Ubiquitin-specific processing protease 1 (USP1) compounds

Abstract

Compounds having the following formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein all substituents are as defined herein, are inhibitors useful in the treatment of diseases, including the treatment of proliferative, metabolic, allergic, autoimmune and inflammatory diseases USP1.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 594,451, filed October 31, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to compounds that are inhibitors of ubiquitin-specific processing protein 1 (USP1), which can be used to treat diseases, particularly including cancer, autoimmune disorders, and inflammatory disorders. The invention further relates to pharmaceutical compositions containing at least one compound according to the invention, which can be used to treat conditions associated with USP1 inhibition in mammals. Background of the Invention

[0005] Ubiquitination is crucial in regulating many cellular functions and homeostasis. The binding of ubiquitin to target proteins is a multi-step process involving the sequential action of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3). The ubiquitin tag can mediate non-covalent interactions between ubiquitinated substrates and other proteins carrying different types of ubiquitin-binding motifs. A family of enzymes called deubiquitinating enzymes act on ubiquitinated substrates, catalyzing the removal of the ubiquitin motif. One such enzyme is ubiquitin-specific protease 1 (USP1), which plays a vital role in regulating DNA repair. USP1 is a regulator of several important steps in the DNA damage response, particularly in the Fanconi anemia pathway and trans-damage synthesis. USP1 has also been reported to promote the repair of double-stranded DNA breaks through homologous recombination. Furthermore, USP1 has been reported to deubiquitinate and stabilize members of the DNA binding inhibitor (ID) protein family, ID1, ID2, and ID3. García-Santisteban, I., Peters, GJ, Giovannetti, E. et al. Mol Cancer 12, 91 (2013); US Patent Nos. 7,754,463, 10,653,676, 9,518,032.

[0006] Invention Summary

[0007] This disclosure provides compounds that modulate USP1 expression or activity. This disclosure also provides compositions comprising pharmaceutical compositions, kits containing said compounds, and methods of using (or administering) and preparing said compounds. The compounds provided herein can be used to treat diseases, disorders, or conditions mediated by USP1. This disclosure also provides compounds for treatment. This disclosure further provides compounds in methods for treating diseases, disorders, or conditions mediated by USP1. Furthermore, this disclosure provides the use of said compounds in the preparation of medicaments for treating diseases, disorders, or conditions mediated (or at least partially mediated) by USP1.

[0008] In one respect, compounds of formula (I) are provided:

[0009] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; R 1 Selected from C6 aryl and 5-6 heteroaryl groups, optionally bonded by 1 to 4 halogens, hydroxyl groups, amino groups, or -C(O)R groups. a -C(O)OR b -C(O)NR a R b -N(R) a )C(O)R b -S(O)NR a R b -S(O)2NR a R b -S(O)R g -S(O)2R g -NR a R b -OR a -SR b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-8 Cycloalkyl substitution; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-8 Each cycloalkyl group is optionally surrounded by 1 to 4 R 100 replace; R 2 Selected from: non-existent, hydrogen, halogen, hydroxyl, amino, -CN, -C(O)R a -C(O)OR b -C(O)NR a R b -N(R) a )C(O)R b -N(R) a )C(O)NR a R b -N(R) a SO2NR a R b -S(O)NR a R b -S(O)2NR a R b -N(R) a )S(O)2Rb -S(O)R g -S(O)2R g -NR a R b -OR a -SR b -OC(O)R a -OC(O)NR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S, and C 3-8 Each cycloalkyl group is optionally surrounded by 1 to 4 R 100 replace; X is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 4 R groups. 100 replace; W 1 and W 2 Each is independently selected from -N(R) a -, -C(O)- and -C(R)- a )-; W 3 Selected from -N- and -C(R) a )-; W 4 Selected from -N- and -C(R) a )-; Among them W 1 W 2 and W 3 At least one of them is -C(R) a )-; G 1 Selected from -C6 aryl-, 5-6 heteroaryl, C 3-8 Cycloalkyl and 5-6 membered heterocyclic groups; including C6 aryl, 5-6 membered heteroaryl, C 3-8 The cycloalkyl group and the 5-6 membered heterocyclic group are each optionally surrounded by 1 to 4 R groups. 100 replace; G 2 It can be selected from 1 to 4 Rs. 100 Substituted 5- or 6-membered heteroaryl or 5-6-membered heterocyclic group; R a and R bEach is independently selected from non-existent, hydrogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S are each optionally surrounded by 1 to 4 R atoms. 200 replace; Each R 100 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R c -C(O)OR c -C(O)NR c R d -N(R) c )C(O)R d -S(O)NR c R d -S(O)2NR c R d -S(O)R h -S(O)2R h -NR c R d -OR c -SR c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 201 replace; R c and R d Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O and S; R 200 and R 201 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R e -C(O)OR e -C(O)NR e R f -N(R) e )C(O)R f -S(O)NR e R f -S(O)2NR e R f -S(O)R i -S(O)2R i -NR e R f -OR e -SR e C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 300 replace; R g R h and R i Each is independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Each alkynyl group is optionally surrounded by 1 to 4 R groups. 300 replace; Each R 300 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R e -C(O)OR e -C(O)NR eR f -N(R) e )C(O)R f -S(O)NR e R f -S(O)2NR e R f -S(O)R e -S(O)2R e -NR e R f -OR e -SR e C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R e and R f Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 400 replace; Each R 400 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R k -C(O)OR k -C(O)NR k R l -N(R) k )C(O)R l -S(O)NR k R l -S(O)2NR k R l -NR k R l S(O)R k -S(O)2R k -NR k R l -OR k -SR k C 1-6 Alkyl, C2-6 alkenyl and C 2-6 alkynyl group; R k and R l Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O and S.

[0010] In one aspect, methods and intermediates for preparing compounds of formula I are provided.

[0011] In one aspect, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and at least one compound disclosed herein.

[0012] This application also provides a method for inhibiting USP1, the method comprising administering a therapeutically effective amount of at least one of Formula I.

[0013] This application also provides methods for treating proliferative, metabolic, allergic, autoimmune, and inflammatory diseases, the methods comprising administering a therapeutically effective amount of at least one of the compounds disclosed herein to a host in need of such treatment. Compounds of Formula I or pharmaceutically acceptable salts thereof may be used to treat cancers mediated by, dependent on, or associated with USP1 activity. In some embodiments, the disease is a solid tumor. Invention Details

[0015] In the first aspect, compounds of formula (I) that function as USP1 inhibitors are provided:

[0016] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; R 1 Selected from C6 aryl and 5-6 heteroaryl groups, optionally bonded by 1 to 4 halogens, hydroxyl groups, amino groups, or -C(O)R groups. a -C(O)OR b -C(O)NR a R b -N(R) a )C(O)R b -S(O)NR a R b -S(O)2NR a R b -S(O)R g -S(O)2Rg -NR a R b -OR a -SR b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-8 Cycloalkyl substitution; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-8 Each cycloalkyl group is optionally surrounded by 1 to 4 R 100 replace; R 2 Selected from: non-existent, hydrogen, halogen, hydroxyl, amino, -CN, -C(O)R a -C(O)OR b -C(O)NR a R b -N(R) a )C(O)R b -N(R) a )C(O)NR a R b -N(R) a SO2NR a R b -S(O)NR a R b -S(O)2NR a R b -N(R) a )S(O)2R b -S(O)R g -S(O)2R g -NR a R b -OR a -SR b -OC(O)R a -OC(O)NR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S, and C 3-8 Each cycloalkyl group is optionally surrounded by 1 to 4 R 100 replace; X is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 4 R groups. 100 replace; W 1 and W 2 Each is independently selected from -N(R) a -, -C(O)- and -C(R)- a )-; W 3 Selected from -N- and -C(R) a )-; W 4 Selected from -N- and -C(R) a )-; Among them W 1 W 2 and W 3 At least one of them is -C(R) a ); G 1 Selected from -C6 aryl-, 5-6 heteroaryl, C 3-8 Cycloalkyl and 5-6 membered heterocyclic groups; including C6 aryl, 5-6 membered heteroaryl, C 3-8 The cycloalkyl group and the 5-6 membered heterocyclic group are each optionally surrounded by 1 to 4 R groups. 100 replace; G 2 It can be selected from 1 to 4 Rs. 100 Substituted 5- or 6-membered heteroaryl or 5-6-membered heterocyclic group; R a and R b Each is independently selected from non-existent, hydrogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S, are each optionally surrounded by 1 to 4 R atoms. 200 replace; Each R 100 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R c -C(O)OR c -C(O)NR c R d -N(R) c )C(O)Rd -S(O)NR c R d -S(O)2NR c R d -S(O)R h -S(O)2R h -NR c R d -OR c -SR c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 201 replace; R c and R d Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O and S; R 200 and R 201 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R e -C(O)OR e -C(O)NR e R f -N(R) e )C(O)R f -S(O)NR e R f -S(O)2NR e R f -S(O)R i -S(O)2R i -NR e R f -OR e -SRe C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 300 replace; R g R h and R i Each is independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Each alkynyl group is optionally surrounded by 1 to 4 R groups. 300 replace; Each R 300 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R e -C(O)OR e -C(O)NR e R f -N(R) e )C(O)R f -S(O)NR e R f -S(O)2NR e R f -S(O)R e -S(O)2R e -NR e R f -OR e -SR e C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R e and R f Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 3-8 cycloalkyl, C6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 400 replace; Each R 400 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R k -C(O)OR k -C(O)NR k R l -N(R) k )C(O)R l -S(O)NR k R l -S(O)2NR k R l -NR k R l S(O)R k -S(O)2R k -NR k R l -OR k -SR k C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R k and R l Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O and S.

[0017] In one embodiment, a compound of formula (IIa or IIb) is provided:

[0018] In one embodiment, compounds of formulas (IIIa, IIIb, and IIIc) are provided:

[0019] Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0020] In one embodiment, compounds of formula (IVa), (IVb), or (IVc) are provided:

[0021] Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0022] In one implementation, a compound of formula (V) is provided:

[0023] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

[0024] In one implementation, a compound of formula (VI) is provided:

[0025] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

[0026] In one embodiment, compounds of formula (VIIa), (VIIb), or (VIIc) are provided:

[0027] Where R 3 and R 4 Each is independently selected from hydrogen, halogen, and -OR a -SR b and C 3-8 cycloalkyl; Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0028] In one embodiment, compounds of formula (VIIIa), (VIIIb), or (VIIIc) are provided:

[0029] Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0030] In one embodiment, a compound is provided, wherein R 1 Selected from: and

[0031] Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0032] In one embodiment, a compound is provided, wherein R 2 Selected from: -OCH3, -H, -SCH3, -S(O)2CH3, -S(O)2CH3, -C(O)OCH3, -C(O)OCH2CH3 and -C(O)NH2, Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue.

[0033] In one implementation, a compound is provided, wherein G 2 Selected from: , Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue.

[0034] The compounds described herein (e.g., compounds of formulas I, IIa, IIb, IIIa, IIIb, IIIc, Iva, IVb, IVc, V, VI, VIIa, VIIb, VIIc, VIIIa, VIIIb, VIIIc, or compounds from Table A) or pharmaceutically acceptable salts thereof may be used to treat cancers mediated by, dependent on, or associated with USP1 activity. In some embodiments, the disease is a solid tumor. In specific embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine carcinoma, central nervous system cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is selected from non-small cell lung cancer or small cell lung cancer.

[0035] The following are definitions of terms used in this specification and the appended claims. Unless otherwise stated, the initial definitions of groups or terms provided herein apply to that group or term throughout the specification and claims, whether used alone or as part of another group.

[0036] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0037] The compounds of this invention may have one or more asymmetric centers. Unless otherwise stated, all chiral forms (enantiomers and diastereomers) and racemic forms of the compounds of this invention are included in this invention. Numerous geometric isomers, such as alkenes and C=N double bonds, may also be present in the compounds, and all such stable isomers are considered in this invention. Cis and trans geometric isomers of the compounds of this invention are described and can be isolated as mixtures of isomers or as separate isomer forms. The compounds of this invention can be isolated in optically active or racemic forms. How to prepare optically active forms is well known in the art, for example by resolution of racemic forms or by synthesis from optically active starting materials. Unless a specific stereochemical or isomer form is specifically specified, all chiral forms (enantiomers and diastereomers) and racemic forms, as well as all geometric isomer forms of the structure, are intended to be included.

[0038] When any variable (e.g., R) 3 When a group appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for each subsequent occurrence. Thus, for example, if a group is shown as being surrounded by 0-2 R... 3 Substitution, in which the group may optionally be replaced by at most two R groups. 3 Group substitution, and R 3 Each time it appears, it is independently selected from R. 3 The definition of [the specific compound is missing]. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce stable compounds.

[0039] When the bond connecting a substituent is shown as crossing the bonds of two atoms in the ring, the substituent can bond to any atom in the ring. When a substituent is listed without specifying which atom it bonds to the rest of the compound in the given formula, the substituent can bond to any atom in that substituent. Combinations of substituents and / or variables are only permitted if such combinations produce stable compounds.

[0040] In the presence of nitrogen atoms (e.g., amines) in the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, all nitrogen atoms shown and claimed are considered to simultaneously cover the shown nitrogen and its N-oxide (N→O) derivatives.

[0041] According to the conventions used in this field, In the structural formula of this paper, the bonds used to describe the connection points between parts or substituents and the core or skeleton structure are used.

[0042] A hyphen “-” not between two letters or symbols is used to indicate the connection point of a substituent. For example, -CONH2 is connected by a carbon atom. The hyphen at the beginning or end of a chemical group is for convenience; a chemical group may be depicted with or without one or more hyphens without losing its usual meaning. A wavy line passing through a line in a structure indicates the connection point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0043] The term "optionally substituted" in relation to a specific portion (e.g., an optionally substituted heteroaryl group) of a compound of formula I refers to a portion having 0, 1, 2, or more substituents. For example, "optionally substituted alkyl" encompasses "alkyl" and "substituted alkyl" as defined below. Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is spatially impractical, synthetically infeasible, and / or inherently unstable.

[0044] As used herein, the term “at least one chemical entity” and the term “compound” are used interchangeably.

[0045] prefix "C" u-v "" indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0046] As used herein, the term "alkyl" or "alkylene" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1-10 Alkyl (or alkylene) is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10Alkyl groups. Furthermore, for example, "C1-C6 alkyl" refers to alkyl groups having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted, such that one or more of their hydrogen atoms are replaced by another chemical group. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.

[0047] "Alkenyl" or "alkenylyl" is intended to include hydrocarbon chains with straight or branched configurations, having one or more carbon-carbon double bonds that can occur at any stable point on the chain. For example, "C 2-6 "Alkenyl" (or alkenylylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.

[0048] "Alynyl" or "hypoynyl" is intended to include hydrocarbon chains of straight or branched configurations having one or more carbon-carbon triple bonds that can occur at any stable point on the chain. For example, "C 2-6 "Alynyl" (or ynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl groups; for example, ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc.

[0049] Those skilled in the art will understand that when the label “CO2” is used herein, it is intended to refer to the group [unclear - possibly a specific group or functional group]. .

[0050] When the term "alkyl" is used with another group, such as in "arylalkyl," the conjunction more specifically defines the substituted alkyl group that will contain at least one substituent. For example, "arylalkyl" refers to a substituted alkyl group as defined above, wherein at least one substituent is aryl, such as benzyl. Therefore, the term aryl (C 0-4 Alkyl groups include substituted lower alkyl groups having at least one aryl substituent, and also include aryl groups directly bonded to another group, i.e., aryl(CO)alkyl groups. The term “heteroarylalkyl” refers to a substituted alkyl group as defined above, wherein at least one substituent is a heteroaryl group.

[0051] When referring to substituted alkenyl, ynyl, alkylene, alkenyl, or ynylene groups, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.

[0052] The term "alkoxy" refers to an oxygen atom substituted with an alkyl or substituted alkyl group as defined herein. For example, the term "alkoxy" includes the -OC group. 1-6Alkyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. "Lower alkoxy groups" refer to alkoxy groups having 1 to 4 carbons.

[0053] The term "cycloalkyl" refers to cyclic alkyl groups, including monocyclic, bicyclic, or polycyclic cyclic systems. 3-7 Cycloalkyl groups are intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc. As used herein, "carbocyclic" or "carbocyclic residue" is intended to represent any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic, or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracene, and tetrahydronaphthyl (tetrahydronaphthalene). As shown above, bridging rings are also included in the definition of carbocyclic rings (e.g., [2.2.2]bicyclooctane). Unless otherwise stated, preferred carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocyclic ring" is used, it is intended to include "aryl". A bridging ring occurs when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is worth noting that bridging always transforms a single ring into a double ring. When a ring is bridged, the substituents for that ring can also be present on the bridge.

[0054] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group with a ring moiety of 6 to 12 carbon atoms, such as phenyl and naphthyl, which may each be substituted.

[0055] Therefore, in compounds of formula I, the term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, and the following ring systems: , , , , , , , , , , , , , etc., which may optionally be substituted on any available atom of one or more rings.

[0056] The term "halogenated" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0057] The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0058] The term "haloalkoxy" refers to an alkoxy group having one or more halogen substituents. For example, "haloalkoxy" includes OCF3.

[0059] The terms “heterocyclic,” “heterocyclic alkyl,” “heterocyclic group,” or “heterocyclic” are used interchangeably to refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, wherein at least one ring has at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such heteroatom-containing groups may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The fused ring constituting the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclic group may be attached to any available nitrogen or carbon atom. As used herein, the terms “heterocyclic,” “heterocyclic alkyl,” “heterocyclic group,” and “heterocyclic” include “heteroaryl” groups as defined below.

[0060] In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclic groups include azirrobutyl, pyrrolyl, oxacyclobutyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, 2-oxacycloheptyl, azirroheptyl, 1-pyridinoneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxopentane, and tetrahydro-1,1-dioxothiopheneyl, etc. Exemplary bicyclic heterocyclic groups include quinine cycloyl.

[0061] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups, having at least one heteroatom (O, S, or N) in at least one ring, preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of a heteroaryl containing heteroatoms may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring has at least one carbon atom. The fused rings constituting the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Nitrogen and sulfur atoms may optionally be oxidized, and nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, but the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached to any available nitrogen or carbon atom in any ring. If the additional ring is a cycloalkyl or heterocyclic group, it may optionally be substituted with =O (oxo) provided that the valence allows.

[0062] Exemplary monocyclic heteroaryl groups include pyrrole, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.

[0063] Exemplary bicyclic heteroaryl groups include indole, benzothiazolyl, benzodioxazolyl, benzoxazolyl, benzothiophene, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoimidazolyl, benzopyranyl, indoleyl, benzofuranyl, chromonel, coumarinyl, benzopyranyl, cinolinyl, quinoxalinyl, indazole, pyrrolopyridyl, furanopyridyl, dihydroisoindole, tetrahydroquinolinyl, etc.

[0064] Exemplary tricyclic heteroaryl groups include carbazolyl, benzoindolyl, phenanthrolinel, acridinel, phenanthidyl, xanthonyl, etc.

[0065] In compounds of formula I, preferred heteroaryl groups include: and These can be optionally substituted on any available carbon or nitrogen atom.

[0066] Unless otherwise stated, when referring to aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclic (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furanyl) by specific names, the reference is intended to include a ring having 0 to 3, preferably 0 to 2, substituents selected from those listed above for aryl, cycloalkyl, heterocyclic, and / or heteroaryl (as the case may be).

[0067] The term "carbocyclic" or "carbocyclic" refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Therefore, the term includes cycloalkyl and aryl rings. Monocyclic carbocyclic rings have 3 to 6 ring atoms, more typically 5 or 6. Bicyclic carbocyclic rings have 7 to 12 ring atoms, for example, arranged in bicyclic [4,5], [5,5], [5,6], or [6,6] systems, or 9 or 10 ring atoms arranged in bicyclic [5,6] or [6,6] systems. Examples of monocyclic and bicyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, and naphthyl. The carbocyclic ring can be substituted, in which case the substituents are selected from those listed above for cycloalkyl and aryl groups.

[0068] The term "alkylthio" refers to the "alkyl-S-" group.

[0069] The term "acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0070] The term "amide group" refers to a "C-amide group" (referring to the group -C(O)NR). g R h ) and "N-amide group" (referring to the group -NR) g C(O)R h ), where R g and R h It is independently selected from hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may optionally be substituted.

[0071] The term "amino" refers to the -NR group. g R h , where R g and R h It is independently selected from hydrogen, alkyl, haloalkyl, aryl or heteroaryl; each of which may optionally be substituted.

[0072] The term "azido group" refers to -N3.

[0073] The term "carbamoyl" refers to "O-carbamoyl" (referring to the group -OC(O)NR). i R j ) and "N-carbamoyl" (referring to the group -NR) i C(O)OR j ), where R i and R j It is independently selected from hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may optionally be substituted.

[0074] The term "carboxyl group" refers to -C(O)OH.

[0075] The term "carboxylic acid ester" refers to -OC(O)R and -C(O)OR. g , where R g It is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0076] The terms "cyano" or "nitrile" refer to the -CN group.

[0077] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings (including fused, bridged, and spirocyclic systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] The term "heteroatoms" should include oxygen, sulfur, and nitrogen.

[0079] When the term “unsaturated” is used in this document to describe a ring or group, the ring or group may be completely unsaturated or partially unsaturated.

[0080] Throughout the specification, those skilled in the art can select groups and their substituents to provide stable moieties and compounds, as well as compounds that can be used as pharmaceutically acceptable compounds and / or intermediate compounds for the preparation of pharmaceutically acceptable compounds.

[0081] It should be understood that the selection of all groups (including, for example, alkoxy, thioalkyl, and aminoalkyl) will be made by those skilled in the art to provide stable compounds.

[0082] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by a group selected from the specified group, provided that the substitution does not exceed the normal valence of the specified atom. When the substituent is oxo or ketone (i.e., =O), two hydrogen atoms on the atom are replaced. Ketone substituents are not present on the aromatic moiety. Unless otherwise stated, substituents are named within the core structure. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the connection point of the substituent to the core structure is at the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0083] Combinations of substituents and / or variables are permitted only if such combinations produce stable compounds or useful synthetic intermediates. Stable compounds or stable structures mean that the compounds are stable enough to be isolated from the reaction mixture with useful purity and subsequently formulated into effective therapeutic agents. Preferably, the compounds listed herein do not contain N-halogens, S(O)₂H, or S(O)H groups.

[0084] The compounds described herein may exist in a free form (unionized) or may form salts, which are also within the scope of this invention. Unless otherwise stated, reference to the compounds of this invention should be understood to include reference to both the free form and its salts. The term "salt" means an acidic and / or basic salt formed with inorganic and / or organic acids and bases. Furthermore, the term "salt" may include zwitterions (internal salts), for example, when a compound of formula I contains both a basic moiety (e.g., an amine or pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, such as acceptable metal salts and amine salts in which the cation has no significant effect on the toxicity or biological activity of the salt. However, other salts may be useful, for example, in separation or purification steps that may be employed during preparation, and therefore, these salts are also considered within the scope of this invention. Salts of the compounds described herein may be formed, for example, by reacting the compounds described herein with a certain amount (e.g., an equimolar amount) of an acid or base in a medium (e.g., a medium in which the salt precipitates) or by reacting in an aqueous medium followed by lyophilization.

[0085] Exemplary acid addition salts include acetates (e.g., salts formed with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipic acid salts, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionate, diglucuronide, dodecyl sulfate, ethanesulfonate, fumarate, glucohepanoate, glycerophosphates, hemisulfates, heptahydrates, hexanoates, hydrochlorides (forming with hydrochloric acid), and hydrobromide (forming with hydrogen bromide). (Formed), hydroiodates, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., salts formed with sulfuric acid), sulfonates (e.g., those mentioned in this article), tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, undecanoates, etc.

[0086] Exemplary basic salts include ammonium salts; alkali metal salts, such as sodium, lithium, and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts formed with organic bases (e.g., organic amines), such as salts formed with trialkylamines (e.g., triethylamine), procaine, dibenzylamine, N-benzyl-β-phenylethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabimethamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines; and salts formed with amino acids such as arginine, lysine, etc. The basic nitrogen-containing group can be quaternized with reagents such as lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl), and aralkyl halides (e.g., benzyl and phenethyl bromides). Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0087] The compounds described herein can be provided as amorphous or crystalline solids. Lyophilization can be used to provide the compounds in solid form.

[0088] It should also be understood that solvates of the compounds described herein (e.g., hydrates) are also within the scope of this invention. The term "solvate" refers to a physical association of a compound with one or more solvent molecules (whether organic or inorganic). Such physical associations include hydrogen bonds. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. "Solvate" encompasses both the solution phase and the separable solvate. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0089] Furthermore, the compounds described herein can be isolated and purified after preparation to obtain a component containing an amount equal to or greater than 99% by weight of the compound (“substantially pure”), which can then be used or formulated as described herein. Such “substantially pure” compounds described herein are also considered as part of this invention.

[0090] The phrase “pharmaceutically acceptable” as used in this article means compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0091] As used herein, a “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound in which the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali metal or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts formed from parent compounds, such as salts formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and hydroxyethanesulfonic acid.

[0092] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture thereof; typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. See the list of suitable salts. Remington's Pharmaceutical Science, 18th edition, Mack Publishing Company, Easton, PA (1990), the contents of which are incorporated herein by reference.

[0093] "Stable compound" and "stable structure" mean that the compound is stable enough to be isolated from the reaction mixture with useful purity and formulated into an effective therapeutic agent. This invention aims to cover stable compounds.

[0094] "Therapeutic effective amount" is intended to include the amount of a single compound of the present invention that is effective as a USP1 inhibitor, or effective in treating or preventing proliferative disorders such as cancer, or the amount of a claimed combination of compounds of the present invention in combination with other active ingredients.

[0095] As used herein, “treatment” encompasses the treatment of disease states in mammals (particularly humans) and includes: (a) preventing the occurrence of disease states in mammals, particularly when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state; (b) suppressing disease states, i.e., preventing their development; and / or (c) alleviating disease states, i.e. leading to the extinction of the disease state.

[0096] All stereoisomers of the compounds of this invention are considered, whether in mixture form or in pure or substantially pure form. Stereoisomers may include optical isomers arising from having one or more chiral atoms, and optical isomers arising from restricted rotation around one or more bonds (restricted rotation isomers). The definition of compounds according to the invention covers all possible stereoisomers and mixtures thereof. It particularly covers racemic forms with specified activities and isolated optical isomers. Racemic forms can be resolved by physical methods, such as stepwise crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by conventional methods, such as crystallization after salting with an optically active acid.

[0097] This invention aims to include all isotopes of the atoms appearing in the compounds of this invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example, and not limited thereto, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14 C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotope-labeling reagents instead of unlabeled reagents.

[0098] Prodrugs and solvates of the compounds of this invention are also considered. The term "prodrug" refers to a compound, and / or its salts and / or solvates, which, upon administration to an individual, undergoes a chemical transformation through metabolism or a chemical process to produce a compound of formula I. Any compound that will be converted in vivo to provide a bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of this invention. For example, compounds containing a carboxyl group can form physiologically hydrolyzable esters, which, as prodrugs, can be hydrolyzed in vivo to produce the compound of formula I itself. Such prodrugs are preferably administered orally because, in many cases, hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of formula I compounds include C 1-6 Alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl, C 1-6 Alkyloxy C 1-6 Alkyl groups (e.g., acetoxymethyl, neopentyloxymethyl, or propionyloxymethyl), C 1-6 Alkoxycarbonyloxy C 1-6 Alkyl groups (e.g., methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl), glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)-methyl esters, and other well-known physiologically hydrolyzable esters, such as those used in the fields of penicillin and cephalosporins. Such esters can be prepared using conventional techniques known in the art.

[0099] Various forms of prodrugs are well known in the art, and in Rautio, J. et al., Nature Drug Discovery Review, It is described in 17, 559-587 (2018).

[0100] The compounds and their salts described in this application can exist in their tautomer forms, wherein hydrogen atoms are transferred to other parts of the molecule and the chemical bonds between atoms in the molecule are thus rearranged. It should be understood that all tautomer forms (wherever they can exist) are included within the scope of this invention. Furthermore, the compounds of this invention can have trans and cis isomers.

[0101] The disclosure herein further relates to the compounds described herein used as pharmaceuticals, their tautomer and stereoisomer forms, and their pharmaceutically acceptable addition salts and solvates. Furthermore, the disclosure herein relates to the compounds described herein, their tautomer or stereoisomer forms, or their pharmaceutically acceptable addition salts or solvates, or the use of pharmaceutical compositions according to the invention in the preparation of pharmaceuticals.

[0102] The compositions of the present invention may contain other therapeutic agents as described above, and may be formulated, for example, using conventional solid or liquid carriers or diluents, and pharmaceutical additives of a type suitable for the desired manner of administration (e.g., excipients, binders, preservatives, stabilizers, flavorings, etc.) according to techniques well known in the field of pharmaceutical formulations.

[0103] Therefore, the present invention further includes compositions comprising one or more of the compounds described herein and a pharmaceutically acceptable carrier.

[0104] "Pharmaceutically acceptable carriers" refer to media generally accepted in the art for delivering bioactive agents to animals (particularly mammals). Pharmaceutically acceptable carriers are formulated based on several factors well known to those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the individual administering the composition containing the active agent; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. In addition to the active agent, such carriers may contain a variety of different ingredients and additives, which are included in the formulation for various reasons (e.g., stabilizing the active agent, acting as a binder, etc.) well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources, such as... Remington's Pharmaceutical Science , 17th edition (1985), which is incorporated into this paper in its entirety by reference.

[0105] The compounds described herein can be administered in any manner suitable for the condition to be treated, depending on the need for site-specific treatment or the amount of drug to be delivered. For skin-related diseases, topical administration is generally preferred; for cancer or precancerous conditions, systemic treatment is preferred, but other delivery methods are also considered. For example, the compounds can be delivered orally, such as in tablets, capsules, granules, powders, or liquid dosage forms (including syrups); topically, such as in solutions, suspensions, gels, or ointments; sublingually; buccally; parenterally, such as via subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, such as by inhalation sprays; topically, such as in creams or ointments; rectally, such as in suppositories; or liposomes. Dosage unit formulations containing non-toxic, pharmaceutically acceptable carriers or diluents can be administered. The compounds can be administered in forms suitable for immediate or prolonged release. Immediate or prolonged release can be achieved through suitable pharmaceutical compositions, or, particularly in the case of prolonged release, through devices such as subcutaneous implants or osmotic pumps.

[0106] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for increasing volume, alginate or sodium alginate as a suspending agent, methylcellulose as a thickener, and sweeteners or flavoring agents known in the art; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, fillers, disintegrants, diluents, and lubricants, such as those known in the art. The compounds of the present invention may also be administered sublingually and / or buccally, for example, orally in the form of molded, compressed, or lyophilized tablets. Exemplary compositions may include readily soluble diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations may also include high molecular weight excipients, such as cellulose (AVICEL®) or polyethylene glycol (PEG); excipients that promote mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymers (e.g., GANTREZ®); and agents for controlled release, such as polyacrylic acid copolymers (e.g., CARBOPOL 934®). Lubricants, flow aids, flavoring agents, colorants, and stabilizers may also be added to facilitate preparation and use.

[0107] Formulations intended for parenteral administration may be aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more carriers or diluents mentioned in oral administration formulations, or by using other suitable dispersants or wetting and suspending agents. The compounds are soluble in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragali gum, and / or various buffer solutions. Other adjuvants and methods of administration are well known in the pharmaceutical field. The active ingredient may also be administered by injection as a composition comprising a suitable carrier, including saline, dextran, or water, or containing cyclodextrin (i.e., Captisol), a solubilizer (i.e., propylene glycol), or a micellar solubilizer (i.e., Tween 80).

[0108] Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable non-toxic, parenteral acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants or wetting agents and suspending agents, including synthetic monoglycerides or diglycerides, and fatty acids, including oleic acid.

[0109] Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents, such as solutions in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are typically used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can be used in the preparation of injectable formulations.

[0110] Sterile injectable water-in-oil microemulsions can be prepared, for example, by: 1) dissolving at least one of the compounds described herein in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) mixing the oil phase containing the compound with a water-glycerol mixture; and 3) treating the combination to form a microemulsion.

[0111] Sterile aqueous or oily suspensions can be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions can be prepared using non-toxic, parenteral-acceptable diluents or solvents (e.g., 1,3-butanediol); and sterile oily suspensions can be prepared using sterile, non-toxic, and acceptable solvents or suspension media (e.g., sterile, non-volatile oils, such as synthetic monoglycerides or diglycerides; and fatty acids, such as oleic acid).

[0112] Exemplary compositions for nasal aerosol or inhalation administration include solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to improve absorption and / or bioavailability, and / or other solubilizers or dispersants known in the art.

[0113] For example, dispersible powders and granules can be prepared by mixing at least one compound described herein or a pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. Furthermore, dispersible powders and granules may also contain at least one excipient, including, but not limited to, sweeteners, flavoring agents, and coloring agents.

[0114] Exemplary compositions for rectal administration include suppositories that may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycol, which are solid at room temperature but liquefy and / or dissolve in the rectal lumen to release the drug.

[0115] The therapeutically effective amount of the compounds of this invention can be determined by those skilled in the art, and includes, for mammals, an exemplary dose range of about 0.05 to 1000 mg / kg daily; 1-1000 mg / kg; 1-50 mg / kg; 5-250 mg / kg; 250-1000 mg / kg body weight of active compounds, which can be administered in a single dose or in multiple divided doses, for example, 1 to 4 times daily. It should be understood that the specific dose level and frequency of administration for any particular individual can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the individual's species, age, weight, general health condition, sex and diet, method and time of administration, excretion rate, drug combination, and the severity of the specific condition. Preferred individuals for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, etc. Therefore, when the term "patient" is used herein, it is intended to include all individuals, most preferably mammalian species affected by USP1-mediated functional regulation.

[0116] The compounds described in this article can be used to treat cancer.

[0117] In one embodiment, this application provides a combination formulation of the compound described herein and / or its pharmaceutically acceptable salt, its stereoisomers or tautomers, and one or more other therapeutic agents for use simultaneously, separately or sequentially to treat and / or prevent a variety of diseases or disorders associated with USP1.

[0118] On the other hand, this application provides a method for treating patients who have or are susceptible to medical conditions related to USP1. Many medical conditions can be treated. The method includes administering to the patient a therapeutically effective amount of a composition comprising the compounds described herein and / or their pharmaceutically acceptable salts, stereoisomers, or tautomers. For example, the compounds described herein can be used to treat proliferative disorders such as cancer, immune disorders, or inflammatory disorders.

[0119] In other embodiments, the compounds described herein can be used to treat cancers mediated by, dependent on, or associated with USP1 activity. In some embodiments, the disease is a solid tumor. In specific embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine carcinoma, central nervous system cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer or small cell lung cancer.

[0120] In one embodiment, the compounds described herein can be used to treat hematologic malignancies. In one embodiment, the hematologic malignancies are selected from multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, T-cell leukemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma. In one embodiment, the solid tumor is selected from pancreatic cancer, breast cancer, melanoma, and non-small cell lung cancer.

[0121] In one implementation, the cancer is selected from carcinoma, preferably bladder cancer, breast cancer, colon cancer (including colorectal cancers such as colonic adenocarcinoma and colonic adenoma), kidney cancer, urothelial carcinoma, uterine cancer, epidermal cancer, liver cancer, lung cancer (including adenocarcinoma, small cell lung cancer, non-small cell lung cancer and squamous cell lung cancer), esophageal cancer, head and neck cancer, gallbladder cancer, ovarian cancer, pancreatic cancer (including exocrine pancreatic cancer), gastric cancer, gastrointestinal cancer (including gastrointestinal stromal tumor), cervical cancer, endometrial cancer, thyroid cancer, prostate cancer and skin cancer.

[0122] In one implementation, the cancer is selected from pituitary carcinoma, lymphoid hematopoietic tumors such as leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, B-cell lymphoma (e.g., diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukemia / lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, piloblastic lymphoma, or Burkitt lymphoma; and myeloid hematopoietic tumors such as leukemia, acute and chronic myeloid leukemia, chronic myelomonocytic leukemia (CMML), myeloproliferative disorders, myeloproliferative syndromes, and myelodysplastic syndromes. Or promyelocytic leukemia; multiple myeloma; follicular thyroid carcinoma; hepatocellular carcinoma, mesenchymal tumors (e.g., Ewing's sarcoma), such as fibrosarcoma or rhabdomyosarcoma; tumors of the central or peripheral nervous system, such as astrocytoma, neuroblastoma, glioma (e.g., glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; follicular thyroid carcinoma; or Kaposi's sarcoma.

[0123] In other embodiments, the compounds described herein can be used to treat cancers mediated by, dependent on, or associated with USP1 activity. In some embodiments, the disease is a solid tumor. In specific embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine carcinoma, central nervous system cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer or small cell lung cancer.

[0124] In other embodiments, the disease is a hematologic malignancy. In some embodiments, the disease is lymphoma, multiple myeloma, or leukemia. In some embodiments, the hematologic malignancy is leukemia or lymphoma. In the specific implementation plan, the diseases mentioned are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM), Hodgkin lymphoma, indolent non-Hodgkin lymphoma (iNHL), refractory iNHL, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenström macroglobulinemia (WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), lymphoplasmacytic lymphoma, marginal zone lymphoma, or Burkitt lymphoma. In one embodiment, the disease is T-cell acute lymphoblastic leukemia (T-ALL) or B-cell acute lymphoblastic leukemia (B-ALL). In some embodiments, non-Hodgkin lymphoma can be an indolent B-cell disease, including follicular lymphoma, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma, as well as aggressive lymphomas such as Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL).

[0125] In some embodiments, the cancer is selected from hematologic malignancies and lymphomas. In some embodiments, the cancer comprises cancer cells with defects in DNA damage repair pathways. In some embodiments, the cancer is a homologous recombination-deficient cancer. In some embodiments, the cancer comprises cancer cells with mutations in the gene encoding p53. In some embodiments, the mutation in the gene encoding p53 is a germline mutation or a somatic mutation. In some embodiments, the cancer comprises cancer cells with loss-of-function mutations in the gene encoding p53. In some embodiments, the cancer is a BRCA1 and / or BRCA2-deficient cancer. In some embodiments, the cancer is a somatic or germline BRCA1 and / or BRCA2-mutant cancer. In some embodiments, the cancer is a poly(ADP-ribose) polymerase (“PARP”) inhibitor-refractory or drug-resistant cancer. In some embodiments, the cancer is a PARP inhibitor-resistant or drug-refractory BRCA1 and / or BRCA2-deficient cancer. In some embodiments, the cancer cells have germline or somatic mutations in the gene encoding ataxia-telangiectasia mutant (ATM) protein kinase, or are ATM-deficient. In some embodiments, the cancer has mutations in two or more genes encoding p53, BRCA1, BRCA2, and ATM.

[0126] In some implementations, the disease is an autoimmune or inflammatory disease or disorder. These autoimmune or inflammatory diseases or disorders can be chronic or acute, and include, but are not limited to, inflammatory pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, pericarditis, nephritis (including lupus nephritis), osteomyelitis, myositis, eczema, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, primary biliary cirrhosis, cholecystitis, sclerosing cholangitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's syndrome, and tissue transplant rejection. Rejection (such as acute graft-versus-host disease), hyperacute rejection of transplanted organs, asthma, chronic obstructive airway disease, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, vasculitis, glomerulonephritis, giant cell arteritis, Wegener's granulomatosis, polyarteritis nodosa, dermatomyositis, multiple sclerosis, scleroderma, autoimmune hemolytic and thrombocytopenic states, and pulmonary hemorrhage nephritis syndrome (Goodpasture's disease). (Syndrome), atherosclerosis, Addison's disease, pituitary inflammation, Parkinson's disease, Alzheimer's disease, Kawasaki disease, Takayasu's arteritis, depression, retinitis, uveitis, scleritis, type I diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, gout, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, bullous dermatitis, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleracierma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.In some implementations, autoimmune and inflammatory diseases and conditions may also include systemic or tissue inflammation, inflammatory responses to hypoxia, cell activation and proliferation, lipid metabolism, fibrosis, bacterial infections, viral infections (e.g., herpesviruses, human papillomaviruses, adenoviruses, poxviruses, and other DNA viruses), fungi, parasites, or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxemia, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postoperative syndrome, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections (such as influenza, herpes zoster, herpes simplex, and coronaviruses).

[0127] Combination therapy

[0128] In some embodiments, the compounds described herein may be administered in combination with standard therapies (e.g., surgery, radiation therapy, and / or chemotherapy). In some embodiments, the compounds may be administered in combination with chemotherapy agents. In some embodiments, the compounds may be administered in combination with one or more of carboplatin, cisplatin, paclitaxel, nab-paclitaxel, gemcitabine, or FOLFOX. In some embodiments, the compounds may be administered in combination with carboplatin or nab-paclitaxel. In some embodiments, the compounds may be administered in combination with carboplatin and paclitaxel. In some embodiments, the compounds may be administered in combination with cisplatin and pemetrexed. In some embodiments, the compounds may be administered in combination with cisplatin and gemcitabine. In some embodiments, the compounds may be administered in combination with FOLFOX. In some embodiments, the compounds may be administered in combination with FOLFIRI. In one embodiment, the compounds may be combined with decarbazine for the treatment of melanoma. In some embodiments, cisplatin is administered intravenously at a dose of 100 mg / ml every four weeks. In some embodiments, the compound may be administered in combination with doxorubicin, cisplatin, bleomycin sulfate, carmustine, chlorambucil, dacarbazine, and / or cyclophosphamide hydroxyurea. In some embodiments, doxorubicin is administered intravenously at a dose of 60 mg / ml to 75 mg / ml every 21 days.

[0129] In one embodiment, the compounds of this application (e.g., the compounds described herein, or pharmaceutically acceptable salts, prodrugs, or solvates thereof) may be used in combination with one or more additional therapeutic agents for the treatment of cancer or inflammatory disorders. The one or more additional therapeutic agents may be Janus kinase (JAK) inhibitors, such as JAK1, JAK2 and / or JAK3, tyrosine kinase (TYK), K-Ras, mitogen-activated protein kinase (MAPK), Bruton's tyrosine kinase (BTK), bromine-containing domain protein inhibitors (BRD) such as BRD4, lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL1-5, matrix metalloproteinases (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal-regulated kinase (ASK) such as ASK1, serine / threonine kinase TPL2, discoid domain receptors (DDR) such as DDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), or any combination thereof.

[0130] In one embodiment, the compounds of this application (e.g., the compounds described herein, or pharmaceutically acceptable salts, prodrugs, or solvates thereof) may be used in combination with other chemotherapeutic agents, immunotherapeutic agents, radiotherapy agents, antitumor agents, anticancer agents, antifibrotic agents, antiangiogenic agents, therapeutic antibodies, or any combination thereof.

[0131] Chemotherapy agents can be classified according to their mechanisms of action, for example, into the following categories: antimetabolites / anticancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folic acid antagonists, and related inhibitors; antiproliferative / antimitotic agents, including natural products such as vinblastine and vincristine, and microtubules such as taxanes (paclitaxel and docetaxel), vinblastin, nocodazole, epothilone, navelbine, epidipodophyllotoxin (etoposide and teniposide); and DNA damaging agents (actinomycin, amsacrifice, etc.). (ne), busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cyclophosphamide, dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, paclitaxel, taxotere, teniposide, etoposide, triethylenethiophosphoramide; antibiotics such as actinomycin D. D)), daunorubicin, doxorubicin (doxorubicin), idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin; enzymes (L-asparaginase, which systemically metabolizes L-asparagine and deprives cells that cannot synthesize asparagine themselves); antiplatelet agents;Antiproliferative / antimitotic alkylating agents such as nitrogen mustards (cyclophosphamide and analogs, melphalan, chlorambucil) and (hexamethylmelamine and thiotepa), alkyl nitrosourea (BCNU and analogs, streptozocin), and trazenes-dacarbazine. DTIC; antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxaliplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogens, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin. Dipyridamole, ticlopidine, clopidogrel; anti-migration agents; anti-secretion agents (breveldin); immunosuppressants tacrolimus, sirolimus, azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blockers, nitric oxide donors; antisense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin);Inhibitors, topoisomerase inhibitors (doxorubicin, daunorubicin, daunorubicin, etoposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin. Toxin, as well as caspase activators; and chromatin.

[0132] Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylene imines and memylamelamines, including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; polyacetogenins (especially bullatacin and bullatacinone); camptothecin (including its synthetic analogue topotecan); and lichens. Bryostatin; Callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); Cryptophycins (especially Cryptophycin 1 and Cryptophycin 8); Dolastatin; Duocarmycin (including synthetic analogs KW-2189 and CBI-TMI); Elutherobin; Pancratistatin; Sarcodictyin; Spongistatin; Nitrogen mustards such as chlornaphazine, chlorphosphamide, estramustine, ifosfamide, mechlorethamine, and mechlorethamine hydrochloride. Oxygen hydrochloride, melphalan, novobichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ramustine;Antibiotics such as enediyne antibiotics (e.g., calicheamicin, calicheamicin gammall, dynemicin, dynemicin A); bisphosphonates such as clophosphonate; esperamicin; and neocarzinostatin chromophores and related chromogens of enediyne antibiotics), aclacinomysins, actinomycins, autramycin, azaserine, bleomycin, and actinomycin C. (cactinomycin), carabicin, carrninomycin, carzinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin (including morpholine doxorubicin, cyanomorpholine doxorubicin, 2-pyrrolinoline doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid The following are listed as potential drug derivatives: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptonigrin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; and purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine.Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergic drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; and aminolevulinic acid. acid); eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; epomycin; etoglucid; gallium nitrate nitrate); hydroxyurea; lentinan; leucovorin; lonidamine; maytansine alkaloids such as maytansine and ansamitocin; mitoguazone; mitoxazone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazine; procarbazine; razoxane; rhizoxin;Sizofiran; spirogermanium; tenuazonicacid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A) A) and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipebroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxanes, such as paclitaxel and docetaxel, chlorambucil; Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vancristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan); and pharmaceutically acceptable salts, acids, or derivatives of any of the above drugs. This application uses or contains one or more chemotherapeutic agents.

[0133] Chemotherapy agents may also include, for example, antihormonal agents that modulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and enzymes that inhibit aromatase (which regulates estrogen production in the adrenal glands), such as, for example, 4(5)-imidazole, aminoglutethimide, and megestrol acetate. Acetate), exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts thereof.

[0134] Anti-angiogenic agents include, but are not limited to, retinoic acid and its derivatives, 2-methoxyestradiol, suramin, squalamine, tissue inhibitor of metalloproteinases-1, tissue inhibitor of metalloproteinases-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, chondroitin-derived inhibitors, paclitaxel (albumin-bound paclitaxel), platelet factor 4, protamine sulfate (herring protamine), and sulfated chitin derivatives (derived from queen crab shells). Shell preparation), sulfated polysaccharide peptidoglycan complex (sp-pg), astrococcalin, matrix metabolism regulators, including, for example, proline analogs (1-azacyclobutane-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thioproline, α,α'-bipyridine, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridyl)-2(3h)-oxazolone; methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chimp-3, chymotrypsin inhibitor, beta-cyclodextrin tetradecasulfate, epomycin; fumagillin, gold sodium thiomalate. Thiomalate), D-penicillamine (CDPT), β-1-anticollagenase-serum, α-2-antifibrinolytic enzyme, bismuth subcitrate, lobenzarit disodium, n-2-carboxyphenyl-4-chloro-o-aminobenzoate disodium or "CCA", thalidomide; angiotensin-releasing steroids, carboxyaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenic agents include antibodies against these angiogenic growth factors, preferably monoclonal antibodies: β-FGF, α-FGF, FGF-5, VEGF subtypes, VEGF-C, HGF / SF, and Ang-1 / Ang-2.

[0135] This application also provides a method for treating an individual who is receiving one or more standard therapies (such as chemotherapy, radiotherapy, immunotherapy, surgery, or combinations thereof). Therefore, one or more therapeutic agents or inhibitors can be administered before, during, or after chemotherapy, radiotherapy, immunotherapy, surgery, or combinations thereof.

[0136] In some implementations, an individual may be (i) substantially refractory to at least one chemotherapy treatment, or (ii) relapsed after chemotherapy treatment, or both (i) and (ii). In some implementations, an individual may be refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy).

[0137] In some implementations, an individual is refractory to at least one, at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy), said chemotherapy treatments being selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab, and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone); Bortezomib and Rituximab; Temsirolimus and Rituximab; Temsirolimus and Velcade® (RTM); Iodine-131 Tositumomab (Bexxar®) and CHOP; CVP (Cyclophosphamide, Vincristine, Prednisone); R-CVP (Rituximab-CVP); ICE (Ifosfamide, Carboplatin, Etoposide); R-ICE (Rituximab-ICE); FCR (Fludarabine, Cyclophosphamide, Rituximab); FR (Fludarabine, Rituximab); and DT PACE (Dexamethasone, Thalidomide, Cisplatin, Doxorubicin®, Cyclophosphamide, Etoposide).

[0138] Examples of immunotherapeutic agents for treating lymphoma or leukemia include, but are not limited to, rituximab (e.g., Rituxan), alenzumab (e.g., Camppath, MabCampath), anti-CD19 antibody, anti-CD20 antibody, anti-MN-14 antibody, anti-TRAIL, anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibody, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 peptide-like vaccine, and WT1. 126-134 peptide vaccines, tosimomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Other immunotherapeutic agents include cancer vaccines based on the genetic composition of an individual patient's tumor, such as the lymphoma vaccine GTOP-99.

[0139] Therapeutic treatments can complement or combine with any of the aforementioned stem cell transplantation or therapeutic therapies. One modified approach is radioimmunotherapy, in which monoclonal antibodies are bound to radioactive isotope particles (such as indium In-111, yttrium Y-90, and iodine I-131). Examples of combination therapies include, but are not limited to, the combination of iodine-131 tosimomab, yttrium-90 timimomab, and CHOP.

[0140] The compounds of this application can be used in combination with other therapeutic methods. Other therapeutic methods include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, stem cell-supported bone marrow ablation, in vitro processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, pharmacological studies, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0141] The compounds of this application can be used in combination with antifibrotic agents. Antifibrotic agents include, but are not limited to, ethylene amine, hydrazine, phenylhydrazine and its derivatives, aminourea and urea derivatives, aminonitriles (such as β-aminopropionitrile (BAPN) or 2-nitroethylamine), unsaturated or saturated haloamines (such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamine), and selenocysteine ​​lactone. Furthermore, the antifibrotic agents are copper chelators, which may or may not penetrate cells. Exemplary compounds include indirect inhibitors, such as compounds that block the formation of aldehyde derivatives from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase, such as thiolamides, particularly D-penicillamine, or analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetaminoethyl)dithio)butyric acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butyric acid, sodium 4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butanesulfonate, 2-acetaminoethyl-2-acetaminoethylthiol sulfonate, and sodium 4-mercaptobutanesulfinate trihydrate.

[0142] The compounds of this application can be used in combination with immunotherapy and anti-inflammatory therapy. Immunotherapy agents include, but are not limited to, therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, and bivacizumab. tuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutuzumab, cixutuzumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, duligotumab Dusigitumab, Detumomab, Dacetuzumab, Dalotuzumab, Ecomeximab, Elotuzumab, Ensituximab, Ertumaxomab, Etaracizumab, Farietuzumab, Ficlatuzumab, Flanvotuma b) Futuximab, Ganitumab, Gemtuzumab, Girentuximab, Glembatumumab, Ibritumomab, Igovomab, Imgatuzumab, Indatuximab, Inotuzumab, Intetumumab, Ipilimumab, IratumumabLabetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucarumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab Nexituzumab, Nimotuzumab, Nofetumomab, Ocaratuzumab, Ofatuzumab, Olaratumab, Onartuzumab, Oportuzumab, Oregovomab, Panitumumab, Parsatuzumab, Patritumab, Pemtumomab b) Pertuzumab, Pintumomab, Pretumumab, Racotumomab, Radretumab, Rilotumumab, Rituximab, Robatumumab, Satumomab, Siboruzumab, Siltuximab, Simtuzumab, Solitomab, Tizotumab Tacatuzumab, Taplitumomab, Tenatumomab, Teprotumumab, Tigazumab, Tositumomab, Trastuzumab, Tucotuzumab, Ublituximab, Veltuzumab, Vorsetuzumab, Votumumab, ZalutumumabCC49 and 3F8. Exemplary therapeutic antibodies can be further labeled or combined with radioactive isotope particles (such as indium In-111, yttrium Y-90, iodine I-131).

[0143] On the one hand, immuno-oncology agents are either (i) agonists of stimulatory (including co-stimulatory) receptors or (ii) antagonists of inhibitory (including co-inhibitory) signals on T cells, both of which lead to an amplification of antigen-specific T cell responses (commonly referred to as immune checkpoint modulators).

[0144] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF molecule family that binds to members of the homologous TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, and lymphotoxin α. 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0145] On the one hand, T cell responses can be stimulated by combination of compounds of formula (I) with one or more of the following: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galactagogue 9, CEACAM-1, BTLA, CD69, galactagogue-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0146] Other agents that can be combined with the compounds described herein for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of formulas I, II, and III can be combined with antagonists of KIRs (such as lirilumab).

[0147] Other combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0148] On the other hand, the compounds of this application may be used in combination with one or more of the following substances: agonists that connect to positive costimulatory receptors, blockers that attenuate signal transduction by inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or depleting them by in vitro anti-CD25 magnetic beads), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0149] On the one hand, immuno-oncology agents are CTLA-4 antagonists, such as antagonistic CTLA-4 antibodies. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0150] On the other hand, immuno-oncology agents are PD-1 antagonists, such as antagonistic PD-1 antibodies. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for binding to PD-1 is questionable. Another approach to targeting the PD-1 receptor is a recombinant protein, AMP-224, which is formed by fusing the extracellular domain of PD-L2 (B7-DC) with the Fc portion of IgG1.

[0151] On the other hand, immuno-oncology agents are PD-L1 antagonists, such as antagonistic PD-L1 antibodies. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0152] On the other hand, immuno-oncology agents are LAG-3 antagonists, such as antagonistic LAG-3 antibodies. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0153] On the other hand, immuno-oncology agents are CD137 (4-1BB) agonists, such as agonistic CD137 antibodies. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0154] On the other hand, immuno-oncology agents are GITR agonists, such as GITR-activating antibodies. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0155] On the other hand, immuno-oncology agents are IDO antagonists. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, BMS-986205, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0156] On the other hand, immuno-oncology agents are OX40 agonists, such as agonist OX40 antibodies. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0157] On the other hand, immuno-oncology agents are OX40L antagonists, such as antagonistic OX40 antibodies. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0158] On the other hand, immuno-oncology agents are CD40 agonists, such as agonist CD40 antibodies. In another embodiment, immuno-oncology agents are CD40 antagonists, such as antagonist CD40 antibodies. Suitable CD40 antibodies include, for example, rucamumab or dasiclobutrazol.

[0159] On the other hand, immuno-oncology agents are CD47 antagonists, such as CD47 antagonists selected from MIAP301, MIAP410, TTI-621, CV1, Hu5F9-G4, CC-90002, B6H12 and 2D3.

[0160] On the other hand, immuno-oncology agents are CD27 agonists, such as agonist CD27 antibodies. Suitable CD27 antibodies include, for example, varlilumab.

[0161] On the other hand, the immuno-oncology reagent is MGA271 (anti-B7H3) (WO11 / 109400).

[0162] Combination therapy aims to cover the sequential administration of these therapeutic agents, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to an individual a single dosage form of each therapeutic agent in a fixed proportion or multiple single dosage forms of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissues. The therapeutic agents can be administered via the same or different routes. For example, the first therapeutic agent in a selected combination can be administered intravenously, while the other therapeutic agents in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. Combination therapy may also include further combinations of the therapeutic agents as described above with other bioactive ingredients and non-pharmacological treatments (e.g., surgical or radiation therapy). When combination therapy further includes non-pharmacological treatments, these treatments can be administered at any suitable time, provided that the beneficial effects of the combined action of the therapeutic agents and non-pharmacological treatments are achieved. For example, when appropriate, beneficial effects can still be achieved when non-pharmacological treatments and the administration of therapeutic agents are time-staggered (perhaps by several days or even weeks).

[0163] The present invention also provides compounds of the present invention for therapeutic purposes.

[0164] In another embodiment, the compound of Formula I is selected from the exemplary compounds or combinations of exemplary compounds or other embodiments herein.

[0165] In another embodiment, IC is measured in at least one of the following methods. 50 Compounds with a molecular weight of < 1000 nM.

[0166] This invention may be embodied in other specific forms without departing from its spirit or essential attributes. This invention encompasses all combinations of preferred aspects and / or embodiments of the invention described herein. It should be understood that any and all embodiments of the invention may be combined with any other one or more embodiments to describe further, more preferred embodiments. It should also be understood that each individual element of a preferred embodiment is its own independent preferred embodiment. Furthermore, any element of one embodiment is intended to be combined with any and all other elements of any embodiment to describe further embodiments.

[0167] Preparation method

[0168] The compounds of the present invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. All references cited herein are incorporated herein by reference in their entirety.

[0169] The compounds of the present invention can be prepared using the reactions and techniques described in this section. Reactions are carried out in solvents suitable for the reagents and materials used, and the transformations are suitable for the reactions. Furthermore, in the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and post-treatment methods, are chosen as standard conditions for the reaction, which should be readily apparent to those skilled in the art. Those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule must be compatible with the proposed reagents and reactions. Limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods must be used. Sometimes judgments must be made to modify the order of synthetic steps or to choose a particular process flow over another to obtain the desired compound of the present invention. It should also be recognized that another major consideration when planning any synthetic route in the art is the prudent selection of protecting groups for protecting the reactive functional groups present in the compounds of the present invention. The authoritative account for describing various alternatives for trained practitioners is that of Greene and Wuts (…). Protective Groups In Organic Synthesis (3rd edition, Wiley and Sons, 1999).

[0170] Example

[0171] The preparation of compounds of Formula I and the intermediates used to prepare compounds of Formula I can be carried out using the methods shown in the following examples and related methods. The methods and conditions used in these examples and the actual compounds prepared in these examples are not limiting, but are intended to illustrate how compounds of Formula I can be prepared. The starting materials and reagents used in these examples, if not prepared by the methods described herein, are generally commercially available or reported in the chemical literature, or can be prepared using the methods described in the chemical literature.

[0172] Example

[0173] The following examples illustrate specific and preferred embodiments of the invention and do not limit the scope of the invention. Unless otherwise stated, chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their usual and conventional meanings. Common intermediates are typically used to prepare the various examples shown in the table.

[0174] Chemical names were determined using ChemBioDraw Ultra version 14.0.0.126 (CambridgeSoft).

[0175] Use the following abbreviations:

[0176] Description of analytical LCMS methods: Method A: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size; Mobile phase A: ACN / H2O (5:95), containing 0.05% TFA; Mobile phase B: ACN / H2O (95:5), containing 0.05% TFA; Temperature: 50℃; Gradient: 0-100% B (0-3 min), 100% B (3-3.5 min); Flow rate: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -).

[0177] Intermediate 1: 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1 H -imidazol

[0178] Step 1: 4-(4-(trifluoromethyl)-1 H 1-Imidazol-2-yl)methyl benzoate

[0179] A mixture of 3,3-dibromo-1,1,1-trifluoroprop-2-one (49.3 g, 183 mmol) and sodium acetate (20.0 g, 244 mmol) in water (100 mL) was stirred at 95 °C for 30 min. The mixture was cooled to 0 °C, and a cold solution of methyl 4-formylbenzoate (20.0 g, 122 mmol) in a mixture of NH4OH (28% aq, 100 mL) and MeOH (300 mL) was added. The contents were stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel (230-400 mesh) chromatography to give 4-(4-(trifluoromethyl)-1 H Methyl 1-imidazol-2-yl)benzoate (19 g, 61 mmol, 50%) is a yellow solid. LC-MS, m / z :271.0 [M+H].

[0180] Step 2: 4-(1-methyl-4-(trifluoromethyl)-1 H 2-Imidazol-2-yl)methyl benzoate

[0181] At 0°C, towards 4-(4-(trifluoromethyl)-1 H Methyl 1-imidazol-2-yl)benzoate 1 (2.50 g, 9.25 mmol) was added to a stirred solution in DMF (20 mL) with sodium hydride (60% dispersion, in mineral oil, 0.740 g, 18.5 mmol), followed by methyl iodoform (0.87 mL, 13.9 mmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC), cold water was added, and the contents were extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel (230-400 mesh) chromatography to give 4-(1-methyl-4-(trifluoromethyl)-1 H Methyl 2-imidazolium-2-yl)benzoate 2 (1.40 g, 4.87 mmol, 53%), is a white solid. LC-MS, m / z :285.0 [M+H].

[0182] Step 3: 4-(1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)phenyl)methanol3

[0183] At 0°C, 4-(1-methyl-4-(trifluoromethyl)-1 H Methyl 2-imidazolium-2-yl)benzoate 2 (1.20 g, 4.22 mmol) was added to a stirred solution of lithium aluminum hydride (2 M, 4.22 mL, 8.44 mmol, in THF) in 25 mL of THF, and the contents were stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel (230-400 mesh) chromatography to give (4-(1-methyl-4-(trifluoromethyl)-1-yl)benzoate. H (-Imidazol-2-yl)phenyl)methanol 3 (0.90 g, 3.42 mmol, 81%), is a white solid. LC-MS, m / z :257.0 [M+H].

[0184] Step 4: 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1 H -Imidazole, intermediate 1

[0185] At 0°C, towards (4-(1-methyl-4-(trifluoromethyl)-1 HA solution of 100 mg (100 mg, 0.390 mmol) of 2-imidazol-2-yl)phenyl)methanol in tetrahydrofuran (1.5 mL) was added fractionally with carbon tetrabromide (259 mg, 0.781 mmol), followed by dropwise addition of a solution of triphenylphosphine (205 mg, 0.781 mmol) in tetrahydrofuran (1.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, followed by stirring at room temperature for 16 h. The reaction mixture was poured into ice water and extracted into ethyl acetate. The organic layer was washed with saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography using a gradient of 0–15% ethyl acetate (in petroleum ether). The product fraction was concentrated to give 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1-methyl ... H -Imidazole, intermediate 1 (70 mg, 0.213 mmol, 54.5% yield), is a white solid. LC-MS, m / z : 319.1 [M+H]; 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (m,1H), 7.74 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 4.79 (s, 2H), 3.80 (s, 3H).

[0186] Intermediate 2: 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1 H -imidazol

[0187] Step 1: 4-(1-Isopropyl-4-(trifluoromethyl)-1 H 4-Imidazol-2-yl)methyl benzoate

[0188] At 0°C, towards 4-(4-(trifluoromethyl)-1 HMethyl 1-imidazol-2-yl)benzoate 1 (2.0 g, 7.4 mmol) was added to a stirred solution of acetonitrile (30 mL) with Cs₂CO₃ (4.82 g, 14.8 mmol), followed by the addition of 2-iodopropane (1.1 mL, 11.1 mmol) over 5 minutes. The reaction mixture was stirred at room temperature for 16 hours, followed by heating at 50 °C for 16 hours. After cooling, the reaction was concentrated. The resulting residue was diluted with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude substance was purified by rapid silica gel (230-400 mesh) chromatography to give 4-(1-isopropyl-4-(trifluoromethyl)-1 H Methyl 4-imidazol-2-yl)benzoate (0.80 g, 2.23 mmol, 30%) is a white solid. LC-MS, m / z :313.2 [M+H].

[0189] Steps 2 and 3: 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1 H -Imidazole, intermediate 2

[0190] Intermediate 2 was prepared using the same methods described in steps 3 and 4 regarding intermediate 1. LC-MS, m / z 347.0 [M+H]; 1 ¹H NMR (400 MHz, chloroform-d) δ 7.59 - 7.54 (m, 2H), 7.54 - 7.50 (m, 2H), 7.45 (d, J = 1.1 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.56 (s, 2H), 1.49 (d, J = 6.6Hz, 6H).

[0191] Intermediate 3: 2-(4-(bromomethyl)phenyl)-1-ethyl-4-(trifluoromethyl)-1 H -imidazol

[0192] Intermediate 3 was prepared using the same method described for intermediate 1. LC-MS, m / z : 333.1 [M+H]; 1 HNMR (400 MHz, DMSO-d6) δ 8.06 (m, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 4.80 (s, 2H), 4.11 (q, J = 7.6 Hz, 2H), 1.53 (t, J = 7.6 Hz, 3H).

[0193] Intermediate 4: 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1 H -Pyrazole

[0194] Step 1: (4-(5-methyl-3-(trifluoromethyl)-1 H -pyrazole-1-yl)phenyl)methanol6

[0195] At 0°C, 4-(5-methyl-3-(trifluoromethyl)-1 H 5-(5-pyrazole-1-yl)methyl benzoate [WO2020 / 132269] (5.0 g, 17.6 mmol) was added to a stirred solution of tetrahydrofuran (20 mL) with DIBAL-H (1.2 M, in toluene, 44.0 mL, 52.8 mmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was slowly poured into cold water containing crushed ice and filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate, and the organic layer was dried (Na2SO4), filtered, and concentrated to give (4-(5-methyl-3-(trifluoromethyl)-1-yl)benzoate. H 1-Pyrazol-1-yl)phenyl)methanol 6 (3.8 g, 14.2 mmol, 81%), is a pale yellow liquid. LC-MS, m / z :257.0 [M+H].

[0196] Step 2: 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1 H -Pyrazole, intermediate 4

[0197] To (4-(5-methyl-3-(trifluoromethyl)-1 H1-(4-(chloromethyl)phenyl)methanol 6 (0.25 g, 0.98 mmol) was added to a stirred solution of 1,2-dichloroethane (2.5 mL) with thionyl chloride (0.21 mL, 2.9 mmol). The reaction was stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated to remove the solvent and excess thionyl chloride. The crude product was diluted with DCM, adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (100-200), petroleum ether, and ethyl acetate. The fraction containing the desired product was collected to give 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1 H -Pyrazole, intermediate 4 (0.25 g, 93%), is a grayish-white solid. LC-MS, m / z: 274.9 [M+H]; 1 H NMR (400 MHz, DMSO-d6)δ 7.64 (d, J = 8.03 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 6.78 (s, 1H), 4.87 (s, 2H), 2.37 (s, 3H).

[0198] Intermediate 5: 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1 H -Pyrazole

[0199] Step 1: 4-Chloro-1-isopropyl-1 H -Pyrazole7

[0200] To 4-chloro-1 H 4-Pyrazole (5.0 g, 49 mmol) was added to a stirred solution in acetonitrile (60 mL) with Cs₂CO₃ (32 g, 98 mmol), followed by 2-iodopropane (5.7 mL, 59 mmol). The mixture was heated at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the contents were extracted with diethyl ether. The organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude 4-chloro-1-isopropyl-1- H -Pyrazole 7 (6.0 g, 39 mmol, 81%), a pale yellow oil (which is used directly in the next step). LC-MS, m / z :145.00 [M+H].

[0201] Step 2: 4-Chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole intermediate 5

[0202] At 0°C, 4-chloro-1-isopropyl-1 H β-Pyrazole 7 (5.50 g, 38.0 mmol) was added to a stirred solution of β-butyllithium (1.6 M, in hexane, 28.5 mL, 45.6 mmol) in tetrahydrofuran (50 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to -78 °C, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (8.49 g, 45.6 mmol) was added. It was stirred at -78 °C for 2 hours. The reaction was warmed to room temperature, quenched with a saturated aqueous solution of NH4Cl (50 mL), and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated to give crude 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)-1 H -Pyrazole, intermediate 5 (6.0 g, 14 mmol, 38%), is a dark brown oil (which is used directly in subsequent steps). LC-MS, m / z :271.10 [M+H].

[0203] Example 1: 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1-yl) H -imidazol-2-yl)benzyl)-1 H -Pyrazolo[4,3-b]pyridine

[0204] Step 1: 3-Bromo-1-(4-(1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)-1 H -Pyrazolo[4,3-b]pyridine, compound 1a

[0205] To 3-bromo-1 H4,3-pyrazolo[4,3-b]pyridine (46.0 mg, 0.232 mmol) was added to a stirred solution of pyrazolo[4,3-b]pyridine in tetrahydrofuran (2 mL) along with Cs₂CO₃ (151 mg, 0.465 mmol) and intermediate 1 (82.1 mg, 0.256 mmol). The reaction mixture was heated at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated. The crude product was added to a silica gel (12 g) column and eluted with 0–100% EtOAc (in hexane). The fraction containing the desired product was collected to give compound 1a (65 mg, 0.15 mmol, 64% yield) as a white solid. MS m / z = 435.8 (M+H); 1 H NMR (400MHz, CDCl3) δ 8.64 (dd, J = 4.4, 1.2 Hz, 1H), 7.72 - 7.63 (m, 1H), 7.59 (d, J =8.3 Hz, 2H), 7.41 - 7.25 (m, 4H), 5.63 (s, 2H), 3.73 (s, 3H).

[0206] Step 2: 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1) H -imidazol-2-yl)benzyl)-1 H -Pyrazolo[4,3-b]pyridine, Example 1

[0207] Dioxane (1 mL) and water (0.1 mL) were added to a pressure-resistant vial containing 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrimidine (7.60 mg, 0.0281 mmol), compound 1a (10.1 mg, 0.023 mmol), PdCl2(dppf) (1.68 mg, 2.29 µmol), and Cs2CO3 (14.9 mg, 0.0461 mmol). The reaction mixture was evacuated and purged with N2, cyclically repeated three times, and then heated in a microwave oven to 120 °C for 30 minutes. The reaction mixture was cooled to room temperature, filtered, concentrated under vacuum, and purified by preparative reversed-phase chromatography under the following conditions: column: XBridge C18, 19 mm x 200 mm, 5 μm particle size; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by MS (ESI+) triggering. Fractions containing the desired product were combined and centrifuged to evaporate to dryness to obtain 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[4,3-b]pyridine (Example 1) (4.2 mg, 36%). MS m / z = 506.0 (M+H); HPLC method A, Rt = 1.78 min; Purity: 100%; 1 H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.54 (dd, J =4.3, 1.2 Hz, 1H), 8.33 (dd, J = 8.6, 1.2 Hz, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.54 - 7.45 (m, 1H), 7.42 (d, J = 8.3 Hz, 2H), 5.87(s, 2H), 3.82 (s, 3H), 3.75 (s, 3H), 1.82 - 1.69 (m, 1H), 1.13 - 0.96 (m,2H), 0.86 (br dd, J = 8.0, 3.2 Hz, 2H).

[0208] Examples 2 to 6 were prepared using the same method described in Example 1.

[0209]

[0210] Example 7: 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methoxy-1-(4-(1-methyl-4-(trifluoromethyl)-1) H -imidazol-2-yl)benzyl)-1 H -Pyrazolo[4,3-b]pyridine

[0211] Step 1: 3-Bromo-7-chloro-1 H -Pyrazolo[4,3-b]pyridine, compound 7a

[0212] To 7-chloro-1 H 1,3-pyrazolo[4,3-b]pyridine (110 mg, 0.716 mmol) was added to NBS (147 mg, 0.824 mmol) in a stirred solution of acetonitrile (5 mL). The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure. The crude product was added to a silica gel (12 g) column and eluted with 0–100% EtOAc (in hexane) followed by 0–40% MeOH / DCM. The fraction containing the desired product was collected to give compound 7a (112 mg, 0.482 mmol, 67% yield) as a white solid. MS m / z = 231.7 (M+H); 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.48 (d, J = 4.9 Hz, 1H), 7.55 (d, J = 4.9 Hz, 1H).

[0213] Step 2: 3-Bromo-7-methoxy-1 H -Pyrazolo[4,3-b]pyridine, compound 7b

[0214] To 3-bromo-7-chloro-1 H 50.1 mg, 0.215 mmol, of pyrazolo[4,3-b]pyridine was added to a stirred solution of 1 mL MeOH with sodium methoxide (0.199 mL, 1.08 mmol). The reaction was stirred at 80 °C for 24 h, concentrated under vacuum, and diluted with EtOAc. The organic layer was washed with saturated aqueous NH4Cl solution, dried over MgSO4, filtered, and concentrated under vacuum to give compound 6b (50 mg, 0.22 mmol, 102% yield) as a white solid. MS m / z = 227.8 (M+H);1 HNMR (500 MHz, methanol-d4) δ 8.40 (d, J = 5.4 Hz, 1H), 6.97 (d, J = 5.3 Hz, 1H), 4.11 (s, 3H).

[0215] Steps 3 and 4: 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methoxy-1-(4-(1-methyl-4-(trifluoromethyl)-1) H -imidazol-2-yl)benzyl)-1 H -Pyrazolo[4,3-b]pyridine, Example 7

[0216] Example 7 was prepared using the same methods described in steps 1 and 2 of Example 1.

[0217] MS m / z = 536.1 (M+H); HPLC method A, Rt = 1.66 min; Purity: 99%; 1 H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.38 (br d, J = 5.3 Hz, 1H), 7.90 (s, 1H), 7.68 (br d, J = 8.3 Hz, 2H), 7.36 (br d, J = 8.2 Hz, 2H), 7.02 (d, J = 5.3Hz, 1H), 5.88 (s, 2H), 4.07 (s, 3H), 3.82 (s, 3H), 3.74 (s, 3H), 1.80 - 1.63(m, 1H), 1.10 - 0.98 (m, 2H), 0.93 - 0.79 (m, 2H).

[0218] Example 8: 3-(4-chloro-1-isopropyl-1-) H -pyrazol-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)-7-(3-fluorozacrito-1-yl)-1 H -Pyrazolo[4,3-b]pyridine

[0219] Step 1: 3-Bromo-7-(3-Fluoro-azacyclobut-1-yl)-1 H -Pyrazolo[4,3-b]pyridine, compound 8a

[0220] To a stirred solution of compound 7a (20 mg, 0.086 mmol) in acetonitrile (5 mL), 3-fluorozahexacyclobutane (19.4 mg, 0.258 mmol) and Et3N (0.060 mL, 0.430 mmol) were added. The reaction was maintained at 100 °C for 2 days, cooled to room temperature, and concentrated under vacuum. The crude product was loaded onto a silica gel (4 g) column and eluted with 0–100% EtOAc (in hexane). The fraction containing the desired product was collected to give compound 8a (10 mg, 0.037 mmol, 43% yield) as a white solid. MS m / z = 271.0 (M+H); 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.17 (d, J = 5.2Hz, 1H), 6.15 (d, J = 5.2 Hz, 1H), 5.68 - 5.35 (m, 1H), 4.70 - 4.50 (m, 2H), 4.45 - 4.28 (m, 2H).

[0221] Steps 2 and 3: 3-(4-chloro-1-isopropyl-1-) H -pyrazol-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)-7-(3-fluorozacrito-1-yl)-1 H -Pyrazolo[4,3-b]pyridine, Example 8

[0222] Example 8 was prepared using the same methods described in steps 1 and 2 of Example 1. MS m / z = 587.2 (M+H); HPLC method A, Rt = 1.80 min; Purity: 100%; 1 H NMR (500 MHz, DMSO-d6) δ 8.33(d, J = 5.3 Hz, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 7.60 (br d, J = 8.2 Hz, 2H), 7.24 (br d, J = 8.2 Hz, 2H), 6.67 (d, J= 5.3 Hz, 1H), 5.88 (s, 2H), 5.67 -5.39 (m, 1H), 4.72 - 4.51 (m, 2H), 4.45 - 4.29 (m, 3H), 4.06 (q, J = 7.2 Hz, 2H), 1.39 - 1.20 (m, 9H).

[0223] Example 9: 3-(4-chloro-1-isopropyl-1-) H -pyrazol-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)-7-(oxetyl-3-yloxy)-1 H -Pyrazolo[4,3-b]pyridine

[0224] Step 1: 3-Bromo-7-chloro-1-(4-(1-ethyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)-1 H -Pyrazolo[4,3-b]pyridine, compound 9a

[0225] Cs₂CO₃ (210 mg, 0.645 mmol) and intermediate 3 (118 mg, 0.355 mmol) were added to a stirred solution of compound 7a (75.0 mg, 0.323 mmol) in tetrahydrofuran (2 mL). The reaction mixture was heated at 60 °C for 4 hours, cooled to room temperature, filtered, and concentrated. The crude product was fed into a silica gel (24 g) column and eluted with 0–100% EtOAc (in hexane). The fraction containing the desired product was collected to give compound 9a (100 mg, 0.206 mmol, 64% yield) as a white solid. MS m / z = 484.0 (M+H); 1 ¹H NMR (400 MHz, chloroform-d) δ 8.51 (d, J =4.8 Hz, 1H), 7.65 - 7.48 (m, 2H), 7.38 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 1.1Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 5.94 (s, 2H), 4.03 (q, J = 7.3 Hz, 2H), 1.41 (t, J= 7.3 Hz, 3H).

[0226] Step 2: 3-Bromo-1-(4-(1-ethyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)-7-(oxetyl-3-yloxy)-1 H -Pyrazolo[4,3-b]pyridine, compound 9b

[0227] NaH (12.4 mg, 0.309 mmol) was added to a stirred solution of oxadiazine-3-ol (22.9 mg, 0.309 mmol) in THF (1 mL), and the reaction mixture was stirred at room temperature for 20 min. Compound 9a (30 mg, 0.062 mmol) was added to THF (0.5 mL), and the reaction mixture was heated at 80 °C for 14 h. The reaction mixture was cooled to room temperature, concentrated under vacuum, and diluted with EtOAc. The organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was fed into a silica gel (4 g) column and eluted with 0–100% EtOAc (in hexane). The fraction containing the desired product was collected to give compound 9b (35 mg, 0.067 mmol, 108% yield) as a white solid. MS m / z = 521.9 (M+H); 1 ¹H NMR (400 MHz, chloroform-d) δ 8.43 (d, J = 5.3 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 1.0 Hz, 1H), 7.33 - 7.29 (m, 2H), 6.29 (d, J = 5.1 Hz, 1H),5.85 (s, 2H), 5.49 - 5.36 (m, 1H), 5.05 (t, J = 7.1 Hz, 2H), 4.74 (dd, J =8.2, 4.9 Hz, 2H), 4.04 (q, J = 7.3 Hz, 2H), 1.42 (t, J = 7.3 Hz, 3H).

[0228] Step 3: 3-Bromo-7-chloro-1-(4-(1-ethyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)-1 H -Pyrazolo[4,3-b]pyridine, compound 9a

[0229] Example 9 was prepared using the same method described in step 2 of Example 1. MS m / z = 586.0 (M+H); HPLC method A, Rt = 1.98 min; Purity: 100%; 1 H NMR (500 MHz, DMSO-d6) δ 8.41 (d, J = 5.0 Hz, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.62 (br d, J = 8.2 Hz, 2H), 7.40 (br d, J = 8.2 Hz, 2H), 6.72 (d, J = 5.1 Hz, 1H), 6.01 (s, 2H), 5.60(dt, J = 10.0, 5.2 Hz, 1H), 5.00 (br t, J = 6.6 Hz, 2H), 4.66 (br dd, J =7.1, 4.9 Hz, 2H), 4.59 - 4.44 (m, 1H), 4.06 (q, J = 7.3 Hz, 2H), 1.36 (br d, J = 6.5 Hz, 6H), 1.28 (br t, J = 7.2 Hz, 3H).

[0230] Example 10 was prepared using the same method described in Example 9.

[0231]

[0232] Rhodamine determination of USP1-UAF1

[0233] The USP1 activity of the compounds of the present invention was evaluated using the known USP1-UAF1 rhodamine assay described herein. The USP1 / UAF1 ubiquitin-rhodamine 110 hydrolysis assay was performed at room temperature in black low-volume 384-well plates (Corning 3821). 100X solutions of the compounds in DMSO were prepared by serial 3-fold dilutions starting with 10 mM stock solution. 2X solutions of His6-USP1 / His6-UAF1 (200 pM, in-house manufactured) and ubiquitin-rhodamine 110 (10 μM, South BayBio SBB-PS0001) were prepared in assay buffer (50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EDTA, 1 mM TCEP, 100 ng / μL BSA). The serially diluted compounds in DMSO were transferred to the assay plates (100 nL per well) by ultrasonic dispensing. Add 5 μL of assay buffer to column 1 of the plate, and add 5 μL of 2X USP1 / UAF1 solution to columns 2-24, and incubate with the compounds for 3 hours. Initiate the reaction by adding 5 μL of 2X ubiquitin-rhodamine 110 solution to each well (final concentration: 100 pM USP1 / UAF1 and 5 μM ubiquitin-rhodamine 110). Use a BioTek Synergy HTX microplate reader (Agilent Technologies) with minimum kinetic intervals for 1 hour, excitation wavelength 485 nm, and emission wavelength 528 nm. The initial rate was calculated by fitting the linear range of the fluorescence versus time plot to a linear equation. The IC50 was calculated from the dose-response curve. 50 value.

[0234] IC50 of the compound of the present invention in the USP1-UAF1 rhodamine assay 50 The values ​​are shown below.

[0235] Table 1: Results of Rhodamine assay for USP1-UAF1 after 3 hours of incubation .

Claims

1. Compounds having the structure of formula (I): Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; R 1 Selected from C6 aryl and 5-6 heteroaryl groups, optionally bonded by 1 to 4 halogens, hydroxyl groups, amino groups, or -C(O)R groups. a -C(O)OR b -C(O)NR a R b -N(R) a )C(O)R b -S(O)NR a R b -S(O)2NR a R b -S(O)R g -S(O)2R g -NR a R b -OR a -SR b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-8 Cycloalkyl substitution; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-8 Each cycloalkyl group is optionally surrounded by 1 to 4 R 100 replace; R 2 Selected from: non-existent, hydrogen, halogen, hydroxyl, amino, -CN, -C(O)R a -C(O)OR b -C(O)NR a R b -N(R) a )C(O)R b -N(R) a )C(O)NR a R b -N(R) a SO2NR a R b -S(O)NR a R b -S(O)2NR a R b -N(R) a )S(O)2R b -S(O)R g -S(O)2R g -NR a R b -OR a -SR b -OC(O)R a -OC(O)NR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S, and C 3-8 Each cycloalkyl group is optionally surrounded by 1 to 4 R 100 replace; X is C 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 4 R groups. 100 replace; W 1 and W 2 Each is independently selected from -N(R) a -, -C(O)- and -C(R)- a )-; W 3 Selected from -N- and -C(R) a )-; W 4 Selected from -N- and -C(R) a )-; Among them W 1 W 2 and W 3 At least one of them is -C(R) a ); G 1 Selected from -C6 aryl-, 5-6 heteroaryl, C 3-8 Cycloalkyl and 5-6 membered heterocyclic groups; including C6 aryl, 5-6 membered heteroaryl, C 3-8 The cycloalkyl group and the 5-6 membered heterocyclic group are each optionally surrounded by 1 to 4 R groups. 100 replace; G 2 It can be selected from 1 to 4 Rs. 100 Substituted 5- or 6-membered heteroaryl or 5-6-membered heterocyclic group; R a and R b Each is independently selected from non-existent, hydrogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S are each optionally surrounded by 1 to 4 R atoms. 200 replace; Each R 100 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R c -C(O)OR c -C(O)NR c R d -N(R) c )C(O)R d -S(O)NR c R d -S(O)2NR c R d -S(O)R h -S(O)2R h -NR c R d -OR c -SR c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 201 replace; R c and R d Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O and S; R 200 and R 201 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R e -C(O)OR e -C(O)NR e R f -N(R) e )C(O)R f -S(O)NR e R f -S(O)2NR e R f -S(O)R i -S(O)2R i -NR e R f -OR e -SR e C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 300 replace; R g R h and R i Each is independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Each alkynyl group is optionally surrounded by 1 to 4 R groups. 300 replace; Each R 300 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R e -C(O)OR e -C(O)NR e R f -N(R) e )C(O)R f -S(O)NR e R f -S(O)2NR e R f -S(O)R e -S(O)2R e -NR e R f -OR e -SR e C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R e and R f Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl groups, 5-10 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, and 4-10 heterocyclic groups are each optionally coupled with 1 to 4 R groups. 400 replace; Each R 400 Independently selected from hydrogen, halogen, cyano, hydroxyl, amino, oxo, thio, vinyl, -C(O)R k -C(O)OR k -C(O)NR k R l -N(R) k )C(O)R l -S(O)NR k R l -S(O)2NR k R l -NR k R l S(O)R k -S(O)2R k -NR k R l -OR k -SR k C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R k and R l Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and 4-10 membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O and S.

2. The compound of claim 1, having the structure of formula (IIa) or (IIb): Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

3. The compound of claim 1, having a structure of formula (IIIa), (IIIb) or (IIIc): Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

4. The compound of claim 1, having a structure of formula (IVa), (IVb) or (IVc): Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

5. The compound of claim 1, having the structure of formula (V) or (VI): Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

6. The compound according to any one of claims 1-5, wherein R 1 Selected from: and Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

7. The compound according to any one of claims 1-5, having the structure of formula (VII): Where R 3 and R 4 Each is independently selected from hydrogen, halogen, and -OR a -SR b and C 3-8 cycloalkyl; Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

8. The compound according to any one of claims 1-5, having a structure of formula (VIIIa), (VIIIb) or (VIIIc): Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

9. The compound according to any one of claims 1-8, wherein R 2 Selected from: -OCH3, -H, -SCH3, -S(O)2CH3, -S(O)2CH3, -C(O)OCH3, -C(O)OCH2CH3 and -C(O)NH2, Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue.

10. The compound according to any one of claims 1-4, 6-7 and 9, wherein G 2 Selected from: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue.

11. The compound of claim 1, wherein the compound is selected from Table A, or a pharmaceutically acceptable salt thereof; 。 12. A pharmaceutical composition comprising one or more compounds according to any one of the preceding claims and a pharmaceutically acceptable carrier or diluent.

13. A method for treating or preventing diseases or disorders associated with inhibition of ubiquitin-specific protease 1 (USP1), comprising administering an effective amount of the compound of any of the preceding claims to a patient in need.

14. A method of treating cancer, comprising administering to a patient in need a therapeutically effective amount of the compound according to claims 1-11 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the disease or symptom is a solid tumor selected from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine carcinoma, central nervous system cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, and soft tissue sarcoma.

16. The method of claim 14, wherein the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, or colon cancer.

17. The method of claim 14, wherein the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular cell lymphoma, Waldenström macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma (DLBCL).

18. The method according to any one of claims 13-17, further comprising administering at least one additional anticancer agent or therapy.

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