916, epacadostat, linrodostat, BMT-297376, palmatine, PF-06840003, or a pharmaceutically acceptable salt thereof (page 64 / 84, CN 122094689 A).

[0206] In some embodiments, the IDO-2 antagonist is IDO2-IN-1, GNF-PF-3777, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the A2aR antagonist is ciforadenant, imaradenant, etrumadenant, NIR178, inupadenant, CS3005, PBF-999, or INCB106385, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the CD73 antagonist is quemliclustat, AB680, methADP, OP-5244, MRS4620, PSB-12379 or BK50164, or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the CCR2 antagonist is JNJ-41443532, CCR2-RA-[R], PF-4136309, BMS CCR2 22, RS 504393, MK-0812, AZD2423, PF-0463481, BMS-813160, BMS-753426, RS102895, JNJ-27141491, cenicriviroc, BX471, INCB 3284 or INCB3344, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, an anti-A2aR antibody, an anti-CD73 antibody, an anti-NKG2A antibody, an anti-CCR2 antibody, an anti-HVEM antibody, an anti-KIR antibody, an anti-OX40 antibody, an anti-IgG antibody, an anti-IDO-1 antibody, an anti-IDO-2 antibody, an anti-CEACAM1 antibody, an anti-BTLA antibody, an anti-OX40L antibody, an anti-TIM-3 antibody, an anti-GAL9 antibody, an anti-VISTA antibody, an anti-TIGIT antibody, or a variant thereof or a biosimilar thereof.

[0211] In some implementations, the anti-PD-L1 antibody is AUNP12, JS003, CS-1001, BMS-936559, atezolizumab, avelumab, betifisolimab, durvalumab, garivulimab, opucolimab, sugemalimab, tagitanlimab, envafolimab, cosibelimab, adebrelimab, socazolimab, or variants thereof or biosimilars thereof.

[0212] In some embodiments, the anti-PD-1 antibody is AMP-224, AMP-514, 14C12H1L1, BAT-1306, AK103, AK104, AK105, SG001, nivolumab, nofazinlimab, pembrolizumab, finotonlimab, genolimzumab, spartalizumab, serplulimab, dostarlimab, cemiplimab, toripalimab.

[0213] In some embodiments, the anti-CTLA-4 antibody is botensilimab, ipilimumab, zalifrelimab, or tremelimumab, or a variant thereof or a biosimilar thereof.

[0214] In some embodiments, the anti-LAG-3 antibody is relatlimab, fianlimab, miptenalimab, favezelimab, or eralalimab.(ieramilimab), Sym022, GSK2831781, INCAGN02385, TSR-033, or variants thereof or biosimilars thereof.

[0215] In some embodiments, the anti-TIGIT antibody is tiragolumab, domvanalimab, vibostolimab, etigilimab, tamgiblimab (tajiglipramab), M6223, ociperlimab, or EOS884448, or variants thereof or biosimilars thereof.

[0216] In some embodiments, the anti-TIM-3 antibody is sabatolimab, surzebiclimab, cobolimab, Sym023, R07121661, LY3321367, ICAGN02390, or BMS-986258, or a variant thereof or a biosimilar thereof.

[0217] In some embodiments, the anti-B7-H3 antibody is enoblituzumab, omburtamab, vobramitamab, mirzotamab, B7-H3 TriKE, 131I-omburtamab, DS-7300a, or 177Lu-DTPA-omburtamab, or a variant thereof or a biosimilar thereof.

[0218] In some embodiments, the anti-B7-H4 antibody is alsevalimab, FPA150, or a variant thereof or a biosimilar thereof.

[0219] In some embodiments, the anti-CD73 antibody is oleclumab, mupadolimab, uliledlimab, MEDI9447, AK119, HLX23, IPH5301, Sym042, IBI325, PT199, JAB-BX102, NZV930, INCA00186, or BMS-986179, or a variant thereof or a biosimilar thereof.

[0220] In some embodiments, the anti-NKG2A antibody is monalizumab, or a variant thereof or a biosimilar thereof.

[0221] In some embodiments, the anti-CCR2 antibody is lozalizumab (plozalizumab), or a variant thereof or a biosimilar thereof.

[0222] In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, or pildizumab.Monoclonal antibodies (pidilizumab), AMP-224, PF-06801591, MEDI0680, PDR001, REGN2810, SHR-1210, TSR-042, CA-170, atezolizumab, durvalumab, KN035, BMS-936559, ipilimumab, trimemumab, avelumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013 or TSR-022, or their variants or biosimilars.

[0223] In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, ipilimumab, trimemumab, avelumab, or a variant thereof or a biosimilar thereof.

[0224] In some embodiments, the immune checkpoint inhibitor is nivolumab, or a variant thereof or a biosimilar thereof.

[0225] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, or a variant thereof or a biosimilar thereof.

[0226] In some embodiments, the immune checkpoint inhibitor is pildizumab, or a variant thereof or a biosimilar thereof.

[0227] In some embodiments, the immune checkpoint inhibitor is atezolizumab, or a variant thereof or a biosimilar thereof.

[0228] In some embodiments, the immune checkpoint inhibitor is ipilimumab, or a variant thereof or a biosimilar thereof.

[0229] In some embodiments, the immune checkpoint inhibitor is trimemumab, or a variant thereof or a biosimilar thereof.

[0230] In some embodiments, the immune checkpoint inhibitor is avelumab or a variant thereof or a biosimilar thereof.

[0231] In some embodiments, an additional active agent is a PRMT1 inhibitor.

[0232] In some embodiments, the PRMT1 inhibitor is GSK3368715 (EPZ019997), C7280948, EPZ020411 2HC1, MS023, furamidine, C21 or TC-E 5003, or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the PRMT1 inhibitor is GSK3368715 (EPZ019997) or a pharmaceutically acceptable salt thereof, as per page 66 / 84 of the specification, CN 122094689 A.

[0234] In some embodiments, an additional active agent is a PRMT6 inhibitor.

[0235] In some embodiments, the PRMT6 inhibitor is SGC 6870 or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, an additional active agent is a protein arginine methyltransferase 5 (PRMT5) inhibitor or a protein arginine methyltransferase 7 inhibitor.(PRMT7) inhibitor or protein arginine methyltransferase 9 (PRMT9) inhibitor.

[0237] In some embodiments, an additional active agent is a PRMT5 inhibitor.

[0238] In some embodiments, the PRMT5 inhibitor is JNJ-64619178 (AGI-931), HLCL-61, GSK591, EPZ015666 (GSK3235025), GSK3326595 (EPZ015938; AGI-219), TNG908, TNG462, AMG193, AMG9747, MRTX1719, P305-05313, CTS3157, PH-020-803 or AZ-PRMT5i-1, or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the PRMT5 inhibitor is TNG908, TNG462, AMG193, AMG9747, MRTX1719, or P305-05313, or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or JNJ-64619178 (AGI-931), or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the PRMT5 inhibitor is GSK3326595, or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the PRMT5 inhibitor is JNJ-64619178 (AGI-931), or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the PRMT5 inhibitor is [the specific ingredient] or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the PRMT5 inhibitor is or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the PRMT5 inhibitor is or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the PRMT5 inhibitor is selected from WO2021050915, WO2021086879, WO2021 / 163344, WO2022 / 026892, WO 2022 / 256806, WO2023036974, WO2021050915, WO2022192745, WO2023278564, WO2022132914, WO2022169948, WO2022115377, WO2021163344, WO2021086879, WO2022026892, US11077101, Malik, R., et al., AACR Annual Meeting, 2021Compounds disclosed in abstract number 1140 or Bonday, ZQ, et al., ACS Med. Chem. Lett. 2018, 9, 612-617, the entire contents of which are incorporated herein by reference.

[0247] In some embodiments, an additional active agent is a PRMT7 inhibitor.

[0248] In some embodiments, the PRMT7 inhibitor is SGC 3027 or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, an additional active agent is a PRMT9 inhibitor.

[0250] In some embodiments, an additional active agent is an ATR inhibitor.

[0251] In some embodiments, the ATR inhibitor is RP-3500, M-6620, bexostatinib (M-6620, VX-970; VE-822), AZD-6738, AZ-20, M-4344 (VX-803), BAY-1895344, M-1774, IMP-9064, nLs-BG-129, SC-0245, BKT-300, ART-0380, ATRN-119, ATRN-212, or NU-6027, or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, an additional active agent is a WEE1 inhibitor.

[0253] In some embodiments, the WEE1 inhibitor is AZD1775 (MK1775), ZN-c3, debio 0123, IMP7068, SDR-7995, SDR-7778, NUV-569, PD0166285, PD0407824, SC-0191, DC-859 / A, bosutinib, or Bos-I, or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, an additional active agent is a topoisomerase inhibitor.

[0255] In some embodiments, 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, cyclophosphamide.(cyclosphosphamide), amsacrine, etoposide, etoposide phosphate, teniposide, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, doxorubicin, or HU-331, or pharmaceutically acceptable salts thereof.

[0256] In some embodiments, the topoisomerase inhibitor is topotecan, daunorubicin, mitoxantrone, or doxorubicin, or pharmaceutically acceptable salts thereof.

[0257] In some embodiments, the additional active agent is a cytotoxic agent.

[0258] In some embodiments, the cytotoxic agent is an alkylating agent, a cytotoxic antibiotic, an antimetabolite, vinca alkaloids, platinum-based drugs, taxanes, or a topoisomerase inhibitor. In some embodiments, the additional active agent is a cytotoxic antibiotic. In some embodiments, the cytotoxic antibiotic is anthracycline (e.g., doxorubicin and valrubicin). In some embodiments, the cytotoxic antibiotic is a non-anthracycline compound (e.g., bleomycin and actinomycin D). In some embodiments, the additional active agent is an active agent that is detrimental to cell viability.

[0259] In some embodiments, the additional active agent is a platinum drug. In some embodiments, the platinum drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthreneplatin, picoplatin, or satraplatin.

[0260] In some embodiments, the additional active agent is taxane. Instructions for Use, pages 68 / 84, CN 122094689 A

[0261] In some embodiments, taxane is docetaxel, paclitaxel, accatin III, 10-deacetylated paclitaxel, 7-xylosyl-10-deacetylated paclitaxel, chalcomenite, 10-deacetylated 7-epitaxel, 7-epitaxel, 10-deacetylated accatin III or 10-deacetylated chalcomenite, or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, taxane is docetaxel or paclitaxel, or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, taxane is docetaxel or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, taxane is paclitaxel or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the additional active agent is a CDK7 inhibitor.

[0266] In some embodiments, the CDK7 inhibitor is LDC4297, THZ1, THZ2, YKL-5-124, BS-181, samuraciclib, LY3405105, PHA-793887, SNS-032 (BMS-387032), PF-562271, or milciclib (PHA-848125), or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the additional active agent is a CDK9 inhibitor.

[0268] In some embodiments, the CDK9 inhibitor is SNS-032 (BMS-387032), LY2857785, avocidib, or riviciclib hydrochloride (P276-00), or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, an additional active agent is a DNA synthesis inhibitor.

[0270] In some embodiments, the DNA synthesis inhibitor is 5-fluorouracil (5-FE1), 6-mercaptopurine (6-MP), capecitabine, cytarabine, fluorouridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, or pemetrexed, or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the DNA synthesis inhibitor is 5-fluorouracil (5-FE1), fludarabine, gemcitabine, or pemetrexed, or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the DNA synthesis inhibitor is 5-fluorouracil (5-FE1) or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the DNA synthesis inhibitor is fludarabine or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the DNA synthesis inhibitor is gemcitabine or a pharmaceutically acceptable salt thereof. In some embodiments, the DNA synthesis inhibitor is pemetrexed or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, an additional active agent is an antimetabolite.

[0276] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cytarabine, fluorouridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or phototrexate, or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the antimetabolite is pemetrexed or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the additional active agent is an AURORA inhibitor.

[0279] In some implementations, AURORA inhibitors include alisertib (MLN8237), tozasertib (VX-680, MK-0457), barasertib (AZDI 152-HQPA), ZM 447439, MLN8054, danusertib (PHA-739358), AT9283, JNJ-7706621, hesperidin, aurora A inhibitor I (TC-S 7010), KW-2449, SNS-314, ENMD-2076, PHA-680632, MK-5108 (VX-689), CYC116, AMG-900, PF-03814735, and CCT. 129202, GSK1070916, TAK-901, CCT137690, MK-8745, ENMD-2076, aurora kinase inhibitor III, SNS-314 mesylate, BI-847325, reversine, or ABT-348, or pharmaceutically acceptable salts thereof. Specification 69 / 84 pages 79 CN 122094689 A

[0280] In some embodiments, an additional active agent is a KRAS inhibitor.

[0281] In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor.

[0282] In some embodiments, the KRAS inhibitor is a KRAS G12D inhibitor.

[0283] In some embodiments, the KRAS inhibitor is a KRAS G12S inhibitor.

[0284] In some embodiments, the KRAS inhibitor is 6H05, adagrasib, ARS-1323, ARS-1323-alkyne, ARS-1620, ARS-1630, ARS-853, ASP2453, AZD4625, BAY-293, BI-0474, BI-2852, BI-3406, divarasib, G12Si-1, G12Si-5 formic acid, G12Si-5, garsorasib, K2O, KRAS G12C inhibitor 1, KRAS G12C inhibitor 2, KRAS G12C inhibitor 3, KRAS G12C inhibitor 4, KRAS G12C inhibitor 5, KRAS G12C inhibitor 13, KRAS G12C inhibitor 14, KRAS G12C inhibitor 15, KRASKRAS G12C inhibitor 16, KRAS G12C inhibitor 17, KRAS G12C inhibitor 18, KRAS G12C inhibitor 23, KRAS G12C inhibitor 24, KRAS G12C inhibitor 25, KRAS G12C inhibitor 26, KRAS G12C inhibitor 27, KRAS G12C inhibitor 28, KRAS G12C inhibitor 32, KRAS G12C inhibitor 43, KRAS G12C inhibitor 44, KRAS G12C inhibitor 45, KRAS G12C inhibitor 46, KRAS G12C inhibitor 47, KRAS G12C inhibitor 48, KRAS G12C inhibitor 49, KRAS G12C inhibitor 50, KRAS G12C inhibitor 51, KRAS G12C inhibitor 52, KRAS G12C inhibitor 53, KRAS G12C inhibitor 54, KRAS KRAS G12C inhibitor 55, KRAS G12C inhibitor 57, K-Ras G12C-IN-2, KRAS G12D inhibitor 3, KRAS G12D inhibitor 7, KRAS G12D inhibitor 14, KRAS G12D inhibitor 16, KRAS G12D inhibitor 17, KRAS inhibitor-3, KRAS inhibitor-6, KRAS inhibitor-7, KRAS inhibitor-8, KRAS inhibitor-10, KRAS inhibitor-11, KRAS inhibitor-12, KRAS inhibitor-13, KRAS inhibitor-14, KRAS inhibitor- 15. KRAS inhibitor-16, KRAS inhibitor-17, KRAS inhibitor-18, KRAS inhibitor-20, K-Ras (G12C) inhibitor-6, KRpep-2d, LC-2, MRTX1133, MRTX-1257, MRTX849 acid, MRTX-EX185 formic acid, opnurasib, pan-KRas-IN-1, PROTAC K-Ras degrader-1, RM-018, SAH-SOS1A, SOS1-IN-4, SOS1-IN-9, sotorasib, or ZG1077, or pharmaceutically acceptable salts thereof.

[0285] In some embodiments, the KRAS inhibitor is ARS-3248 (JNJ-74699157), AMG510, MRTX849, MRTX1133, ASP245, 3GDC6036, BI-2852, BI 1701963, mRNA-5671, JDQ443, RAS(ON) inhibitor, BBP-454, RM-018, RMC-6291 or RMC-6236, or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the KRAS inhibitor is adagrasisib, divarasib, gisorasib, openurasisib, or sotorasib, or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the KRAS inhibitor is sotorasib, or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the KRAS inhibitor is adagrasisib, or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the KRAS inhibitor is selected from WO 201 811 91 83, WO201 8217 651, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019232419, WO2019241157, WO2020106640, WO2021081212, WO2022083569, WO2022093856, WO2022232332, WO2022232331, WO2020146613, WO2020097537, WO2015054572. WO2020177629, WO2019141250, WO2020081282, WO2020085493, WO2018143315, WO2018206539, WO2019110751, WO2019195609, WO2021207172, WO2021041671, WO2021150613, WO2021142252, WO2021152149, WO2021248090, WO2021216770, WO2022002102, WO2022031678, US10662204B2, US10689377B2, US10689377B2, Compounds disclosed in US10689377B2, US10689377B2 or US10519146B2, the entire contents of which are incorporated herein by reference. Specification 70 / 84 pages 80 CN 122094689 A

[0290] In some embodiments, the additional active agent is an EGFR inhibitor.

[0291] In some embodiments, the EGFR inhibitor is erlotinib (OSI-774) HCl, gefitinib (ZD1839), lapatinib (GW-572016) xylenesulfonate, afatinib (BIBW2992), cescatinib (AZD0530), vandetanib (ZD6474), lenalidomide, etc.Neratinib (HKI-272), Canertinib (CI-1033), Lapatinib (GW-572016), AG-490 (tyrosine phosphorylation inhibitor B42), CP-724714, Dacomitinib (PF-00299804), WZ4002, Sapitinib (AZD8931), CUDC-101, AG-1478 (tyrosine phosphorylation inhibitor AG-1478), PD153035 HCl, Pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), AP26113 analog (ALK-IN-1), OSI-420, WZ3146, Allitinib tosylate, Rociletinib (CO-1686), Varlitinib, Icotinib (BPI-2009H), TAK-285, WHI-P154, Daphnetin, PD168393, CNX-2006, Tyrosine phosphorylation inhibitor 9, AG-18, O-desmethylgefitinib, AST-1306, BDTX-189, Epertinib hydrochloride, JND3229, BI-4020, Tyrosine phosphorylation inhibitor AG-528, AG 556. Canatinib dihydrochloride, EGFR inhibitors, gefitinib-based PROTAC 3, SU5214, RG 13022, TQB3804 (EGFR-IN-7), zipalertinib, Pyrotinib (SHR-1258) dimaleate, PD153035, AG 494, AG 555. Theliatinib (HMPL-309), Avitinib (AC0010), Lazertinib, Gefitinib hydrochloride, Cetuximab (anti-EGFR), Lifirafenib (BGB-283), Nazartinib (EGF816), Brigatinib (AP26113), Tucatinib, Zorifertinib(AZD3759), Afatinib (BIBW2992) dimaleate, Erlotinib (OSI-774), CL-387785 (EKI-785), Poziotinib (HM781-36B), Osimertinib (AZD9291), AZ5104, AV-412 free base, WZ8040, Genistein (NPI 031L), Falnidamol, BLU-945, Sunvozertinib, CH7233163, Licochalcone D, Alflutinib (AST2818) mesylate, (Rac)-JBJ-04-125-02, Mobocertinib (TAK788), tyrosine phosphorylation inhibitors AG30 (AG30), AG-1557, AG99, MTX-211, RG14620, Almonertinib (HS-10296), Cyasterone, Osimertinib mesylate, Norcantharidin, Naquotinib (ASP8273), EAI045, Lidocaine hydrochloride, Olmutinib (BI 1482694), Butein, Chrysophanic acid, or (-)-epigallocatechin gallate, or pharmaceutically acceptable salts thereof.

[0292] In some embodiments, an additional active agent is a VEGFR inhibitor.

[0293] In some embodiments, the VEGFR inhibitors are sorafenib (BAY 43-9006) tosylate, sunitinib (SU11248) malate, cabozantinib (BMS-907351), ponatinib (AP24534), axitinib (AG 013736), foretinib (GSK1363089), vandetanib (ZD6474), nintedanib (BIBF 1120), regorafenib (BAY 73-4506), pazopanib HCl (GW786034 HCl), and cediranib.(AZD2171), PD173074, Dovitinib (TKI-258), Linifanib (ABT-869), Vatalanib (PTK787) 2HCl, RAF265 (CHIR-265), Tivozanib (AV-951), Motesanib Diphosphate (AMG-706), Lenvatinib (E7080), Brivanib (BMS-540215), MGCD-265 analogues, Product Information 71 / 84 pages 81 CN 122094689 A AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, Telatinib, PP121, Pazopanib, KRN 633, SAR131675, Apatinib (YN968D1) mesylate, BMS-794833, Sorafenib (BAY 43-9006), Cabozantinib malate, Brinib alanine (BMS-582664), Golvatinib (E7050), Semaxanib (SU5416), ZM 323881 HCl, ZM 306416, ENMD-2076 L-(+)-Tartrate, R1530, Chiauranib, Emvododstat (PTC299), XL092, Regorafenib Hydrochloride, Lucitinib (E3810) Hydrochloride, Ningetinib, Donafenib (Sorafenib D3), Ki20227, Tyrosine Phosphorylation Inhibitor AG1433, SU14813, Sulfatinib, CS-2660 (JNJ-38158471), SU5204, SU5214, SU5205, SU5408, Pamufetinib (TAS-115), ODM-203, WHI-P180, Altiratinib, Motesanib (AMG-706), Fruquintinib (HMPL-013), Lenvatinib (E7080) Mesylate, Nintedanib Isylate, Apatinib, Sildinib Maleate, Toceranib PhosphateAnlotinib (AL3818) dihydrochloride, regorafenib (BAY-734506) monohydrate, sitravatinib (MGCD516), ramucirumab, BFH772, BAW2881 (NVP-BAW2881), SU5402, sunitinib (SU11248), dovirtinib (TKI258) lactate monohydrate, LY2874455, SKLB1002, AZD2932, lenalidomide (CC-5013), WAY-340935, ozonafenide, hVEGF-IN-1, 4SC-203, chebulinic acid, nastorazepide, X-82 (Vorolanib), MAZ51, TMTD (tetramethylthiuram disulfide), SU5208, SU5614, AG-13958, SKLB 610, SU1498, ZD-4190, PDGFR inhibitor 1, bevacizumab, erdafitinib (JNJ-42756493), vitamin E or taxifolin (dihydroquercetin), or pharmaceutically acceptable salts thereof.

[0294] In some embodiments, an additional active agent is an aromatase inhibitor.

[0295] In some embodiments, the aromatase inhibitor is letrozole (CGS 20267), anastrozole (ZD-1033), exemestane (FCE 24304), formestane, fadrozole (CGS16949A), α-naphthylflavonoid or obacunone (AI3-37934), or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the additional active agent is a mitosis inhibitor.

[0297] In some embodiments, the mitosis inhibitor is taxane (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vincristine, vindesine, and vinblastine), etc.Vinorelbine, colchicine, podophyllotoxin, griseofulvin, or Glaziovianin A, or pharmaceutically acceptable salts thereof.

[0298] In some embodiments, an additional active agent is a microtubule stabilizer.

[0299] In some embodiments, the microtubule stabilizer is paclitaxel, nab-paclitaxel, docetaxel, colchicine, podophyllin, epothilone A, or epothilone B, or pharmaceutically acceptable salts thereof.

[0300] In some embodiments, an additional active agent is a radiopharmaceutical.

[0301] In some embodiments, an additional active agent is a DNA cross-linking agent.

[0302] In some embodiments, the DNA cross-linking agent is oxaliplatin, cisplatin, or pharmaceutically acceptable salts thereof.

[0303] In some embodiments, an additional active agent is vinca alkaloid. Specification 72 / 84 pages 82 CN 122094689 A

[0304] In some embodiments, vinca alkaloid is vinorelbine, vincristine, vincaine, vincaine N-oxide, vindesine, vinflunine, vincamine, vintafolide, or deacetoxyvinzolidine, or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, an additional active agent is an alkylating agent.

[0306] In some embodiments, the alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, platinum coordination complexes, or pharmaceutically acceptable salts thereof.

[0307] In some embodiments, additional active agents are folic acid analogs, pyrimidine analogs, purine analogs, antibiotics, etc.L-asparaginase, interferon, anthracenedione-substituted urea, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progestins, estrogens, anti-estrogen receptor inhibitors, androgens, anti-androgen receptor inhibitors, endocrine / hormonal agents or gonadotropin-releasing hormone analogs, or pharmaceutically acceptable salts thereof.

[0308] In some embodiments, the anti-estrogen receptor inhibitor is fulvestrant (ICI-182780), raloxifene HCl, bazedoxifene (WAY-140424) HCl, G-1, amcenestrant (SAR439859), estrogen receptor modulator 1, lasofoxifene tartrate, H3B-5942, raloxifene, brilanestrant (GDC-0810), tamoxifen (ICI 46474) citrate, or toremifene citrate (NK 622). Clomifene citrate, estriol, estrone, bardoxifen (TSE-424) acetate, SPP-86, enclomiphene citrate, phenol red sodium salt, Camizestrant (AZD9833), G15 (GRB-G15), Cyclofenil, PHTPP, AZD9496, chlortetracycline, endoxifen HCl, ospermide, or tamoxifen (ICI 46474), or pharmaceutically acceptable salts thereof.

[0309] In some embodiments, the anti-androgen receptor inhibitor is enzalutamide (MDV3100), bicalutamide (ICI-176334), oseltamine, apalutamide (ARN-509), gastrodinone, flutamide, cyproterone acetate, AZD3514, spironolactone, ORM-15341, CLP-3094, or proxalutamide (GT091 8), JNJ-63576253 (TR C-253), Bavdegalutamide (ARV-110), ACP-105, Ailanthone, UT-34, Triptophenolide, 4,4'-DDE, EPI-001, Darolutamide (ODM-201), Megestrol Acetate, Clascoterone, Inobrodib (CCS-1477), GSK-2881078, (S,R,S)-AHPC (MDK7526), ​​Dimethylcurcumin (ASC-J9), RU58841, Nilutamide, 3,3'-diindolemethane or chlormedrone acetate, or pharmaceutically acceptable salts thereof.

[0310] In some embodiments, the additional active agent is a chemotherapeutic drug.

[0311] In some embodiments, this disclosure provides a method of treating cancer in an individual in need, the method comprising administering to the individual: (a) a compound of formula (I) or (II) described herein or a pharmaceutically acceptable salt thereof; and (b) an immune checkpoint inhibitor.

[0312] In some embodiments, this disclosure provides a method of treating cancer in an individual in need, the method comprising administering to the individual: (a) compound 23 or compound 13A or a pharmaceutically acceptable salt thereof; and (b) an immune checkpoint inhibitor.

[0313] In some embodiments, the immune checkpoint inhibitor is an inhibitor or antagonist of PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, or CCR2.

[0314] In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, ipilimumab, trimemumab, avelumab, or a variant thereof or a biosimilar thereof.

[0315] In some embodiments, the immune checkpoint inhibitor is nivolumab, or a variant thereof or a biosimilar thereof.

[0316] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, or a variant thereof or a biosimilar thereof.

[0317] In some embodiments, the immune checkpoint inhibitor is pildizumab, or a variant thereof or a biosimilar thereof.

[0318] In some embodiments, the immune checkpoint inhibitor is atezolizumab, or a variant thereof or a biosimilar thereof.

[0319] In some embodiments, the immune checkpoint inhibitor is ipilimumab or a variant thereof or a biosimilar thereof.

[0320] In some embodiments, the immune checkpoint inhibitor is trimemumab or a variant thereof or a biosimilar thereof.

[0321] In some embodiments, the immune checkpoint inhibitor is avelumab or a variant thereof or a biosimilar thereof.

[0322] On the other hand, this disclosure provides the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the medicament is formulated for administration in combination with an additional active agent.

[0323] On the other hand, this disclosure provides the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in combination with an additional active agent in the preparation of a medicament for treating cancer.

[0324] On the other hand, this disclosure provides the use of compound 23 or compound 13A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the medicament is formulated for administration in combination with an additional active agent.

[0325] On the other hand, this disclosure provides the use of compound 23 or compound 13A or a pharmaceutically acceptable salt thereof with additional active agents in the preparation of a medicament for treating cancer.

[0326] In some embodiments, the additional active agent is an immune checkpoint inhibitor. In some embodiments, the additional active agent is nivolumab, pembrolizumab, pildizumab, atezolizumab, ipilimumab, trimemumab, avelumab or variants thereof or bioanalyses thereof.

[0327] Administration

[0328] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic and intranasal injection.

[0329] Pharmaceutical Compositions / Formulations

[0330] According to standard pharmaceutical practice, the compounds described herein, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, are administered as pharmaceutical compositions to individuals in need. In some embodiments, the compounds described herein are administered to animals. Specification 74 / 84 pages 84 CN 122094689 A

[0331] In another aspect, pharmaceutical compositions are provided herein comprising the compounds described herein or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a formulation suitable for use as a pharmaceutical product. A suitable formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science andPractice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0332] Examples

[0333] The following examples are included for illustrative purposes. However, it should be understood that these examples are not limiting of this disclosure and are intended only to illustrate methods of carrying out this disclosure. Those skilled in the art will recognize that the chemical reactions described can be readily applied to the preparation of a variety of other compounds of this disclosure, and alternative methods for preparing the compounds of this disclosure are considered to be within the scope of this disclosure. For example, the synthesis of compounds not illustrated in this disclosure can be successfully carried out with modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art instead of those described, and / or by making conventional variations to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art would be considered suitable for the preparation of other compounds of this disclosure.

[0334] Example A Synthesis of Compounds

[0335] Intermediate 1 (Int1)

[0336] PPA (25 g, 73.98 mmol) was added to a mixture of compound Int1-1 (5 g, 38.71 mmol) and compound Int1-2 (5.01 g, 40.65 mmol), and the mixture was stirred at 180 °C for 2 hours. After cooling to 20 °C, the reaction was quenched with water. The mixture was adjusted to pH=12 with a 50% aqueous potassium hydroxide solution and then extracted with dichloromethane (2 × 200 mL). The organic layer was washed with saturated brine, dried with Na2SO4, and evaporated under reduced pressure to obtain intermediate compound Int1. MS (ESI) m / z (M+H)+ = 217.0.

[0337] Intermediate 2 (Int2) SpecificationPage 75 / 84 85 CN 122094689 A

[0338] Pyridine (10.45 mL, 129.84 mmol) was added to a mixture of Int2-1 (10.0 g, 43.28 mmol) in DCM (300 mL). The mixture was cooled to 0 °C and AcCl (4.62 mL, 64.92 mmol) was added. The mixture was stirred at 15 °C under N2 for 18 hours. The mixture was poured into water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give Int2-2. LCMS: MS m / z (ESI) [M+H]+ = 272.9.

[0339] Cs2CO3 (26.23 g, 80.52 mmol) and MeI (8.57 g, 60.39 mmol) were added to a mixture of Int2-2 (11.0 g, 40.26 mmol) in DMF (150 mL). The mixture was stirred at 25 °C under N2 for 18 hours. The mixture was poured into water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to give Int2-3. LCMS: MS m / z (ESI) [M+H]+ = 287.1.

[0340] B2(pin)2 (4.03 g, 15.88 mmol), Pd(dppf)Cl2 (1.55 g, 2.12 mmol), and KOAc (3.12 g, 31.77 mmol) were added to a mixture of Int2-3 (3.2 g, 10.59 mmol) in dioxane (150 mL). The mixture was stirred at 100 °C for 3 hours under N2. The mixture was poured into water (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give Int2-4. LCMS: MS m / z (ESI) [M+H]+ = 252.5.

[0341] CO(NH2)2·H2O2 (2.13 g, 22.62 mmol) was added to a mixture of Int2-4 (3.0 g, 11.31 mmol) in CH3CN (300 mL). The mixture was stirred at 25 °C under N2 for 18 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to obtain Int2-5. LCMS: MS m / z(ESI) [M+H]+ = 225.0.

[0342] Benzyl bromide (15.06 g, 88.04 mmol) and K2CO3 (40.56 g, 293.46 mmol) were added to a solution of Int2-5 (7.0 g, 29.34 mmol) in DMF (100 mL). The mixture was stirred at 60 °C for 3 hours under N2. The mixture was poured into water (80 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give Int2-6 (9.0 g, 97.6%). LCMS: MS m / z (ESI) [M+H]+ = 315.2.

[0343] Urea hydrogen peroxide (17.91 g, 190.4 mmol) and TFAA (39.99 g, 190.4 mmol) were added to a solution of Int2-6 (9 g, 27.200 mmol) in DCE (200 mL). The mixture was stirred at 70 °C for 2 hours under N2. After cooling to room temperature, the mixture was adjusted to pH = 8.0 with saturated NaHCO3 (aqueous solution) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give Int2-7 (8.0 g, 84.6%). LCMS: MS m / z (ESI) [M+ H]+ = 331.1.

[0344] POCl3 (10.69 mL, 115.03 mmol) was added to a solution of Int2-7 (8.0 g, 23.01 mmol) in CH3CN (100 mL). The mixture was stirred at 60 °C for 3 hours under N2. The mixture was concentrated under reduced pressure, adjusted to pH = 8.0 with saturated NaHCO3 (aqueous solution), and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give Int2-8 (7.0 g, 78.5%). LCMS: MS m / z (ESI) [M+H]+ = 349.0.

[0345] At 80 °C, KHMDS (0.72 g, 3.60 mmol) was added to a solution of Int2-8 (1.1 g, 3.00 mmol) in THF (30 mL). The reaction mixture was stirred at 80 °C under N2 for 10 minutes. The mixture was adjusted to pH = 1N HCl.6.0, and concentrated under reduced pressure to give Int2-9 (950 mg, 95.1%). LCMS: MS m / z (ESI) [M+H]+ = 317.0. Specification 76 / 84 pages 86 CN 122094689 A

[0346] The mixture of Int2-9 (950 mg, 2.85 mmol) in POCl3 (10 mL) was stirred for 3 hours at 85 °C. The mixture was poured into ice water (100 mL) and adjusted to pH = 8.0 with saturated NaHCO3 solution. The resulting mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to give intermediate compound Int2 (600 mg, 59.7%). LCMS: MS m / z (ESI) [M+H]+ = 334.8.

[0347] Intermediate 3 (Int3)

[0348] At 0 °C, lithium aluminum hydride (51.8 mL, 1.0 M THF solution) was added dropwise to a mixture of Int3-1 (8.0 g, 37.03 mmol) in anhydrous THF (200 mL). After addition, the reaction mixture was heated to room temperature and stirred overnight. The mixture was quenched with water (30 mL) and then with 15% NaOH solution (7.7 mL). The mixture was stirred for another 1 hour and filtered. The filtrate was concentrated to give Int3-2. LCMS: MS m / z (ESI) [M-17]+ = 183.9.

[0349] At room temperature, Int3-2 (5.0 g, 24.75 mmol) was added to a mixture of chloroacetyl chloride (3.07 g, 27.22 mmol) in dry DCM (200 mL), followed by diisopropylethylamine (9.59 g, 74.24 mmol). The mixture was stirred at ambient temperature for 18 hours. The mixture was quenched with saturated sodium bicarbonate. The organic layer was separated and washed with saturated NaHCO3 solution (50 mL) and water (50 mL × 2). The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated to obtain Int3-3. LCMS: MS m / z (ESI) [M‑17]+ = 260.0. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.1, 0.9 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H), 4.97 (s, 2H), 4.20 (s, 2H).

[0350] A suspension of sodium tert-butoxide (2.42 g, 25.20 mmol) in t-BuOH (80 mL) was heated to 80 °C until a clear solution was obtained. Then, Int3-3 (3.90 g, 14.00 mmol) was added in one go, and the reaction was stirred at 80 °C for 2 hours. The reaction mixture was cooled, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by rapid column chromatography to give Int3-4. LCMS: MS m / z (ESI) [M +H]+ = 241.9.

[0351] At 0 °C, BH3-Me2S (20.4 mL, 2.0 M) was slowly added to a mixture of Int3-4 (3.3 g, 13.63 mmol) in anhydrous THF (200 mL). The reaction was refluxed for 2 hours. The mixture was cooled to 0 °C and slowly quenched with water (200 mL). The mixture was extracted with ethyl acetate and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography to give intermediate compound Int3. LCMS: MS m / z (ESI) [M+H]+ = 229.9.

[0352] Intermediate 4 (Int4)

[0353] At room temperature and N2, CDI (15.78 g, 97.44 mmol) was added to a solution of Int4-1 (10 g, 64.94 mmol) in DCM (200 mL). The reaction mixture was stirred for 0.5 h. Then Et3N (19.68 g, 194.82 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.6 g, 77.93 mmol) were added to the above solution. The reaction mixture was stirred at room temperature for 48 h. The mixture was diluted with DCM (100 mL) and washed with 1 M HCl (3 × 300 mL) and saturated NaHCO3 solution (300 mL). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain Int4-2, which was used directly in the next step without further purification.

[0354] At 0 °C and N2, LiAlH4 (25.36 mL, 1 M) was added to a mixture of Int4-2 (5 g, 25.36 mmol) in dioxane (50 mL). The mixture was stirred at 0–20 °C for 2 hours. The mixture was quenched with H2O (1 mL), 15% NaOH (1 mL), and H2O (31 mL). The mixture was purified by distillation under standard atmospheric pressure to obtain Int4-3, which was used directly in the next step without further purification.

[0355] Dimethyl (1-diazo-2-oxopropyl)phosphonate (5.84 g, 30.42 mmol) was added to a mixture of Int4-3 (10 g, 15.21 mmol) and K2CO3 (6.31 g, 45.62 mmol) in MeOH (25 mL) at 0 °C and N2. The mixture was stirred at 20 °C for 18 hours. The mixture was diluted with toluene (50 mL) and washed with H2O (3 × 50 mL). The mixture was purified by distillation under standard atmospheric pressure to give intermediate compound Int4, which was used directly in the next step without further purification.

[0356] Intermediate 5 (Int5)

[0357] SO2Cl2 (8.94 g, 66.23 mmol) was added to a solution of Int5-1 (10.0 g, 55.2 mmol) in CHCl3 (100 mL) at an ice bath temperature. The mixture was refluxed for 12 hours. The reaction mixture was concentrated under reduced pressure to give Int5-2. MS (ESI) m / z (M+H)+ = 216.1.

[0358] Int5-2 (9.0 g, 34.64 mmol) was added to a solution of NaOH (2.77 g, 69.3 mmol) in H2O (100 mL) and THF (100 mL). The mixture was stirred overnight at 105 °C. The reaction mixture was acidified with HCl (2 M) to form a precipitate. The precipitate was collected by filtration. The filter cake was washed with water and dried under reduced pressure to obtain Int5-3, MS (ESI) m / z (M+MeCN+H)+ = 243.1.

[0359] A mixture of Int5-3 (6.0 g, 29.8 mmol) and CDI (4.83 g, 29.76 mmol) in THF (100 mL) was stirred at room temperature for 12 hours. The mixture was quenched with water to form a precipitate. The precipitate was collected by filtration, the filter cake was washed with water and dried under reduced pressure to obtain Int5-4. MS (ESI) m / z (M-H)+ = 226.0.

[0360] DIEA (6.10 mL, 36.9 mmol) and CH3I (7.86 g, 55.4 mmol) were added to a mixture of Int5-4 (4.2 g, 18.5 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with ice to form a precipitate. The precipitate was collected by filtration, the filter cake was washed with water and dried under reduced pressure to obtain Int5-5. MS (ESI) m / z (M + H)+ = 242.1.

[0361] To Int5-5 (3.0 g,NH4OH (0.96 mL, 24.8 mmol) was added to a mixture of Int5-6 (2.0 g, 9.32 mmol) in TMF (20 mL). After stirring at 60 °C for 2 hours, the reaction mixture was diluted with EtOAc (80 mL) and washed with water and brine. The organic layer was collected, dried with Na2SO4, filtered, and concentrated under vacuum to give Int5-6. MS (ESI) m / z (M + H)+ = 214.9.

[0362] NaH (1.86 g, 46.6 mmol, 60%, in mineral oil) was added to a mixture of Int5-6 (2.0 g, 9.32 mmol) in DMF (50 mL) at 0 °C. After stirring at room temperature for 1 hour, CDI (2.27 g, 13.98 mmol) was added to the mixture. The reaction mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) according to the instructions on page 78 / 84 of CN 122094689 A and filtered. The filter cake was washed with 1 M HCl solution and dried under reduced pressure to give Int5-7. MS (ESI) m / z (M + H)+ = 241.1.

[0363] POCl3 (1.93 mL, 20.8 mmol) and DIEA (3.43 mL, 20.8 mmol) were added to a suspension of Int5-7 (1.0 g, 4.16 mmol) in dry toluene (30 mL). The reaction mixture was heated at 110 °C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure to give intermediate compound Int5, which was used directly in the next step without further purification.

[0364] Example 23: Synthesis of 3-(2-hydroxyethoxy)-5-methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthidium-2-carboxynitrile (compound 23)

[0365] Int1 (735.6 mg, 3.40 mmol) and DIPEA (2.81 mL, 17.01 mmol) were added to a solution of Int2 (600 mg, 1.70 mmol) in i-PrOH (10 mL). The mixture was stirred at 110 °C for 32 hours under N2. The mixture was poured into water (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 23-1 (440 mg, 47.7%). LCMS: MS m / z (ESI) [M+H]+ = 515.0.

[0366] At -78 °C, BBr3 (5.13 mL, 5.13 mmol) was added to a solution of 23-1 (550 mg, 1.03 mmol) in DCM (5 mL). After stirring at room temperature and N2 for 18 hours, the mixture was quenched with MeOH (10 mL) and adjusted to pH = 8-9 with NH3·H2O (0.5 mL). The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 23-2 (300 mg, 66.8%). LCMS: MS m / z (ESI) [M+H]+ = 425.0.

[0367] To a mixture of 23-2 (100 mg, 0.24 mmol) in DMF (10 mL), (2-bromoethoxy)-(tert-butyl)dimethylsilane (169 mg, 0.72 mmol) and Cs₂CO₃ (383 mg, 1.18 mmol) were added. After stirring at 100 °C for 3 hours, the mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (see page 79 / 84 of the specification, CN 122094689 A) to give compound 23-3 (50 mg, 36.4%). LCMS: MS m / z (ESI) [M+H]⁺ = 583.2.

[0368] To a mixture of 23-3 (50 mg, 0.086 mmol) in DMA (1 mL), Zn(CN)2 (50.5 mg, 0.43 mmol), Zn (5.61 mg, 0.086 mmol), zinc bis(acetate) (15.7 mg, 0.086 mmol), dppf (23.8 mg, 0.043 mmol), and Pd(dba)3·CHCl3 (34.8 mg, 0.043 mmol) were added. The mixture was stirred in a microwave at 160 °C for 1.5 hours. The mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was washed with brine (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 23-4. LCMS: MS m / z (ESI) [M+H]+ = 574.0.

[0369] TBAF (0.35 mL, 0.35 mmol) was added to a mixture of 23-4 (100 mg, 0.17 mmol) in THF (4 mL).After stirring at room temperature for 1 hour, the mixture was diluted with EtOAc (15 mL) and washed with water (3 × 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give compound 23 (10.6 mg). LCMS: MS m / z (ESI) [M+H]+ = 460.0. 1H NMR (400 MHz, DMSO) δ 7.58 – 7.52 (m, 2H), 7.50 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.01 (s, 1H) , 5.06 (t, J = 5.2 Hz, 1H) , 4.40 (t, J = 4.7 Hz, 2H) , 4.08 – 3.98 (m, 2H) , 3.88 – 3.78 (m, 2H) , 3.55 (s, 3H) , 3.29 – 3.24 (m, 1H) , 3.18 – 3.08 (m, 2H), 2.41 (s, 3H), 2.25 – 2.16 (m, 2H), 2.09 – 1.94 (m, 2H).

[0370] Example 13A: Synthesis of 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazolidinyl-1(5H)-yl)quinazolin-2(1H)-one (compound 13A)

[0371] LiHMDS (18.7 mL) was added to a mixture of Int3 (1.42 g, 6.23 mmol) in THF (30 mL) at 20 °C and N2. The mixture was stirred at 20 °C for 5 minutes under N2. Then, a solution of DIEA (6.86 mL, 41.53 mmol) and Int5 (1.08 g, 4.15 mmol) in THF (10 mL) was added to the mixture. The mixture was stirred at 20 °C for 1 hour under N2. The mixture was quenched with an aqueous solution of NH4Cl (50 mL) and extracted with DCM (50 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 13A-1. MS (ESI) m / z (M + H)+ = 450.0.

[0372] LiCl (113 mg, 2.66 mmol) was added to a mixture of 13A-1 (200 mg, 0.44 mmol) in DMF (1 mL).mmol). The mixture was stirred at 140 °C for 18 hours. The mixture was concentrated under reduced pressure. The residue was diluted with DCM / MeOH (10 / 1, 15 mL) and filtered. The filtrate was concentrated under reduced pressure to give 13A-2, which was used directly for the next step without further purification. MS (ESI) m / z (M + H)+ = 436.0. Specification 80 / 84 pages 90 CN 122094689 A

[0373] Cs2CO3 (228 mg, 1.65 mmol) was added to a mixture of 13A-2 (120 mg, 0.28 mmol) and 13-1 (197 mg, 0.82 mmol) in DMF (5 mL). The reaction was stirred at 60 °C for 16 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with water and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum to obtain 13A-3. MS (ESI) m / z (M + H)+ = 594.2.

[0374] ZnBr2 (208 mg, 0.93 mmol), Pd(dppf)Cl2 (13.5 mg, 0.019 mmol), TEA (0.51 mL, 3.70 mmol), and Int4 (121 mg, 0.22 mmol) were added to a mixture of 13A-3 (110 mg, 0.19 mmol) in DMF (1 mL). The reaction mixture was stirred in a sealed tube at 100 °C for 15 minutes. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine. The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain Example 13A-4. MS (ESI) m / z (M + H)+ = 648.3.

[0375] TBAF (0.12 mL, 0.12 mmol) was added to a mixture of 13A-4 (40 mg, 0.063 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give compound 13A. MS (ESI) m / z (M + H)+ = 534.1. 1H NMR (400 MHz, DMSO) δ 7.46 (d, J = 7.7 Hz, 1H) , 7.24 (t, J = 7.9 Hz, 1H) , 7.00 (d, J = 7.9 Hz, 1H) , 6.94 (s , 1H) , 6.57 (s , 1H) , 5.25-4.75 (m, 3H), 4.25 (t, J = 4.6 Hz, 2H), 3.99 - 3.86 (m, 2H), 3.80 - 3.74 (m, 2H), 3.56 (s, 3H), 3.50 - 3.24 (m, 2H), 1.54 - 1.46 (m, 4H).

[0376] Example B DGKA Inhibition ADP-Glo Assay

[0377] The DGKA inhibition reaction was carried out using the ADP-glo assay. The reaction was carried out with a working solution of 50 mM HEPES, 100 mM NaCl, 10 mM MgCl2, 1 mM CaCl2, 0.005% Triton X-100 and 1 mM DTT (pH = 7.5). 30 nL of the DMSO solution of each test compound (the top concentration of each compound is 0.4 μM, 10 points, 4-fold dilution series) was transferred to a 384-well plate by Echo, and 5 μL of the DGKA (SignalChem, D21-10BG) enzyme working solution at 2x the final reaction concentration was added to each well. After incubation at 25 °C for 15 min, 5 μL of the substrate working solution containing 40 μM ATP (Promega, V915B) and 200 μM DLG (SignalChem, D430-59) was added to initiate the reaction. After the enzymatic reaction at 25 °C for 60 min, the ADP Glo assay reagent (Promega, V9102) was added, and the luminescence was recorded using EnVision according to the following manual instructions. The percentage of inhibition was calculated from the luminescence of the enzyme-free control reaction with 100% inhibition and the DMSO-only reaction with 0% inhibition. The IC50 value was calculated by regression analysis of the inhibition rate. The results are shown in Table 5.

[0378] Table 5 Page 81 / 84 of the specification 91 CN 122094689 A Page 82 / 84 of the specification 92 CN 122094689 A

[0379] IC50 (nM): 0 < A ≤ 10; 10 < B ≤ 100; 100 < C ≤ 1000

[0380] Example C In Vivo MC38, CT26 and B16F10 Homologous Models

[0381] Each mouse will be subcutaneously inoculated with MC38, CT26 or B16F10 tumor cells in 0.1 mL of DPBS in the right flank for tumor growth. For each in vivo efficacy study, when the average tumor volume reaches approximately ~30 - 100 mm3, the animals will be randomly grouped and treatment will be initiated. Anti-mPD-1 (BP0146), anti-mPD-L1 (BP0101) and anti-mCTLA-4 (BP0164) are used in the single-arm group and combined-arm treatment. The primary endpoint is to observe whether tumor growth is delayed or the mouse isWhether cured. Tumor size was measured three times a week using calipers in two dimensions. The volume was expressed in mm3 using the formula: V = 0.5 ax b2, where a and b are the long and short diameters of the tumor, respectively. The tumor size was then used to calculate the TGI value.

[0382] The TGI for each group was calculated using the following formula: TGI (%) = [1 - (Ti - T0) / (Vi - V0)] × 100; Ti is the mean tumor volume of the treatment group on a given date, T0 is the mean tumor volume of the treatment group on the first day of treatment, Vi is the mean tumor volume of the mediator control group on the same number of days as Ti, and V0 is the mean tumor volume of the mediator group on the first day of treatment.

[0383] Summary statistics of tumor volume for each group at each time point were provided, including the mean and the standard error of the mean (SEM).

[0384] Statistical analysis of intergroup differences in tumor volume was performed on the data obtained on the last day.

[0385] For comparisons between three or more groups, one-way ANOVA was performed, followed by a multiple comparison procedure. When a significant statistic was obtained, the Games-Howell test was used for intergroup comparisons. When a non-significant statistic was obtained, the Tukey test was used for intergroup comparisons. All data were analyzed using SPSS 24 software, and p < 0.05 was considered statistically significant.

[0386] The drug interaction coefficient (CDI) was used to analyze the synergistic potential of the two drugs. The CDI value was calculated using the formula CDI = AB / (A×B), where AB is the ratio of the mean TV of the combination group to the control group; A or B is the ratio of the mean TV of the corresponding single drug group to the control group. CDI < 1 indicates synergy, CDI < 0.7 indicates significant synergy, CDI = 1 indicates additive effect, and CDI > 1 indicates antagonistic effect.

[0387] The results are shown in Table 6.

[0388] Table 6: Summary of the efficacy of the MC38, CT26 and B16F10 homology models. Instructions for use, pages 83 / 84, 93 CN 122094689 A

[0389] . Instruction manual, 84 / 84 pages, 94 pages, CN 122094689 A

Claims

1. A method for treating cancer in an individual in need, the method comprising administering to the individual: (a) A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof: Equation (I), Equation (II), in: Ring A is phenyl or a 6-membered heteroaryl group; Each R 1 Independently halogen, -CN, -NO2, -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)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; n is an integer between 0 and 4; R 2 It can be hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; U is N or CR U ; R U Hydrogen, halogen, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; Each R 3 Independently halogen, -CN, -NO2, -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)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; Or two R atoms on the same atom 3 Together they form oxygen; Or two Rs on adjacent carbons 3 Together they form alkenyl groups; Or two Rs on the same or different carbons 3 Together they form cycloalkyl or heterocycloalkyl groups, each of which is optionally substituted with one or more R groups; m is an integer between 0 and 8; T is N or CR T ; R T It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; Each R 4 Independently halogen, -CN, -NO2, -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)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R; p is an integer between 0 and 4; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; Or two Rs a Together with the atoms to which they are attached, they form heterocyclic alkyl groups, which are optionally substituted with one or more R atoms; Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; Or two Rs b Together with the atoms to which they are attached, they form heterocyclic alkyl groups, which may optionally be substituted with one or more R atoms; R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; Or R c and R d Together with the atoms they are attached to, they form heterocyclic alkyl groups, which may optionally be substituted with one or more R atoms; and Each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl or C3-C6 cycloalkyl; Or two R atoms on the same atom can form an oxo group; R 1a’ Halogen, -CN, -NO2, -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)2R a’ -S(=O)2NR 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)2R a’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; W' is N or CR 1b’ ; Each R 1b’ Independently hydrogen, halogen, -CN, -NO2, -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)2R a’ -S(=O)2NR 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)2R a’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; R 2’ It can be hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; U' is N or CR U’ ; R U’ Hydrogen, halogen, -CN, -OH, -OR a’ -NR c’ R d’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; Ring B' is a heterocyclic alkyl group; Each R 3’ Independently halogen, -CN, -NO2, -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)2R a’ -S(=O)2NR 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)2R a’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; Or two R atoms on the same atom 3’ Together they form oxygen; Or two Rs on the same or different carbons 3’ Together they form cycloalkyl or heterocycloalkyl groups, each of which is optionally substituted by one or more R'; m' is an integer between 0 and 6; X' is N or CR X’ ; R X’ Hydrogen, halogen, -CN, -OH, -OR a’ -NR c’ R d’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; Y' is N or CR Y’ ; R Y’ Hydrogen, halogen, -CN, -OH, -OR a’ -NR c’ R d’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; Z' is N or CR Z’ ; R Z’ Hydrogen, halogen, -CN, -OH, -OR a’ -NR c’ R d’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; R 5’ Hydrogen, halogen, -CN, -NO2, -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)2R a’ -S(=O)2NR 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)2R a’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; R 4’ The alkyl group is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally separated by one or more R groups. 4a’ replace; Each R 4a’ Independently halogen, -CN, -NO2, -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)2R a’ -S(=O)2NR 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)2R a’ -C(=O)R a’ -C(=O)OR b’ -C(=O)NR c’ R d’ C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted by one or more R'; Or two R atoms on the same atom 4a’ Together they form oxygen; Each R a’ Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R'; Or two Rs a’ Together with the atoms to which they are attached, they form heterocyclic alkyl groups, which are optionally substituted with one or more R's; Each R b’ Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R'; Or two Rs b’ Together with the atoms to which they are attached, they form heterocyclic alkyl groups, which are optionally substituted with one or more R's; R c’ and R d’ Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R'; Or R c’ and R d’ Together with the atoms to which they are attached, they form heterocyclic alkyl groups, which are optionally substituted with one or more R's; and Each R' is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl or C3-C6 cycloalkyl; Or two R' atoms on the same atom can form an oxo group; as well as (b) Other surfactants, The combination of the compound of formula (I) or (II) or its pharmaceutically acceptable salt with other active agents is therapeutically effective for treating cancer.

2. The method of claim 1, wherein the compound of formula (I) or formula (II) is selected from Table 1, Table 2 or Table 3.

3. The method of claim 1 or 2, wherein the cancer is primary leukemia, hematologic malignancy, 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's lymphoma, or mesothelioma.

4. The method of any one of claims 1-3, wherein the cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, B-cell acute lymphoblastic leukemia (ALL), lymphoma, or T-cell leukemia.

5. The method of any one of claims 1-4, wherein the additional active agent is a PARP inhibitor, CHK1 inhibitor, MDM2 inhibitor, demethylating agent, mTOR inhibitor, ATM inhibitor, CDK4 / 6 inhibitor, BCL-2 inhibitor, PRMT5 inhibitor, PRMT1 inhibitor, ATR inhibitor, WEE1 inhibitor, APE1 inhibitor, topoisomerase inhibitor, taxane, immune checkpoint inhibitor, CDK7 inhibitor, CDK9 inhibitor, DNA synthesis inhibitor, antimetabolite, AURORA inhibitor, microtubule stabilizer, DNA cross-linking agent, vinca alkaloid, alkylating agent, PRMT6 inhibitor, PRMT7 inhibitor, PRMT9 inhibitor, KRAS inhibitor, EGFR inhibitor, VEGFR inhibitor, MEK inhibitor, SHP2 inhibitor, PI3K inhibitor, AKT inhibitor, BRAF inhibitor, aromatase inhibitor, mitotic inhibitor, radiopharmaceutical, cytotoxic agent, or any combination thereof.

6. The method of any one of claims 1-5, wherein the additional active agent is an immune checkpoint inhibitor.

7. The method of any one of claims 1-5, wherein the immune checkpoint inhibitor is PD-1, PD-L1, PD-2, PD-L2, IDO-1, IDO-2, CTNNB1 (β-catenin), SIRPα, VISTA, RNASE H2, DNase II, CLEVER-1 / Stabilin-1, LIGHT, HVEM, CTLA-4, LAG-3, TIGIT, galactoglobulin-9, KIR, GITR, TIM-1, TIM-3, TIM-4, CEACAM1, OX40, OX40L, CD27, CD40 / CD40L, CD48, CD70, CD80, CD86, CD112, CD137 (4-1BB), CD155, CD160, CD200, CD226, CD244 (2B4), CD272 Inhibitors or antagonists of (BTLA), B7-H2, B7-H3, B7-H4, B7-H6, A2aR, CD73, NKG2A, CCR2, ICOS, A2bR, HHLA2, ILT-2, ILT-4, gp49B, PIR-B, HLA-G, ILT-2 / 4, MDR1, arginase 1, iNOs, IL-10, TGF-β, pGE2, STAT3, VEGF, KSP, HER2, Ras, EZH2, NIPP1, PP1, TAK1, or PLK1.

8. The method of claim 7, wherein the immune checkpoint inhibitor is an antagonist of IDO-1, IDO-2, A2aR, CD73 or CCR2, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the IDO-1 antagonist is LY3381916, icardostat, linrostat, BMT-297376, palmatine, PF-06840003, or a pharmaceutically acceptable salt thereof.

10. The method of claim 8, wherein the IDO-2 antagonist is IDO2-IN-1, GNF-PF-3777, or a pharmaceutically acceptable salt thereof.

11. The method of claim 8, wherein the A2aR antagonist is cefranal, imadenland, ictredinam, NIR178, inudinam, CS3005, PBF-999 or INCB106385, or a pharmaceutically acceptable salt thereof.

12. The method of claim 8, wherein the CD73 antagonist is quimritarasht, AB680, methADP, OP-5244, MRS4620, PSB-12379 or BK50164, or a pharmaceutically acceptable salt thereof.

13. The method of claim 8, wherein the CCR2 antagonist is JNJ-41443532, CCR2-RA-[R], PF-4136309, BMS CCR2 22, RS 504393, MK-0812, AZD2423, PF-0463481, BMS-813160, BMS-753426, RS102895, JNJ-27141491, sinevirol, BX471, INCB 3284 or INCB 3344, or a pharmaceutically acceptable salt thereof.

14. The method of claim 7, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, an anti-A2aR antibody, an anti-CD73 antibody, an anti-NKG2A antibody, an anti-CCR2 antibody, an anti-HVEM antibody, an anti-KIR antibody, an anti-OX40 antibody, an anti-IgG antibody, an anti-IDO-1 antibody, an anti-IDO-2 antibody, an anti-CEACAM1 antibody, an anti-BTLA antibody, an anti-OX40L antibody, an anti-TIM-3 antibody, an anti-GAL9 antibody, an anti-VISTA antibody, an anti-TIGIT antibody, or a variant thereof or a bioanalyst thereof.

15. The method of claim 14, wherein the anti-PD-L1 antibody is AUNP12, JS003, CS-1001, BMS-936559, atezolizumab, avelumab, betifestolimumab, durvalumab, garevelumab, octolimumab, sugemalimab, tetralimumab, envorimab, cochilimumab, adebenone, socarzolimumab, or a variant thereof or a biosimilar thereof.

16. The method of claim 14, wherein the anti-PD-1 antibody is AMP-224, AMP-514, 14C12H1L1, BAT-1306, AK103, AK104, AK105, SG001, nivolumab, nofazilimumab, pembrolizumab, fenolinumab, genolimumab, spartazumab, slulimumab, dostalimumab, simiprelimumab, toripalimab, camrelizumab, tislelizumab, penamprolium, pimivalimab, rivelimab, sintilimumab, cepalimumab, or a variant thereof or a biosimilar thereof.

17. The method of claim 14, wherein the anti-CTLA-4 antibody is botecilimab, ipilimumab, zefulimab, or trimemumab or a variant thereof or a biosimilar thereof.

18. The method of claim 14, wherein the anti-LAG-3 antibody is rilatolimab, fumarazolimab, miptalimab, malizalimumab, erralimab, Sym022, GSK2831781, INCAGN02385, TSR-033, or a variant thereof or a biosimilar thereof.

19. The method of claim 14, wherein the anti-TIGIT antibody is tireliumab, dovanalimab, vimbrolizumab, ateribimab, tangipilimab, M6223, osperimab, or EOS884448, or a variant thereof or a biosimilar thereof.

20. The method of claim 14, wherein the anti-TIM-3 antibody is sabatolimab, sozebimab, cobbimumab, Sym023, R07121661, LY3321367, ICAGN02390 or BMS-986258, or a variant thereof or a biosimilar thereof.

21. The method of claim 14, wherein the anti-B7-H3 antibody is enotozumab, octotumab, vorbretazumab, mirtuzumab, B7-H3 TriKE, 131 I-Olbetuzumab, DS-7300a or 177 Lu-DTPA (Orbatomab) or its variants or biosimilars thereof.

22. The method of claim 14, wherein the anti-B7-H4 antibody is esvorimab, FPA150, or a variant thereof or a biosimilar thereof.

23. The method of claim 14, wherein the anti-CD73 antibody is olelenumab, moparibumab, eulenumab, MEDI9447, AK119, HLX23, IPH5301, Sym042, IBI325, PT199, JAB-BX102, NZV930, INCA00186 or BMS-986179, or a variant thereof or a biosimilar thereof.

24. The method of claim 14, wherein the anti-NKG2A antibody is monalizumab or a variant thereof or a bioanalyte thereof.

25. The method of claim 14, wherein the anti-CCR2 antibody is lozalizumab or a variant thereof or a bioanalyte thereof.

26. The method of claim 6, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, AMP-224, PF-06801591, MEDI0680, PDR001, REGN2810, SHR-12-1, TSR-042, CA-170, atezolizumab, durvalumab, KN035, BMS-936559, ipilimumab, trimemumab, avelumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR-022, or a variant thereof or a biosimilar thereof.

27. The method of claim 26, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pildizumab, atezolizumab, ipilimumab, trimemumab, avelumab, or a variant thereof or a biosimilar thereof.

28. The method of claim 26, wherein the immune checkpoint inhibitor is nivolumab or a variant thereof or a biosimilar thereof.

29. The method of claim 26, wherein the immune checkpoint inhibitor is pembrolizumab or a variant thereof or a biosimilar thereof.

30. The method of claim 26, wherein the immune checkpoint inhibitor is pildizumab or a variant thereof or a bioanalyst thereof.

31. The method of claim 26, wherein the immune checkpoint inhibitor is atezolizumab or a variant thereof or a biosimilar thereof.

32. The method of claim 26, wherein the immune checkpoint inhibitor is ipilimumab or a variant thereof or a biosimilar thereof.

33. The method of claim 26, wherein the immune checkpoint inhibitor is trimemumab or a variant thereof or a biosimilar thereof.

34. The method of claim 26, wherein the immune checkpoint inhibitor is avirumab or a variant thereof or a biosimilar thereof.

35. Use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the medicament is formulated for administration in combination with an additional active agent.

36. Use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof with an additional active agent in the preparation of a medicament for the treatment of cancer.

37. Use of compound 23 or compound 13A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein said medicament is formulated for administration in combination with another active agent: Compound 23; Compound 13A.

38. Use of compound 23 or compound 13A or a pharmaceutically acceptable salt thereof with an additional active agent in the preparation of a medicament for the treatment of cancer: Compound 23; Compound 13A.

39. The use as described in claim 37 or 38, wherein the additional active agent is an immune checkpoint inhibitor.

40. The use of claim 39, wherein the additional active agent is nivolumab, pembrolizumab, pildizumab, atezolizumab, ipilimumab, trimemumab, avelumab, or a variant thereof or a biosimilar thereof.

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