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-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 594,458, 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, G.J., 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; Among them, 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 selected from non-existent and C. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 4 R groups. 100 replace; Y does not exist or is -O-; W 1 W 2 W 3 and W 4 Each is independently selected from -N(R) a -, -C(O)- and -C(R)- a )-; W 5 Selected from -N- and -C(R) a )-; Among them W 1 W 2 W 3 and W 4 At least one of them is -C(R) a - or -C(O)-; 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; Ra 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 and 4-6 membered heterocyclic groups; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are each optionally surrounded by 1 to 4 R groups. 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 -NR 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 -SRk 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.

[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; Among them, 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 Rb -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 C3-8 Each cycloalkyl group is optionally surrounded by 1 to 4 R 100 replace; X is selected from non-existent and C. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 4 R groups. 100 replace; Y does not exist or is -O-; W 1 W 2 W 3 and W 4 Each is independently selected from -N(R) a -, -C(O)- and -C(R)- a )-; W 5 Selected from -N- and -C(R) a )-; Among them W 1 W 2 W 3 and W 4 At least one of them is -C(R) a - or -C(O)-; 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 and 4-6 membered heterocyclic groups; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are each optionally surrounded by 1 to 4 R groups. 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 Rd -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 Rf -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 -NR 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.

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

[0018] Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0019] In one embodiment, compounds of formula (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) are provided:

[0020] Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0021] In one embodiment, compounds of formula (IVa), (IVb), or (IVc) are provided:

[0022] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

[0023] In one embodiment, compounds of formula (Va), (Vb), or (Vc) are provided:

[0024] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

[0025] In one embodiment, compounds of formula (VIa) or (VIb) are provided:

[0026] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

[0027] In one embodiment, compounds of formula (VIIa), (VIIb), or (VIIc) are provided:

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

[0029] Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

[0030] In one embodiment, a compound is provided, wherein R 1 Selected from: and ; Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0031] 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.

[0032] In one implementation, a compound is provided, wherein G 2 Selected from: and ; Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue.

[0033] In one implementation, a compound from Table A or a pharmaceutically acceptable salt thereof is provided; Table A

[0034] The compounds described herein (e.g., compounds of formulas I, II, IIIa, IIIb, IIIc, IIId, IIIe, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, 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 implementations, 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) 3When 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 bond is used to describe the connection point between a part or substituent and the core or skeleton structure.

[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 10 Alkyl 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 (C0-4 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. 1-6 Alkyl 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 described 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 their 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 a compound of formula I, II, III, or IV 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 Sciences, 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 Review Drug Discovery, 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 Sciences , 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] 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.

[0117] 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.

[0118] 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.

[0119] 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 tumors are selected from pancreatic cancer, breast cancer, melanoma, and non-small cell lung cancer.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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).

[0124] 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.

[0125] 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).

[0126] Combination therapy

[0127] 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.

[0128] 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.

[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 other chemotherapeutic agents, immunotherapeutic agents, radiotherapy agents, antitumor agents, anticancer agents, antifibrotic agents, antiangiogenic agents, therapeutic antibodies, or any combination thereof.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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).

[0136] 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® (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).

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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).

[0142] 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).

[0143] 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.

[0144] 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.

[0145] 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).

[0146] 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).

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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).

[0151] 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).

[0152] 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).

[0153] 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).

[0154] 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).

[0155] 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.

[0156] 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).

[0157] 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.

[0158] 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.

[0159] On the other hand, immuno-oncology agents are CD27 agonists, such as agonist CD27 antibodies. Suitable CD27 antibodies include, for example, varlilumab.

[0160] On the other hand, the immuno-oncology reagent is MGA271 (anti-B7H3) (WO11 / 109400).

[0161] 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).

[0162] The present invention also provides compounds of the present invention for therapeutic purposes.

[0163] In another embodiment, the compound of Formula I is selected from the exemplary compounds or combinations of exemplary compounds or other embodiments herein.

[0164] In another embodiment, IC is measured in at least one of the following methods. 50 Compounds with a molecular weight of < 1000 nM.

[0165] 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.

[0166] Preparation method

[0167] 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.

[0168] 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).

[0169] Example

[0170] 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.

[0171] 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.

[0172] Chemical names were determined using ChemBioDraw Ultra version 14.0.0.126 (CambridgeSoft).

[0173] Use the following abbreviations:

[0174] LCMS - Method 1: Column: Kinetex XB-C18(75X3.0) mm, 2.6um Mobile phase A: 5 mm ammonium formate, pH 3.3: acetonitrile (98:2) Mobile phase B: ACN: 5 mm ammonium formate, pH 3.3 (98:2) Flow rate: 1 ml / min Temperature: 25℃ Gradient: 20% B to 100% B over 4 minutes at a flow rate of 1.5 mL / min, maintaining 100% B for 0.5 minutes. MS and UV: 220 & 254 LCMS - Method 2: Pillar: Kinetex-C18 (75 x 3.0) mm, 2.6 μm Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Flow rate: 1 ml / min Temperature: 25℃ Gradient: 0.5%B to 95%B over 2.5 min at a flow rate of 1.5 mL / min, maintaining 95%B for 1.49 min. MS and UV: 220 & 254 nm LCMS - Method 3: Column: Acquity BEH C18(50X3.0) mm, 1.7um Mobile phase A: 5 mm ammonium formate, pH 3.3: acetonitrile (98:2) Mobile phase B: ACN: 5 mm ammonium formate, pH 3.3 (98:2) Flow rate: 0.7 ml / min Temperature: 25℃ Gradient: 20%B to 98%B over 1.5 minutes, then maintain 98%B for 0.5 minutes. MS and UV: 220 nm LCMS - Method 4: Column: Acquity Uplc BEH C18(50X3.0) mm, 1.7um Mobile phase A: 5 mm ammonium formate, pH 3.3: acetonitrile (98:2) Mobile phase B: ACN: 5 mm ammonium formate, pH 3.3 (98:2) Flow rate: 0.7 ml / min Temperature: 25℃ Gradient: 20%B to 98%B over 1.5 minutes, then maintain 98%B for 0.5 minutes. MS and UV: 220 nm LCMS - Method 5: Column: Kinetex XB-C18(75X3.0) mm, 2.6um Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Flow rate: 1 ml / min Temperature: 25℃ Gradient: 0.5% B to 95% B over 2.5 min at a flow rate of 1.5 mL / min, maintaining 95% B for 1.49 min. MS and UV: 220 & 254 nm LCMS - Method 6: Pillar: Kinetex-C18 (75 x 3.0) mm, 2.6 μm Mobile phase A: 5 mm ammonium formate, pH 3.3: acetonitrile (98:2) Mobile phase B: ACN: 5 mm ammonium formate, pH 3.3 (98:2) Flow rate: 0.7 ml / min Temperature: 25℃ Gradient: 20% B to 100% B over 4 minutes at a flow rate of 1.5 mL / min, maintaining 100% B for 0.5 minutes. MS and UV: 220 & 254 LCMS - Method 7: Column: Acquity BEH C18(50X3.0) mm, 1.7um Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Flow rate: 0.7 ml / min Temperature: 25℃ Gradient: 20%B to 98%B over 1.5 minutes, then maintain 98%B for 0.5 minutes. MS and UV: 220 nm LCMS - Method 8: Column: X-bridge C8 (50X4.5) mm, 5um Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Flow rate: 1 ml / min Temperature: Environment Gradient: 5% B to 95% B over 2.5 min at a flow rate of 1.5 mL / min, maintaining 95% B for 1.5 min. MS and UV: 220 LCMS - Method 9: Column: Waters Acquity BEH C18 1.7um 2.1 x 50 mm Mobile phase A: 0.05% TFA in CH3CN:water (5:95) Mobile phase B: 0.05% TFA in CH3CN:water (95:5) Flow rate: 1 ml / min Temperature: 50℃ Gradient: 0%B to 100%B, lasting 1 minute, with a stop time of 1.5 minutes.

[0175] MS and UV: 220, 254

[0176] LCMS - Method 10: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size Mobile phase A: 0.05% TFA in CH3CN:water (5:95) Mobile phase B: 0.05% TFA in CH3CN:water (95:5) Flow rate: 1 ml / min Temperature: 50℃ Gradient: 0-100%B (0-3 minutes), 100%B (3-3.5 minutes).

[0177] MS and UV: 220

[0178] intermediate

[0179] Option 1: Synthesis of intermediates I-1 and I-2:

[0180] Synthesis of I-1

[0181] Step 1: 4-(4-(trifluoromethyl)-1 H Methyl 2-imidazol-2-yl)benzoate:

[0182] A mixture of 3,3-dibromo-1,1,1-trifluoroprop-2-one (49.3 g, 183 mmol) and sodium acetate (19.99 g, 244 mmol) in water (100 mL) was stirred at 95 °C for 30 min. The reaction mixture was cooled to 0 °C, and a cold solution of methyl 4-formylbenzoate (20.00 g, 122.00 mmol) in a mixture of NH4OH (28% aq, 100 mL) and MeOH (300 mL) was added. The resulting mixture was stirred at 25 °C for 16 h, the volatiles were evaporated, and the resulting residue was diluted with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by rapid silica gel (230-400 mesh) chromatography to give 4-(4-(trifluoromethyl)-1 H Methyl 2-imidazol-2-yl)benzoate (19.00 g, 60.5 mmol, 49.7%), is a yellow solid. LCMS (ESI) m / z: 271.0 [M+H] + LC retention time: 1.206 minutes (LCMS method 3).

[0183] Step 2: 4-(1-methyl-4-(trifluoromethyl)-1 H Methyl 2-imidazol-2-yl)benzoate:

[0184] At 0 °C, sodium hydride (60% dispersion, 0.740 g, 18.50 mmol in mineral oil) was added to a stirred solution of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.50 g, 9.25 mmol) in DMF (20 mL), followed by methyl iodoform (0.868 mL, 13.88 mmol). The reaction mixture was warmed to room temperature, stirred at room temperature for 3 hours, quenched with cooling water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel (230-400 mesh) chromatography to obtain 4-(1-methyl-4-(trifluoromethyl)-1-yl)benzoate. HMethyl 2-imidazolium-2-yl)benzoate (1.40 g, 4.87 mmol, 52.7%), is a white solid. LCMS (ESI) m / z: 285.0 [M+H] + LC retention time: 1.280 minutes (LCMS method 3).

[0185] Step 3: (4-(1-methyl-4-(trifluoromethyl)-1 H Synthesis of 1-imidazol-2-yl)phenyl)methanol (I-1):

[0186] At 0°C, 4-(1-methyl-4-(trifluoromethyl)-1 H Methyl 4-(1-methyl-4-(trifluoromethyl)-1-yl)benzoate (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 mixture was stirred at 25 °C for 3 h. The reaction was quenched with a saturated aqueous solution of NH4Cl and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (230-400 mesh) to give (4-(1-methyl-4-(trifluoromethyl)-1-yl)benzoate. H (-Imidazol-2-yl)phenyl)methanol (0.900 g, 3.42 mmol, 81%), is a white solid. LCMS (ESI) m / z: 257.0 [M+H] + LC retention time: 0.940 minutes (LCMS method 3).

[0187] Synthesis of I-2

[0188] Step 1: 4-(1-Isopropyl-4-(trifluoromethyl)-1 H Methyl 2-imidazol-2-yl)benzoate:

[0189] At 0°C, towards 4-(4-(trifluoromethyl)-1 HMethyl 2-imidazolium-2-yl)benzoate (2.0 g, 7.40 mmol) was added to a stirred solution of acetonitrile (30 mL) with Cs₂CO₃ (4.82 g, 14.80 mmol), followed by 2-iodopropane (1.110 mL, 11.10 mmol). The reaction mixture was stirred at 25 °C for 16 h and then heated at 50 °C for another 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with water. The ethyl acetate layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (230-400 mesh) to give 4-(1-isopropyl-4-(trifluoromethyl)-1 H Methyl 2-imidazolium-2-yl)benzoate (0.800 g, 2.229 mmol, 30.1%), is a white solid. LCMS (ESI) m / z: 313.2 [M+H] + LC retention time: 1.434 minutes (LCMS method 3).

[0190] Step 2: (4-(1-Isopropyl-4-(trifluoromethyl)-1 H Synthesis of 1-imidazol-2-yl)phenyl)methanol (I-2):

[0191] At 0°C, 4-(1-isopropyl-4-(trifluoromethyl)-1 H Methyl 4-(1-isopropyl-4-(trifluoromethyl)-1-yl)benzoate (0.70 g, 2.241 mmol) was added to a stirred solution of lithium aluminum hydride (2 M, 2.241 mL, 4.48 mmol, in THF) in 10 mL of THF, and the mixture was stirred at 25 °C for 3 h. The reaction was quenched with a saturated aqueous solution of NH4Cl and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (230-400 mesh) to give (4-(1-isopropyl-4-(trifluoromethyl)-1-yl)benzoate. H (-Imidazol-2-yl)phenyl)methanol (0.650 g, 2.242 mmol, 100%), is a white solid. LCMS (ESI) m / z: 285.0 [M+H] + LC retention time: 1.127 minutes (LCMS method 3).

[0192] Scheme 2: Intermediate 3: Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)methanol:

[0193] DIBAl-H (1.2 M, in toluene, 44.0 mL, 52.8 mmol) was added to a stirred solution of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (5.0 g, 17.59 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was slowly poured into cooling water containing crushed ice and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (3.8 g, 14.24 mmol, 81%) as a pale yellow liquid. LCMS (ESI) m / z: 257.0 [M+H] + LC retention time: 1.224 minutes. (LCMS method 3).

[0194] Option 3: Synthesis of intermediate 4:

[0195] Step 1: 4-Chloro-1-isopropyl-1H-pyrazole:

[0196] Cs₂CO₃ (31.8 g, 98 mmol) was added to a stirred solution of 4-chloro-1H-pyrazole (5.0 g, 48.8 mmol) in acetonitrile (60 mL), followed by 2-iodopropane (5.69 mL, 58.5 mmol), and the contents were heated at 80 °C for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with diethyl ether. The organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure at ~35 °C to give crude 4-chloro-1-isopropyl-1H-pyrazole (6.0 g, 39.4 mmol, 81%) as a pale yellow solid, which was used directly in the next step. LCMS (ESI) m / z: 145.0 [M+H] + LC retention time: 1.187 minutes. (LCMS method 7).

[0197] Step 2: Synthesis of 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (I-4):

[0198] At 0 °C, n-butyllithium (1.6 M, in hexane, 28.5 mL, 45.6 mmol) was added to a stirred solution of 4-chloro-1-isopropyl-1H-pyrazole (5.50 g, 38.0 mmol) in tetrahydrofuran (50 mL), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was cooled to -78 °C, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (8.49 g, 45.6 mmol) was added and stirred for 2 hours. A saturated aqueous solution of NH4Cl was added to the reaction mixture, and the contents were extracted with ethyl acetate. The organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a dark brown, oily crude 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (6.00 g, 14.41 mmol, 37.9%), which was used directly in subsequent steps. LCMS (ESI) m / z: 271.0 [M+H] + LC retention time: 1.327 minutes. (LCMS method 4).

[0199] Option 4: A general synthetic sequence for the final target product. Representative examples are shown below.

[0200] Step 1: Synthesis of 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine:

[0201] Cs₂CO₃ (0.489 g, 1.50 mmol) and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (0.256 g, 1.00 mmol) were added to a stirred solution of 2,4-dichloropyrido[3,2-d]pyrimidine (0.200 g, 1.00 mmol) in acetonitrile (10 mL), and the mixture was heated at 60 °C for 16 hours. The reaction mixture was cooled to ambient temperature, cooling water was added, and the contents were extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography using RediSep cartridgre to give 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine (0.214 g, 0.484 mmol, 48.4%) as a light brown solid. LCMS (ESI) m / z: 420.0 [M+H] + LC retention time: 2.65 minutes (LCMS method 1).

[0202] The intermediates in Table 1 were synthesized according to the process described in step 1 above.

[0203] Table 1

[0204] Step 2: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine (Example 1):

[0205] Under a nitrogen atmosphere, tripotassium phosphate (0.202 g, 0.953 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidine (0.145 g, 0.524 mmol) and tetra(triphenylphosphine)palladium(0) (0.0551 g, 0.048 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine (200 mg, 0.476 mmol) (0.200 g, 0.476 mmol) in a mixture of 1,4-dioxane and water (4 mL, 10:1). The mixture was then heated at 80 °C for 16 hours. The reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by reversed-phase preparative HPLC [method: diluent: THF:water:MeCN (40:10:40); column: XSelect-C181 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 50, 7 / 80, 10 / 80]. The residue was purified to 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine (0.060 g, 0.112 mmol, 23.52%), as a white solid. LCMS (ESI) m / z: 534.0 [M+H] + LC retention time: 2.69 minutes. (LCMS Method 1); 1 H-NMR: (400 MHz, DMSO-d) 6 ) δ = 9.07 (q, J =2.8 Hz & 1.6 Hz, 1H), 8.72 (s, 1H), 8.42 (dd, J = 7.2 Hz & 1.6 Hz, 1H), 8.02(dd, J = 4.4 Hz & 4.4 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 6.4 Hz, 2H), 7.70 (d, J= 8.0 Hz, 2H), 5.74 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 1.89-1.81 (m, 1H), 1.12-1.05 (m, 2H), 0.93-0.85 (m, 2H).

[0206] The embodiments in Table 2 were synthesized according to the process described in step 2 above.

[0207] Table 2

[0208] The intermediates in Table 4 were synthesized according to the process described in step 1 above.

[0209] Table 4

[0210] The embodiments in Table 5 were synthesized according to the process described in step 2 above.

[0211] Table 5

[0212] Examples 24 and 25: Chiral decomposition of Example 21

[0213] Enantiomers of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[3,2-d]pyrimidine: Enantiomer-1 and enantiomer-2 were obtained by chiral enantiomer separation of compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyridino[3,2-d]pyrimidinyl.

[0214] SFC method: Column / Specifications: Luxcellulose-4 (250 x 30) mm, 5 μm; % CO2: 73%; % Co-solvent: 27% MeOH; Total Flow Rate: 70.0 g / min; Back Pressure: 100 bar; Temperature: 40℃; UV: 220 nm. SFC Retention Time of Enantiomer Peak 1: 6.8 min. SFC Retention Time of Enantiomer Peak 2: 8.0 min.

[0215] Example 24: Enantiomer-1 [SFC retention time of enantiomer (peak) 1: 6.8 minutes.]

[0216] [α] D 25 = -12.0 (c = 0.05, in MeOH). HPLC: 99.9% ee (Cellulose-4 (250X4.6)mm, 5μm_methanol_30_2.lcd, flow rate = 3.0 mL / min, λ = 220 nm, cosolvent: 30.0%, Oven-A temperature: 40℃, Oven A column position: 1, BPR pressure: 100.0 bar, BPR temperature: 50℃), HPLC retention time: = 3.936 min (major), 4.533 min (secondary). LC-MS (ESI) m / z: 548.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ = 9.10 (dd, J = 1.6, 4.2 Hz, 1H), 8.70 (s, 1H), 8.40 (dd, J = 1.5, 8.5 Hz, 1H), 8.03 (dd, J = 4.2, 8.6 Hz, 1H), 7.94 (d, J = 1.1 Hz, 1H), 7.74 (d, J =8.4 Hz, 2H), 7.70 - 7.65 (m, 2H), 6.59 (q, J= 6.3 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 1.79 (d, J = 6.5 Hz, 3H), 1.76 - 1.69 (m, 1H), 1.09 - 0.97 (m, 2H), 0.89 - 0.73 (m, 2H).

[0217] Example 25: Enantiomer-2 [SFC retention time of enantiomer (peak) 2: 8.0 minutes.]

[0218] [α] D 25 = +12.0 (c = 0.05, in MeOH). HPLC: 98.4% ee (Cellulose-4 (250X4.6)mm, 5μm_methanol_30_2.lcd, flow rate = 3.0 mL / min, λ = 220 nm, cosolvent: 30.0%, Oven-A temperature: 40℃, Oven A column position: 1, BPR pressure: 100.0 bar, BPR temperature: 50℃), HPLC retention time: = 4.501 min (major), 3.936 min (secondary). LC-MS (ESI) m / z: 548.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ = 9.09 (dd, J = 1.6, 4.2 Hz, 1H), 8.70 (s, 1H), 8.39 (dd, J = 1.6, 8.5 Hz, 1H), 8.02 (dd, J = 4.1, 8.5 Hz, 1H), 7.93 (d, J = 1.1 Hz, 1H), 7.75 (d, J =8.4 Hz, 2H), 7.68 - 7.63 (m, 2H), 6.58 (q, J = 6.5 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 1.78 (d, J = 6.6 Hz, 3H), 1.75 - 1.69 (m, 1H), 1.09 - 0.96 (m, 2H), 0.90 - 0.72 (m, 2H).

[0219] Examples 26 and 27: Chiral decomposition of Example 22:

[0220] Enantiomers of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[3,2-d]pyrimidine: The compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[3,2-d]pyrimidinium was subjected to chiral enantiomer separation to obtain enantiomer-1 and enantiomer-2.

[0221] SFC method: Column / Specifications: Luxcellulose-4 (250 x 30) mm, 5 μm; % CO2: 75%; % Co-solvent: 25% MeOH; Total Flow Rate: 100.0 g / min; Back Pressure: 100 bar; Temperature: 40℃; UV: 220 nm. SFC Retention Time of Enantiomer Peak 1: 4.5 min. SFC Retention Time of Enantiomer Peak 2: 5.5 min.

[0222] Example 26: Enantiomer-1 [SFC retention time of enantiomer (peak) 1: 4.5 minutes.]

[0223] [α] D 25 = -12.0 (c = 0.1, in MeOH). HPLC: >99.9% ee (Cellulose-4 (250X4.6)mm, 5μm_methanol_30_3.lcd, flow rate = 3.0 mL / min, λ = 220 nm, cosolvent: 30.0%, Oven-A temperature: 40℃, Oven A column position: 1, BPR pressure: 100.0 bar, BPR temperature: 50℃), LC-MS (ESI) m / z: 576.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.10 (dd, J = 1.6, 4.3 Hz, 1H), 8.70 (s,1H), 8.40 (dd, J = 1.6, 8.6 Hz, 1H), 8.18 (d, J= 1.1 Hz, 1H), 8.03 (dd, J =4.2, 8.6 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.61 - 7.57 (m, 2H), 6.59 (q, J = 6.5Hz, 1H), 4.47 (spt, J = 6.7 Hz, 1H), 3.81 (s, 3H), 1.79 (d, J = 6.5 Hz, 3H),1.76 - 1.69 (m, 1H), 1.41 (dd, J = 3.1, 6.5 Hz, 6H), 1.05 – 1.01 (m, 2H), 0.91 – 0.70 (m, 2H).

[0224] Example 27: Enantiomer-2 [SFC retention time of enantiomer (peak) 2: 5.5 minutes.]

[0225] [α] D 25 = +14.0 (c = 1.0, in MeOH). HPLC: 99.4% ee (Cellulose-4 (250X4.6)mm, 5μm_methanol_30_3.lcd, flow rate = 3.0 mL / min, λ = 220 nm, cosolvent: 30.0%, Oven-A temperature: 40℃, Oven A column position: 1, BPR pressure: 100.0 bar, BPR temperature: 50℃), LC-MS (ESI) m / z: 576.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.09 (dd, J = 1.6, 4.1 Hz, 1H), 8.70 (s,1H), 8.40 (dd, J = 1.6, 8.6 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 8.02 (dd, J =4.3, 8.5 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.61 - 7.50 (m, 2H), 6.59 (q, J = 6.4Hz, 1H), 4.46 (spt, J= 6.7 Hz, 1H), 3.81 (s, 3H), 1.78 (d, J = 6.5 Hz, 3H),1.76 - 1.68 (m, 1H), 1.40 (dd, J = 3.1, 6.6 Hz, 6H), 1.07 - 0.99 (m, 2H), 0.90 - 0.69 (m, 2H).

[0226] Intermediate 24: 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenoxy)pyrido[3,2-d]pyrimidine

[0227] At 25 °C, Cs₂CO₃ (977 mg, 3.00 mmol) was added to a stirred solution of 2,4-dichloropyrido[4,3-d]pyrimidine (300 mg, 1.500 mmol) in acetonitrile (10 mL), followed by 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenol (291 mg, 1.200 mmol), and the mixture was stirred at 80 °C for 16 hours. After the reaction was complete (monitored by TLC), the volatiles were removed under reduced pressure, diluted with ethyl acetate, and washed with water. The organic extract was dried over anhydrous Na₂SO₄, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography using a gradient of 0-30% ethyl acetate (in petroleum ether) to give 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenoxy)pyrido[3,2-d]pyrimidine (160 mg, 0.371 mmol, 24.71% yield) as a grayish-white solid. LC-MS (ESI) m / z: 406.0 [M+H] + 。

[0228] The intermediates in Table 6 were prepared according to the process described above.

[0229] Table 6

[0230] Example 28: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenoxy)pyrido[3,2-d]pyrimidine:

[0231] Under a nitrogen atmosphere, tripotassium phosphate (167 mg, 0.789 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)pyrido[3,2-d]pyrimidine (160 mg, 0.394 mmol) in a stirred solution of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-phenoxy)pyrimidine (120 mg, 0.434 mmol) and tetrakis(triphenylphosphine)palladium(0) (45.6 mg, 0.039 mmol) were added to a stirred solution of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-pyrimidine (10 mL, 9:1). The mixture was then heated at 120 °C under microwave irradiation for 2 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from the mixture of filtrate and washings under reduced pressure to obtain the crude product, which was purified by reversed-phase preparative HPLC [method: diluent: THF:water:MeCN (40:20:40); column: X-select C18 (150 X 19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 60, 12 / 90] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenoxy)pyrido[3,2-d]pyrimidine (85 mg, 0.160 mmol, 40.6% yield), as a white solid. LC-MS (ESI) m / z: 520.1 [M+H] + . 1 H-NMR: (400 MHz, DMSO-d6) δ = 9.19 (dd, J = 1.6, 4.2 Hz, 1H), 8.64 (s, 1H), 8.51 (dd, J = 1.2, 8.6 Hz,1H), 8.12 (dd, J = 4.4, 8.6 Hz, 1H), 7.96 (q, J = 1.2 Hz, 1H), 7.85 (d, J =2.0, 6.4 Hz, 2H), 7.56 (d, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.02-1.96 (m, 1H), 1.04-1.01 (m, 2H), 0.94-0.92 (m, 2H).

[0232] The examples in Table 7 were prepared according to the process described above.

[0233] Table 7

[0234] Intermediate 27: 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

[0235] At 0°C, towards (4-(1-methyl-4-(trifluoromethyl)-1 H Triphenylphosphine (3.69 g, 14.1 mmol) and carbon tetrabromide (6.21 g, 18.7 mmol) were added to a stirred solution of 2-(4-(-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1-methyl)methanol (2.40 g, 9.40 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM, washed with water, and the organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography using 230-400 silica gel to give a white solid 2-(4-(-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1-methyl H -Imidazole (2.00 g, 5.3 mmol, 57% yield): LC-MS (ESI) m / z: 319.0 [M+H] + . 1 H-NMR: (400 MHz, CDCl3) δ = 7.63-7.61 (m,2H), 7.53-7.51 (m, 2H), 7.34 (s, 1H), 4.55 (s, 2H), 3.81 (s, 3H).

[0236] The intermediates in Table 8 were synthesized according to the process described above.

[0237] Table 8

[0238] Option 4: Synthesis of Intermediate 29

[0239] Intermediate 29: 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidine: At room temperature, the dried flask was purged with N2, and zinc (327 mg, 5.00 mmol) and tetrahydrofuran (10 mL) were added, followed by 1,2-dibromoethane (0.022 mL, 0.250 mmol) and TMS-Cl (0.032 mL, 0.250 mmol). The contents were heated to 62 °C under N2 atmosphere. After 60 minutes, a solution of 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazolium (877 mg, 2.75 mmol) in THF (5 mL) was added. The reaction was stirred at 62 °C under N2 for 10 minutes, and then treated with a solution of 2,4-dichloropyridinium[3,2-d]pyrimidine (500 mg, 2.500 mmol) in THF (5 mL) and tetrakis (289 mg, 0.250 mmol). The mixture was stirred at 65 °C for 2 hours. After the reaction was complete (monitored by UPLC), the reaction mixture was filtered through a diatomaceous earth pad and concentrated under reduced pressure. The crude product was purified by column chromatography using 60-120 silica gel, eluting with 0-50% ethyl acetate (in petroleum ether). 2-Chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidine (150 mg, 0.334 mmol, 13.37% yield) was given as a pale yellow gelatinous solid. LC-MS (ESI) m / z: 404.0 [M+H] + The intermediates in Table 9 were prepared according to the process described above.

[0240] Table 9

[0241] Solution: Synthesis of Examples 31 and 32

[0242] Examples 31 and 32: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidine and (2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-yl)(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl) methyl ketone: To a stirred solution of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidine (150 mg, 0.371 mmol)) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (108 mg, 0.557 mmol) in 1,4-dioxane (10 mL), tripotassium phosphate (237 mg, 1.114 mmol) was added and the mixture was purged with N2. Then, a PdCl2(dppf)-CH2Cl2 adduct (30.3 mg, 0.037 mmol) was added. The reaction mixture was heated at 90 °C for 4 hours. After the reaction was complete (monitored by UPLC), the reaction mixture was concentrated using a rotary evaporator and extracted with ethyl acetate (2 x 50 mL). The organic layer was separated, dried over Na2SO4, and concentrated using a rotary evaporator. The crude product was purified by column chromatography using 60-120 silica gel, eluting with 0-50% ethyl acetate (in petroleum ether). The crude product yielded 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,2-d]pyrimidine (42 mg, 0.079 mmol, 21.32% yield) as a yellow solid. LC-MS (ESI), m / z: 518.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.24 (dd, J = 1.5, 4.0 Hz, 1H), 8.73 (s, 1H), 8.52 (dd, J =1.5, 8.5 Hz, 1H), 8.11 - 8.06 (m, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.64 (d, J =8.0 Hz, 2H), 7.57 - 7.53 (m, 2H), 4.93 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H),1.76 - 1.63 (m, 1H), 1.12 - 1.01 (m, 2H), 0.92 - 0.81 (m, 2H).

[0243] The examples in Table 10 were prepared according to the process described above.

[0244] Table 10

[0245] Option 6: Synthesis of Intermediate 38

[0246] Intermediate 38: 1-(4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)pyridine-2(1H)-one

[0247] Step A: 4-(2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)benzaldehyde

[0248] A mixture of 4-fluorobenzaldehyde (560 mg, 4.51 mmol), cesium carbonate (1470 mg, 4.51 mmol), and 3-(trifluoromethyl)pyridin-2-ol (736 mg, 4.51 mmol) in DMA (10 mL) was stirred at 140 °C for 18 h. The mixture was diluted with EtOAc (25 mL) and washed with 10% lithium chloride aqueous solution (3 x 15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient). 4-(2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)benzaldehyde (800 mg, 2.99 mmol, 66.4% yield) was given. LC-MS (ESI) m / z: 267.9 [M+H] + .

[0249] Step B: 1-(4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0250] Sodium borohydride (57.9 mg, 1.531 mmol) was added to a solution of 4-(2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)benzaldehyde (409 mg, 1.531 mmol) in THF (5.0 mL) and MeOH (5.0 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated. The crude product was subjected to ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient). 1-(4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (294 mg, 1.092 mmol, 71.3% yield) was given as a grayish-white solid. LC-MS (ESI) m / z: 269.9 [M+H] + .

[0251] The intermediates in Table 11 were prepared according to the process described above.

[0252] Table 11

[0253] Option 7: Synthesis of Intermediate 40

[0254] Intermediate 40: 1-(4-(((2-chloropyridino[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0255] Under nitrogen atmosphere, a solution of 1.0 M sodium bis(trimethylsilyl)amino in THF (223 µl, 0.223 mmol) was added to a solution of 1-(4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (60 mg, 0.223 mmol) and 2,4-dichloropyrido[3,2-d]pyrimidine (44.6 mg, 0.223 mmol) in anhydrous THF (2.0 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (5 mL) and washed with 10% lithium chloride aqueous solution (3 x 15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient). 1-(4-(((2-chloropyridano[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (41 mg, 0.095 mmol, 42.5% yield) was given as a white solid. LC-MS (ESI) m / z: 432.8 [M+H] + .

[0256] The intermediates in Table 12 were prepared according to the process described above.

[0257] Table 12

[0258] Scheme 8: Synthesis of Example 45

[0259] Example 45: 1-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0260] Under nitrogen atmosphere, a mixture of 1-(4-(((2-chloropyridino[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (41 mg, 0.095 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (18.38 mg, 0.095 mmol), 2.0 M tripotassium phosphate (118 µl, 0.237 mmol), and dichloro[1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) (3.09 mg, 4.74 µmol) in dioxane (3 mL) was stirred at 60 °C for 18 hours. The mixture was diluted with EtOAc (2 mL), and the ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. Column: XBridge C18, 19 mm x 200 mm, 5 μm particle size; flow rate: 20 mL / min; column temperature: 25 °C. Mobile phase A (ACN / H2O (5:95), containing 10 mM AA); mobile phase B (ACN / H2O (95:5), containing 10 mM AA); gradient: 0% B to 100% B, over 20 min. 1-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (10.30 mg, 0.018 mmol, 19.24% yield). LC-MS (ESI) m / z: 547.2 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6) δ ppm 0.91(br dd, J =7.86, 3.05 Hz, 2 H) 1.04 - 1.10 (m, 2 H) 1.83 (br dd, J =8.09, 3.59Hz, 1 H) 3.87 (s, 3 H) 5.73 (s, 2 H) 6.49 (t, J =7.00 Hz, 1 H) 7.51 (br d, J =7.39 Hz, 2 H) 7.72 (br d, J =8.39 Hz, 2 H) 7.97 - 8.08 (m, 3 H) 8.41 (d, J =8.36 Hz, 1 H) 8.71 (s, 1 H) 9.06 (dd, J =4.04, 1.53 Hz, 1 H).

[0261] The examples in Table 13 were prepared according to the process described above.

[0262] Table 13

[0263] Scheme 9: Synthesis of Intermediate 44

[0264] Intermediate 44: 2-(2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol

[0265] Step A: Methyl 2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazolium-4-carboxylate

[0266] Under nitrogen atmosphere, a mixture of methyl 2-bromo-1-methyl-1H-imidazolium-4-carboxylate (200 mg, 0.913 mmol), (4-(hydroxymethyl)phenyl)boronic acid (166 mg, 1.096 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene palladium chloride (29.8 mg, 0.046 mmol), and 2.0 M tripotassium phosphate (1141 µl, 2.283 mmol) in dioxane (6.0 mL) was stirred at 60 °C for 18 hours. The mixture was diluted with EtOAc (5 mL) and washed with 10% lithium chloride aqueous solution (3 x 15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient). Methyl 2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazolium-4-carboxylate (210 mg, 0.853 mmol, 93% yield) was obtained as a brown gel. LC-MS (ESI) m / z: 246.9 [M+H] + .

[0267] Step B: 2-(2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol:

[0268] Under nitrogen atmosphere, a solution of 3.0 M magnesium methyl bromide in diethyl ether (853 µl, 2.56 mmol) was added to a solution of methyl 2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazolium-4-carboxylate (210 mg, 0.853 mmol) in anhydrous THF (10 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated NH4Cl solution (10 mL), and the mixture was extracted with EtOAc (2 x 25 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient). 2-(2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol (142 mg, 0.548 mmol, 64.2% yield) was obtained as a white gel. LC-MS (ESI) m / z: 247.0 [M+H] + . 1 H NMR (500 MHz, CHLOROFORM- d ) δ ppm 1.58 -1.63 (m, 6 H) 3.69 (s, 3 H) 4.75 (s, 2 H) 6.83 (s, 1 H) 7.38 (d, J =8.46 Hz, 2H) 7.53 (d, J =7.53 Hz, 2 H).

[0269] Scheme 10: Synthesis of Example 50

[0270] Example 50: 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol:

[0271] Step A: 2-(2-(4-(((2-chloropyridino[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol: A mixture of 2-(2-(4-(hydroxymethyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol (42 mg, 0.171 mmol), cesium carbonate (55.6 mg, 0.171 mmol), and 2,4-dichloropyrido[3,2-d]pyrimidine (34.1 mg, 0.171 mmol) in ACN (2.0 mL) was stirred at 80 °C for 18 hours. Ppt was filtered off and the filtrate was concentrated. The crude product was subjected to ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient). 2-(2-(4-(((2-chloropyridano[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol (30 mg, 0.073 mmol, 42.9% yield) was obtained as a white foam. LC-MS (ESI) m / z: 409.8 [M+H] + .

[0272] Step B: 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol:

[0273] Under nitrogen atmosphere, a mixture of 2-(2-(4-(((2-chloropyridino[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol (30 mg, 0.073 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (14.20 mg, 0.073 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene palladium chloride (47.7 mg, 0.073 mmol), and 2.0 M tripotassium phosphate (36.6 µl, 0.073 mmol) in dioxane (3.0 mL) was stirred at 80 °C for 18 hours. The mixture was diluted with EtOAc (5 mL), and the ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. Column: XBridge C18, 19 mm x 200 mm, 5 μm particle size; flow rate: 20 mL / min; column temperature: 25 ℃. Mobile phase A (ACN / H2O (5:95), containing 10 mM AA); mobile phase B (ACN / H2O (95:5), containing 10 mM AA); gradient: 0% B to 100% B, over 20 min. 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-yl)oxy)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)prop-2-ol (4.90 mg, 9.36 µmol, 12.79% yield). LC-MS (ESI) m / z: 523.9 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6)δ ppm 0.84 - 0.95 (m, 2 H) 1.03 - 1.13 (m, 2 H) 1.42 (s, 6 H) 1.77 - 1.89 (m,1 H) 3.71 (s, 3 H) 3.88 (s, 3 H) 5.71 (s, 2 H) 7.03 (s, 1 H) 7.64 (m, J =8.24Hz, 2 H) 7.71 (m, J =8.09 Hz, 2 H) 8.02 (dd, J =8.54, 4.20 Hz, 1 H) 8.41 (d, J =8.33 Hz, 1 H) 8.72 (s, 1 H) 9.06 (dd, J =4.12, 1.53 Hz, 1 H).

[0274] Scheme 22: Synthesis of intermediates 91 to 109

[0275] Intermediate 91: 4-(4-(trifluoromethyl)-1 H Synthesis of methyl 2-imidazolium-2-yl)benzoate:

[0276] A mixture of 3,3-dibromo-1,1,1-trifluoroprop-2-one (49.3 g, 183 mmol) and sodium acetate (19.99 g, 244 mmol) in water (100 mL) was stirred at 95 °C for 30 min. The mixture was then cooled to 0 °C, and a cold solution of methyl 4-formylbenzoate (20.00 g, 122.00 mmol) in a mixture of NH4OH (28% aq, 100 mL) and MeOH (300 mL) was added. The resulting mixture was stirred at 25 °C for 16 h. After the reaction was complete (monitored by TLC), the volatiles were evaporated, and the resulting residue was diluted with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated from the filtrate. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 4-(4-(trifluoromethyl)-1 H Methyl 2-imidazol-2-yl)benzoate (19.00 g, 60.5 mmol, 49.7%), is a yellow solid. LCMS (ESI) m / z: 271.0 [M+H] + .

[0277] Intermediate 92: 4-(1-methyl-4-(trifluoromethyl)-1 H Synthesis of methyl 2-imidazolium-2-yl)benzoate:

[0278] At 0 °C, sodium hydride (60% dispersion, 0.740 g, 18.50 mmol in mineral oil) was added to a stirred solution of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.50 g, 9.25 mmol) in DMF (20 mL), followed by methyl iodoform (0.868 mL, 13.88 mmol). The mixture was stirred at 25 °C for 3 hours. After the reaction was complete (monitored by TLC), cooling water was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous Na₂SO₄, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate. HMethyl 2-imidazolium-2-yl)benzoate (1.40 g, 4.87 mmol, 52.7%), is a white solid. LCMS (ESI) m / z: 285.0 [M+H] + .

[0279] The intermediates in Table 14 were prepared according to the process described above.

[0280] Table 14

[0281] Intermediate 94: (4-(1-methyl-4-(trifluoromethyl)-1 H Synthesis of 2-imidazolium-2-yl)phenyl)methanol:

[0282] At 0°C, 4-(1-methyl-4-(trifluoromethyl)-1 H Methyl 4-(imidazol-2-yl)benzoate (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 mixture was stirred at 25 °C for 3 h. After the reaction was complete (monitored by TLC), a saturated aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain (4-(1-methyl-4-(trifluoromethyl)-1-yl)benzoate. H (-Imidazol-2-yl)phenyl)methanol (0.900 g, 3.42 mmol, 81%), is a white solid. LCMS (ESI) m / z: 257.0 [M+H] + .

[0283] The intermediates in Table 15 were prepared according to the process described above.

[0284] Table 15

[0285] Intermediate 96: 4-(1-isopropyl-4-(trifluoromethyl)-1 H Synthesis of methyl 2-imidazolium-2-yl)benzoate:

[0286] Process B: At 0°C, to 4-(4-(trifluoromethyl)-1 HMethyl 2-imidazolium-2-yl)benzoate (2.0 g, 7.40 mmol) was added to a stirred solution of acetonitrile (30 mL) with Cs₂CO₃ (4.82 g, 14.80 mmol), followed by 2-iodopropane (1.110 mL, 11.10 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was then heated at 50 °C for 16 h. After the reaction was complete (monitored by TLC), the volatiles were removed under reduced pressure, diluted with ethyl acetate, and washed with water. The organic extract was dried over anhydrous Na₂SO₄, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 4-(1-isopropyl-4-(trifluoromethyl)-1 H Methyl 2-imidazol-2-yl)benzoate (0.800 g, 2.229 mmol, 30.1%), is a white solid. LCMS (ESI) m / z: 313.2 [M+H] + .

[0287] The intermediates in Table 16 were synthesized according to the process described above.

[0288] Table 16

[0289] Intermediate 99: (4-(1-isopropyl-4-(trifluoromethyl)-1 H Synthesis of 2-imidazolium-2-yl)phenyl)methanol:

[0290] At 0°C, 4-(1-isopropyl-4-(trifluoromethyl)-1 H Methyl 4-(1-isopropyl-4-(trifluoromethyl)-1-yl)benzoate (0.70 g, 2.241 mmol) was added to a stirred solution of lithium aluminum hydride (2 M, 2.241 mL, 4.48 mmol, in THF) in 10 mL of THF, and the mixture was stirred at 25 °C for 3 h. After the reaction was complete (monitored by TLC), a saturated aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated from the filtrate. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain (4-(1-isopropyl-4-(trifluoromethyl)-1-yl)benzoate. H (-Imidazol-2-yl)phenyl)methanol (0.650 g, 2.242 mmol, 100%), is a white solid. LCMS (ESI) m / z: 285.0 [M+H] + .

[0291] The intermediates in Table 17 were prepared according to the process described above.

[0292] Table 17

[0293] Intermediate 102: Synthesis of 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazolium:

[0294] Triphenylphosphine (3.07 g, 11.71 mmol) and carbon tetrabromide (5.18 g, 15.61 mmol) were added to a stirred solution of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (2 g, 7.81 mmol) in dichloromethane (40 mL), and the mixture was stirred at 25 °C for 16 hours. After the reaction was complete (monitored by TLC), water was added and the mixture was extracted with dichloromethane. The organic extract was dried over anhydrous Na₂SO₄, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to give 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazolium (2 g, 6.27 mmol, 80% yield) as a grayish-white solid. LCMS (ESI) m / z: 318.9 [M+H] + .

[0295] The intermediates in Table 18 were prepared according to the process described above.

[0296] Table 18

[0297] Intermediate 104: 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0298] In a 250 mL round-bottom flask, (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (500.0 mg, 1.717 mmol) was dissolved in DCM (10 mL) at 25 °C, then cooled to 0 °C. At 0 °C, Dess–Martin periodin (1.457 g, 3.43 mmol) was added in portions. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete (monitored by TLC), a saturated aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated from the filtrate. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (430.0 mg, 1.600 mmol, 93% yield)) as a semi-solid. LCMS(ESI) m / z: 255.1 [MH] + .

[0299] The intermediates in Table 19 were prepared according to the process described above.

[0300] Table 19

[0301] Intermediate 106: 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl-1-ol:

[0302] In a 10 mL round-bottom flask, 330.0 mg (1.228 mmol) of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde was dissolved in diethyl ether (5.0 mL) at 25 °C and cooled to 0 °C. At 0 °C, a solution of methyl-magnesium bromide in diethyl ether (1.0 M, 0.818 mL, 2.455 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete (monitored by TLC), a saturated ammonium chloride solution was added, diluted with ethyl acetate, and washed with water. The organic extract was dried over anhydrous Na₂SO₄, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain (1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl-1-ol (330.0 mg, 1.220 mmol, 94% yield)) as a semi-solid. LCMS (ESI) m / z: 271.0 [MH] + .

[0303] The intermediates in Table 20 were prepared according to the process described above.

[0304] Table 20

[0305] Intermediate 108: Synthesis of 1-methyl-4-(trifluoromethyl)-2-(4-((trimethyltinyl)methyl)phenyl)-1H-imidazolium:

[0306] Under a nitrogen atmosphere, at 25 °C, hexamethyldistin (2.60 mL, 12.53 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.880 g, 1.253 mmol) were added to a stirred solution of 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (2.0 g, 6.27 mmol) in toluene (15 mL). The reaction mixture was heated to 90 °C for 2 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from a mixture of filtrate and washings under reduced pressure to obtain a crude product, which was purified by silica gel (60-120 mesh) column chromatography to give 1-methyl-4-(trifluoromethyl)-2-(4-((trimethyltinyl)methyl)phenyl)-1H-imidazolium (1.7 g, 3.92 mmol, 62.6% yield) as a grayish-white solid. LCMS (ESI) m / z: 405.0 [MH] + .

[0307] Intermediate 109: Synthesis of 1-isopropyl-4-(trifluoromethyl)-2-(4-((trimethyltinyl)methyl)phenyl)-1H-imidazolium:

[0308] Under a nitrogen atmosphere, at 25 °C, hexamethyldistin (0.179 mL, 0.864 mmol) and bis(triphenylphosphine)palladium(II) dichloride (81 mg, 0.115 mmol) were added to a stirred solution of 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (200 mg, 0.576 mmol) in toluene (5 mL). The reaction mixture was heated to 90 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washes were mixed with the filtrate. The solvent was evaporated from a mixture of filtrate and washings under reduced pressure to obtain a crude product, which was purified by silica gel (60-120 mesh) column chromatography to give 1-isopropyl-4-(trifluoromethyl)-2-(4-((trimethyltinyl)methyl)phenyl)-1H-imidazole (150 mg, 0.344 mmol, 59.8% yield) as a grayish-white solid. LCMS (ESI) m / z: 433.0 [MH] + .

[0309] Option 7: Synthesis of target intermediates 110 to 116

[0310] Intermediate 110: Synthesis of 2-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile:

[0311] A mixture of 3,3-dibromo-1,1,1-trifluoroprop-2-one (9.21 g, 34.100 mmol) and sodium acetate (5.09 g, 62.100 mmol) in water (20 mL) was stirred at 95 °C for 30 min. The mixture was then cooled to 0 °C, and a cold solution of 4-formyl-2-methoxybenzonitrile (5.0 g, 31.000 mmol) in a mixture of NH4OH (28% aq, 24 mL) and MeOH (100 mL) was added. The resulting mixture was stirred at 25 °C for 16 h. After the reaction was complete (monitored by TLC), the volatiles were evaporated, and the resulting residue was diluted with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na₂SO₄, filtered, and the solvent was evaporated from the filtrate to give 2-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (4.5 g, 12.29 mmol, 39.6% yield) as a pale brown solid. The desired product was not ionized in LCMS and was confirmed in the next step.

[0312] Intermediate 111: Synthesis of 2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile:

[0313] At 0 °C, sodium hydride (60%, in mineral oil, 0.674 g, 11.230 mmol) was added dropwise to a stirred solution of 2-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1.5 g, 5.61 mmol) in DMF (15 mL), and the reaction mixture was stirred at room temperature for 30 min. After 30 min, iodomethane (0.702 mL, 11.230 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (monitored by UPLC / TLC), the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were concentrated under reduced pressure using Na₂SO₄ to obtain a crude product, which was then purified by rapid silica gel (230-400 mesh) column chromatography using a gradient of 15% ethyl acetate (in petroleum ether) to give 2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1.4 g, 4.430 mmol, 79% yield) as a light brown solid. LCMS (ESI) m / z: 282.0 [M+H] + 。

[0314] Intermediate 112: Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzonitrile:

[0315] Cesium carbonate (3.17 g, 9.730 mmol) and 2-iodopropane (0.730 mL, 7.300 mmol) were added to a stirred solution of 2-methoxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1.3 g, 4.870 mmol) in acetonitrile (15 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC / TLC), the reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was then purified by rapid column chromatography on silica gel (230-400 mesh) using a gradient of 35% ethyl acetate (in petroleum ether) to obtain 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzonitrile (1.2 g, 3.260 mmol, 67.0% yield) as a light brown solid. LCMS (ESI) m / z: 310.2 [M+H] + .

[0316] Intermediate 113: Synthesis of 2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoic acid:

[0317] At room temperature, an aqueous solution of NaOH (213 mg, 5.330 mmol) in H₂O (5 mL) was added to a stirred solution of 2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (750 mg, 2.670 mmol) in ethanol (5 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC / TLC), the reaction mixture was concentrated and acidified with citric acid (to pH = 4), and extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were concentrated under reduced pressure using Na₂SO₄ to obtain a crude product, which was then purified by rapid silica gel (230-400 mesh) column chromatography using a gradient of 50% ethyl acetate (in petroleum ether) to give 2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoic acid (700 mg, 2.173 mmol, 81% yield) as an orange solid. LCMS (ESI) m / z: 301.0 [M+H] + .

[0318] The intermediates in Table 21 were prepared according to the process described above.

[0319] Table 21

[0320] Synthesis of Intermediate 115: (2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol:

[0321] At 0 °C, lithium aluminum hydride (1 M, 13.32 mL, 13.320 mmol) was added to a stirred solution of 2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoic acid (800 mg, 2.660 mmol) in THF (15 mL), and the reaction mixture was stirred at 0 °C for 4 hours. After the reaction was complete (monitored by UPLC / TLC), the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. This crude product was then purified by rapid silica gel (230-400 mesh) column chromatography using a gradient of 40-50% ethyl acetate (in petroleum ether) to obtain (2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (600 mg, 79.0% yield), as a colorless liquid. LCMS (ESI) m / z: 287.0 [M+H] + .

[0322] The intermediates in Table 22 were prepared according to the process described above.

[0323] Table 22

[0324] Scheme 20: Synthesis of Examples 60 to 73

[0325] Intermediate 60: Synthesis of 2-chloro-4-((2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0326] Cesium carbonate (683 mg, 2.096 mmol) and 2,4-dichloropyrido[2,3-d]pyrimidine (210 mg, 1.048 mmol) were added to a stirred solution of (2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (300 mg, 1.048 mmol) in acetonitrile (10 mL), and the reaction mixture was heated at 80 °C for 16 h. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (130 mg, 0.254 mmol, 24.27% yield), as a brown solid. LCMS (ESI) m / z: 450.0 [M+H] + .

[0327] Intermediate 61: Synthesis of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzyl)oxy)pyrido[2,3-d]pyrimidine:

[0328] At 0 °C, bis(trimethylsilyl)aminolithium (LiHMDS) (1 M solution, 2.55 mL, 2.55 mmol) was added to a stirred solution of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxyphenyl)methanol (400 mg, 1.273 mmol) and 2,4-dichloropyrido[2,3-d]pyrimidine (305 mg, 1.527 mmol) in THF (10 mL), and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled back to 0 °C, a cooled saturated ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel (60-120 mesh) column chromatography to obtain 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzyl)oxy)pyrido[2,3-d]pyrimidine (100 mg, 0.209 mmol, 16.44% yield), as a pale yellow gel. LCMS (ESI) m / z: 478.2 [M+H] + .

[0329] Intermediate 62: Synthesis of 2-chloro-4-((4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0330] Cesium carbonate (696 mg, 2.136 mmol) and 2,4-dichloropyrido[2,3-d]pyrimidine (256 mg, 1.281 mmol) were added to a stirred solution of (300 mg, 1.068 mmol) in acetonitrile (5 mL), and the reaction mixture was heated at 60 °C for 4 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (200 mg, 0.403 mmol, 37.8% yield), as a grayish-white solid. LCMS (ESI) m / z: 434.2 [M+H] + LC retention time: 2.59 minutes (LCMS method 9).

[0331] Intermediate 63: Synthesis of 2-chloro-4-((4-(1-isobutyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0332] Cesium carbonate (397 mg, 1.220 mmol) and 2,4-dichloropyrido[2,3-d]pyrimidine (146 mg, 0.732 mmol) were added to a stirred solution of (200 mg, 0.610 mmol) in acetonitrile (5 mL), and the reaction mixture was heated at 60 °C for 6 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(1-isobutyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (150 mg, 0.288 mmol, 47.2% yield), as a grayish-white solid. LCMS (ESI) m / z: 462.2 [M+H] + .

[0333] Intermediate 64: Synthesis of 2-chloro-4-((4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0334] Cesium carbonate (2.62 g, 8.05 mmol) and 2,4-dichloropyrido[2,3-d]pyrimidine (0.806 g, 4.03 mmol) were added to a stirred solution of (4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)methanol (1.5 g, 4.03 mmol) in acetonitrile (25 mL), and the reaction mixture was heated at room temperature for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (850 mg, 1.507 mmol, 37.4% yield), as a grayish-white solid. LCMS (ESI) m / z: 536.3 [M+H] + .

[0335] Intermediate 65: Synthesis of 2-chloro-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine:

[0336] At -35 o C. To a stirred solution of 2,4-dichloropyrido[2,3-d]pyrimidine (100 mg, 0.500 mmol) and 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl-1-ol (135 mg, 0.500 mmol) in anhydrous tetrahydrofuran (14 mL), NaHMDS (1 M solution, 0.550 mL, 0.550 mmol in THF) was added, and the mixture was stirred at -35 °C for 20 min. After the reaction was complete (monitored by UPLC-MS and TLC), a cooled saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel (60-120 mesh) column chromatography to obtain 2-chloro-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine (90 mg, 0.191 mmol, 38.2% yield), as a grayish-white solid. LCMS (ESI) m / z: 434.0 [M+H] + .

[0337] Intermediate 66: Synthesis of 2-chloro-4-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine:

[0338] At -35 °C, NaHMDS (1 M solution, 0.500 mL, in THF, 0.500 mmol) was added to a stirred solution of 2,4-dichloropyrido[2,3-d]pyrimidine (100 mg, 0.500 mmol) in anhydrous tetrahydrofuran (14 mL), and the mixture was stirred at -35 °C for 20 min. After the reaction was complete (monitored by UPLC-MS and TLC), a cooled saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel (60-120 mesh) column chromatography to obtain 2-chloro-4-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine (75 mg, 0.155 mmol, 31.1% yield), as a grayish-white solid. LCMS (ESI) m / z: 462.0 [M+H] + .

[0339] Intermediate 67: Synthesis of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[2,3-d]pyrimidine:

[0340] Lithium chloride (191 mg, 4.50 mmol) and 1-methyl-4-(trifluoromethyl)-2-(4-((trimethyltinyl)methyl)phenyl)-1H-imidazolium (1088 mg, 2.70 mmol) were added to a stirred solution of 2,4-dichloropyridino[2,3-d]pyrimidine (600 mg, 3.00 mmol) in 1,4-dioxane (8 mL), and the mixture was purged with N2 gas for 10 min. Then, bis(tri-tert-butylphosphine)palladium(0) (153 mg, 0.300 mmol) was added at 25 °C, and the reaction mixture was heated at 100 °C for 2 h. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washes were mixed with the filtrate. The solvent was evaporated from a mixture of filtrate and washings under reduced pressure to obtain a crude product, which was purified by silica gel (60-120 mesh) column chromatography to give 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[2,3-d]pyrimidine (80 mg, 0.143 mmol, 4.76% yield), as a pale yellow gel. LCMS (ESI) m / z: 404.0 [M+H] + .

[0341] Example 60: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0342] To a stirred solution of 2-chloro-4-((2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (120 mg, 0.267 mmol) in 1,4-dioxane (10 mL), tripotassium phosphate (113 mg, 0.534 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (104 mg, 0.534 mmol) were added, and the mixture was purged with N2 gas for 5 min. Then, tetrakis(triphenylphosphine)palladium(0) (30.8 mg, 0.028 mmol) was added, and the reaction mixture was heated at 120 °C under MW irradiation for 2 h. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC (HPLC method: diluent: THF:water:ACN (30:30:40); column: XBridge Prep C8 OBD (19x150mm) 5μm; temperature: ambient; mobile phase A: 5mM ammonium formate; mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 30, 15 / 70, 17 / 70) to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (9 mg, 0.016 mmol, 5.96% yield), a pale yellow solid. LCMS (ESI) m / z: 564.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ = 9.24 (dd, J = 4.4, 2.0 Hz, 1H), 8.72-8.69 (m, 2H), 7.96 (d, J = 1.2 Hz,1H), 7.77 (dd, J = 8.0, 4.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.35-7.31 (m,2H), 5.70 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 1.89-1.82 (m,1H), 1.11-1.07 (m, 2H), 0.91-0.89 (m, 2H).

[0343] Example 61: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzyl)oxy)pyrido[2,3-d]pyrimidine:

[0344] To a stirred solution of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzyl)oxy)pyrido[2,3-d]pyrimidine (90 mg, 0.188 mmol) in 1,4-dioxane (9 mL), tripotassium phosphate (80 mg, 0.377 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (73.1 mg, 0.377 mmol) were added, and the mixture was purged with N2 gas for 5 min. Then, tetrakis(triphenylphosphine)palladium(0) (21.76 mg, 0.019 mmol) was added, and the reaction mixture was heated at 120 °C under MW irradiation for 2 h. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washes were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC (HPLC method: diluent: THF:water:ACN (30:30:40); column: XBridge Prep C8 OBD (19x150mm) 5μm; temperature: ambient; mobile phase A: 5mM ammonium formate; mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 40, 8 / 80, 12 / 80) to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzyl)oxy)pyrido[2,3-d]pyrimidine (25 mg, 0.042 mmol, 22.17% yield), a grayish-white solid. LCMS (ESI) m / z: 592.2 [M+H] + (400 MHz, DMSO-d) 6 ) δ=9.25 (dd, J = 4.4, 2.0 Hz, 1H), 8.74-8.71 (m, 2H), 8.20 (d, J = 1.2 Hz, 1H),7.78 (dd, J = 8.0, 4.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 1.6Hz, 1H), 7.17 (dd, J = 8.0, 2.0 Hz, 1H), 5.71 (s, 2H), 4.56-4.50 (m, 1H), 3.889 (s, 3H), 3.885 (s, 3H), 1.89-1.82 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H), 1.11-1.08 (m, 2H), 0.90-0.87 (m, 2H).

[0345] Example 62: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0346] Under a nitrogen atmosphere, tripotassium phosphate (86 mg, 0.403 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (46.9 mg, 0.242 mmol), and tetrakis(triphenylphosphine)palladium(0) (23.29 mg, 0.020 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (100 mg, 0.202 mmol) in 1,4-dioxane (10 mL). The reaction mixture was then heated at 60 °C under MW irradiation for 1 hour. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (30:30:40); X-Bridge C8 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 60, 7 / 90, 10 / 90] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (32 mg, 29% yield), as a grayish-white solid. LCMS (ESI) m / z: 548.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ = 9.26 (dd, J = 2.0, 4.4 Hz, 1H), 8.74 (dd, J = 2.1,8.2 Hz, 1H), 8.73 (s, 1H), 8.05 (d, J = 1.3 Hz, 1H), 7.79 (dd, J = 4.4, 8.3Hz, 1H), 7.74 - 7.67 (m, 4H), 5.76 (s, 2H), 4.11 (q, J = 7.3 Hz, 2H), 3.88(s, 3H), 1.91 - 1.82 (m, 1H), 1.34 (t, J= 7.3 Hz, 3H), 1.13 - 1.06 (m, 2H), 0.94 - 0.84 (m, 2H).

[0347] Example 63: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isobutyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0348] Under a nitrogen atmosphere, tripotassium phosphate (81 mg, 0.384 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (44.7 mg, 0.230 mmol), and tetrakis(triphenylphosphine)palladium(0) (22.18 mg, 0.019 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-isobutyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (100 mg, 0.192 mmol) in 1,4-dioxane (5 mL). The reaction mixture was then heated at 60 °C under MW irradiation for 1 hour. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (20:40:40); X-Select C18 (150 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 60, 15 / 90] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isobutyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (15 mg, 14% yield), as a grayish-white solid. LCMS (ESI) m / z: 576.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ = 9.25 (dd, J = 2.0, 4.4 Hz, 1H), 8.74 (dd, J = 2.1,8.2 Hz, 1H), 8.72 (s, 1H), 8.00 (d, J= 1.3 Hz, 1H), 7.79 (dd, J = 4.4, 8.1Hz, 1H), 7.73 - 7.65 (m, 4H), 5.76 (s, 2H), 4.00 - 3.91 (m, 2H), 3.87 (s,3H), 1.99 - 1.80 (m, 2H), 1.12 - 1.02 (m, 2H), 0.93 - 0.83 (m, 2H), 0.71 (d, J = 6.6 Hz, 6H).

[0349] Intermediate 68: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0350] Under a nitrogen atmosphere, tripotassium phosphate (277 mg, 1.306 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (152 mg, 0.784 mmol), and Pd(dppf)Cl2 (96 mg, 0.131 mmol) were added to a stirred solution of 2-chloro-4-((4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (350 mg, 0.653 mmol) in 1,4-dioxane (15 mL), and the reaction mixture was heated at 60 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth mat was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from a mixture of filtrate and washings under reduced pressure to obtain a crude product, which was purified by silica gel (230-400 mesh) column chromatography to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (300 mg, 0.462 mmol, 70.7% yield), as a yellow gel. LCMS (ESI) m / z: 650.2 [M+H] + .

[0351] Example 64: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine:

[0352] Under a nitrogen atmosphere, tripotassium phosphate (72.0 mg, 0.339 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidine (65.6 mg, 0.238 mmol), and tetra(triphenylphosphine)palladium(0) (19.61 mg, 0.017 mmol) were added to a stirred solution of 2-chloro-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrimidine (65.6 mg, 0.238 mmol) and tetra(triphenylphosphine)palladium(0) (19.61 mg, 0.017 mmol) in a mixture of 1,4-dioxane and water (4 mL, 9:1). The reaction mixture was then heated at 120 °C under MW irradiation for 2 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (30:30:40); X-Bridge C8 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 40, 15 / 80] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine (44 mg, 0.075 mmol, 44.2% yield), as a grayish-white solid. LCMS (ESI) m / z: 548.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.25 (dd, J = 2.0, 4.4 Hz, 1H), 8.80 (dd, J = 2.0, 8.3 Hz,1H), 8.71 (s, 1H), 7.94 (d, J = 1.1 Hz, 1H), 7.81 (dd, J= 4.4, 8.1 Hz, 1H),7.76 - 7.68 (m, 4H), 6.57 (q, J = 6.4 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 1.77 (d, J = 6.5 Hz, 3H), 1.81 - 1.73 (m, 1H), 1.10 - 0.99 (m, 2H), 0.92 -0.75 (m, 2H).

[0353] Example 65: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine:

[0354] Under a nitrogen atmosphere, tripotassium phosphate (75 mg, 0.353 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidine (68.3 mg, 0.247 mmol), and tetra(triphenylphosphine)palladium(0) (20.42 mg, 0.018 mmol) were added to a stirred solution of 2-chloro-4-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrimidine (68.3 mg, 0.247 mmol) and tetra(triphenylphosphine)palladium(0) (20.42 mg, 0.018 mmol) in a mixture of 1,4-dioxane and water (4 mL, 9:1). The reaction mixture was then heated at 120 °C under MW irradiation for 2 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then rapidly purified by reverse-phase chromatography (method: diluent: THF:water:ACN (50:20:30); column: Redisep 40 gmC18, 20–40 μM; temperature: ambient; mobile phase A: water; mobile phase B: acetonitrile; eluent (%): 52% acetonitrile / water, flow rate: 30 mL / min). Purification yielded 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)pyrido[2,3-d]pyrimidine (30 mg, 0.049 mmol, 27.7% yield), a grayish-white solid. LCMS (ESI) m / z: 576.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6)δ = 9.25 (dd, J = 2.0, 4.4 Hz, 1H), 8.81 (dd, J = 2.0, 8.3 Hz, 1H), 8.71 (s,1H), 8.18 (d, J = 1.3 Hz, 1H), 7.81 (dd, J = 4.4, 8.1 Hz, 1H), 7.71 (d, J =8.3 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 6.58 (q, J = 6.4 Hz, 1H), 4.52 - 4.41(m, 1H), 3.82 (s, 3H), 1.78 (d, J = 6.5 Hz, 3H), 1.80 - 1.72 (m, 1H), 1.48 -1.35 (m, 8H), 1.05 (dd, J = 2.6, 4.4 Hz, 2H).

[0355] Example 66: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridino[2,3-d]pyrimidine:

[0356] Under a nitrogen atmosphere, tripotassium phosphate (126 mg, 0.594 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (57.7 mg, 0.297 mmol), and tetrakis(triphenylphosphine)palladium(0) (22.89 mg, 0.020 mmol) were added to a stirred solution of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[2,3-d]pyrimidine (80 mg, 0.198 mmol) in 1,4-dioxane (4 mL). The reaction mixture was then heated at 120 °C under MW irradiation for 3 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (30:30:40); X-Bridge Prep C8 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 30, 15 / 70] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[2,3-d]pyrimidine (28 mg, 0.051 mmol, 25.8% yield), a pale yellow solid. LCMS (ESI) m / z: 518.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.30 (dd, J = 1.9, 4.4 Hz, 1H), 9.05 (dd, J = 1.9, 8.4 Hz, 1H), 8.73 (s, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.85 (dd, J =4.4, 8.4 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.54 (d, J = 8.4 Hz, 2H), 4.85 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 1.83 - 1.69 (m, 1H), 1.12 - 1.06 (m, 2H), 0.93 - 0.86 (m, 2H).

[0357] Intermediate 69: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine:

[0358] A solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (300 mg, 0.462 mmol) in trifluoroacetic acid (10 mL) was stirred at 0 °C (in an ice bath) for 1 h, during which time the temperature of the solution was raised to ambient temperature and stirred continuously at 25 °C for 4 h. After the reaction was complete (monitored by TLC and UPLC-MS), a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0 °C and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (300 mg, 0.577 mmol), as a yellow gel. LCMS (ESI) m / z: 520.0 [M+H] + .

[0359] Example 67: Synthesis of methyl 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetate:

[0360] Cesium carbonate (188 mg, 0.577 mmol) and methyl 2-bromoacetate (0.041 mL, 0.433 mmol) were added to a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (150 mg, 0.289 mmol) in acetonitrile (10 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by reversed-phase preparative HPLC [Method: Diluent: Water:THF:MeCN (20:40:40); X-Bridge C18 (150 x19) mm, 5 μM; Temperature: Ambient; Mobile phase A: 5 mM ammonium formate (aqueous solution), Mobile phase B: Acetonitrile; Flow rate: 15 mL / min; Time / gradient: 0 / 40, 10 / 80] to obtain methyl 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetate (18 mg, 0.029 mmol, 10.04% yield), as a grayish-white solid. LCMS (ESI) m / z: 592.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 9.25 (dd, J = 2.0, 4.4 Hz, 1H), 8.74 (d, J = 2.0Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 7.99 (q, J = 1.2 Hz, 1H), 7.79 (dd, J =4.4, 8.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 5.75(s, 2H), 5.09 (s, 2H), 3.87 (s, 3H), 3.64 (s, 3H), 1.85-1.87 (m, 1H), 1.07-1.10 (m, 2H), 0.86-0.91 (m, 2H).

[0361] Example 68: Synthesis of 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetamide:

[0362] Potassium bicarbonate (38.9 mg, 0.281 mmol) and 2-chloroacetamide (11.58 mg, 0.124 mmol) were added to a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (80 mg, 0.113 mmol) in acetonitrile (2 mL), and the reaction mixture was heated at 80 °C for 3 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (20:50:30); Agilent C18 (50 x21.2) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 20, 12 / 60] to obtain 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetamide (33 mg, 50% yield), as a grayish-white solid. LCMS (ESI) m / z: 577.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.25 (dd, J = 1.9, 4.4 Hz, 1H), 8.76 - 8.72 (m, 2H), 7.92 (d, J = 0.9 Hz, 1H), 7.79 (dd, J= 4.4, 8.1 Hz, 1H), 7.74 - 7.68 (m, 3H), 7.65 -7.60 (m, 2H), 7.37 (s, 1H), 5.75 (s, 2H), 4.76 (s, 2H), 3.88 (s, 3H), 1.92 -1.82 (m, 1H), 1.14 - 1.05 (m, 2H), 0.94 - 0.86 (m, 2H).

[0363] Example 69: Synthesis of 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)-N-methylacetamide:

[0364] Cesium carbonate (188 mg, 0.577 mmol) and 2-chloro-N-methylacetamide (0.041 mL, 0.433 mmol) were added to a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (150 mg, 0.289 mmol) in acetonitrile (10 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (20:40:40); X-Bridge C18 (150x19)mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 25, 10 / 65] to obtain 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)-N-methylacetamide (5 mg, 8.34 µmol, 2.89% yield), a white solid. LCMS (ESI) m / z: 591.2 [M+H] + .1H-NMR (400 MHz, DMSO-d6): δ 9.25 (dd, J = 2.0, 4.4 Hz, 1H), 8.75 (d, J =2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.17 (q, J = 4.8 Hz, 1H), 7.92 (q, J =1.2 Hz, 1H), 7.79 (q, J = 4.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.63 (d, J =8.4 Hz, 2H), 5.75 (s, 2H), 4.75 (s, 2H), 3.88 (s, 3H), 2.62 (d, J = 4.80 Hz,3H), 1.85-1.89 (m, 1H), 1.08-1.11 (m, 2H), 0.87-0.92 (m, 2H).

[0365] Example 70: Synthesis of 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)-N,N-dimethylacetamide:

[0366] Potassium bicarbonate (48.6 mg, 0.352 mmol) and 2-chloro-N,N-dimethylacetamide (18.81 mg, 0.155 mmol) were added to a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[2,3-d]pyrimidine (100 mg, 0.141 mmol) in acetonitrile (5 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by reversed-phase preparative HPLC [Method: Diluent: Water:THF:MeCN (30:30:40); X-Bridge C8 (250 x19) mm, 5 μM; Temperature: Ambient; Mobile phase A: 5 mM ammonium formate (aqueous solution), Mobile phase B: Acetonitrile; Flow rate: 15 mL / min; Time / gradient: 0 / 40, 10 / 80] to obtain 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)-N,N-dimethylacetamide (33 mg, 38% yield) as a grayish-white solid. LCMS (ESI) m / z: 605.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ = 9.25 (dd, J = 2.0, 4.4 Hz, 1H), 8.73 (s, 1H),8.73 (dd, J = 2.0, 8.1 Hz, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.81 - 7.77 (m,1H), 7.71 - 7.68 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 5.74 (s, 2H), 5.09 (s,2H), 3.88 (s, 3H), 2.98 (s, 3H), 2.86 (s, 3H), 1.92 - 1.80 (m, 1H), 1.14 -1.05 (m, 2H), 0.93 - 0.85 (m, 2H).

[0367] Examples 71 and 72: Synthesis of 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)ethanol-1-ol and 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)ethanol-1-ol:

[0368] At 0 °C, lithium aluminum hydride (2 M, 0.169 mL, 0.338 mmol) was added to a stirred solution of methyl 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetate (100 mg, 0.169 mmol) in THF (10 mL), and the mixture was stirred at 25 °C for 2 h. After the reaction was complete (monitored by TLC), a saturated aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated from the filtrate. The crude product was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (20:50:30); X-Select C18 (150 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 30, 15 / 70] to obtain 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)ethanol-1-ol (20 mg, 0.035 mmol, 20.77% yield), a white solid. LCMS (ESI) m / z: 564.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.25 (dd, J = 2.0, 4.4 Hz, 1H), 8.76 - 8.72 (m, 2H), 8.00 (d, J = 1.3 Hz, 1H), 7.78 (dd, J= 4.4, 8.2 Hz, 1H), 7.76 - 7.73 (m,2H), 7.72 - 7.69 (m, 2H), 5.75 (s, 2H), 5.09 (t, J = 4.9 Hz, 1H), 4.11 (t, J = 5.4 Hz, 2H), 3.87 (s, 3H), 3.72 (q, J = 5.0 Hz, 2H), 1.95 - 1.79 (m, 1H), 1.14 - 1.05 (m, 2H), 0.94 - 0.84 (m, 2H).

[0369] Example 72 of the reduced compound: 2-(2-(4-(((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)ethanol-1-ol (15 mg, 0.026 mmol, 15.29% yield) was obtained as a white solid. LCMS (ESI) m / z: 566.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1H), 7.99 (s, 1H), 7.70 (d, J = 7.0 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.30 (s, 1H), 6.38 (d, J = 10.0 Hz, 1H), 5.58(d, J = 9.8 Hz, 1H), 5.39 (s, 2H), 5.09 (s, 1H), 4.36 (s, 2H), 4.10 (s, 2H), 3.86 (s, 3H), 3.72 (s, 2H), 1.85 - 1.73 (m, 1H), 1.03 - 0.97 (m, 2H), 0.93 -0.84 (m, 2H).

[0370] Scheme 21: Synthesis of Examples 73 to 80

[0371] Intermediate 70: Synthesis of 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0372] Cesium carbonate (1.310 g, 4.02 mmol) and 2,4-dichloroquinazoline (400 mg, 2.010 mmol) were added to a stirred solution of (566 mg, 2.211 mmol) in acetonitrile (10 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (420 mg, 0.919 mmol, 45.7% yield), as a grayish-white solid. LCMS (ESI) m / z: 419.1 [M+H] + .

[0373] Intermediate 71: Synthesis of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0374] Cesium carbonate (655 mg, 2.010 mmol) and 2,4-dichloroquinazoline (200 mg, 1.005 mmol) were added to a stirred solution of (314 mg, 1.105 mmol) in acetonitrile (10 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (220 mg, 0.438 mmol, 43.6% yield), as a grayish-white solid. LCMS (ESI) m / z: 447.2 [M+H] + .

[0375] Intermediate 72: Synthesis of 2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)oxy)quinazoline:

[0376] Cesium carbonate (819 mg, 2.51 mmol) and 2,4-dichloroquinazoline (250 mg, 1.256 mmol) were added to a stirred solution of ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (354 mg, 1.382 mmol) in acetonitrile (15 mL), and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)oxy)quinazoline (160 mg, 0.382 mmol). [30.4% yield], a white solid. LCMS (ESI) m / z: 419.2 [M+H] + .

[0377] Intermediate 73: Synthesis of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-methoxyquinazoline:

[0378] Cesium carbonate (427 mg, 1.310 mmol) and 2,4-dichloro-5-methoxyquinazoline (150 mg, 0.655 mmol) were added to a stirred solution of (186 mg, 0.655 mmol) in acetonitrile (4 mL), and the reaction mixture was heated at 80 °C for 3 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-methoxyquinazoline (100 mg, 0.186 mmol, 28.3% yield), as a grayish-white solid. LCMS (ESI) m / z: 477.1 [M+H]+ .

[0379] Intermediate 74: Synthesis of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-6-methoxyquinazoline:

[0380] Cesium carbonate (427 mg, 1.310 mmol) and 2,4-dichloro-6-methoxyquinazoline (150 mg, 0.655 mmol) were added to a stirred solution of (205 mg, 0.720 mmol) in acetonitrile (5 mL), and the reaction mixture was heated at 80 °C for 6 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-6-methoxyquinazoline (180 mg, 0.245 mmol, 37.5% yield), as a pale yellow gel. LCMS (ESI) m / z: 477.2 [M+H] + .

[0381] Synthesis of intermediate 75: 2-chloro-5-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0382] At 0 °C, sodium bis(trimethylsilyl)amino (NaHMDS) (1 M solution, 1.037 mL, 1.037 mmol) was added to a stirred solution of 2,4-dichloro-5-fluoroquinazoline (150 mg, 0.691 mmol) and (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (196 mg, 0.691 mmol) in anhydrous tetrahydrofuran (5 mL), and the mixture was stirred at 25 °C for 2 h. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled back to 0 °C, a cooled saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel (60-120 mesh) column chromatography to obtain 2-chloro-5-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (120 mg, 0.250 mmol, 36.2% yield), as a pale yellow gel. LCMS (ESI) m / z: 465.0 [M+H] + .

[0383] Synthesis of intermediate 76: 2-chloro-6-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazolino:

[0384] At 0 °C, sodium bis(trimethylsilyl)amino (NaHMDS) (1 M solution, 1.037 mL, 1.037 mmol) was added to a stirred solution of 2,4-dichloro-6-fluoroquinazoline (150 mg, 0.691 mmol) and (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (196 mg, 0.691 mmol) in anhydrous tetrahydrofuran (4 mL), and the mixture was stirred at 25 °C for 2 h. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled back to 0 °C, a cooled saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel (60-120 mesh) column chromatography to obtain 2-chloro-6-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (80 mg, 0.143 mmol, 20.67% yield), as a pale yellow gel. LCMS (ESI) m / z: 465.0 [M+H] +。

[0385] Example 73: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0386] Under a nitrogen atmosphere, tripotassium phosphate (122 mg, 0.573 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidine (87 mg, 0.315 mmol), and tetrakis(triphenylphosphine)palladium(0) (33.1 mg, 0.029 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine (120 mg, 0.287 mmol), 10 mL, and water (10 mL, 9:1), and the reaction mixture was heated at 120 °C under MW irradiation for 2 h. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from the mixture of filtrate and washings under reduced pressure to obtain the crude product, which was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (20:40:40); Sunfire C18 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 13 mL / min; time / gradient: 0 / 60, 12 / 90] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (30 mg, 0.056 mmol, 19.56% yield), a white solid. LCMS (ESI) m / z: 533.2 [M+H] + (400 MHz, DMSO-d) 6 ) δ = 8.71 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.08-8.00 (m, 2H), 7.95 (d, J = 1.2 Hz, 1H), 7.81-7.75(m, 3H), 7.70 (d, J= 8.4 Hz, 2H), 5.74 (s, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 1.82-1.74 (m, 1H), 1.10-1.05 (m, 2H), 0.91-0.85 (m, 2H).

[0387] Example 74: Synthesis of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0388] Under a nitrogen atmosphere, tripotassium phosphate (203 mg, 0.955 mmol), 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (155 mg, 0.573 mmol), and tetrakis(triphenylphosphine)palladium(0) (55.2 mg, 0.048 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1H-pyrazole (10 mL, 9:1) in a mixture of 1,4-dioxane and water, and the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from the mixture of filtrate and washings under reduced pressure to obtain the crude product, which was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (20:40:40); Sunfire C18 (150 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 13 mL / min; time / gradient: 0 / 60, 7 / 90] to obtain 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (25 mg, 0.047 mmol, 9.88% yield), as a grayish-white solid. LCMS (ESI) m / z: 527.0 [M+H] + (400 MHz, DMSO-d) 6 ) δ 8.30 (dt, J= 8.4 Hz & 0.8Hz, 1H), 8.09-8.00 (m, 2H), 7.95 (d, J = 1.2 Hz, 1H), 7.82-7.75 (m, 4H), 7.71(d, J = 8.4 Hz, 2H), 5.84 (s, 2H), 5.45-5.34 (m, 1H), 3.81 (s, 3H), 1.43 (d, J = 6.8 Hz, 6H).

[0389] Example 75: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0390] Under a nitrogen atmosphere, tripotassium phosphate (190 mg, 0.895 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrimidine (136 mg, 0.492 mmol), and tetrakis(triphenylphosphine)palladium(0) (51.7 mg, 0.045 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-benzyl)pyrimidine (10 mL, 9:1) and water (10 mL, 9:1). The reaction mixture was then heated at 120 °C under MW irradiation for 2 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from the mixture of filtrate and washings under reduced pressure to obtain the crude product, which was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (20:40:40); Sunfire C18 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 13 mL / min; time / gradient: 0 / 60, 5 / 90, 10 / 90] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (30 mg, 0.053 mmol, 11.94% yield), as a white solid. LCMS (ESI) m / z: 561.2 [M+H]+ . (400 MHz, DMSO-d6): 8.71 (s, 1H), 8.33-8.29 (m, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.04-7.98 (m, 2H), 7.80-7.75 (m, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.74(s, 2H), 4.52-4.40 (m, 1H), 3.86 (s, 3H), 1.79-1.71 (m, 1H), 1.41 (d, J = 6.8Hz, 6H), 1.10-1.01 (m, 2H), 0.89-0.84 (m, 2H).

[0391] Example 76: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)oxy)quinazoline:

[0392] Under a nitrogen atmosphere, tripotassium phosphate (152 mg, 0.716 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1H-pyrazol-1-yl)benzyl)oxy)quinazoline (150 mg, 0.358 mmol) in a stirred solution of 2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrimidine (109 mg, 0.394 mmol) and tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.072 mmol) were added to a stirred solution of 1,4-dioxane and water (10 mL, 9:1), and the reaction mixture was heated at 90 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from the mixture of filtrate and washings under reduced pressure to obtain the crude product, which was purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (60:10:30); X-Bridge C18 (150 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 60, 5 / 90, 7 / 80] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)oxy)quinazoline (32 mg, 0.060 mmol, 16.65% yield), as a grayish-white solid. LCMS (ESI) m / z: 533.2 [M+H] + . (400 MHz, DMSO-d6): δ = 8.71 (s, 1H), 8.31(d, J = 8.4 Hz, 1H), 8.06-7.98 (m, 2H), 7.82-7.73 (m, 3H), 7.62 (d, J = 8.4Hz, 2H), 6.78 (s, 1H), 5.75 (s, 2H), 3.87 (s, 3H), 2.37 (s, 3H), 1.83-1.72(m, 1H), 1.09-1.01 (m, 2H), 0.91-0.86 (m, 2H).

[0393] Example 77: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-methoxyquinazoline:

[0394] Under a nitrogen atmosphere, tripotassium phosphate (70.9 mg, 0.334 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (48.6 mg, 0.251 mmol), and tetrakis(triphenylphosphine)palladium(0) (19.30 mg, 0.017 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-methoxyquinazoline (90 mg, 0.167 mmol) in 1,4-dioxane (4 mL), and the reaction mixture was heated at 90 °C for 12 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth mat was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC (HPLC method: diluent: THF:water:ACN (40:20:40); column: X Select CSH C18 (19x250mm) 5μm; temperature: ambient; mobile phase A: 5mM ammonium formate (aqueous solution); mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 40, 10 / 80) to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-methoxyquinazoline (60 mg, 0.095 mmol, 57.1% yield), as a grayish-white solid. LCMS (ESI) m / z: 591.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.19 (d, J = 1.3 Hz, 1H), 7.91 (t, J = 8.3 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.65 - 7.61 (m, 2H), 7.52(dd, J = 0.8, 8.3 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 5.70 (s, 2H), 4.51 (spt, J= 6.6 Hz, 1H), 4.04 (s, 3H), 3.86 (s, 3H), 1.82 - 1.73 (m, 1H), 1.42 (d, J = 6.6 Hz, 6H), 1.08 - 1.03 (m, 2H), 0.90 - 0.84 (m, 2H).

[0395] Example 78: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0396] Under a nitrogen atmosphere, tripotassium phosphate (106 mg, 0.501 mmol), (4-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (120 mg, 0.250 mmol) in 1,4-dioxane (4 mL) with stirring was added to the mixture, and the reaction mixture was heated at 90 °C for 8 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then rapidly purified by reverse-phase chromatography (method: diluent: THF:water:ACN (50:20:30); column: Redisep 40 gm C18, 20–40 μM; temperature: ambient; mobile phase A: water; mobile phase B: acetonitrile; eluent (%): 72% acetonitrile / water, flow rate: 30 mL / min). Purification yielded 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (68 mg, 0.117 mmol, 46.9% yield), as a grayish-white solid. LCMS (ESI) m / z: 579.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.72 (s, 1H), 8.19 (d, J = 1.3 Hz, 1H), 8.01 (dt, J= 5.6, 8.2Hz, 1H), 7.85 (dd, J = 0.7, 8.4 Hz, 1H), 7.72 - 7.68 (m, 2H), 7.64 - 7.60 (m,2H), 7.56 (ddd, J = 0.8, 8.1, 10.9 Hz, 1H), 5.75 (s, 2H), 4.50 (spt, J = 6.6Hz, 1H), 3.87 (s, 3H), 1.86 - 1.78 (m, 1H), 1.42 (d, J = 6.6 Hz, 6H), 1.10 -1.05 (m, 2H), 0.91 - 0.85 (m, 2H).

[0397] Example 79: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-6-methoxyquinazoline:

[0398] Under a nitrogen atmosphere, tripotassium phosphate (106 mg, 0.498 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (72.5 mg, 0.374 mmol), and tetrakis(triphenylphosphine)palladium(0) (28.8 mg, 0.025 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-6-methoxyquinazoline (180 mg, 0.249 mmol) in 1,4-dioxane (4 mL), and the reaction mixture was heated at 90 °C for 12 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from a mixture of filtrate and washings under reduced pressure to obtain the crude product, which was then rapidly purified by reverse-phase chromatography (method: diluent: THF:water:ACN (50:20:30); column: Redisep 40 gm C18, 20–40 μM; temperature: ambient; mobile phase A: water; mobile phase B: acetonitrile; eluent (%): 72% acetonitrile / water, flow rate: 30 mL / min) to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-6-methoxyquinazoline (70 mg, 0.118 mmol, 47.4% yield), as a grayish-white solid. LCMS (ESI) m / z: 591.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.69 (s, 1H), 8.19 (d, J = 1.3 Hz, 1H), 7.95 (d, J = 9.1Hz, 1H), 7.72 - 7.69 (m, 2H), 7.66 (dd, J = 2.9, 9.1 Hz, 1H), 7.63 - 7.59 (m,2H), 7.55 (d, J = 2.9 Hz, 1H), 5.76 (s, 2H), 4.49 (spt, J = 6.6 Hz, 1H), 3.96(s, 3H), 3.85 (s, 3H), 1.80 - 1.68 (m, 1H), 1.42 (d, J= 6.6 Hz, 6H), 1.08 -1.01 (m, 2H), 0.88 - 0.81 (m, 2H).

[0399] Example 80: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline:

[0400] Under a nitrogen atmosphere, tripotassium phosphate (60.6 mg, 0.286 mmol), (4-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (80 mg, 0.143 mmol) in a stirred solution of 2-chloro-6-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)boronic acid (41.6 mg, 0.214 mmol), and tetrakis(triphenylphosphine)palladium(0) (16.51 mg, 0.014 mmol) were added to a stirred solution of 2-chloro-6-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (4 mL) in 1,4-dioxane (4 mL), and the reaction mixture was heated at 90 °C for 12 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC [method: diluent: water:THF:MeCN (30:30:40); X-Bridge C8 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 60, 7 / 90, 10 / 90] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-fluoro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)quinazoline (11 mg, 0.019 mmol, 13.17% yield), as a grayish-white solid. LCMS (ESI) m / z: 579.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.19 (d, J = 1.3 Hz, 1H), 8.11 (dd, J = 5.1, 9.2 Hz, 1H), 8.01 (dd, J= 2.7, 8.4 Hz, 1H), 7.98 - 7.92 (m, 1H),7.72 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 5.74 (s, 2H), 4.49 (spt, J = 6.6 Hz, 1H), 3.85 (s, 3H), 1.81 - 1.72 (m, 1H), 1.41 (d, J = 6.6 Hz, 6H), 1.09 - 1.04 (m, 2H), 0.89 - 0.83 (m, 2H).

[0401] Scheme 24: Synthesis of Example 81.

[0402]

[0403] Intermediate 77: Synthesis of tert-butyl 2,4-dichloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate:

[0404] To a stirred solution of 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid tert-butyl ester (1.0 g, 3.290 mmol) in ethyl acetate (1 mL) and water (1 mL), sodium periodate (3.38 g, 15.780 mmol) and ruthenium(III) chloride hydrate (0.136 g, 0.658 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by UPLC-MS and TLC), water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) using a gradient of 25-30% ethyl acetate (in petroleum ether) to give tert-butyl 2,4-dichloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (700 mg, 2.115 mmol, 64.3% yield), as a white solid, LCMS (ESI) m / z: 316.0 [MH]. + .

[0405] Intermediate 78: Synthesis of tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid:

[0406] To a stirred solution of (1.028 g, 3.620 mmol) bis(trimethylsilyl)aminolithium solution (1 M, 4.93 mL, 4.930 mmol in THF) in THF (10 mL), 1.0 g, 3.290 mmol of tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylate was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was quenched with NH4Cl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography using a gradient of 30-40% ethyl acetate (in petroleum ether) to give tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid (1.1 g, 1.878 mmol, 57.1% yield), as a white solid, LCMS (ESI) m / z: 552.2 [M+H] + .

[0407] Intermediate 79: Synthesis of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid:

[0408] To a stirred solution of 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid tert-butyl ester (1.0 g, 1.707 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.397 g, 2.048 mmol) in 1,4-dioxane (10 mL), tripotassium phosphate (0.725 g, 3.410 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.197 g, 0.171 mmol) were added, and the reaction mixture was purged with nitrogen for 2 min and stirred at 80 °C for 2 h. After the reaction was complete (monitored by UPLC-MS and TLC), water was added and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. This crude product was purified by rapid silica gel (230-400 mesh) chromatography using a gradient of 35% ethyl acetate (in petroleum ether) to give tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid (800 mg, 1.175 mmol, 68.8% yield), as a grayish-white solid. LCMS (ESI) m / z: 666.6 [M+H] + .

[0409] Intermediate 80: Synthesis of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid:

[0410] At 0 °C, potassium permanganate (93 mg, 0.588 mmol) and 18-crown-6 (7.76 mg, 0.029 mmol) were added to a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid tert-butyl ester (200 mg, 0.294 mmol) in 1,2-dichloroethane (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by UPLC-MS), water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic extract was concentrated under reduced pressure to obtain a crude product, which was purified by rapid silica gel (230-400 mesh) chromatography using a gradient of 38% ethyl acetate (in petroleum ether) to give tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid (51 mg, 0.061 mmol, 20.75% yield), as a grayish-white solid. LCMS (ESI) m / z: 680.3 [M+H] + .

[0411] Example 81: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one:

[0412] At 0 °C, trifluoroacetic acid (0.023 mL, 0.299 mmol) was added to a stirred solution of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylate (50 mg, 0.060 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by UPLC-MS), water was added to the reaction mixture, which was neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic extract was concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (method: diluent: THF:water:ACN (40:10:40); column: XBridge-C8 (250 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate; mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 40, 7 / 80, 9 / 80) to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (12 mg, 33.9% yield), a grayish-white solid. LCMS (ESI) m / z: 580.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ = 8.69 (s, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.04 (bs, 1H), 7.67 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 5.60 (s, 2H), 4.52-4.45 (m, 1H), 3.87 (s,3H), 3.46-3.42 (m, 2H), 3.03 (t, J = 6.8 Hz, 2H), 1.80-1.74 (m, 1H), 1.42 (d,J = 6.8 Hz, 6H), 1.06-1.04 (m, 2H), 0.91-0.89 (m, 2H).

[0413] Scheme 22: Synthesis of Examples 82 and 83

[0414] Intermediate 81: Synthesis of tert-butyl 2,4-dichloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate:

[0415] Sodium periodate (3.38 g, 15.780 mmol) and ruthenium(III) chloride hydrate (0.136 g, 0.658 mmol) were added to a stirred solution of 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid tert-butyl ester (1.0 g, 3.290 mmol) in ethyl acetate (1 mL) and water (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by UPLC-MS and TLC), water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain tert-butyl 2,4-dichloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (700 mg, 2.115 mmol, 64.3% yield), a white solid, LCMS (ESI) m / z: 316.0 [MH]. + .

[0416] Intermediate 82: Synthesis of tert-butyl 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate:

[0417] Under a nitrogen atmosphere, trimethylsilyl chloride (0.012 mL, 0.094 mmol) was added to a stirred solution of zinc (123 mg, 1.886 mmol) and 1,2-dibromoethane (8.13 µl, 0.094 mmol) in 10 mL of THF, and the mixture was heated at 65 °C for 1 hour. Then, 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (331 mg, 1.037 mmol) in 2 mL of THF was added to the reaction mixture, and the mixture was stirred continuously at 65 °C for 10 minutes. Subsequently, tert-butyl 2,4-dichloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylate (300 mg, 0.943 mmol) and tetrakis(triphenylphosphine)palladium(0) (109 mg, 0.094 mmol) were added under a nitrogen atmosphere, and the mixture was heated at 65 °C for 2 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The solvent was evaporated from the mixture of filtrate and washings under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel (230-400 mesh) chromatography to obtain tert-butyl 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (110 mg, 0.211 mmol, 22.35% yield), as a pale yellow gel, LCMS (ESI) m / z: 520.0 [MH]. + .

[0418] Intermediate 83: Synthesis of tert-butyl 2-chloro-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate:

[0419] To a stirred solution of 1-isopropyl-4-(trifluoromethyl)-2-(4-((trimethyltinyl)methyl)phenyl)-1H-imidazolium (134 mg, 0.311 mmol) in 1,4-dioxane (10 mL), tert-butyl 2,4-dichloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid (90 mg, 0.283 mmol) was added, and the mixture was purged with N2 gas for 10 min. Then, XPhos Pd G3 (47.9 mg, 0.057 mmol) was added at 25 °C, and the reaction mixture was heated at 110 °C for 16 h. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washes were mixed with the filtrate. The solvent was evaporated from a mixture of filtrate and washings under reduced pressure to obtain a crude product, which was purified by silica gel (60-120 mesh) column chromatography to give tert-butyl 2-chloro-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid (30 mg, 0.055 mmol, 19.28% yield), as a pale yellow gel. LCMS (ESI) m / z: 550.0 [M+H] + .

[0420] Intermediate 84: Synthesis of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one:

[0421] A solution of tert-butyl 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylate (110 mg, 0.211 mmol) in trifluoroacetic acid (3 mL) was stirred at 0 °C (in an ice bath) for 1 hour, during which the temperature of the solution was raised to ambient temperature and stirred continuously at 25 °C for 1 hour. After the reaction was complete (monitored by TLC and UPLC-MS), a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0 °C and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (60-120 mesh) chromatography to obtain 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (70 mg, 0.166 mmol, 79% yield), as a pale yellow gel. LCMS (ESI) m / z: 422.0 [M+H] + .

[0422] Intermediate 85: Synthesis of 2-chloro-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one:

[0423] A solution of tert-butyl 2-chloro-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylate (30 mg, 0.055 mmol) in trifluoroacetic acid (1 mL) was stirred at 0 °C (in an ice bath) for 1 hour, during which the temperature of the solution was raised to ambient temperature and stirred continuously at 25 °C for 30 minutes. After the reaction was complete (monitored by TLC and UPLC-MS), a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0 °C and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (60-120 mesh) chromatography to obtain 2-chloro-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (20 mg, 0.044 mmol, 82% yield), as a brown gel. LCMS (ESI) m / z: 450.0 [M+H] + .

[0424] Example 82: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one:

[0425] Under a nitrogen atmosphere, at 25 °C, tripotassium phosphate (101 mg, 0.474 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-1,3,2-dioxaborane-2-yl)pyrimidine (72.0 mg, 0.261 mmol), and tetrakis(triphenylphosphine)palladium(0) (27.4 mg, 0.024 mmol) were added to a stirred solution of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-one (100 mg, 0.237 mmol) in a mixture of 1,4-dioxane and water (5 mL, 9:1), and the reaction mixture was heated at 90 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC (HPLC method: diluent: THF:water:ACN (40:20:40); column: X-Select C8 OBD (19x150mm) 5μm; temperature: ambient; mobile phase A: 5mM ammonium formate (aqueous solution); mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 30, 12 / 70) to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (32 mg, 0.060 mmol, 25.2% yield), a white solid. LCMS (ESI) m / z: 536.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.68 (s, 1H), 8.35 (s, 1H), 7.90 (d, J =1.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.44 (d, J= 8.4 Hz, 2H), 4.74 (s,2H), 3.85 (s, 3H), 3.75 (s, 3H), 3.46 (dt, J = 3.2, 6.5 Hz, 2H), 3.09 (t, J =6.6 Hz, 2H), 1.70 - 1.60 (m, 1H), 1.08 - 0.99 (m, 2H), 0.88 - 0.82 (m, 2H).

[0426] Example 83: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one:

[0427] Under a nitrogen atmosphere, at 25 °C, tripotassium phosphate (56.6 mg, 0.267 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-1,3,2-dioxaborane-2-yl)pyrimidine (40.5 mg, 0.147 mmol), and tetrakis(triphenylphosphine)palladium(0) (15.41 mg, 0.013 mmol) were added to a stirred solution of 2-chloro-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-one (60 mg, 0.133 mmol) in a mixture of 1,4-dioxane and water (5 mL, 9:1), and the reaction mixture was heated at 90 °C for 16 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was further washed with ethyl acetate, and the washings were mixed with the filtrate. The crude product was obtained by evaporating the solvent from a mixture of filtrate and washings under reduced pressure. It was then purified by reversed-phase preparative HPLC (HPLC method: diluent: THF:ACN (50:50); column: X-Bridge C18 (21.2x250mm) 5μm; temperature: ambient; mobile phase A: 0.1% TFA (aqueous solution); mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 50, 12.75 / 85.80) to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (15 mg, 0.025 mmol, 18.86% yield), a white solid. LCMS (ESI) m / z: 564.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.68 (s, 1H), 8.36 (s, 1H), 8.15 (d, J =1.3 Hz, 1H), 7.46 (s, 4H), 4.75 (s, 2H), 4.44 (spt, J = 6.7 Hz, 1H), 3.86 (s,3H), 3.47 (dt, J = 3.1, 6.5 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 1.69 - 1.61(m, 1H), 1.39 (d, J= 6.6 Hz, 6H), 1.06 - 1.01 (m, 2H), 0.87 - 0.81 (m, 2H).

[0428] Scheme 25: Synthesis of Examples 84 and 85

[0429] Synthesis of intermediate 86: 2,6-dichloro-5-nitropyrimidine-4-amine

[0430] At -78 °C, ammonia (7 M, 1.876 mL, 13.13 mmol) in methanol was added to a solution of 2,4,6-trichloro-5-nitropyrimidine (3.0 g, 13.13 mmol) in THF (40 mL), and the mixture was stirred at -78 °C for 30 min. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature, filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The resulting residue was washed with petroleum ether and dried to give crude 2,6-dichloro-5-nitropyrimidine-4-amine (2.8 g, 13.40 mmol, 100%) as a pale yellow solid, which was used directly in the next reaction. LCMS (ESI) m / z: 208.9 [M+H] + .

[0431] Intermediate 87: Synthesis of 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-nitropyrimidine-4-amine:

[0432] At ambient temperature, NaHMDS (1 M, 7.18 mL, 7.18 mmol in THF) and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (1.349 g, 5.26 mmol) were added to a stirred solution of 2,6-dichloro-5-nitropyrimidine-4-amine (1.0 g, 4.79 mmol) in tetrahydrofuran (15 mL), and the mixture was stirred for 3 hours. The reaction progress was monitored by UPLC-MS. After 3 hours, a saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid silica gel (230-400 mesh) using a gradient of 53-54% ethyl acetate (in petroleum ether) to obtain pure 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-nitropyrimidine-4-amine (0.650 g, 1.213 mmol, 25.3%) as a light brown gel. LCMS (ESI) m / z: 429.0 [M+H] + .

[0433] Intermediate 88: Synthesis of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-nitropyrimidine-4-amine:

[0434] At ambient temperature, 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (0.451 g, 1.67 mmol), tripotassium phosphate (0.644 g, 3.03 mmol), water (0.133 mL), and tetra(triphenylphosphine)palladium(0) (0.350 g, 0.303 mmol) were added to a stirred solution of 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidine-4-amine (0.650 g, 1.52 mmol) in 1,4-dioxane (2 mL). The reaction mixture was purged with nitrogen under a nitrogen atmosphere and then stirred at 45 °C for 4 hours. After the reaction was complete (monitored by UPLC-MS and TLC), the reaction mixture was cooled to ambient temperature and mixed with another batch from the same reaction (containing 0.200 g of 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-nitropyrimidine-4-amine), cooled with water, and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by rapid chromatography using an Isolara system with ethyl acetate and petroleum ether (3:7) as eluent to give 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-nitropyrimidine-4-amine (0.450 g, 0.84 mmol, 42.3%) as a yellow solid. LCMS (ESI) m / z: 537.2 [M+H] + .

[0435] Intermediate 89: Synthesis of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrimidine-4,5-diamine:

[0436] At 25 °C, ammonium formate (0.528 g, 8.38 mmol) and zinc (0.548 g, 8.38 mmol) were added to a stirred solution of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-nitropyrimidine-4-amine (0.450 g, 0.84 mmol) in acetonitrile (15 mL), and the mixture was stirred for 2 hours. After the reaction was complete (monitored by UPLC-MS), the reaction mixture was filtered and the solvent was evaporated from the filtrate to obtain crude 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrimidine-4,5-diamine (0.400 g, 0.79 mmol, 94% yield), a yellow gel, which was used directly in the next reaction. LCMS (ESI) m / z: 507.2 [M+H] + .

[0437] Example 84: Synthesis of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one:

[0438] At ambient temperature, a solution of methyl 2-oxoacetate in toluene (0.208 g, 1.18 mmol) and acetic acid (4.52 µl, 0.08 mmol) was added to a stirred solution of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrimidine-4,5-diamine (0.400 g, 0.79 mmol) in ethanol (20 mL), and the mixture was heated at 90 °C for 4 hours. The mass of the product 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one (10 mg, 0.016 mmol, 2.080% yield) was observed by UPLC-MS. After the reaction was complete (monitored by UPLC-MS), cooling water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by reversed-phase preparative HPLC [Method: Diluent: Water:THF:MeCN (30:30:40); XBridge C8 (250 x19) mm, 5 μM; Temperature: Ambient; Mobile phase A: 5 mM ammonium formate (aqueous solution), Mobile phase B: acetonitrile; Flow rate: 15 mL / min; Time / gradient: 0 / 40, 7 / 80, 9 / 80] to obtain 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one (0.010 g, 0.016 mmol, 2.08%), as a grayish-white solid. LCMS (ESI) m / z: 545.0 [M+H] + . 1 H-NMR: (400 MHz, DMSO-d) 6 ) δ = 13.26 (s, 1H), 8.17 (s, 1H), 7.95 (m,1H), 7.76-7.79 (m, 3H), 7.60-7.66 (m, 2H), 5.75 (s, 2H), 5.44-5.48 (m, 1H), 3.80 (s, 3H), 1.41 (d, J = 6.40 Hz, 6H).

[0439] Intermediate 90: Synthesis of 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrimidine-4,5-diamine:

[0440] Iron powder (0.228 g, 4.09 mmol) was added to a stirred solution of 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-5-nitropyrimidine-4-amine (0.400 g, 0.68 mmol) in a mixture of ethanol (4 mL) and acetic acid (4 mL), and the mixture was heated at 60 °C for 6 hours. After the reaction was complete (monitored by TLC and UPLC-MS), the reaction mixture was cooled to ambient temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous ammonium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The obtained crude 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrimidine-4,5-diamine (0.700 g), which was a brown solid, was washed with diethyl ether, dried, and used for the next step without further purification. LCMS (ESI) m / z: 399.0 [M+H] + .

[0441] Intermediate 91: Synthesis of 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-6(5H)-one and / or 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one:

[0442] At ambient temperature, methyl 2-oxoacetate (0.204 mL, 1.475 mmol) and acetic acid (8.44 µL, 0.147 mmol) were added to a stirred solution of 2-chloro-6-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrimidine-4,5-diamine (0.700 g crude, considered as 1.47 mmol) in ethanol (10 mL), and the mixture was heated at 60 °C for 3 hours. The reaction progress was monitored by UPLC-MS. After 3 hours, the reaction mixture was cooled to ambient temperature. The precipitate was intentionally filtered and washed with diethyl ether to obtain 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-6(5H)-one and / or 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one (0.350 g, 0.745 mmol, 50.5%) as a grayish-white solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: 437.0 [M+H] + .

[0443] Example 85: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one:

[0444] At 25 °C under a nitrogen atmosphere, (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.0496 g, 0.256 mmol), cesium carbonate (0.173 g, 0.532 mmol), and Xphos-Pd-G2 (0.0168 g, 0.021 mmol) were added to a stirred solution of 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one (0.100 g, 0.213 mmol) in 1,4-dioxane (2 mL), and the mixture was heated at 80 °C for 16 h. The reaction progress was monitored by TLC and UPLC-MS. After 16 hours, the reaction mixture was cooled to ambient temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by preparative HPLC [method: diluent: THF: MeCN: water (10:30:60); X-SELECT-C18 (150 x19) mm, 5 μM; temperature: ambient; mobile phase A: 5 mM ammonium formate (aqueous solution), mobile phase B: acetonitrile; flow rate: 15 mL / min; time / gradient: 0 / 20, 3 / 20, 15 / 70] to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pteridine-7(8H)-one (0.0018 g, 3.05 µmol, 1.43%), as a grayish-white solid. LCMS (ESI) m / z: 551.2 [M+H] + . 1 H-NMR: (400 MHz, DMSO-d) 6 ) δ = 10.59 (s, 1H), 8.68 (d, J = 3.2 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.73 - 7.65 (m, 4H), 6.84 (d, J = 6.4 Hz, 1H), 5.51 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 1.72-1.66 (m, 1H), 1.05-0.98 (m, 2H), 0.88-0.83(m, 2H).

[0445] Rhodamine determination of USP1-UAF1

[0446] The USP1 / UAF1 ubiquitin-rhodamine 110 hydrolysis assay was performed at room temperature in a black, low-volume 384-well plate (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 Bay Bio 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). Serially diluted compounds in DMSO were transferred to the assay plate (100 nL per well) by ultrasonic dispensing. Add 5 μL of assay buffer to column 1 of the plate, and 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). Fluorescence was read at minimum kinetic intervals using a BioTek Synergy HTX microplate reader (Agilent Technologies) for 1 hour, with excitation at 485 nm and emission at 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.

[0447] IC50 of the compound of the present invention in the USP1-UAF1 rhodamine assay 50 The values ​​are shown below.

[0448] Table 3: 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 selected from non-existent and C. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 4 R groups. 100 replace; Y does not exist or is -O-; W 1 W 2 W 3 and W 4 Each is independently selected from -N(R) a -, -C(O)- and -C(R)- a )-; W 5 Selected from -N- and -C(R) a )-; Among them W 1 W 2 W 3 and W 4 At least one of them is -C(R) a - or -C(O)-; 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 and 4-6 membered heterocyclic groups; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are each optionally surrounded by 1 to 4 R groups. 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 -NR 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 (II): ； Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

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

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

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

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

7. The compound of claim 1, having a structure of formula (VIIa), (VIIb) or (VIIc): Or its pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers; Where R 5 It is C 1-6 alkyl.

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

9. The compound according to any one of claims 1-8, wherein R 1 Selected from: and ; Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

10. The compound according to any one of claims 1-9, 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.

11. The compound according to any one of claims 1-3, wherein G 2 Selected from: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue.

12. The compound according to any one of claims 1-11, wherein Y is selected from absent and O, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers or deuterated analogs thereof.

13. The compound of claim 1, wherein the compound is selected from Table A, or a pharmaceutically acceptable salt thereof; Table A 。 14. A pharmaceutical composition comprising one or more compounds according to any one of the preceding claims and a pharmaceutically acceptable carrier or diluent.

15. 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.

16. A method of treating cancer, comprising administering to a patient in need a therapeutically effective amount of the compound according to claims 1-13 or a pharmaceutically acceptable salt thereof.

17. The method of claim 16, 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.

18. The method of claim 16, 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.

19. The method of claim 16, 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).

20. The method according to any one of claims 15-19, further comprising administering at least one additional anticancer agent or therapy.

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