Therapeutic combinations comprising ubiquitin-specific processing protease 1 (USP1) inhibitors and chemotherapeutic agents - Patent Application 20070233333

Abstract

The present invention relates to a method for treating a chemotherapeutic agent comprising administering to a subject a therapeutic agent comprising administering to said subject a chemotherapeutic agent and a ubiquitin-specific processing protease 1 (USP1) inhibitor having formula I: The present invention also relates to a method of treating cancer, delaying, reducing and / or preventing tumor rebound comprising administering the combination.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 380,735, filed October 24, 2022, and U.S. Provisional Application No. 63 / 329,228, filed April 8, 2022, each of which is incorporated by reference in its entirety herein.

[0002] Sequence listings submitted electronically via EFS-WEB The contents of the electronically submitted sequence listing (name: 4195_025PC03_Seqlisting_ST26.txt; size: 2,997 bytes; and creation date: April 6, 2023) are incorporated herein by reference in their entirety.

[0003] 2. Background of the Invention Field The present invention provides a combination of a chemotherapeutic agent and a ubiquitin-specific processing protease 1 (USP1) inhibitor. Methods for treating cancer, delaying, reducing and / or preventing tumor rebound, comprising administering the combination, are provided. [Background technology]

[0004] background Ubiquitin is a small (76 amino acid) protein that post-transcriptionally binds to target proteins. The outcome of ubiquitination is determined by the number and linkage topology of ubiquitin molecules conjugated to the target protein. For example, proteins that display lysine 48-linked poly-ubiquitin chains are generally targeted to the proteasome for degradation, while mono-ubiquitination or poly-ubiquitin linked through other lysines controls non-proteolytic functions such as cell cycle control, DNA damage repair, transcription and endocytosis. Ubiquitination is a reversible process, and enzymes called deubiquitinases remove ubiquitin from target proteins.

[0005] USP1 is a deubiquitinase that has a role in DNA damage repair. USP1 interacts with UAF1 (USP1-associated factor 1) to form a complex required for deubiquitinase activity. The USP1 / UAF1 complex deubiquitinates mono-ubiquitinated PCNA (proliferating cell nuclear antigen) and mono-ubiquitinated FANCD2 (Fanconi anemia complementation group D2), proteins with important functions in the translesion synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. The USP1 / UAF1 complex also deubiquitinates Fanconi anemia complementation group I (FANCI). These two pathways are essential for the repair of DNA damage induced by DNA cross-linking agents such as cisplatin and mitomycin C (MMC).

[0006] Chemotherapeutic agents induce a wide variety of DNA damage that cells must recognize and counteract in order to survive. Chemotherapeutic agents can be divided into two groups based on the mechanism of action and the type of damage they induce, although there is considerable crossover between the groups. Alkylating agents directly modify DNA and often induce bulky DNA damage that is repaired via the nucleotide excision repair pathway (NER). Platinum-based agents also induce bulky DNA damage that is repaired by the NER pathway and are effective in treating a wide range of cancers. Most groups of agents target DNA metabolism and include DNA intercalators, topoisomerase poisons and antimetabolites. Many chemotherapeutic agents damage DNA, causing DNA adducts, strand breaks or DNA replication fork stalling / collapse, the repair or restart of which often requires homologous recombination (HR) and Fanconi anemia proteins. Summary of the Invention [Problem to be solved by the invention]

[0007] There remains an unmet medical need for more effective therapeutic agents, including combination therapeutic agents, for the treatment of cancer. [Means for solving the problem]

[0008] Summary of the Invention Provided herein is a combination of (i) a ubiquitin-specific processing protease 1 (USP1) inhibitor and (ii) a chemotherapeutic agent. Also provided herein is a method of treating a subject with cancer using such a combination.

[0009] In one embodiment, the present invention relates to a combination comprising (i) a chemotherapeutic agent and (ii) a ubiquitin-specific processing protease 1 (USP1) inhibitor, wherein the USP1 inhibitor is represented by Formula I: [ka] [In the formula: X 1 and X 2 Each of N and CR 2 are independently selected from; R 1 and R 2 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl; X 11 and X 12 each is independently selected from N and CH; R 5’ is hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14 )ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 14 )aryl, optionally substituted -O-(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl; R 5 is optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31aC(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14 )ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 14 )aryl, optionally substituted -O-(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl; or R of adjacent atoms 5 and R 5’ are optionally substituted together with the atom to which they are attached (C6-C 14 ) forms an aryl ring; or adjacent atoms R 5 and R 5’ together with the atom to which they are attached form an optionally substituted heteroaryl ring; or 5 and R 5’ together with the atom to which they are attached form an optionally substituted (C-C)cycloalkyl ring; or 5 and R 5’together with the atom to which they are attached form an optionally substituted heterocycloalkyl ring; or R 5 and R 5’ and the atom to which they are attached together form an optionally substituted spirocycloalkyl ring; or R 5 and R 5’ and the atom to which they are attached together form an optionally substituted spiroheterocycloalkyl ring; R 6 and R 7 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 23 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R 31a and R 31b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; and R 24 , R 25 , R27 , R 32a and R 32b Each of R 24 , R 25 , R 27 , R 32a and R 32b are independently selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the chemotherapeutic agent is a platin, a monofunctional alkylating agent, a bifunctional alkylating agent, an antimetabolite, a topoisomerase inhibitor, or a combination thereof.

[0011] In other embodiments, the chemotherapeutic agent is a platin selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, and triplatin, hi other embodiments, the chemotherapeutic agent is cisplatin or carboplatin.

[0012] In other embodiments, the chemotherapeutic agent is a monofunctional alkylating agent selected from the group consisting of alkyl sulfonates, nitrosoureas, and temozolomide; or a bifunctional alkylating agent selected from the group consisting of nitrogen mustards and mitomycin C.

[0013] In other embodiments, the chemotherapeutic agent is an antimetabolite selected from the group consisting of gemcitabine, 5-fluorouracil, thiopurines, and folic acid analogs.

[0014] In other embodiments, the chemotherapeutic agent is a topoisomerase inhibitor selected from the group consisting of camptothecins, anthracyclines, and etoposide.

[0015] In other embodiments, the chemotherapeutic agent comprises a combination of leucovorin calcium, 5-fluorouracil and oxaliplatin.

[0016] In certain embodiments, the present invention relates to a method of treating cancer in a subject comprising administering such a combination as described in the previous embodiments.

[0017] In another embodiment, the present invention relates to a method for delaying, reducing and / or preventing tumor rebound in a subject comprising administering such a combination as described in the previous embodiment.

[0018] In one embodiment, the invention relates to the use of a combination in the manufacture of a medicament for the treatment of cancer.

[0019] In another aspect, the invention relates to a pharmaceutical composition comprising the combination and a pharma- ceutically acceptable carrier.

[0020] In some embodiments, the pharmaceutical composition is for use in treating cancer.

[0021] In one embodiment, the invention relates to a kit comprising the combination or pharmaceutical composition and instructions for administering the combination to a subject with cancer.

[0022] In some embodiments, the USP1 inhibitor has the following structure: [ka] [During the ceremony, X 1 and X 2 Each of N and CR 2 are independently selected from; R 1 is selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 5 teeth: [ka] and; X 6 is NR 13 and C.R. 18Selected from; X 7 is NR 14 and C.R. 19 Selected from; X 8 is NR 15 and C.R. 20 Selected from; X 9 is NR 16 and C.R. 21 Selected from; X 10 is NR 17 and C.R. 22 Selected from; R 13 , R 14 , R 15 , R 16 and R 17 Each of is absent or independently R 13 , R 14 , R 15 , R 16 and R 17 Selected from; and R 18 , R 19 , R 20 , R 21 and R 22 each is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl; R 6 and R 7 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and R 8 , R 9 and R 11 Each of R 8 , R 9 and R 11 are independently selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

[0023] In other embodiments, the USP1 inhibitor is: (a) Compound 1: [ka] (b) Compound 2: [ka] (c) Compound 3: [ka] and a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof. In another embodiment, Compound 1, Compound 2, or Compound 3 is provided as a crystal. In another embodiment, Compound 1, Compound 2, or Compound 3 is provided as a crystal with a pharma- ceutically acceptable acid.

[0024] In some embodiments, the USP1 inhibitor is compound 1 or its pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid or polymorph.In other embodiments, compound 1 is provided as a crystal with a pharma- ceutically acceptable acid.In some embodiments, the USP1 inhibitor is a cocrystal of compound 1 and gentisic acid, i.e., a cocrystal of gentisic acid and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine.

[0025] In another embodiment, the USP1 inhibitor is compound 2 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid or polymorph thereof. In another embodiment, compound 2 is provided as a crystal with a pharma- ceutically acceptable acid.

[0026] In another embodiment, the USP1 inhibitor is compound 3 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid or polymorph thereof. In another embodiment, compound 3 is provided as a crystal with a pharma- ceutically acceptable acid.

[0027] In other embodiments, the USP1 inhibitor is the gentisate salt of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine.

[0028] In some embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

[0029] In certain embodiments, the subject's cancer cells are homologous directed repair (HRR) positive.

[0030] In some embodiments, the cancer or tumor is an advanced solid tumor. In some embodiments, the cancer or tumor is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, endometrial cancer, pancreatic cancer, gastric cancer, cholangiocarcinoma, and breast cancer.

[0031] In some embodiments, the chemotherapeutic agent and the USP1 inhibitor are administered sequentially. In other embodiments, the chemotherapeutic agent and the USP1 inhibitor are administered simultaneously.

[0032] In some embodiments, the USP1 inhibitor and the chemotherapeutic agent are provided in separate dosage forms. In other embodiments, the USP1 inhibitor is provided in an oral dosage form. In other embodiments, the chemotherapeutic agent is provided in an injectable dosage form. In other embodiments, the chemotherapeutic agent is provided in an oral dosage form.

[0033] In certain embodiments, the chemotherapeutic agent and USP1 inhibitor are administered in therapeutically effective amounts sufficient to produce one or more therapeutic effects selected from the group consisting of: (i) a reduction in tumor size, (ii) an increase in tumor regression rate, and (iii) a reduction or inhibition of tumor growth.

[0034] In other embodiments, the chemotherapeutic agent and the USP1 inhibitor delay, reduce and / or prevent tumor rebound.

[0035] In some embodiments, the USP1 inhibitor, gemcitabine and carboplatin are administered. In other embodiments, the subject has ovarian cancer, triple-negative breast cancer or non-small cell lung cancer.

[0036] In some embodiments, a USP1 inhibitor, leucovorin calcium, 5-fluorouracil and oxaliplatin are administered. In other embodiments, the subject has colorectal cancer, pancreatic cancer, cholangiocarcinoma, esophageal cancer or gastric cancer.

[0037] In some embodiments, the cancer or tumor has been previously treated with platinum therapy. In some embodiments, the cancer or tumor is platinum-resistant or platinum-refractory. In some embodiments, the platinum therapy is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, and combinations thereof.

[0038] In certain embodiments, the chemotherapeutic agent and the USP1 inhibitor are administered in amounts effective to reduce unacceptable toxicity and / or unacceptable adverse reactions of the chemotherapeutic agent administered as monotherapy.

[0039] In some embodiments, the present invention relates to a combination for use in the treatment of cancer. In other embodiments, the present invention relates to the use of such a combination for the manufacture of a medicament for the treatment of cancer. In some embodiments, the cancer is an advanced solid tumor. In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, endometrial cancer, pancreatic cancer, gastric cancer, cholangiocarcinoma and breast cancer. In some embodiments, the cancer was previously treated with platinum therapy. In some embodiments, the cancer is platinum-resistant or platinum-refractory. In some embodiments, the platinum therapy is selected from the group consisting of cisplatin, carboplatin, oxaliplatin and combinations thereof.

[0040] Additional aspects and advantages of the invention will be set forth in part in the description which follows and in part may result from the description or may be learned by practice of the invention. The aspects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0041] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief description of the drawings]

[0042] [Figure 1(A)] 1 shows the tolerability of the combination of 4 mg / kg cisplatin and compound (1)-gentisic acid cocrystal in non-tumor-bearing female Balb / c nude mice.

[0043] [Figure 1(B)] 1 shows the survival of the combination of 4 mg / kg cisplatin and compound (1)-gentisic acid cocrystal in non-tumor-bearing female Balb / c nude mice.

[0044] [Figure 2(A)] 1 shows the tolerability of the combination of 5 mg / kg cisplatin and compound (1)-gentisic acid cocrystal in non-tumor-bearing female Balb / c nude mice.

[0045] [Figure 2(B)] 1 shows the survival of the combination of 5 mg / kg cisplatin and compound (1)-gentisic acid cocrystal in non-tumor-bearing female Balb / c nude mice.

[0046] [Figure 3(A)] 1 shows the tolerability of the combination of 6 mg / kg cisplatin and compound (1)-gentisic acid cocrystal in non-tumor-bearing female Balb / c nude mice.

[0047] [Figure 3(B)]1 shows the survival of the combination of 6 mg / kg cisplatin and compound (1)-gentisic acid cocrystal in non-tumor-bearing female Balb / c nude mice.

[0048] [Figure 4] 1 shows an XRPD pattern corresponding to crystalline form 2.

[0049] [Diagram 5] 1 shows DSC and TGA thermograms corresponding to crystalline Form 2.

[0050] [Figure 6(A)] 1 shows the tumor volume change of a combination of 2 mg / kg cisplatin and 100 mg / kg compound (1)-gentisic acid cocrystal in MDA-MB-436 tumor-bearing female NOD SCID mice.

[0051] [Figure 6(B)] 1 shows the tolerability of the combination of 2 mg / kg cisplatin and 100 mg / kg compound (1)-gentisic acid cocrystal in MDA-MB-436 tumor-bearing female NOD SCID mice.

[0052] [Figure 7(A)] 1 shows the change in tumor volume of a combination of 5 mg / kg cisplatin and 100 mg / kg compound (1)-gentisic acid cocrystal in HBCx-8 tumor-bearing female athymic nude mice.

[0053] [Figure 7(B)] 1 shows the tolerability of the combination of 5 mg / kg cisplatin and 100 mg / kg compound (1)-gentisic acid cocrystal in HBCx-8 tumor-bearing female athymic nude mice.

[0054] [Figure 8(A)] 1 shows the change in tumor volume of a combination of 3 mg / kg cisplatin and 100 mg / kg compound (1)-gentisic acid cocrystal in HBCx-8 tumor-bearing female athymic nude mice.

[0055] [Figure 8(B)] 1 shows the tolerability of the combination of 3 mg / kg cisplatin and 100 mg / kg compound (1)-gentisic acid cocrystal in HBCx-8 tumor-bearing female athymic nude mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] Detailed Description of the Invention One embodiment of the present invention is based on the use of a combination of (i) a chemotherapeutic agent and (ii) a ubiquitin-specific processing protease 1 (USP1) inhibitor, which is useful for inhibiting the USP1 protein and treating a disease, disorder or condition that responds to a chemotherapeutic agent and / or USP1 protein inhibition, such as cancer.

[0057] In certain embodiments, the combination of a USP1 inhibitor and a chemotherapeutic agent provides a synergistic effect.

[0058] In some embodiments, the USP1 inhibitor and the chemotherapeutic agent are in therapeutically effective amounts sufficient to produce a therapeutic effect including (i) reducing tumor size, (ii) increasing the rate of cancer tumor regression, (iii) reducing or inhibiting cancer tumor growth, and / or (iv) reducing the toxic effects of the chemotherapeutic agent administered as monotherapy. In some embodiments, the USP1 inhibitor and the chemotherapeutic agent can delay, reduce, or prevent tumor rebound (rapid regrowth).

[0059] definition All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present application, including definitions, will control. Unless otherwise required by context, the singular includes the plural and the plural includes the singular. All publications, patents, and other references mentioned herein are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0060] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the present invention will be apparent from the detailed description and claims.

[0061] In order to further define this invention, the following terms and definitions are provided.

[0062] It is understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments. As used herein, the singular includes plural referents unless specifically stated otherwise. The use of the term "or" herein is not intended to imply that the options are mutually exclusive.

[0063] In this specification, the use of "or" means "and / or" unless expressly stated or understood by one of ordinary skill in the art. In a multiple dependent claim, the use of "or" refers to more than one previous independent or dependent claim.

[0064] The term "and / or" as used herein is to be construed as a specific disclosure of each of two particular features or components, with or without the other. Thus, the term "and / or" as used herein in expressions such as "A and / or B" is intended to include "A and B," "A or B," "A" (single) and "B" (single). Similarly, the term "and / or" as used herein, such as "A, B and / or C," is intended to encompass each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0065] As used herein, the term "about" includes the recited number ±10%. Thus, "about 10" means 9 to 11. As will be understood by those of skill in the art, the description of "about" a value or parameter herein includes (and describes) the case where the value or parameter itself is indicated. For example, a description that refers to "about X" includes the description of "X."

[0066] As used herein, "treatment" is an approach to obtain beneficial or desired clinical results. As used herein, "treatment" encompasses any administration or application of a therapy for a disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of the following: alleviation of one or more symptoms, reduction in the extent of the disease, prevention or delay of disease spread (e.g., metastasis), prevention or delay of disease recurrence, delay or slowing of disease progression, improvement of the disease state, prevention of disease or disease progression, prevention or slowing of disease or its progression, halting and remission (whether partial or complete). Reduction of the pathological consequences of a proliferative disease is also included in "treatment". The methods provided herein contemplate any one or more of these aspects of treatment. Consistent with the above, the term treatment does not require 100 percent elimination of all aspects of the disorder.

[0067] In the context of cancer, the term "treatment" includes, but is not limited to, inhibiting cancer cell proliferation, inhibiting cancer cell replication, reducing overall tumor burden, and delaying, halting, or slowing tumor growth, progression, or metastasis.

[0068] As used herein, "delaying" refers to postponing, preventing, slowing, impeding, stabilizing, inhibiting, and / or postponing the development or progression of a disease (e.g., cancer). This delay can be of varying duration depending on the history of the disease and / or the individual being treated.

[0069] A "therapeutically effective amount" of a substance may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to induce a desired response in the individual. A therapeutically effective amount is also a therapeutically beneficial effect that outweighs any toxic or adverse effects of the substance. A therapeutically effective amount may be provided by one or more administrations. A therapeutically effective amount refers to an amount effective, at the dosage and for the period of time necessary, to achieve a desired therapeutic effect.

[0070] The term "combination," "therapeutic combination," "combination composition," "combination therapy," or "pharmaceutical combination" as used herein may include a fixed combination in the form of a single dosage unit, separate dosage units, or a kit-of-parts or instructions for combined administration, where the USP1 inhibitor and the chemotherapeutic agent may be administered independently simultaneously or separately within a fixed interval. A combined pharmaceutical composition may be adapted for simultaneous, separate, or sequential administration.

[0071] Combination therapy provides a "synergistic effect" and is shown to be "synergistic", i.e., the effect of using multiple active ingredients together is greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can include a significant reduction in the effective dose of the combination of two active ingredients compared to the effective dose of each active ingredient administered separately. Synergistic effects can also include a significant reduction in the toxicity of the combination of two active ingredients compared to the toxicity of each active ingredient administered separately. Synergistic effects can also be effects that could not be achieved by administering any of the active ingredients as a single agent. Synergistic effects can include, but are not limited to, the effect of treating cancer by reducing tumor size, inhibiting tumor growth, or prolonging the survival of a subject. Synergistic effects can also include reducing cancer cell viability, inducing cancer cell death, and inhibiting or slowing cancer cell growth. A synergistic effect can be achieved, for example, when multiple active ingredients are: (1) co-formulated, combined, and administered or delivered simultaneously in a unit dosage formulation; (2) delivered sequentially, alternating or in parallel, in separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be achieved when multiple compounds are administered or delivered sequentially.

[0072] The determination of synergistic interaction between USP1 inhibitor and chemotherapeutic agent may be based on the results from the assay described herein. For example, the combination effect may be evaluated using the Bliss independence model. The Bliss score quantifies the degree of potentiation from a single agent, with a Bliss score >0 indicating greater than simple additive. In some embodiments, a Bliss score of more than 10 indicates strong synergy. In other embodiments, a score of 6 or greater indicates synergy. In some embodiments, the Bliss score is about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20 or about 25.

[0073] As used herein, "homologous recombination deficiency score" or "HRD score" refers to an algorithmic assessment of three indicators of tumor genomic instability: loss of heterozygosity, telomeric allele imbalance, and large-scale state transitions.

[0074] The term "HRR+" refers to homology-directed repair positivity. The HRR+ status of cancer cells can be determined based on biopsy. Homologous recombination repair is an important cellular mechanism by which double-stranded DNA breaks (DSBs) are corrected with high fidelity. For the purposes of the present invention, HRR+, HRP, HRR-functional cells and HRR-positive cells are used interchangeably.

[0075] The terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a therapeutic agent to a desired site of biological action. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. Administration of two or more therapeutic agents includes simultaneous (concurrent) and sequential administration in any order.

[0076] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a formulation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. Such formulations may be sterile.

[0077] As used herein, the term "pharmacologically acceptable" refers to compounds, substances, compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0078] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. A pharmaceutically acceptable carrier is non-toxic to a recipient at the dosage and concentration used and is compatible with the other components of the formulation. A pharmaceutically acceptable carrier is suitable for the formulation in which it is used. In some embodiments, each component is "pharmaceutically acceptable" in that it is compatible with the other components of the pharmaceutical formulation, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated by reference).

[0079] The terms "active ingredient" and "active substance" refer to a compound that is administered to a subject, alone or in combination with one or more pharma- ceutically acceptable excipients, for the treatment, prevention, or amelioration of one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.

[0080] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease.

[0081] The term "solvate" refers to a compound provided herein or a salt thereof, which further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.When the solvent is water, the solvate is a hydrate.When the solvent comprises ethanol, the compound can be an ethanol solvate.

[0082] The term "anhydrous" as applied to a compound refers to the solid state in which the compound does not contain structural water within the crystal lattice.

[0083] A "sterile" preparation is sterile or essentially free of viable microorganisms and their spores.

[0084] The term "container" refers to any container or closure and thus suitable for storing, transporting, dispensing and / or manipulating pharmaceutical products.

[0085] The term "insert" or "package insert" means the information that accompanies a drug product that describes how to administer the product, along with the safety and effectiveness data necessary to enable physicians, pharmacists, and patients to make informed decisions about the product's use. The package insert is commonly considered to be the "label" of the drug.

[0086] The term "disease" or "condition" or "disorder" as used herein refers to a condition for which treatment is necessary and / or desired, and refers to disorders and / or abnormalities that are generally considered pathological conditions or functions and may manifest themselves in the form of specific signs, symptoms and / or dysfunctions. As shown below, the combination of USP1 inhibitors and chemotherapeutic agents of the present invention can be used to treat diseases and conditions, such as proliferative diseases, in which chemotherapeutic agents and / or USP1 protein inhibition provides benefit.

[0087] As used herein, "USP1" and "ubiquitin-specific processing protease 1" refer to any naturally occurring polypeptide or polynucleotide encoding USP1. The term "USP1" encompasses "full-length," unprocessed USP1 polypeptides, and any form of USP1 resulting from processing within the cell (e.g., removal of the signal peptide). The term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allelic variants. The USP1 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from other sources, or produced by recombinant or synthetic methods. Human USP1 sequences are known, including, for example, the sequence publicly available as UniProt No. O94782 (including isoforms). As used herein, the term "human USP1 protein" refers to a USP1 protein comprising the amino acid sequence set forth in SEQ ID NO:1: (Sequence number 1).

[0088] USP1 refers to a deubiquitinase that acts as part of a complex with UAF1. The "deubiquitinase activity" of USP1 includes its ability to deubiquitinate as part of the USP1-UAF1 complex.

[0089] The term "reduce" or "reduction" or "inhibition" or "prevention" refers to a decrease or cessation of any phenotypic characteristic or a decrease or cessation of the incidence, extent or likelihood of that characteristic. "Reduce" or "inhibit" refers to a decrease, reduction or abrogation of an activity, function and / or amount compared to a reference. In some embodiments, by "reduce" or "inhibit" it is meant the ability to cause an overall decrease of 20% or more. In some embodiments, by "reduce" or "inhibit" it is meant the ability to cause an overall decrease of 50% or more. In some embodiments, by "reduce" or "inhibit" it is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95% or more. In some embodiments, the amount is inhibited or reduced over a period of time compared to a control over the same period of time.

[0090] In some embodiments, the inhibition of USP1 protein is the inhibition of one or more of the activities or functions of USP1 protein. It should be recognized that one or more of the activities or functions of USP1 protein can be inhibited in vitro or in vivo. Non-limiting examples of USP1 activities and functions include deubiquitinase activity and complex formation with UAF1, as described herein. Examples of inhibition levels of one or more of the activities of USP1 protein include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition and up to 100% inhibition.

[0091] The terms "individual" or "subject" are used interchangeably to refer to animals, e.g., mammals, such as humans. In some instances, methods of treating mammals are provided, including, but not limited to, humans, rodents, apes, cats, dogs, horses, cows, pigs, sheep, goats, mammalian laboratory animals, mammalian livestock, mammalian sport animals, and mammalian pets. In some instances, "individual" or "subject" refers to an individual or subject in need of treatment for a disease or disorder. In some instances, the subject to be treated may be a patient, which designates the fact that the subject has been identified as having or at particular risk of developing a disorder suitable for treatment.

[0092] The terms "cancer" and "tumor" as used herein refer to or describe a physiological condition in a mammal characterized by uncontrolled cell proliferation of a cell population. The terms include solid and hematological / lymphatic cancers. Examples of cancers include DNA damage repair pathway defective cancers. Further examples of cancers include, but are not limited to, ovarian cancer, breast cancer (including triple negative breast cancer), non-small cell lung cancer (NSCLC) and osteosarcoma. The cancer can be BRCA1 or BRCA2 wild type. The cancer can be BRCA1 or BRCA2 mutant. Furthermore, the cancer can be chemoresistant or refractory cancer or chemoresistant or refractory BRCA1 or BRCA2 mutant cancer. The cancer can be BARD1 wild type. The cancer can be BARD1 mutant. The cancer can be BRIP1 wild type. The cancer can be BRIP1 mutant. The cancer can be FANCA wild type. The cancer can be FANCA mutant. The cancer can be NBN wild type. The cancer can be NBN mutant. The cancer can be PALB2 wild type. The cancer can be PALB2 mutant. The cancer can be RAD51 wild type. The cancer can be RAD51 mutant. The cancer can be RAD51B wild type. The cancer can be RAD51B mutant. The cancer can be RAD51C wild type. The cancer can be RAD51C mutant. The cancer can be RAD51D wild type. The cancer can be RAD51D mutant.

[0093] In some embodiments, the cancer is a cancer that is homologous recombination DNA repair positive (HRR+ or HRP). The combination of the chemotherapeutic agent and the USP1 inhibitor of the present invention provides good efficacy / outcome in cancer cells that are HRR+. Homologous recombination DNA repair (HRR) is an important mechanism by which DNA damage is repaired. Homologous recombination DNA repair is a process in which double-stranded DNA is broken and interstrand crosslinks are inserted into sister chromatids as repair templates. DNA damage can be removed in an error-free manner by this mechanism. Furthermore, during DNA replication, the HRR pathway supports the recovery of stalled replication forks. Curtin, N, Nature Reviews / Cancer 12: 801-817 (2012); Creeden et al., BMC Cancer 21: 1154 (2021) and Scott et al., Oncotarget 12(16):1600-1614 (2021).

[0094] The term "loss-of-function" mutation as used herein refers to a mutation that results in the absence of a gene, reduced gene expression, or the production of a gene product (e.g., a protein) with reduced or no activity. Loss-of-function mutations include, for example, missense mutations, nucleotide insertions, nucleotide deletions, and gene deletions. Loss-of-function mutations also include dominant-negative mutations. Thus, cancer cells with a loss-of-function mutation in the gene encoding p53 include cancer cells with a missense mutation in the gene encoding p53 and cancer cells that lack the gene encoding p53.

[0095] I. USP1 Inhibitors USP1 inhibitors are disclosed, for example, in WO2020 / 132269 and WO2022 / 094096, each of which is incorporated by reference in its entirety herein.

[0096] In certain embodiments, the ubiquitin-specific processing protease 1 (USP1) inhibitor of the present invention has Formula I: [ka] [During the ceremony, X1 and X 2 Each of N and CR 2 are independently selected from; R 1 and R 2 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl; X 11 and X 12 each is independently selected from N and CH; R 5’ is hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14)ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 14 )aryl, optionally substituted -O-(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl; R 5 is optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14)ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 14 )aryl, optionally substituted -O-(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl; or R of adjacent atoms 5 and R 5’ are optionally substituted together with the atom to which they are attached (C6-C 14 ) forms an aryl ring; or adjacent atoms R 5 and R 5’ together with the atom to which they are attached form an optionally substituted heteroaryl ring; or 5 and R 5’ together with the atom to which they are attached form an optionally substituted (C-C)cycloalkyl ring; or 5 and R 5’ together with the atom to which they are attached form an optionally substituted heterocycloalkyl ring; or R 5 and R 5’ and the atom to which they are attached together form an optionally substituted spirocycloalkyl ring; or R 5 and R 5’and the atom to which they are attached together form an optionally substituted spiroheterocycloalkyl ring; R 6 and R 7 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 23 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R 31a and R 31b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; and R 24 , R 25 , R 27 , R 32a and R 32b Each of R 24 , R 25 , R 27 , R 32a and R 32b are independently selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

[0097] In some embodiments, the USP1 inhibitor has the following structure: [ka] [During the ceremony, X 1 and X 2 Each of N and CR 2 are independently selected from; R 1 is selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 5 teeth: [ka] and; X 6 is NR 13 and C.R. 18 Selected from; X 7 is NR 14 and C.R. 19 Selected from; X 8 is NR 15 and C.R. 20 Selected from; X 9 is NR 16 and C.R. 21 Selected from; X 10 is NR 17 and C.R. 22 Selected from; R 13 , R 14 , R 15 , R 16 and R 17 Each of is absent or independently R 13 , R 14 , R 15 , R 16 and R 17 Selected from; and R 18 , R 19 , R 20 , R21 and R 22 each is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl; R 6 and R 7 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and R 8 , R 9 and R 11 Each of R 8 , R 9 and R 11 are independently selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

[0098] In some embodiments, the USP1 inhibitor is: (a) Compound 1: [ka] (b) Compound 2: [ka] (c) Compound 3: [ka] and a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof.

[0099] In one embodiment, the USP1 inhibitor is (a) Compound 1: [ka] (b) Compound 2: [ka] (c) Compound 3: [ka] and a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, polymorph, or co-crystal thereof.

[0100] The chemical name of compound 1 is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, as described in U.S. Publication US20210115049A1.

[0101] The chemical name of compound 2 is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, as described in US Publication US20210115049A1.

[0102] The chemical name of compound 3 is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, as described in U.S. Publication US20210115049A1.

[0103] In some embodiments, the USP1 inhibitor is Compound 1 or a pharmaceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph. In some embodiments, the USP1 inhibitor is Compound 1 or a pharmaceutically acceptable salt, hydrate, solvate, amorphous solid, polymorph, or cocrystal.

[0104] In some embodiments, the USP1 inhibitor for the uses and methods provided herein is a solid state form that is a pharma- ceutically acceptable salt of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 1).

[0105] In certain embodiments, the USP1 inhibitor for the uses and methods provided herein is a solid state form that is a co-crystal of a pharma- ceutically acceptable acid and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 1). In one embodiment, the co-crystal is a mixture of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 1) and 1-hydroxy-2-naphthoic acid, 4-aminosalicylic acid, ascorbic acid, adipic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, ethanedisulfonic acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hexanoic acid, hippuric acid, odorous acid, benzoic acid, benzoic acid, trans-cinnamic ... The acid is formed between the pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, hydrochloric acid, lactic acid, maleic acid, L-malic acid, malonic acid, R-mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, oxalic acid, palmitic acid, p-toluenesulfonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, vanillic acid, vanillin, ethyl maltol, gallic acid, gallic acid ethyl ester, 4-hydroxybenzoic acid, 4-hydroxybenzoic acid methyl ester, 3,4,5-trihydroxybenzoic acid, nicotinamide, L-proline and D-sorbitol.In some embodiments, the pharmaceutically acceptable acid is selected from the group consisting of gentisic acid, benzoic acid, salicylic acid and gallic acid.In some embodiments, the pharmaceutically acceptable acid is gentisic acid.

[0106] In some embodiments, the co-crystal of gentisic acid and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 1 gentisic acid co-crystal) is an amorphous form. In some embodiments, the amorphous form is substantially free of other polymorphic forms. In some embodiments, the amorphous form has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

[0107] In certain embodiments, a co-crystal of gentisic acid and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 1 gentisic acid salt) is a solid-state crystalline form.

[0108] In certain embodiments, the co-crystal of gentisic acid and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 1 gentisic acid co-crystal) is in crystalline Form 2 (Compound 1 gentisic acid co-crystal Form 2 or "Form 2"). Compound 1 gentisic acid co-crystal, Form 2, is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, and 22.5±0.2 degrees 2θ.

[0109] In certain embodiments, crystalline form 2 is anhydrous.

[0110] In some embodiments, the melting point of crystalline form 2 is about 184° C. to about 190° C. In some embodiments, the melting point of crystalline form 2 is about 186° C. to about 188° C. In some embodiments, the melting point of crystalline form 2 is about 187° C.

[0111] In some embodiments, crystalline form 2 is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, and 22.5±0.2 degrees 2θ as measured with Cu Kα radiation. In other embodiments, crystalline form 2 is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, 22.3±0.2, and 22.5±0.2 degrees 2θ as measured with Cu Kα radiation. In some embodiments, crystalline form 2 is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, 22.3±0.2, 22.5±0.2, and 26.0±0.2 degrees 2θ as measured with Cu Kα radiation. In certain embodiments, crystalline Form 2 is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, 20.8±0.2, 22.3±0.2, 22.5±0.2, and 26.0±0.2 degrees 2θ as measured with Cu Kα radiation.

[0112] In certain embodiments, crystalline Form 2 is characterized by an XRPD pattern substantially as shown in Figure 4. In certain embodiments, crystalline Form 2 is characterized by 3 or more, 4 or more, 5 or more, or 6 or more XRPD peaks listed in Table 2(a and b) below: [Table 1] [Table 2]

[0113] In certain embodiments, crystalline Form 2 is characterized by an endothermic peak at about 181° C. to about 191° C., or about 183° C. to about 189° C., or about 185° C. to about 187° C., as determined by DSC. In certain embodiments, crystalline Form 2 is characterized by an endothermic peak at about 186.0° C., as determined by DSC.

[0114] In certain embodiments, crystalline Form 2 is characterized by a DSC profile substantially as shown in FIG.

[0115] In some embodiments, crystalline Form 2 is characterized by about 2.5 wt% to about 3.5 wt% loss at room temperature to about 170° C. In some embodiments, crystalline Form 2 is characterized by about 3.0 wt% to about 3.4 wt% loss at room temperature to about 170° C. In some embodiments, crystalline Form 2 is characterized by about 3.17 wt% loss at room temperature to about 170° C.

[0116] In certain embodiments, crystalline Form 2 is characterized by a TGA profile substantially as shown in FIG.

[0117] In certain embodiments, crystalline Form 2 is characterized by at least two of: a) the XRPD pattern depicted in FIG. 4; b) the DSC profile depicted in FIG. 5; or c) the TGA profile depicted in FIG.

[0118] In certain embodiments, crystalline Form 2 has unit cell indices as monoclinic.

[0119] In some embodiments, crystalline Form 2 has a unit cell with an a value of about 11.113 Å, a b value of about 12.356 Å, and a c value of about 24.048 Å. 3 It has a unit cell with a volume of

[0120] The unit cell parameters of crystalline form 2 are shown in Table 3. [Table 3]

[0121] In certain embodiments, crystalline Form 2 is substantially free of other polymorphic forms. In certain embodiments, crystalline Form 2 has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

[0122] In some embodiments, the USP1 inhibitor comprises a mixture comprising crystalline Form 2 and a second solid state form of Compound 1. In some embodiments, the second solid state form of Compound 1 is crystalline Form A. In some embodiments, the USP1 inhibitor comprises a mixture comprising a majority of crystalline Form 2 compared to other solid state forms of Compound 1. Suitable solid state forms of Compound 1 are described in WO2022 / 094096, which is incorporated herein by reference.

[0123] In other embodiments, the USP1 inhibitor is compound 2 in solid state form or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid or polymorph.In other embodiments, the USP1 inhibitor is compound 2 in solid state form or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, polymorph or cocrystal.

[0124] In some embodiments, the USP1 inhibitor for the uses and methods provided herein is a solid state form that is a pharma- ceutically acceptable salt of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 2).

[0125] In certain embodiments, the USP1 inhibitor for the uses and methods provided herein is a solid state form that is a co-crystal of a pharma- ceutically acceptable acid and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 2). In certain embodiments, the co-crystal is a mixture of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 2) and 1-hydroxy-2-naphthoic acid, 4-aminosalicylic acid, ascorbic acid, adipic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, ethanedisulfonic acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hexanesulfonic ... The pharmacokinetically acceptable acid is selected from the group consisting of acetic acid, hippuric acid, lactic acid, maleic acid, L-malic acid, malonic acid, R-mandelic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, oxalic acid, palmitic acid, p-toluenesulfonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, vanillic acid, vanillin, ethyl maltol, gallic acid, gallic acid ethyl ester, 4-hydroxybenzoic acid, 4-hydroxybenzoic acid methyl ester, 3,4,5-trihydroxybenzoic acid, nicotinamide, L-proline and D-sorbitol. In some embodiments, the pharmacokinetically acceptable acid is selected from the group consisting of gentisic acid, benzoic acid, salicylic acid and gallic acid.

[0126] Suitable solid state forms of Compound 2 are described in WO2022 / 094096, which is incorporated herein by reference.

[0127] In another embodiment, the USP1 inhibitor is Compound 3 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof. In another embodiment, the USP1 inhibitor is Compound 3 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, polymorph, or cocrystal thereof.

[0128] In some embodiments, the USP1 inhibitor for the uses and methods provided herein is a solid state form that is a pharma- ceutically acceptable salt of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 3).

[0129] In certain embodiments, the USP1 inhibitor for the uses and methods provided herein is a solid state form that is a co-crystal of a pharma- ceutically acceptable acid and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 3). In certain embodiments, the co-crystal is a mixture of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 3) and 1-hydroxy-2-naphthoic acid, 4-aminosalicylic acid, ascorbic acid, adipic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hexanoic acid, or hippuric acid. The medicament is formed between a pharmaceutically acceptable acid selected from the group consisting of lactic acid, maleic acid, L-malic acid, malonic acid, R-mandelic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, oxalic acid, palmitic acid, p-toluenesulfonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, vanillic acid, vanillin, ethyl maltol, gallic acid, gallic acid ethyl ester, 4-hydroxybenzoic acid, 4-hydroxybenzoic acid methyl ester, 3,4,5-trihydroxybenzoic acid, nicotinamide, L-proline and D-sorbitol. In some embodiments, the pharmaceutically acceptable acid is selected from the group consisting of gentisic acid, benzoic acid, salicylic acid and gallic acid.

[0130] Suitable solid state forms of compound 3 are described in WO2022 / 094096, which is incorporated herein by reference.

[0131] The present invention encompasses the preparation and use of salts of USP1 inhibitors, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and base salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt, organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, inorganic acid salts such as hydrochloride, hydrobromide salt, phosphate salt, sulfate salt, organic acid salts such as citrate, lactate salt, tartrate salt, maleate salt, fumarate salt, mandelate salt, acetate salt, dichloroacetate salt, trifluoroacetate salt, oxalate salt, formate salt, sulfonate salts such as methanesulfonate salt, benzenesulfonate salt, p-toluenesulfonate salt, and amino acid salts such as alginate salt, aspartate salt, glutamate salt. The term "pharmaceutical acceptable salt" as used herein refers to any salt, obtained, for example, by reaction of the USP1 inhibitor of the present invention with an acid or base, that is physiologically tolerated in a target patient (e.g., a mammal, e.g., a human).

[0132] Acid addition salts can be formed by mixing a solution of the particular USP1 inhibitor with a solution of a pharma- ceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, etc. Base salts can be formed by mixing a solution of the USP1 inhibitor of the present invention with a solution of a pharma- ceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc.

[0133] In certain embodiments of the present invention, a pharma- ceutically acceptable salt is formed between a compound of Formula I, Formula III, Formula IV, Formula V, Formula VI, Formula VIa, Compound 1, Compound 2 or Compound 3 and a pharma- ceutically acceptable acid. In certain embodiments, the pharma- ceutically acceptable acid is selected from the group consisting of 1-hydroxy-2-naphthoic acid, 4-aminosalicylic acid, ascorbic acid, adipic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, ethanedisulfonic acid, fumaric acid, galactaric acid, gallic acid, gentisic acid, gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, L-malic acid, malonic acid, R-mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, oxalic acid, palmitic acid, p-toluenesulfonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, vanillic acid, and vanillin. In certain embodiments, the pharma- ceutically acceptable acid is selected from the group consisting of benzoic acid, gallic acid, gentisic acid, and salicylic acid.

[0134] The present invention encompasses the preparation and use of solvates of USP1 inhibitors. Solvates typically do not significantly alter the physiological activity or toxicity of the compound, and as such may function as pharmacological equivalents. As used herein, the term "solvate" refers to a combination, physical association and / or solvation of the USP1 inhibitors of the present invention with solvent molecules, such as a disolvate, a monosolvate or a hemisolvate, where the ratio of solvent molecules to the compound of the present invention is about 2:1, about 1:1 or about 1:2, respectively. This physical association includes various degrees of ionic and covalent bonds, including hydrogen bonding. In some cases, the solvate may be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" includes both liquid phase and isolated solvates. The USP1 inhibitors of the present invention may exist in the form of a solvate with a pharma- ceutically acceptable solvent, such as water, methanol, ethanol, and the present invention is intended to encompass both solvated and unsolvated forms of the USP1 inhibitors of the present invention. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates where the solvent molecule is water. Solvates can typically function as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of a solvate of fluconazole with ethyl acetate and water. The preparation of similar solvates, hemisolvates, hydrates, etc. is described by EC van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004) and AL Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting method for preparing solvates includes dissolving the USP1 inhibitor of the present invention in a desired solvent (organic, aqueous or mixtures thereof) at a temperature above 20° C. to about 25° C., followed by cooling the solution at a rate sufficient to form crystals and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in the solvate crystals.

[0135] In some embodiments of the present invention, the USP1 inhibitor and / or the chemotherapeutic agent is deuterated. In some embodiments, the USP1 inhibitor and / or the chemotherapeutic agent is partially or fully deuterated, i.e., one or more hydrogen atoms are replaced with deuterium atoms.

[0136] The term "amorphous" as applied to chemical compounds refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not exhibit distinct X-ray diffraction patterns and are more formally described as liquids, although they exhibit the properties of a solid. Upon heating, a change from solid to liquid properties occurs that is characterized by a change of state (a "glass transition"), typically second order.

[0137] As used herein, the term "polymorph" refers to a crystalline form of a compound or its salt, hydrate or solvate in a particular crystal packing arrangement. All polymorphs have the same elemental composition. As used herein, the term "crystal" refers to a solid state form consisting of ordered structural units. Different crystalline forms of the same compound or its salt, cocrystal, hydrate or solvate result from different packing of molecules in the solid state, resulting in different crystal symmetries and / or unit cell parameters. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. See, e.g., Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23 rd ed., 1843-1844 (1995) (incorporated by reference).

[0138] Crystal forms are most commonly characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (peaks, typically expressed in degrees 2θ) is generally considered the fingerprint of a particular crystal form. The relative intensities of XRPD peaks can vary widely depending on, among other things, sample preparation techniques, crystal size distribution, filters, sample mounting methods, and the particular instrument used. In some embodiments, depending on the type or settings of the instrument, new peaks may be observed or existing peaks may disappear. In some embodiments, any particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type or settings of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystal form. In some embodiments, any particular peak in an XRPD pattern may appear as a symmetrical shape or asymmetrical shape, e.g., with a shoulder. Those skilled in the art who understand these variations can use XRPD and other known physical chemistry techniques to distinguish or confirm the defined properties or characteristics of a particular crystal form.

[0139] In various embodiments, the USP1 inhibitor reduces the level of USP1 protein and / or inhibits or reduces at least one biological activity of the USP1 protein.

[0140] In some embodiments, the USP1 inhibitor specifically binds to USP1 protein. In some embodiments, the USP1 inhibitor specifically binds to USP1 protein in USP1-UAF1 complex. In some embodiments, the USP1 inhibitor specifically binds to USP1 mRNA. In some embodiments, the USP1 inhibitor specifically binds to USP1 protein (alone or in USP1-UAF1 complex) or USP1 mRNA. In some embodiments, the USP1 inhibitor specifically binds to UAF1 (alone or in USP1-UAF1 complex) and inhibits or reduces the formation or activity of USP1-UAF1 complex.

[0141] In some embodiments, the USP1 inhibitor reduces the formation of the USP1-UAF1 complex. In some embodiments, the USP1 inhibitor reduces the activity of the USP1-UAF1 complex. In some embodiments, the USP1 inhibitor reduces the deubiquitinase activity of USP1. In some embodiments, the USP1 inhibitor increases mono-ubiquitinated PCNA. In some embodiments, the USP1 inhibitor increases mono-ubiquitinated FANCD2. In some embodiments, the USP1 inhibitor increases mono-ubiquitinated FANCI.

[0142] In certain embodiments, the USP1 inhibitor does not bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) or binds to deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with an affinity that is at least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold lower than its affinity for USP1 (i.e., the K of a USP1 inhibitor for other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1)). D is the K for USP1 D at least 5 times, at least 10 times, at least 20 times, or at least 100 times higher).

[0143] In certain embodiments, the USP1 inhibitor measures USP1 deubiquitinase activity with an IC of less than about 50 nM, between about 50 nM and about 200 nM, between about 200 nM and about 2 pM, or greater than 2 pM, as measured, for example, using an assay disclosed in U.S. Patent Application Publication No. 2017 / 0145012. 50 or, for example, using the assay disclosed in Liang et al., Nat Chem Biol 10: 289-304 (2014), with an IC of 50 nM to 1000 nM. 50 In some embodiments, the USP1 inhibitor inhibits USP1 at an IC202 value as measured using the assay disclosed in Chen, et al., Chem Biol., 18(11):1390-1400 (2011). 50In some embodiments, the USP1 inhibitor does not inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) or inhibits the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) at an IC for inhibiting USP1 deubiquitinase activity. 50 At least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold higher IC compared to 50 and inhibits.

[0144] In certain embodiments, the USP1 inhibitors of the present invention bind to USP1 protein with an affinity in the range of 1 pM to 100 μM, or 1 pM to 1 μM, or 1 pM to 500 nM, or 1 pM to 100 nM. In certain embodiments, the USP1 inhibitors of the present invention bind to USP1 protein with an affinity of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In certain embodiments, the USP1 inhibitor of the present invention is administered to a USP1 protein at a concentration of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 300 nM, about 100 nM to about 400 nM, about 200 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 nM, about 100 nM to about 800 nM, about 100 nM to about 900 nM, about 100 nM to about 100 nM, about 100 nM to about 200 nM, about 200 nM to about 300 nM, about 100 nM to about 400 nM, about 200 nM to about 500 nM, about 100 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 nM, about 100 nM to about 800 nM, about 100 nM to about 1000 nM, about 100 nM to about 1000 nM, about 100 nM to about 2000 nM, about 100 nM to about 300 nM, about 100 nM to about 400 nM, about 100 It binds with an affinity of about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM.In one embodiment, the USP1 inhibitor of the present invention is administered to a USP1 protein at about 1 nM to about 100 nM, 1 nM to about 90 nM, 1 nM to about 80 nM, 1 nM to about 70 nM, 1 nM to about 60 nM, 1 nM to about 50 nM, 1 nM to about 40 nM, 1 nM to about 30 nM, 1 nM to about 20 nM, 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, M, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM.

[0145] In some embodiments, the USP1 inhibitors of the present invention bind to USP1 protein with an affinity of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. In some embodiments, the USP1 inhibitors bind to USP1 protein with an affinity of less than 1 nM.

[0146] In some embodiments, the USP1 inhibitors of the present invention inhibit USP1 activity with an IC of 1 pM to 100 μM, or 1 pM to 1 μM, or 1 pM to 500 nM, or 1 pM to 100 nM. 50 In certain embodiments, the USP1 inhibitor inhibits USP1 activity with an IC of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. 50In certain embodiments, the USP1 inhibitor inhibits USP1 activity at a concentration of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 300 nM, about 100 nM to about 400 nM, about 200 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 nM, about 100 nM to about 800 nM, about 100 nM to about 900 nM, about 100 nM to about 100 nM, about 100 nM to about 200 nM, about 200 nM to about 300 nM, about 100 nM to about 400 nM, about 100 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 nM, about 100 nM to about 800 nM, about 100 nM to about 100 nM, about 100 nM to about 200 nM, about 100 nM to about 300 nM, about 100 nM to about 400 nM, about 100 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 n IC of about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM 50 and inhibits.

[0147] In certain aspects, the USP1 inhibitor of the present invention inhibits USP1 activity by about 1 nM to about 100 nM, 1 nM to about 90 nM, 1 nM to about 80 nM, 1 nM to about 70 nM, 1 nM to about 60 nM, 1 nM to about 50 nM, 1 nM to about 40 nM, 1 nM to about 30 nM, 1 nM to about 20 nM, 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 10 IC of 0 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM 50 In certain embodiments, the USP1 inhibitor inhibits USP1 activity with an IC of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. 50 In some embodiments, the USP1 inhibitor inhibits USP1 activity with an IC of less than 1 nM. 50 and inhibits.

[0148] Example of USP1 inhibition assay Any suitable assay in the art can be used to determine activity, detect outcomes or effects, or determine efficacy. Suitable assays are provided, for example, in US Publication US20210115049A1.

[0149] In some examples, the method for determining whether USP1 inhibitor compound inhibits USP1 deubiquitinase activity is to measure the mass change caused by di-ubiquitin cleavage of deubiquitinase bond.For example, ubiquitin aldehyde and ubiquitin vinyl sulfone form covalent irreversible bond with deubiquitinase, which causes observable mass change in deubiquitinase.Similarly, cleavage of di-ubiquitin causes observable mass change.

[0150] In some instances, methods for determining whether a USP1 inhibitor compound inhibits USP1 deubiquitinase activity include an increase in luminescence or fluorescence upon cleavage, which can be monitored, for example, with a plate reader. Such assays can use ubiquitin linked to a fluorophore via a linker bond, such as ubiquitin-7-amino-4-methylcoumarin (Ub-AMC) or ubiquitin-rhodamine 110. Such assays can also use di-ubiquitins that contain an isopeptide bond. An example of a di-ubiquitin can include a fluorophore on one ubiquitin and a quencher on the other, such that fluorescence increases following cleavage of the di-ubiquitin. Such assays can also use enzyme-linked systems, in which ubiquitin is linked to an enzyme that is active in producing a fluorescent enzyme product only when released from the ubiquitin.

[0151] II. Chemotherapeutic Agents In certain embodiments, the chemotherapeutic agent of the present invention is a platin, a monofunctional alkylating agent, a bifunctional alkylating agent, an antimetabolite, a topoisomerase inhibitor, or a combination thereof.

[0152] In some embodiments, the chemotherapeutic agent is a platin.

[0153] In some embodiments, the platin is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, and triplatin.

[0154] In some embodiments, the chemotherapeutic agent is cisplatin or carboplatin.

[0155] In some embodiments, the chemotherapeutic agent is a monofunctional alkylating agent. In some embodiments, the monofunctional alkylating agent is selected from the group consisting of alkyl sulfonates, nitrosoureas, and temozolomide.

[0156] In some embodiments, the chemotherapeutic agent is a bifunctional alkylating agent. In some embodiments, the bifunctional alkylating agent is selected from the group consisting of nitrogen mustard and mitomycin C.

[0157] In some embodiments, the chemotherapeutic agent is an antimetabolite, hi some embodiments, the antimetabolite is selected from the group consisting of gemcitabine, 5-fluorouracil, thiopurines, and folic acid analogs.

[0158] In some embodiments, the chemotherapeutic agent is a topoisomerase inhibitor, hi some embodiments, the topoisomerase inhibitor is selected from the group consisting of camptothecin, anthracycline, and etoposide.

[0159] In various embodiments, the platin of the present invention is a platinum-containing compound. Platinum-containing compounds include agents such as cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, and triplatin. Platinum-containing compounds cause cross-linking of DNA as monoadducts, interstrand cross-links, intrastrand cross-links, or DNA-protein cross-links. The resulting cross-links inhibit DNA repair and / or DNA synthesis in cancer cells. These compounds are sometimes referred to as alkylating-like agents, despite the fact that they do not have an alkyl group. Cisplatin was the first platinum-containing compound discovered and was first approved by the U.S. Food and Drug Administration in 1978. Carboplatin was introduced in the 1980s and has been shown to have fewer side effects than cisplatin in ovarian and lung cancer (Hartmann and Lipp, Exper. Opin. Pharmacother. 2003, 4(6) 889-901).

[0160] In some embodiments, the platin is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, or triplatin. In some embodiments, the platin is nedaplatin, cisplatin, carboplatin, or oxaliplatin. In some embodiments, the platin is cisplatin, carboplatin, or oxaliplatin. In some embodiments, the platin is cisplatin or carboplatin. In some embodiments, the platin is cisplatin. In some embodiments, the platin is carboplatin.

[0161] In various embodiments, the alkylating agent of the present invention is an alkylating agent used in cancer treatment, which attaches an alkyl group to DNA. Cancer cells generally grow faster and with less error correction than healthy cells, so cancer cells are more susceptible to DNA damage, such as being alkylated. In some embodiments, the alkylating agent is active under the conditions present in the cell. In some embodiments, the alkylating agent stops tumor growth by cross-linking guanine nucleobases in DNA double helix strands by directly attacking DNA. In some embodiments, the alkylating agent can be a monofunctional alkylating agent or a bifunctional alkylating agent. In some embodiments, the monofunctional alkylating agent can only react with one guanine residue of DNA. In some embodiments, the bifunctional alkylating agent can react with two different guanine residues of DNA.

[0162] In some embodiments, the monofunctional alkylating agent is an alkyl sulfonate, a nitrosourea, or temozolomide. In some embodiments, the monofunctional alkylating agent is an alkyl sulfonate. In some embodiments, the monofunctional alkylating agent is a nitrosourea. In some embodiments, the monofunctional alkylating agent is temozolomide. In some embodiments, the bifunctional alkylating agent is a nitrogen mustard or mitomycin C. In some embodiments, the bifunctional alkylating agent is a nitrogen mustard. In some embodiments, the bifunctional alkylating agent is mitomycin C.

[0163] In various embodiments, the antimetabolite of the present invention is a chemical that inhibits the use of metabolites. In some embodiments, antimetabolites are often structurally similar to the metabolites they interfere with. Thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as impairing cell growth and cell division. In some embodiments, antimetabolites are used in cancer treatment. In some embodiments, antimetabolites interfere with DNA production and thus cell division and tumor growth. In some embodiments, antimetabolites impair DNA replication by incorporating chemically modified nucleotides or by depleting the supply of deoxynucleotides required for DNA replication and cell growth.

[0164] In some embodiments, the antimetabolite is gemcitabine, 5-fluorouracil, thiopurine, folic acid analog, capecitabine, cytarabine, floxuridine, fludarabine or hydroxycarboxamide. In some embodiments, the antimetabolite is gemcitabine, 5-fluorouracil, thiopurine or folic acid analog. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the antimetabolite is 5-fluorouracil. In some embodiments, the antimetabolite is thiopurine. In some embodiments, the antimetabolite is methotrexate, pemetrexed, phototrexate, proguanil, pyrimethamine, trimethoprim and folic acid analog including leucovorin calcium.

[0165] In various embodiments, the topoisomerase inhibitor of the present invention is a chemical compound that blocks the action of topoisomerase. Topoisomerase plays an important role in cell proliferation and DNA organization. Topoisomerase mediates single-stranded and double-stranded DNA breaks in eukaryotic cells, relaxing supercoils, uncoiling catenanes, and condensing chromosomes. In some embodiments, topoisomerase inhibitors prevent topoisomerase from carrying out DNA strand breaks. In some embodiments, topoisomerase inhibitors bind to topoisomerase-DNA complexes and stop the religation step of the topoisomerase machinery. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents because unrepaired single-stranded and double-stranded DNA breaks are produced, which can cause apoptosis and cell death. In some embodiments, topoisomerase inhibitors are used as treatments for infectious and cancerous cells.

[0166] In some embodiments, the topoisomerase inhibitor is camptothecin, topotecan, irinotecan, belotecan, indenoisoquinoline, phenanthridine, indolocarbazole, anthracycline, etoposide, teniposide, dexrazoxane, novobiocin, or mervalone. In some embodiments, the topoisomerase inhibitor is camptothecin, anthracycline, or etoposide. In some embodiments, the topoisomerase inhibitor is camptothecin. In some embodiments, the topoisomerase inhibitor is an anthracycline. In some embodiments, the topoisomerase inhibitor is etoposide.

[0167] In certain embodiments, the chemotherapeutic agent can be a DNA damaging agent.

[0168] III. Method of Treatment Because the combination of the invention is (i) a chemotherapeutic agent and (ii) a ubiquitin-specific processing protease 1 (USP1) inhibitor having formula I, the invention provides a method of damaging DNA and / or inhibiting the USP1 protein comprising administering one or more of the combination of the invention.

[0169] Because the combination of the invention is (i) a chemotherapeutic agent and (ii) a ubiquitin-specific processing protease 1 (USP1) inhibitor having formula I, the invention generally relates to a method of treating a disease, condition, or disorder responsive to DNA damage and / or USP1 protein inhibition in a subject having or at risk of having the disorder, comprising administering to the subject an effective amount of one or more of the combinations of the invention.

[0170] The present invention further relates to a method of damaging DNA and / or inhibiting USP1 protein in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a combination of the present invention.

[0171] In some embodiments, the combination of the present invention can be used to damage DNA and / or inhibit USP1 protein activity.For example, in some embodiments, the method of damaging DNA and / or inhibiting USP1 protein comprises contacting DNA and / or USP1 protein with the combination of the present invention.Contacting can occur in vitro or in vivo.

[0172] In some embodiments, the combination of the present invention can be used to treat DNA and / or USP1 protein mediated disorders. The DNA and / or USP1 protein mediated disorders are any pathology in which DNA and / or USP1 protein are known to play a role. In some embodiments, the DNA and / or USP1 protein mediated disorders are proliferative diseases such as cancer. In some embodiments, the combination of the present invention can delay, reduce or prevent tumor rebound (rapid regrowth). In some embodiments, the combination of the present invention is not significantly more toxic than a chemotherapeutic agent alone. In some embodiments, the combination of the present invention is not significantly more toxic than a USP1 inhibitor alone. In some embodiments, the combination of the present invention is not significantly more toxic than a chemotherapeutic agent alone or a USP1 inhibitor alone.

[0173] In some embodiments, the combination of the present invention is less toxic than a chemotherapeutic agent alone. In some embodiments, the combination of the present invention is less toxic than a USP1 inhibitor alone. In some embodiments, the combination of the present invention is less toxic than a chemotherapeutic agent alone or a USP1 inhibitor alone.

[0174] In some embodiments, the combination of the present invention is administered in an effective amount to reduce the unacceptable toxicity and / or unacceptable adverse reactions of the chemotherapeutic agent administered as monotherapy. In some embodiments, the combination of the present invention is administered in an effective amount to reduce the unacceptable toxicity and / or unacceptable adverse reactions of the USP1 inhibitor administered as monotherapy. In some embodiments, the combination of the present invention is administered in an effective amount to reduce the unacceptable toxicity and / or unacceptable adverse reactions of the chemotherapeutic agent administered as monotherapy or the USP1 inhibitor administered as monotherapy. Examples of toxicity or adverse reactions include hematological toxicity such as thrombocytopenia, anemia or neutropenia, pneumonia, dyspnea, fever, cough, wheezing, radiological abnormalities, hypertension, myelodysplastic syndrome / acute myeloid leukemia (MDS / AML), nausea and / or fatigue.

[0175] Various methods of treating diseases and disorders with the combinations of the present invention are provided herein. Examples of diseases and disorders that can be treated with the combinations of the present invention include, but are not limited to, cancer.

[0176] In some embodiments, methods of treating cancer with the combination of the present invention are provided, comprising administering to a subject with cancer a therapeutically effective amount of the combination of the present invention.

[0177] In certain embodiments, such methods comprise: (a) identifying a cancer in a subject as a chemotherapeutic agent- and / or USP1 inhibitor-sensitive cancer, and then (b) administering to the subject a therapeutically effective amount of a combination of the invention.

[0178] In certain embodiments, the subject's cancer cells are homologous directed repair (HRR) positive.

[0179] In some embodiments, the cancer treated with the combination of the present invention is an advanced solid tumor. The advanced solid tumor is a solid tumor that is unresectable and / or metastatic. In other embodiments, the cancer treated with the combination of the present invention is a solid tumor that is a resectable tumor, either benign or metastatic, and the combination is administered before and / or after surgical resection.

[0180] In some embodiments, the cancer treated with the combination of the present invention is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, endometrial cancer, pancreatic cancer, gastric cancer, cholangiocarcinoma and breast cancer. teeth In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is peritoneal cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is breast cancer.

[0181] In some embodiments, the cancer treated with the combination of the present invention has been previously treated with platinum therapy. In some embodiments, the cancer treated with the combination of the present invention is a platinum-resistant cancer. In some embodiments, the cancer treated with the combination of the present invention is a platinum-refractory cancer. In some embodiments, the platinum therapy is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, and combinations thereof.

[0182] In some embodiments, the chemotherapeutic agent and the USP1 inhibitor are administered sequentially. In some embodiments, the chemotherapeutic agent is administered first and the USP1 inhibitor is administered second. In some embodiments, the USP1 inhibitor is administered first and the chemotherapeutic agent is administered second. In some embodiments, the chemotherapeutic agent and the USP1 inhibitor are administered simultaneously.

[0183] In some embodiments, the combination of the present invention is administered in a therapeutically effective amount sufficient to produce one or more therapeutic effects selected from the group consisting of (i) a decrease in tumor size, (ii) an increase in tumor regression rate, and (iii) a decrease or inhibition of tumor growth. In some embodiments, the combination of the present invention is administered in a therapeutically effective amount sufficient to produce an effect of a decrease in tumor size. In some embodiments, the combination of the present invention is administered in a therapeutically effective amount sufficient to produce an effect of an increase in tumor regression rate. In some embodiments, the combination of the present invention is administered in a therapeutically effective amount sufficient to produce an effect of a decrease or inhibition of tumor growth.

[0184] In certain embodiments, the chemotherapeutic agent is administered at a dose approved for the particular indication. In other embodiments, the chemotherapeutic agent is administered at any dose disclosed herein. In some embodiments, the platinum-based chemotherapy is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or a combination thereof. In some embodiments, the platinum-based chemotherapy is any other platinum-based chemotherapy known in the art. In some embodiments, the chemotherapeutic agent is the nucleotide analog gemcitabine. In some embodiments, the chemotherapeutic agent is an antifolate. In some embodiments, the antifolate is pemetrexed.

[0185] In some embodiments, the USP1 inhibitor, gemcitabine and carboplatin are administered to the subject.In some embodiments, the subject has ovarian cancer, triple-negative breast cancer or non-small cell lung cancer.In some embodiments, the subject has ovarian cancer.In some embodiments, the subject has triple-negative breast cancer.In some embodiments, the subject has non-small cell lung cancer.

[0186] In some embodiments, USP1 inhibitor, leucovorin calcium, 5-fluorouracil and oxaliplatin are administered to the subject.In some embodiments, the subject has colorectal cancer, pancreatic cancer, cholangiocarcinoma, esophageal cancer or gastric cancer.In some embodiments, the subject has colorectal cancer.In some embodiments, the subject has pancreatic cancer.In some embodiments, the subject has cholangiocarcinoma.In some embodiments, the subject has esophageal cancer.In some embodiments, the subject has gastric cancer.

[0187] In some embodiments, the USP1 inhibitor and the chemotherapeutic agent are provided in the same dosage form. In some embodiments, the USP1 inhibitor is provided in an oral dosage form. In some embodiments, the chemotherapeutic agent is provided in an oral dosage form. In some embodiments, the USP1 inhibitor and the chemotherapeutic agent are provided in separate dosage forms. In some embodiments, the USP1 inhibitor is provided in an oral dosage form. In some embodiments, the chemotherapeutic agent is provided in an injectable dosage form.

[0188] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0189] In certain embodiments, the combination of the present invention is used in combination with one or more additional therapeutic agents for the treatment of cancer.

[0190] In certain embodiments, provided herein are combinations of the invention for use as medicaments or in the manufacture of a medicament, e.g., for the treatment of cancer. In certain embodiments, provided herein are combinations of the invention for use in a method of treating cancer.

[0191] IV. Pharmaceutical Compositions and Kits The combination of the present invention can be administered to a mammal in the form of a biochemical without the presence of any other components, or the combination of the present invention can be administered to a mammal as part of a pharmaceutical composition comprising a combination of the compound and a suitable pharma- ceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Such carriers can be selected from pharma- ceutically acceptable additives and auxiliaries. The term "pharma- ceutically acceptable carrier" or "pharma-ceutically acceptable vehicle" includes any standard pharmaceutical carrier, solvent, surfactant, or vehicle. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. The USP1 inhibitor and the chemotherapeutic agent can be present in the same pharmaceutical composition; or the USP1 inhibitor and the chemotherapeutic agent can be separate pharmaceutical compositions that can be administered simultaneously or sequentially.

[0192] The pharmaceutical combination compositions of the present invention may be prepared as liquid suspensions or solutions using a liquid such as an oil, water, an alcohol, and combinations thereof.

[0193] The USP1 inhibitor provided herein (e.g., 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof) may be any pharmaceutical composition, including any composition, in which such inhibitor is combined with one or more pharma- ceutically acceptable carriers. In some embodiments, the USP1 inhibitor is present in the composition in an effective amount to achieve the intended therapeutic purpose.

[0194] In some embodiments, the present invention provides a pharmaceutical composition comprising a USP1 inhibitor (e.g., 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine or a pharma- ceutically acceptable salt, solvate, hydrate, or co-crystal thereof) and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises crystalline Form 2 of a gentisic acid co-crystal of Compound 1.

[0195] Pharmaceutical combination compositions within the scope of the present invention include all compositions in which the USP1 inhibitor of the present invention and the chemotherapeutic agent are combined with one or more pharma- ceutically acceptable carriers. In some embodiments, the USP1 inhibitor of the present invention and the chemotherapeutic agent are present in the composition in an effective amount to achieve the intended therapeutic purpose.

[0196] The pharmaceutical compositions of the present invention may be orally administered in any orally acceptable dosage form including, for example, a capsule, a tablet, an aqueous suspension or solution, hi one embodiment, the capsule is a gelatin capsule.

[0197] For oral administration, known carriers can be included in the pharmaceutical composition. For example, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used with various disintegrating agents such as starch (preferably corn, potato or tapioca starch), methylcellulose, alginic acid and certain silicate complexes, and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia can also be included in the tablet. In addition, magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Similar types of solid compositions can also be used as fillers in gelatin capsules. Preferred materials in this regard include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweeteners or flavorings, colorings or dyes, and, if desired, also emulsifying and / or suspending agents, diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof.

[0198] Pharmaceutical compositions for use in vivo administration can be sterile, which is readily accomplished, for example, by filtration through sterile filtration membranes.

[0199] Pharmaceutical compositions within the scope of the present invention include all compositions in which the USP1 inhibitor is combined with one or more pharma- ceutically acceptable carriers. In some embodiments, the USP1 inhibitor is present in the composition in an amount effective to achieve the intended therapeutic purpose.

[0200] The pharmaceutical composition of the present invention may be administered to any patient who may experience the beneficial effects of the compound of the present invention. Such patients are primarily mammals, such as humans and companion animals, but the present invention does not intend such limitations. In some embodiments, the patient is a human. In some embodiments, the pharmaceutical composition of the present invention may be administered to patients with chemotherapy-resistant or refractory cancer. In some embodiments, the pharmaceutical composition of the present invention may be administered to patients with chemotherapy-resistant or refractory BRCA1-deficient cancer. In some embodiments, the pharmaceutical composition of the present invention may be administered to patients with platinum-resistant or platinum-refractory cancer.

[0201] In some embodiments, the present invention provides a kit comprising a USP1 inhibitor (e.g., 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof) or a pharmaceutical composition comprising the same, packaged to facilitate use in practicing the methods of the present invention. In some embodiments, the kit comprises a USP1 inhibitor packaged in a container, such as a sealed bottle or container, with a label affixed to the container or included in the kit that describes the use of the USP1 inhibitor or a pharmaceutical composition thereof for practicing the methods of the present invention. In some embodiments, the USP1 inhibitor is packaged in a unit dosage form. The kit may further comprise a device suitable for administering the USP1 inhibitor or a pharmaceutical composition thereof by an intended route of administration. In some embodiments, the present invention provides a kit comprising a USP1 inhibitor or a pharmaceutical composition thereof and instructions for administering the inhibitor or composition to a patient having cancer.

[0202] In some embodiments, the present invention provides a pharmaceutical composition comprising a USP1 inhibitor (e.g., 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof), a chemotherapeutic agent, and a pharma- ceutically acceptable carrier, for use in treating cancer (e.g., a solid tumor). In some embodiments, the cancer is an advanced solid tumor.

[0203] In certain embodiments, the present invention provides a pharmaceutical composition comprising a USP1 inhibitor (e.g., 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof) and a chemotherapeutic agent and a pharma- ceutically acceptable carrier, for the manufacture of a medicament for the treatment of cancer (e.g., solid tumors).

[0204] V. Methods for Producing USP1 Inhibitors The USP1 inhibitors for the uses and methods provided herein can be prepared by any method. Methods for the synthesis of USP1 inhibitors are provided, for example, in WO2020 / 132269 and WO2022 / 094096, each of which is incorporated herein by reference in its entirety.

[0205] In some embodiments, the USP1 inhibitor is prepared by a method comprising: a) adding a suitable amount of compound 1 to a suitable amount of a suitable solvent system to obtain a suspension; b) stirring the suspension; and c) recovering the solid product from step b). In some embodiments, a suitable pharma- ceutically acceptable acid is added during step a). In some embodiments, the suitable solvent system is selected from the group consisting of acetonitrile, acetone, cyclohexane, dichloromethane, dimethylacetamide, dimethylsulfoxide, ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate, methanol, methyl ethyl ketone, 4-methyl-2-pentanone, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-heptane, n-methylpyrrolidone, tetrahydrofuran, toluene, water, and mixtures thereof. In some embodiments, the suitable solvent system is selected from the group consisting of ethyl acetate, n-heptane, and mixtures thereof.

[0206] In some embodiments, the USP1 inhibitor is prepared by a method comprising: a) adding a suitable amount of compound 1 to a suitable amount of a suitable solvent system to obtain a solution; b) adding a suitable amount of a suitable anti-solvent; c) adding a seed crystal of a solid state form of compound 1; d) stirring the resulting suspension; and e) recovering the solid product produced from step d). In some embodiments, the method further comprises adding a suitable pharma- ceutically acceptable acid during step a). In some embodiments, the method further comprises adding a suitable anti-solvent after step c) and before step d). In some embodiments, the suitable solvent and anti-solvent are selected from the group consisting of acetonitrile, acetone, cyclohexane, dichloromethane, dimethylacetamide, dimethylsulfoxide, ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate, methanol, methyl ethyl ketone, 4-methyl-2-pentanone, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-heptane, n-methylpyrrolidone, tetrahydrofuran, toluene, water, and mixtures thereof. In some embodiments, the suitable solvent and anti-solvent are selected from the group consisting of ethyl acetate, n-heptane, and mixtures thereof. In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable anti-solvent is n-heptane.

[0207] In some embodiments, compound 1 is added to a suitable solvent system at a temperature of about room temperature to about 100° C., or about room temperature to about 75° C., or about room temperature to about 50° C., or about room temperature to about 40° C. In some embodiments, compound 1 is added to a suitable solvent system at about room temperature.

[0208] In an embodiment, a USP1 inhibitor that is crystalline form 2 of gentisic acid co-crystal of compound 1 is prepared by a process comprising: a) adding a suitable amount of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine and gentisic acid to a suitable amount of a suitable solvent system at room temperature to obtain a suspension; b) stirring the suspension from step a); and c) recovering the solid product from step b). In an embodiment, the suitable solvent system is selected from the group consisting of ethyl acetate, n-heptane, and mixtures thereof.

[0209] In an embodiment, a USP1 inhibitor that is crystalline form 2 of gentisic acid co-crystal of compound 1 is prepared by a process comprising: a) adding a suitable amount of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine and gentisic acid to a suitable amount of a suitable solvent at room temperature to obtain a solution; b) adding a suitable amount of a suitable anti-solvent; c) adding seed crystals of crystalline form 2 of gentisic acid co-crystal of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of compound 1; d) stirring the resulting suspension; and e) recovering the solid product produced from step d). In some embodiments, the method further comprises adding a suitable anti-solvent after step c) and before step d). In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable anti-solvent is n-heptane.

[0210] In one embodiment, the USP1 inhibitor is crystalline form 2 of compound 1, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine co-crystal with gentisic acid, prepared by any of the methods disclosed herein. EXAMPLES

[0211] Example 1: Maximum tolerated dose of the combination of Compound 1 cocrystal and cisplatin in non-tumor-bearing Balb / c nude mice The maximum tolerated dose (MTD) of the combination of USP1 inhibitor compound 1 cocrystal and cisplatin was evaluated in non-tumor-bearing Balb / c nude mice. Six to eight-week-old female Balb / c nude mice from Beijing Anikeeper Biotech Co., Ltd were cultured in the following groups: control, cisplatin (4 mg / kg) alone, cisplatin (5 mg / kg) alone, cisplatin (6 mg / kg) alone, compound 1 (50 mg / kg) and cisplatin (4 mg / kg) combination group, compound 1 (100 mg / kg) and cisplatin (4 mg / kg) combination group, compound 1 (300 mg / kg) and cisplatin (4 mg / kg) combination group, compound 1 (50 mg / kg) and cisplatin (5 ... The mice were randomized into five groups: a combination group of Compound 1 (100 mg / kg) and cisplatin (5 mg / kg), a combination group of Compound 1 (300 mg / kg) and cisplatin (5 mg / kg), a combination group of Compound 1 (50 mg / kg) and cisplatin (6 mg / kg), a combination group of Compound 1 (100 mg / kg) and cisplatin (6 mg / kg), and a combination group of Compound 1 (300 mg / kg) and cisplatin (6 mg / kg). Mice were treated with the appropriate dose of Compound 1 by oral gavage once a day for 28 days or with the appropriate dose of cisplatin once a week on days 0, 7, 14, and 21 by intravenous injection. Cisplatin is generally administered at 4-6 mg / kg once a week, and the MTD of a single dose in Balb / c nude mice has been reported to be 6 mg / kg (Aston W., et al., BMC Cancer, 17:684 (2017)).

[0212] Body weight was measured daily. Tolerability was assessed by monitoring body weight and calculating body weight change as a % from the body weight at the start of treatment (day 0), as shown in Figures 1-3. Treatment was considered to be untolerable if natural death or ≥20% body weight loss occurred in 20% of mice in a group. Based on these criteria, the combination MTD was determined to be compound 1 (100 mg / kg) and cisplatin (6 mg / kg). The ability to treat mice with 4 weekly doses of 6 mg / kg cisplatin and daily doses of 100 mg / kg compound 1 indicates that the combination is well tolerated, as cisplatin is often administered less than weekly or at levels lower than 6 mg / kg in combination therapeutic efficacy studies with other compounds.

[0213] Example 2: In vitro assay Colony formation assay In vitro experiments were performed using colony forming unit (CFU) assays of various cell lines, which first involved establishing a cell seeding density that allowed the development of clearly dispersed colonies in 6-well plates when grown for approximately 14 days. Once this density was identified, cells were seeded on day -1 and on day 0, wells were incubated with DMSO or 300 nM of compound 1, a USP1 inhibitor, along with temozolomide (316 nM, 1 μM, 3.16 μM, 10 μM or 31.6 μM), cisplatin (3.16 nM, 10 nM, 31.6 nM, 100 nM, 316 nM, 1 μM or 3.16 μM), mitomycin C (1 nM, 3.16 nM, 10 nM, 31.6 nM, 100 nM, 316 nM, 1 μM), gemcitabine (31.6 pM, 100 pM, 316 pM, 1 nM), M, 3.16 nM), pemetrexed (31.6 nM, 100 nM, 316 nM, 1 μM, 3.16 μM), camptothecin (316 pM, 1 nM, 3.16 nM, 10 nM, 31.6 nM, 100 nM, 316 nM), doxorubicin (10 nM, 31.6 nM, 100 nM, 316 nM, 1 μM), etoposide (31.6 nM, 100 nM, 316 nM, 1 μM, 3.16 μM) or paclitaxel (3.16 nM, 10 nM, 31.6 nM, 100 nM, 316 nM). On day 8, the medium was replaced with one containing the appropriate concentration of DMSO, USP1 inhibitor, temozolomide, cisplatin, mitomycin C, gemcitabine, pemetrexed, camptothecin, doxorubicin, etoposide, or paclitaxel. At or about day 14, when clearly dispersed colonies were visible in the DMSO-treated wells, the cells were fixed and stained using 0.1% crystal violet in 10% ethanol at room temperature for 20 minutes. The plates were imaged and the amount of crystal violet staining in each well was quantified by extracting the crystal violet into 10% acetic acid and measuring the absorbance at 565 nm. The CFU results are shown in Table 1. [Table 4] [Table 5] [Table 6]

[0214] For a given cell line, multiple IC 50 Synergy scores are in parentheses. For example, testing the combination of Compound 1 and camptothecin in the pancreatic cell line ASPC1 yielded three separate IC 50 A value of 3 was measured and the synergy score was calculated as (-5).

[0215] The results in Table 1 show that synergistic effects were detected in cell lines treated with the combination of USP1 inhibitor and camptothecin, cisplatin or mitomycin C. In some cell lines, the combinations of the present invention are synergistic. In some embodiments, the Bliss score of these combinations is calculated to be about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20 or about 25.

[0216] Example 3: Antitumor activity of the combination of Compound 1 cocrystal and cisplatin in a breast xenograft model derived from the MDA-MB-436 cell line in NOD SCID mice The antitumor activity of the combination of the USP1 inhibitor cocrystal of compound 1 and cisplatin was evaluated in mice using the MDA-MB-436 cell line-derived breast xenograft model in non-obese diabetic / severe combined immunodeficiency (NOD SCID) mice, as shown in Figure 6A-B. 1 × 10 7 MDA-MB-436 cells were subcutaneously transplanted. 3Once tumors were established with a tumor volume of 100 mg / kg, mice were randomized into 5 groups and assigned to the following groups: control, cisplatin (2 mg / kg), compound 1 (100 mg / kg), or a combination of compound 1 (100 mg / kg) and cisplatin (2 mg / kg). Cisplatin was administered intravenously via the tail vein once a week for a total of 4 doses. Compound 1 was administered by oral gavage once a day for 28 days. Body weight and tumor volume were measured twice a week. Tumor volumes were calculated as the mean and standard error of the mean for each treatment group.

[0217] The data in FIG. 6A showed that compared with single-agent treatments of compound 1 or cisplatin at equivalent doses, the combination treatment groups exhibited longer antitumor activity in the MDA-MB-436 cell line-derived subcutaneous mouse model.

[0218] The tolerability of cisplatin (2 mg / kg) and Compound 1 (100 mg / kg) in the combination efficacy study was assessed by monitoring body weight and calculating body weight change as % from the body weight on the day treatment began (day 0), as shown in Figure 6B.

[0219] Example 4: Antitumor activity of the combination of Compound 1 cocrystal and cisplatin in the HBCx-8 patient-derived breast xenograft model in nude mice The antitumor activity of the combination of the USP1 inhibitor cocrystal of compound 1 and cisplatin was evaluated in mice using the HBCx-8 patient-derived breast xenograft model in nude mice, as shown in Figures 7A-7B. Six- to nine-week-old female athymic nude mice from Envigo were anesthetized and injected with 20 mm 3 The tumor fragments were placed subcutaneously through an incision in the flank. 3 Once tumors were established with a tumor volume of 0.01 mg / kg, mice were randomized into three groups and assigned to the following groups: control, Compound 1 (100 mg / kg), Cisplatin (5 mg / kg), or a combination of Compound 1 (100 mg / kg) and Cisplatin (5 mg / kg). Cisplatin was administered intravenously via the tail vein once a week for a total of three doses. Compound 1 was administered by oral gavage once a day for 42 days. Body weight and tumor volume were measured twice a week. Tumor volumes were calculated as the mean and standard error of the mean for each treatment group.

[0220] The data in FIG. 7A showed that compared with single-agent equivalent doses of Compound 1 or cisplatin, the combination treatment group exhibited longer antitumor activity in the HBCx-8 patient-derived subcutaneous mouse model.

[0221] The tolerability of cisplatin (5 mg / kg) and Compound 1 (100 mg / kg) in the combination efficacy study was assessed by monitoring body weight and calculating body weight change as % from the body weight on the day treatment began (day 0), as shown in Figure 7B.

[0222] Example 5: Antitumor activity of the combination of Compound 1 cocrystal and cisplatin in the HBCx-11 patient-derived breast xenograft model in nude mice The antitumor activity of the combination of the USP1 inhibitor cocrystal of compound 1 and cisplatin was evaluated in mice using the HBCx-11 patient-derived breast xenograft model in nude mice, as shown in Figures 8A-8B. Six- to nine-week-old female athymic nude mice from Envigo were anesthetized and injected with 20 mm 3 Tumor fragments were placed subcutaneously through a flank incision. 3 Once tumors were established with a tumor volume of 0.01 mg / kg, mice were randomized into three groups and assigned to the following groups: control, Compound 1 (100 mg / kg), Cisplatin (3 mg / kg), or a combination of Compound 1 (100 mg / kg) and Cisplatin (3 mg / kg). Cisplatin was administered intravenously via the tail vein once a week for a total of four doses. Compound 1 was administered by oral gavage once a day for 28 days. Body weight and tumor volume were measured twice a week. Tumor volumes were calculated as the mean and standard error of the mean for each treatment group.

[0223] The data in FIG. 8A showed that compared with single-agent Compound 1 or cisplatin at equivalent doses, the combination treatment group exhibited superior and longer antitumor activity in the HBCx-11 patient-derived subcutaneous mouse model.

[0224] The tolerability of cisplatin (3 mg / kg) and Compound 1 (100 mg / kg) in the combination efficacy study was assessed by monitoring body weight and calculating body weight change as % from the body weight on the day treatment began (day 0), as shown in Figure 8B.

[0225] All patents and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. 1. A method of treating cancer in a subject, comprising administering to the subject (i) a chemotherapeutic agent and (ii) a compound of formula I: 【Chemistry 1】 [During the ceremony, X １ and X ２ Each of N and CR ２ are independently selected from; R １ and R ２ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ３ is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl; X １１ and X １２ each is independently selected from N and CH; R ５’ is hydrogen, optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ２ -C ６ ) alkenyl, optionally substituted (C ２ -C ６ ) alkynyl, optionally substituted (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C １ -C ６ ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R ２３ , -C(=O)OR ２４ , -NR ３２ａ R ３２ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -C(=O)NR ３１ａ R ３１ｂ , -S(O) ２ R ２７ , -NR ３１ａ SO ２ R ２７ , optionally substituted (C ６ -C １４ ) aryl, optionally substituted (C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C １ -C ２ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, optionally substituted ((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C １ -C ２ ) alkyl, optionally substituted —O—(C ６ -C １４ ) aryl, optionally substituted —O—(C ６ -C １４ ) Al-(C １ -C ２ )alkyl, optionally substituted —O-heteroaryl, optionally substituted —O-heteroar-(C １ -C ２ ) alkyl, optionally substituted —O—(C ３ -C ８ )cycloalkyl, optionally substituted —O—((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted —O-heterocyclo, optionally substituted —O-heterocyclo-(C １ -C ２ ) alkyl; R ５ is optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ２ -C ６ ) alkenyl, optionally substituted (C ２ -C ６ ) alkynyl, optionally substituted (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C １ -C ６ ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R ２３ , -C(=O)OR ２４ , -NR ３２ａ R ３２ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -C(=O)NR ３１ａ R ３１ｂ , -S(O) ２ R ２７ , -NR ３１ａ SO ２ R ２７ , optionally substituted (C ６ -C １４ ) aryl, optionally substituted (C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C １ -C ２ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, optionally substituted ((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C １ -C ２ ) alkyl, optionally substituted —O—(C ６ -C １４ ) aryl, optionally substituted —O—(C ６ -C １４ ) Al-(C １ -C ２ )alkyl, optionally substituted —O-heteroaryl, optionally substituted —O-heteroar-(C １ -C ２ ) alkyl, optionally substituted —O—(C ３ -C ８ )cycloalkyl, optionally substituted —O—((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted —O-heterocyclo, optionally substituted —O-heterocyclo-(C １ -C ２ ) alkyl; or adjacent atoms of R ５ One of and R ５’ are optionally substituted together with the atom to which they are attached (C ６ -C １４ ) forms an aryl ring; or adjacent atoms R ５ One of and R ５’ together with the atom to which they are attached form an optionally substituted heteroaryl ring; or ５ One of and R ５’ are optionally substituted together with the atom to which they are attached (C ３ -C ８ ) forms a cycloalkyl ring; or adjacent atoms of R ５ One of and R ５’ together with the atom to which they are attached form an optionally substituted heterocycloalkyl ring; or ５ One of and R ５’ and the atom to which they are attached together form an optionally substituted spirocycloalkyl ring; or R ５ One of and R ５’ and the atom to which they are attached together form an optionally substituted spiroheterocycloalkyl ring; R ６ and R ７ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ２３ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R ３１ａ and R ３１ｂ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; and R ２４ , R ２５ , R ２７ , R ３２ａ and R ３２ｂ Each of R ２４ , R ２５ , R ２７ , R ３２ａ and R ３２ｂ are independently selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

2. 1. A method for delaying, reducing and / or preventing tumor rebound in a subject, comprising administering to the subject (i) a chemotherapeutic agent and (ii) a compound of formula I: 【Chemistry 2】 [During the ceremony, X １ and X ２ Each of N and CR ２ are independently selected from; R １ and R ２ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ３ is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl; X １１ and X １２ each is independently selected from N and CH; R ５’ is hydrogen, optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ２ -C ６ ) alkenyl, optionally substituted (C ２ -C ６ ) alkynyl, optionally substituted (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C １ -C ６ ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R ２３ , -C(=O)OR ２４ , -NR ３２ａ R ３２ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -C(=O)NR ３１ａ R ３１ｂ , -S(O) ２ R ２７ , -NR ３１ａ SO ２ R ２７ , optionally substituted (C ６ -C １４ ) aryl, optionally substituted (C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C １ -C ２ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, optionally substituted ((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C １ -C ２ ) alkyl, optionally substituted —O—(C ６ -C １４ ) aryl, optionally substituted —O—(C ６ -C １４ ) Al-(C １ -C ２ )alkyl, optionally substituted —O-heteroaryl, optionally substituted —O-heteroar-(C １ -C ２ ) alkyl, optionally substituted —O—(C ３ -C ８ )cycloalkyl, optionally substituted —O—((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted —O-heterocyclo, optionally substituted —O-heterocyclo-(C １ -C ２ ) alkyl; R ５ is optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ２ -C ６ ) alkenyl, optionally substituted (C ２ -C ６ ) alkynyl, optionally substituted (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C １ -C ６ ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R ２３ , -C(=O)OR ２４ , -NR ３２ａ R ３２ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -C(=O)NR ３１ａ R ３１ｂ , -S(O) ２ R ２７ , -NR ３１ａ SO ２ R ２７ , optionally substituted (C ６ -C １４ ) aryl, optionally substituted (C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C １ -C ２ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, optionally substituted ((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C １ -C ２ ) alkyl, optionally substituted —O—(C ６ -C １４ ) aryl, optionally substituted —O—(C ６ -C １４ ) Al-(C １ -C ２ )alkyl, optionally substituted —O-heteroaryl, optionally substituted —O-heteroar-(C １ -C ２ ) alkyl, optionally substituted —O—(C ３ -C ８ )cycloalkyl, optionally substituted —O—((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted —O-heterocyclo, optionally substituted —O-heterocyclo-(C １ -C ２ ) alkyl; or adjacent atoms of R ５ One of and R ５’ are optionally substituted together with the atom to which they are attached (C ６ -C １４ ) forms an aryl ring; or adjacent atoms R ５ One of and R ５’ together with the atom to which they are attached form an optionally substituted heteroaryl ring; or ５ One of and R ５’ are optionally substituted together with the atom to which they are attached (C ３ -C ８ ) forms a cycloalkyl ring; or adjacent atoms of R ５ One of and R ５’ together with the atom to which they are attached form an optionally substituted heterocycloalkyl ring; or ５ One of and R ５’ and the atom to which they are attached together form an optionally substituted spirocycloalkyl ring; or R ５ One of and R ５’ and the atom to which they are attached together form an optionally substituted spiroheterocycloalkyl ring; R ６ and R ７ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ２３ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R ３１ａ and R ３１ｂ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; and R ２４ , R ２５ , R ２７ , R ３２ａ and R ３２ｂ Each of R ２４ , R ２５ , R ２７ , R ３２ａ and R ３２ｂ are independently selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

3. 3. The method of claim 1 or 2, wherein the chemotherapeutic agent is a platin, a monofunctional alkylating agent, a bifunctional alkylating agent, an antimetabolite, a topoisomerase inhibitor, or a combination thereof.

4. 4. The method of claim 3, wherein the chemotherapeutic agent is a platin selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin and triplatin; optionally the platin is cisplatin or carboplatin.

5. 4. The method of claim 3, wherein the chemotherapeutic agent is a monofunctional alkylating agent selected from the group consisting of alkyl sulfonates, nitrosoureas, and temozolomide; or a bifunctional alkylating agent selected from the group consisting of nitrogen mustards and mitomycin C.

6. 4. The method of claim 3, wherein the chemotherapeutic agent is an antimetabolite selected from the group consisting of gemcitabine, 5-fluorouracil, thiopurines and folic acid analogs.

7. 4. The method of claim 3, wherein the chemotherapeutic agent is a topoisomerase inhibitor selected from the group consisting of camptothecins, anthracyclines and etoposide.

8. 8. The method of any of claims 1 to 7, wherein the compound of formula I is provided as a crystal formed between the USP1 inhibitor of formula I and a pharma- ceutically acceptable acid.

9. 4. A USP1 inhibitor having the structure: 【Chemistry 3】 [During the ceremony, X １ and X ２ Each of N and CR ２ are independently selected from; R １ is selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ５ but: 【Chemistry 4】 and X ６ is NR １３ and C.R. １８ Selected from: X ７ is NR １４ and C.R. １９ Selected from: X ８ is NR １５ and C.R. ２０ Selected from: X ９ is NR １６ and C.R. ２１ Selected from: X １０ is NR １７ and C.R. ２２ Selected from: R １３ , R １４ , R １５ , R １６ and R １７ Each of R １３ , R １４ , R １５ , R １６ and R １７ is selected from; and R １８ , R １９ , R ２０ , R ２１ and R ２２ each is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl; R ６ and R ７ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and R ８ , R ９ and R １１ Each of R ８ , R ９ and R １１ are independently selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

10. 10. The method of any of claims 1 to 9, wherein the USP1 inhibitor is a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, polymorph, or co-crystal thereof.

11. USP1 inhibitors: (a) Compound 1: 【Chemistry 5】 (b) Compound 2: 【Chemistry 6】 (c) Compound 3: 【Chemistry 7】 and a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or a pharma- ceutically acceptable salt thereof; or a hydrate thereof; or a solvate thereof; or the amorphous solid; or its polymorphism; or The cocrystal The method according to any one of claims 1 to 9, wherein the method is selected from the group consisting of

12. The USP1 inhibitor is Compound 1 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or The USP1 inhibitor is Compound 1 or a co-crystal thereof; or the USP1 inhibitor is Compound 2 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or The USP1 inhibitor is compound 2 or a co-crystal thereof; or the USP1 inhibitor is Compound 3 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or 12. The method of claim 11, wherein the USP1 inhibitor is compound 3 or a co-crystal thereof.

13. The method of any one of claims 1 to 12, wherein the USP1 inhibitor is provided as a crystal formed between 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine and a pharma- ceutically acceptable acid.

14. 14. The method of claim 13, wherein the pharma- ceutically acceptable acid is selected from the group consisting of gentisic acid, benzoic acid, salicylic acid and gallic acid; and optionally the pharma- ceutically acceptable acid is gentisic acid.

15. 15. The method of any one of claims 1 to 14, wherein the subject is a mammal, optionally wherein the mammal is a human.

16. The method of any one of claims 1 to 15, wherein the subject's cancer cells are HRR positive.

17. 17. The method of any of claims 1 to 16, wherein the cancer or tumor is an advanced solid tumor.

18. 18. The method of any of claims 1-17, wherein the cancer or tumor is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, endometrial cancer, pancreatic cancer, gastric cancer, cholangiocarcinoma and breast cancer.

19. The method of any of claims 1 to 18, wherein the chemotherapeutic agent and the USP1 inhibitor are administered sequentially.

20. The method of any of claims 1 to 18, wherein the chemotherapeutic agent and the USP1 inhibitor are administered simultaneously.

21. administering a chemotherapeutic agent and a USP1 inhibitor in therapeutically effective amounts sufficient to produce one or more therapeutic effects selected from the group consisting of: (i) a decrease in tumor size, (ii) an increase in the rate of tumor regression, and (iii) a reduction or inhibition of tumor growth; or The chemotherapeutic agent and the USP1 inhibitor are administered in amounts effective to reduce unacceptable toxicity and / or unacceptable adverse reactions of the chemotherapeutic agent administered as monotherapy; 21. The method of any one of claims 1 to 20.

22. 2. The method of claim 1, wherein the chemotherapeutic agent and the USP1 inhibitor delay, reduce and / or prevent tumor rebound.

23. 23. The method of any of claims 1, 2 and 8-22, wherein a USP1 inhibitor, gemcitabine and carboplatin are administered; and optionally the subject has ovarian cancer, triple negative breast cancer or non-small cell lung cancer.

24. 23. The method of any of claims 1, 2 and 8-22, wherein a USP1 inhibitor, leucovorin calcium, 5-fluorouracil and oxaliplatin are administered; and optionally the subject has colorectal cancer, pancreatic cancer, esophageal cancer or gastric cancer.

25. 25. The method of any of claims 1-24, wherein the cancer or tumor has been previously treated with platinum therapy, optionally the cancer or tumor is platinum-resistant or platinum-refractory; optionally the platinum therapy is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, and combinations thereof.

26. A combination comprising (i) a chemotherapeutic agent and (ii) a ubiquitin-specific processing protease 1 (USP1) inhibitor, wherein the USP1 inhibitor is represented by formula I: 【Chemistry 8】 [In the formula: X １ and X ２ Each of N and CR ２ are independently selected from; R １ and R ２ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ３ is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl; X １１ and X １２ each is independently selected from N and CH; R ５’ is hydrogen, optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ２ -C ６ ) alkenyl, optionally substituted (C ２ -C ６ ) alkynyl, optionally substituted (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C １ -C ６ ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R ２３ , -C(=O)OR ２４ , -NR ３２ａ R ３２ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -C(=O)NR ３１ａ R ３１ｂ , -S(O) ２ R ２７ , -NR ３１ａ SO ２ R ２７ , optionally substituted (C ６ -C １４ ) aryl, optionally substituted (C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C １ -C ２ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, optionally substituted ((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C １ -C ２ ) alkyl, optionally substituted —O—(C ６ -C １４ ) aryl, optionally substituted —O—(C ６ -C １４ ) Al-(C １ -C ２ )alkyl, optionally substituted —O-heteroaryl, optionally substituted —O-heteroar-(C １ -C ２ ) alkyl, optionally substituted —O—(C ３ -C ８ )cycloalkyl, optionally substituted —O—((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted —O-heterocyclo, optionally substituted —O-heterocyclo-(C １ -C ２ ) alkyl; R ５ is optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ２ -C ６ ) alkenyl, optionally substituted (C ２ -C ６ ) alkynyl, optionally substituted (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C １ -C ６ ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R ２３ , -C(=O)OR ２４ , -NR ３２ａ R ３２ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -C(=O)NR ３１ａ R ３１ｂ , -S(O) ２ R ２７ , -NR ３１ａ SO ２ R ２７ , optionally substituted (C ６ -C １４ ) aryl, optionally substituted (C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C １ -C ２ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, optionally substituted ((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C １ -C ２ ) alkyl, optionally substituted —O—(C ６ -C １４ ) aryl, optionally substituted —O—(C ６ -C １４ ) Al-(C １ -C ２ )alkyl, optionally substituted —O-heteroaryl, optionally substituted —O-heteroar-(C １ -C ２ ) alkyl, optionally substituted —O—(C ３ -C ８ )cycloalkyl, optionally substituted —O—((C ３ -C ８ )cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted —O-heterocyclo, optionally substituted —O-heterocyclo-(C １ -C ２ ) alkyl; or R of adjacent atoms ５ One of and R ５’ are optionally substituted together with the atom to which they are attached (C ６ -C １４ ) forms an aryl ring; or adjacent atoms R ５ One of and R ５’ together with the atom to which they are attached form an optionally substituted heteroaryl ring; or ５ One of and R ５’ are optionally substituted together with the atom to which they are attached (C ３ -C ８ ) forms a cycloalkyl ring; or adjacent atoms of R ５ One of and R ５’ together with the atom to which they are attached form an optionally substituted heterocycloalkyl ring; or ５ One of and R ５’ and the atom to which they are attached together form an optionally substituted spirocycloalkyl ring; or R ５ One of and R ５’ and the atom to which they are attached together form an optionally substituted spiroheterocycloalkyl ring; R ６ and R ７ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ２３ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R ３１ａ and R ３１ｂ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; and R ２４ , R ２５ , R ２７ , R ３２ａ and R ３２ｂ Each of R ２４ , R ２５ , R ２７ , R ３２ａ and R ３２ｂ are independently selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

27. 27. The combination of claim 26, wherein the chemotherapeutic agent is a platin, a monofunctional alkylating agent, a bifunctional alkylating agent, an antimetabolite, a topoisomerase inhibitor, or a combination thereof.

28. the chemotherapeutic agent is a platin selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin and triplatin; optionally the chemotherapeutic agent is cisplatin or carboplatin; or The chemotherapeutic agent is a monofunctional alkylating agent selected from the group consisting of alkyl sulfonates, nitrosoureas, and temozolomide; or a bifunctional alkylating agent selected from the group consisting of nitrogen mustards and mitomycin C; or The chemotherapeutic agent is an antimetabolite selected from the group consisting of gemcitabine, 5-fluorouracil, thiopurines, and folic acid analogs; or the chemotherapeutic agent is a topoisomerase inhibitor selected from the group consisting of camptothecin, anthracycline and etoposide; 28. The combination of claim 27.

29. 28. The combination of claim 27, wherein the chemotherapeutic agents include leucovorin calcium, 5-fluorouracil and oxaliplatin.

30. A USP1 inhibitor of formula I has the following structure: 【Chemistry 9】 [During the ceremony, X １ and X ２ Each of N and CR ２ are independently selected from; R １ is selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ５ but: 【Chemistry 10】 and X ６ is NR １３ and C.R. １８ Selected from: X ７ is NR １４ and C.R. １９ Selected from: X ８ is NR １５ and C.R. ２０ Selected from: X ９ is NR １６ and C.R. ２１ Selected from: X １０ is NR １７ and C.R. ２２ Selected from: R １３ , R １４ , R １５ , R １６ and R １７ Each of R １３ , R １４ , R １５ , R １６ and R １７ is selected from; and R １８ , R １９ , R ２０ , R ２１ and R ２２ each is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl; R ６ and R ７ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and R ８ , R ９ and R １１ Each of R ８ , R ９ and R １１ are independently selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

31. The combination of any of claims 26 to 30, wherein the compound of formula I is provided as a crystal formed between the USP1 inhibitor of formula I and a pharma- ceutically acceptable acid.

32. USP1 inhibitors: (a) Compound 1: 【Chemistry 11】 (b) Compound 2: 【Chemistry 12】 (c) Compound 3: 【Chemistry 13】 and a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or a pharma- ceutically acceptable salt thereof; or a hydrate thereof; or a solvate thereof; or the amorphous solid; or its polymorphism; or The cocrystal Selected from the group consisting of: A combination according to any one of claims 26 to 30.

33. The USP1 inhibitor is Compound 1 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or The USP1 inhibitor is Compound 1 or a co-crystal thereof; or the USP1 inhibitor is Compound 2 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or The USP1 inhibitor is compound 2 or a co-crystal thereof; or the USP1 inhibitor is Compound 3 or a pharma- ceutically acceptable salt, hydrate, solvate, amorphous solid, or polymorph thereof; or The USP1 inhibitor is compound 3 or a co-crystal thereof; 33. The combination of claim 32.

34. 34. The combination of any of claims 26 to 33, wherein the USP1 inhibitor is a co-crystal formed between 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine and a pharma- ceutically acceptable acid.

35. 35. The combination of claim 34, wherein the pharma- ceutically acceptable acid is selected from the group consisting of gentisic acid, benzoic acid, salicylic acid and gallic acid; and optionally the pharma- ceutically acceptable acid is gentisic acid.

36. The combination of any of claims 26 to 35, wherein the USP1 inhibitor and the chemotherapeutic agent are provided in separate dosage forms.

37. 37. The combination of any of claims 26 to 36, wherein the USP1 inhibitor is provided in an oral dosage form.

38. The chemotherapy agent is provided in an injectable form; or The chemotherapy agent is provided in an oral dosage form; A combination according to any one of claims 26 to 37.

39. A combination according to any of claims 26 to 38 for use in the treatment of cancer.

40. Use of a combination according to any of claims 26 to 38 for the manufacture of a medicament for the treatment of cancer.

41. A kit for administering a combination agent to a subject with cancer, comprising the composition of any one of claims 26 to 38 and instructions.

42. The cancer is an advanced solid tumor; or The cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, uterine cancer, peritoneal cancer, endometrial cancer, pancreatic cancer, gastric cancer, cholangiocarcinoma and breast cancer; or 42. The combination of claim 39 or the use of claim 40 or the kit of claim 41, wherein the cancer has been previously treated with platinum therapy, optionally the cancer is platinum-resistant or platinum-refractory, and optionally the platinum therapy is selected from the group consisting of cisplatin, carboplatin, oxaliplatin and combinations thereof.

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