Compounds and compositions as eIF4E inhibitors and uses thereof

Abstract

Described herein are compounds of Formula I and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, and their uses (e.g., as eIF4E inhibitors).

Description

[0001] Related applications

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 424,463, filed on November 10, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] background

[0004] Eukaryotic initiation factor 4E (eIF4E) is a limiting protein factor that enables the initiation of mRNA translation. For example, eIF4E has been shown to regulate the translation of cyclin D mRNA. eIF4E initiates translation by binding to the 7-methylguanosine cap at the 5' end of the mRNA, recruiting other members of the eIF4F complex, including the scaffolding protein eIF4G and the RNA helicase eIF4A. Once assembled at the 5' end of the mRNA, the eIF4F complex recruits additional translation initiation factors, ultimately leading to ribosome recruitment and the initiation of protein translation.

[0005] Under basic conditions, the activity of eIF4E is regulated by multiple mechanisms, including binding to and chelating with the abundant negative regulatory protein 4E binding protein (4EBP). In cancer, eIF4E activity is increased through several mechanisms, including mutation activation of oncogenic signaling pathways, such as receptor tyrosine kinases (RTKs), RAS / RAF family members, PI3K family members, and other pathways that converge on eIF4E (REF). The dysregulated expression of eIF4E itself is tumor-promoting, emphasizing its important role in cell transformation and cancer formation. In addition, it has been shown that increased expression in patients leads to poor prognosis for a variety of indications, including breast cancer, head and neck cancer, ovarian cancer, and colorectal cancer. It has also been reported that the upregulation of eIF4E activity is important for the evolution of resistance to chemotherapeutic agents and targeted cancer agents. Finally, genetic inhibition of eIF4E and other aspects of the destruction of the MNK1-eIF4E axis have demonstrated anti-tumor efficacy in a variety of preclinical models, including melanoma, ovarian cancer, esophageal cancer, lung cancer, and breast cancer.

[0006] Therefore, pharmacological inhibition of eIF4E activity has the potential to be an effective anti-tumor therapy.

[0007] Overview

[0008] In certain aspects, the present disclosure provides compounds of Formula I, Formula I', or Formula I":

[0009]

[0010]

[0011] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein each variable in Formula I and Formula I' is described, reflected, and exemplified herein.

[0012] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0013] In certain aspects, the disclosure provides methods of inhibiting a protein in a subject or a biological sample, the method comprising administering to the subject a compound disclosed herein or contacting the biological sample with a compound disclosed herein.

[0014] In certain aspects, the disclosure provides use of a compound disclosed herein in the preparation of a medicament for inhibiting a protein in a subject or biological sample.

[0015] In certain aspects, the disclosure provides compounds disclosed herein for use in inhibiting a protein in a subject or biological sample.

[0016] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein.

[0017] In certain aspects, the present disclosure provides the use of a compound disclosed herein in the preparation of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0018] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0019] The details of the present disclosure are set forth in the accompanying description below. Illustrative methods and materials are now described, although methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure. Other features, objects, and advantages of the present disclosure will be apparent from the specification and claims. In this specification and the appended claims, unless the context clearly indicates otherwise, the singular also includes the plural. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs.

[0020] All publications and patents mentioned herein are hereby incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0021] Details

[0022] The present disclosure relates to compounds that inhibit eIF4E activity and pharmaceutical compositions thereof. The present disclosure also relates to methods of inhibiting proteins in a subject or biological sample, comprising administering to the subject a compound described herein or contacting the biological sample with a compound described herein. The present disclosure also relates to methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound described herein.

[0023] Compounds of the present application

[0024] In certain aspects, the present disclosure provides compounds of Formula I":

[0025]

[0026] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof,

[0027] in:

[0028] Each -L- is independently -O-, -NR L -、-CR L1 R L2 -、-CR L1 =CR L2 -or-C≡C-;

[0029] Each R L are independently hydrogen or optionally substituted C 1-6 alkyl;

[0030] Each R L1 and each R L2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein the alkyl, alkoxy or alkylamino group is optionally substituted;

[0031] q is an integer selected from 1 to 5;

[0032] Ring C and Ring D are independently C 6-10 aryl or 5- to 10-membered heteroaryl;

[0033] R C1 , each R C2 and each R D are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0034] r and s are independently integers selected from 0 to 6 when valence permits;

[0035] R 2 It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or -C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted,

[0036] R 1 Yes-NR 1a R 1b OR 1c ;

[0037] R 1’ It is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; or

[0038] R 1 and R 1’ Together with the carbon atoms to which they are bonded, they form C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted;

[0039] R 1a and R 1b are independently hydrogen, -CN, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 Carbocyclic), -(C 1-6 alkylene)-(3 to 12 membered heterocyclic group), -S(=O)R a 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d , wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; or

[0040] R 1a and R 1b Together with the nitrogen atom to which they are bound, they form a 3- to 12-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by one or more R ab replace;

[0041] Each R ab are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, or -S(=O)R a , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted; or

[0042] Two adjacent R ab Together with the atoms to which they are bound, they form a C6 aryl or a 5- to 6-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0043] R 1c It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d , wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0044] X is -O- or -C(R X )2-;

[0045] Each R X are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0046] Two R's X Together with the carbon atom to which they are bonded, they form an oxo group; or

[0047] Two R's X Together with the carbon atoms to which they are bonded, they form C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted;

[0048] Each R A1 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; or

[0049] R X and adjacent R A1 Together with the carbon atoms to which they are bonded, they form C 3-4 carbocyclyl or 3- to 4-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted;

[0050] m and m' are independently integers selected from 0 to 2;

[0051] Each RA are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0052] n is an integer selected from 0 to 10 when valence permits;

[0053] R B It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0054] in:

[0055] Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0056] Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and

[0057] Each R c and each R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or

[0058] R c and R dtogether with the nitrogen atom to which they are bound, form a 3- to 12-membered heterocyclic group;

[0059] where R a 、R b 、R c and R d Each occurrence of is independently and optionally substituted.

[0060] In certain embodiments, the present disclosure provides compounds of Formula I':

[0061]

[0062] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof,

[0063] in:

[0064] Each -L- is independently -O-, -NR L -、-CR L1 R L2 -、-CR L1 =CR L2 -or-C≡C-;

[0065] Each R L are independently hydrogen or optionally substituted C 1-6 alkyl;

[0066] Each R L1 and each R L2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein the alkyl, alkoxy or alkylamino group is optionally substituted;

[0067] q is an integer selected from 1 to 5;

[0068] Ring C and Ring D are independently C 6-10 aryl or 5- to 10-membered heteroaryl;

[0069] R C1 , each R C2 and each R D are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0070] r and s are independently integers selected from 0 to 6 when valence permits;

[0071] R 2 It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or -C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted,

[0072] R 1 Yes-NR 1a R 1b OR 1c ;

[0073] R 1’ It is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; or

[0074] R 1 and R 1’ Together with the carbon atoms to which they are bonded, they form C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted;

[0075] R 1a and R 1b are independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 Carbocyclic), -(C 1-6 alkylene)-(3 to 12 membered heterocyclic group), -S(=O)R a 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d , wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; or

[0076] R 1a and R 1b Together with the nitrogen atom to which they are bound, they form a 3- to 12-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by one or more R ab replace;

[0077] Each R ab are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, or -S(=O)R a , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted; or

[0078] Two adjacent R ab Together with the atoms to which they are bound, they form a C6 aryl or a 5- to 6-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0079] R 1c It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d , wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0080] X is -O- or -C(R X )2-;

[0081] Each R X are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0082] Two R's X Together with the carbon atom to which they are bonded, they form an oxo group; or

[0083] Two R's X Together with the carbon atoms to which they are bonded, they form C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted;

[0084] m and m' are independently integers selected from 0 to 2;

[0085] Each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0086] n is an integer selected from 0 to 10 when valence permits;

[0087] R B It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0088] in:

[0089] Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0090] Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and

[0091] Each R c and each R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or

[0092] R c and R d together with the nitrogen atom to which they are bound, form a 3- to 12-membered heterocyclic group;

[0093] where R a 、R b 、R c and R d Each occurrence of is independently and optionally substituted.

[0094] In certain embodiments, the present disclosure provides compounds of Formula I:

[0095]

[0096] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof,

[0097] in:

[0098] Each -L- is independently -O-, -NR L-、-CR L1 R L2 -、-CR L1 =CR L2 -or-C≡C-;

[0099] Each R L are independently hydrogen or optionally substituted C 1-6 alkyl;

[0100] Each R L1 and each R L2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein the alkyl, alkoxy or alkylamino group is optionally substituted;

[0101] q is an integer selected from 1 to 5;

[0102] Ring C and Ring D are independently C 6-10 aryl or 5- to 10-membered heteroaryl;

[0103] R C1 , each R C2 and each R D are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0104] r and s are independently integers selected from 0 to 6 when valence permits;

[0105] R 2 It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a or -C(=O)OR b, wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted,

[0106] R 1 Yes-NR 1a R 1b OR 1c ;

[0107] R 1a and R 1b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 Carbocyclic), -(C 1-6 alkylene)-(3 to 12 membered heterocyclic group), -S(=O)R a 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d , wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; or

[0108] R 1a and R 1b together with the nitrogen atom to which they are bound, form a 3- to 12-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted;

[0109] R 1c It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0110] X is -O- or -C(R X )2-;

[0111] Each R X are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; or

[0112] Two R X Together with the carbon atom to which they are bonded, they form an oxo group;

[0113] m and m' are independently integers selected from 0 to 2;

[0114] Each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0115] n is an integer selected from 0 to 10 when valence permits;

[0116] R B It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0117] in:

[0118] Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0119] Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and

[0120] Each R c and each R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or

[0121] R c and R d together with the nitrogen atom to which they are bound, form a 3- to 12-membered heterocyclic group;

[0122] where R a 、R b 、R c and R d Each occurrence of is independently and optionally substituted.

[0123] In certain embodiments, the compound of Formula I″ is a compound of Formula I″-1-i, Formula I″-1-ii, Formula I″-1-iii, or Formula I″-1-iv:

[0124]

[0125] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0126] In certain embodiments, the compound of Formula I' is a compound of Formula I'-1-i, Formula I'-1-ii, Formula I'-1-iii, or Formula I'-1-iv:

[0127]

[0128] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0129] In certain embodiments, the compound of Formula I is a compound of Formula I-1-i, Formula I-1-ii, Formula I-1-iii, or Formula I-1-iv:

[0130]

[0131] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0132] In certain embodiments, the compound of Formula I″ is a compound of Formula I″-1-i-1, Formula I″-1-i-2, Formula I″-1-i-3, Formula I″-1-iii-1, Formula I″-1-iii-2, or Formula I″-1-iii-3:

[0133]

[0134]

[0135] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0136] In certain embodiments, the compound of formula I' is a compound of formula I'-1-i-1, formula I'-1-i-2, formula I'-1-i-3, formula I'-1-iii-1, formula I'-1-iii-2, or formula I'-1-iii-3:

[0137]

[0138] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0139] In certain embodiments, the compound of Formula I is a compound of Formula I-1-i-1, Formula I-1-i-2, Formula I-1-i-3, Formula I-1-iii-1, Formula I-1-iii-2, or Formula I-1-iii-3:

[0140]

[0141] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0142] Embodiments of the variables in any formula described herein (e.g., Formula I-Formula I-1-iii-3, as applicable) are described below. Any variable can be any moiety as described in the embodiments below. In addition, any moiety described for any variable can be combined with any moiety described for any remaining variable when applicable.

[0143] In certain embodiments, R 1 Yes-NR 1a R 1b OR 1c In certain embodiments, R 1 Yes-NR 1aR 1b In certain embodiments, R 1 Yes-OR 1c .

[0144] In certain embodiments, R 1 Yes-NR 1a R 1b .

[0145] In certain embodiments, R 1a and R 1b are each independently hydrogen; C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)); C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)); C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)); C 6-10 Aryl (eg, phenyl or naphthyl); 5- to 10-membered heteroaryl (eg, a heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S); C 3-12 Carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) carbocyclyl, including, for example, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodec ... 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )); 3 to 12 membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) heterocyclyl, comprising one or two 3 to 8 membered rings and 1-5 heteroatoms selected from N, O and S); -(C 1-6 alkylene)-(C 6-10aryl); -(C 1-6 alkylene)-(5- to 10-membered heteroaryl);-(C 1-6 alkylene)-(C 3-12 carbocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged or fused) carbocyclyl); -(C 1-6 alkylene)-(3- to 12-membered heterocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged, or fused) heterocyclyl); -S(=O)R a ;-S(=O)2R a ; -S(=O)2OR b ;-S(=O)2NR c R d ;-C(=O)R a ;-C(=O)OR b or -C(=O)NR c R d , wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, C 1-6 The olefin is selected from methylene (-CH)2-, ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). In certain embodiments, R 1a and R 1b Each optionally independently replaced by one or more R u replace.

[0146] In certain embodiments, R 1a and R 1b are independently hydrogen, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) carbocyclyl), 3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) heterocyclyl), -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 Carbocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged or fused) carbocyclyl)), -(C 1-6 alkylene)-(3- to 12-membered heterocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged, or fused) heterocyclyl)), -S(=O)Ra 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d , wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 1a and R 1b Each optionally independently replaced by one or more R u replace.

[0147] In certain embodiments, R 1a and R 1b are independently hydrogen, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) carbocyclyl), 3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) heterocyclyl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(C 3-12 Carbocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged or fused) carbocyclyl)), -(C 1-6 alkylene)-(3 to 12 membered heterocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged or fused) heterocyclyl)), -S(=O)2R a or -C(=O)R a , wherein alkyl, alkylene, carbocyclyl, heterocyclyl or heteroaryl is optionally substituted. In certain embodiments, R 1a and R 1b Each optionally independently replaced by one or more R u replace.

[0148] In certain embodiments, R 1a and R 1b are independently hydrogen, -CN, C 1-6 Alkyl, C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) carbocyclyl), 3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) heterocyclyl), -(C1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged or fused) carbocyclyl)) or -(C 1-6 alkylene)-(3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) heterocyclyl), wherein the alkyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0149] In certain embodiments, R 1a and R 1b are each independently hydrogen, optionally substituted C 1-6 Alkyl, -S(=O)R a 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d .

[0150] In certain embodiments, R 1a and R 1b At least one of them is hydrogen, R 1a and R 1b In certain embodiments, at least one of R 1a and R 1b At least one of which is optionally substituted C 1-6 In certain embodiments, R 1a and R 1b At least one of which is optionally substituted C 6-10 In certain embodiments, R 1a and R 1b At least one of is an optionally substituted 5- to 10-membered heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of which is optionally substituted C 3-12 In certain embodiments, R 1a and R 1bAt least one of is an optionally substituted 3- to 12-membered heterocyclyl (e.g., a monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6 alkylene)-(C 6-10 In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6 In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6 alkylene)-(C 3-12 In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6 In certain embodiments, R 1a and R 1b At least one of them is -S(=O)2R a In certain embodiments, R 1a and R 1b At least one of them is -C(=O)R a In certain embodiments, R 1a and R 1b Optionally, one or more R u replace.

[0151] In certain embodiments, R 1a and R 1b At least one of which is optionally substituted C 6-10 In certain embodiments, the aryl group is optionally replaced by one or more R u replace.

[0152] In certain embodiments, R 1a and R 1bAt least one of is an optionally substituted 5- to 10-membered heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b is an optionally substituted heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heteroaryl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heteroaryl group comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heteroaryl group comprising two 5-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heteroaryl group comprising two 6-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heteroaryl group comprising a 5-membered ring and a 6-membered ring and 1-5 heteroatoms selected from N, O and S. In certain embodiments, the heteroaryl group is optionally substituted with one or more R u replace.

[0153] In certain embodiments, R 1a and R 1b At least one of which is optionally substituted C 3-12 Carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged or fused) carbocyclyl, including, for example, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodec ... 10 ), cyclodecenyl (C10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 In certain embodiments, the carbocyclyl group is optionally replaced by one or more R u replace.

[0154] In certain embodiments, R 1a and R 1b At least one of is an optionally substituted 3 to 12 membered heterocyclyl (e.g., a monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprising one or two 3 to 8 membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heterocyclyl group comprising a 3 to 8 membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heterocyclyl group comprising a 3-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b is an optionally substituted heterocyclyl group comprising a 4-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heterocyclyl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heterocyclyl group comprising a 6-membered ring and 1-4 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b is an optionally substituted heterocyclyl group comprising a 7-membered ring and 1-4 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heterocyclyl group comprising an 8-membered ring and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprising two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1bAt least one of is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of the is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprising a 5-membered ring and a 6-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heterocyclyl is optionally substituted by one or more R u replace.

[0155] In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6 alkylene)-(C 6-10 In certain embodiments, aryl is optionally substituted with one or more R u replace.

[0156] In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6 In certain embodiments, the optionally substituted heteroaryl comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heteroaryl comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heteroaryl comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heteroaryl comprises one 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heteroaryl comprises two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heteroaryl comprises two 5-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heteroaryl group comprises two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heteroaryl group comprises one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heteroaryl group is optionally substituted with one or more R u replace.

[0157] In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6 alkylene)-(C 3-12 Carbocyclyl (eg, monocyclic or polycyclic (eg, spiro, bridged or fused) carbocyclyl), wherein C 3-12 Carbocyclyl, for example, monocyclic or polycyclic (e.g., spiro, bridged or fused) carbocyclyl, includes cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodec ... 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) and spiro[4.5]decyl (C 10 ), wherein the alkylene or carbocyclyl is optionally substituted. In certain embodiments, the carbocyclyl is optionally substituted with one or more R u replace.

[0158] In certain embodiments, R 1a and R 1b At least one of them is -(C 1-6In some embodiments, the optionally substituted heterocyclyl comprises one 3 to 8-membered ring and 1-3 heteroatoms selected from N, O and S. In some embodiments, the optionally substituted heterocyclyl comprises one 3 to 8-membered ring and 1-3 heteroatoms selected from N, O and S. In some embodiments, the optionally substituted heterocyclyl comprises one 3 to 12-membered ring and 1-3 heteroatoms selected from N, O and S. In some embodiments, the optionally substituted heterocyclyl comprises one 4-membered ring and 1-3 heteroatoms selected from N, O and S. In some embodiments, the optionally substituted heterocyclyl comprises one 5-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heterocyclyl comprises a 6-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises a 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises an 8-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 3-8 membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, optionally substituted heterocyclyls (e.g., polycyclic (e.g., spiro, bridged, or fused) heterocyclyls) contain two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, optionally substituted heterocyclyls (e.g., polycyclic (e.g., spiro, bridged, or fused) heterocyclyls) contain one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, heterocyclyls are optionally substituted with one or more R u replace.

[0159] In certain embodiments, R 1a and R 1b At least one of them is -S(=O)R a 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R dIn certain embodiments, R 1a and R 1b At least one of them is -S(=O)2R a In certain embodiments, R 1a and R 1b At least one of them is -C(=O)R a .

[0160] In certain embodiments, R 1a and R 1b Together with the nitrogen atom to which they are bound, they form an optionally substituted 3- to 12-membered heterocyclic ring (e.g., a monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclic ring comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). In certain embodiments, R 1a and R 1b Together with the nitrogen atom to which they are bound, they form a u In certain embodiments, R 1a and R 1b Together with the nitrogen atom to which they are bound, they form a abIn certain embodiments, the optionally substituted heterocyclic radical comprises a 3- to 8-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclic radical comprises a 3- to 8-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclic radical comprises a 4-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclic radical comprises a 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclic radical comprises a 6-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclic radical comprises a 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclic radical comprises an 8-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0161] In certain embodiments, each R ab are independently oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., a heterocyclyl comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O and S), C 6-10 Aryl (i.e., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., a heteroaryl group comprising one or two rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted. In certain embodiments, R ab Optionally, one or more R u replace.

[0162] In certain embodiments, each R ab are independently oxo, halogen, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, or -S(=O)R a , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally replaced by one or more R u replace.

[0163] In certain embodiments, each R ab are independently oxo, halogen, -OH, C1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, or -S(=O)R a , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally replaced by one or more R u replace.

[0164] In certain embodiments, two adjacent R ab Together with the atoms to which they are bound, they form a C6 aryl (i.e., phenyl) or a 5- to 6-membered heteroaryl (e.g., a heteroaryl comprising a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S), wherein the aryl or heteroaryl is optionally substituted. In certain embodiments, the two ortho-positions R ab Together with the atoms to which they are bound, they form a C6 aryl or a 5- to 6-membered heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by one or more R u replace.

[0165] In certain embodiments, R 1 Yes-OR 1c .

[0166] In certain embodiments, R 1c is hydrogen, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O and S), C 3-12Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), -C(=O)R a ,-C(=O)OR b or -C(=O)NR c R d , wherein alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 1c Optionally, one or more R u replace.

[0167] In certain embodiments, R 1c It is hydrogen, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d , wherein alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 1c Optionally, one or more R u replace.

[0168] In certain embodiments, R 1c It is C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 In certain embodiments, R 1c Optionally, one or more R u replace.

[0169] In certain embodiments, R 1c It is C 1-6 In certain embodiments, R 1c is optionally substituted C 1-6 In certain embodiments, R 1c is an optionally substituted 3 to 12 membered heterocyclyl. In certain embodiments, R 1c Optionally, one or more R u replace.

[0170] In certain embodiments, R 1c is optionally substituted C 6-10 In certain embodiments, the aryl group is optionally replaced by one or more R u replace.

[0171] In certain embodiments, R 1c is an optionally substituted 5- to 10-membered heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1c is an optionally substituted heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heteroaryl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heteroaryl group comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heteroaryl group comprising two 5-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heteroaryl group comprising two 6-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heteroaryl group comprising one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O and S. In certain embodiments, the heteroaryl group is optionally substituted with one or more R u replace.

[0172] In certain embodiments, R 1c is optionally substituted C 3-12Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 In certain embodiments, the carbocyclyl group is optionally replaced by one or more R u replace.

[0173] In certain embodiments, R 1c is an optionally substituted 3 to 12 membered heterocyclyl group comprising one or two 3 to 8 membered rings and 1 to 5 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising a 3- to 8-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising a 3-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising a 4-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising a 6-membered ring and 1-4 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising a 7-membered ring and 1-4 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising an 8-membered ring and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising two 3 to 8 membered rings and 1 to 5 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising two 5-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1cis an optionally substituted heterocyclyl group comprising two 6-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1c is an optionally substituted heterocyclyl group comprising one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O and S. In certain embodiments, the heterocyclyl group is optionally substituted with one or more R u replace.

[0174] In certain embodiments, R 1’ is hydrogen, deuterium, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, R 1’ Optionally, one or more R u replace.

[0175] In certain embodiments, R 1’ is hydrogen, deuterium or optionally substituted C 1-6 alkyl.

[0176] In certain embodiments, R 1 and R 1’ Together with the carbon atoms to which they are bonded, they form C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )) or a 3 to 12 membered heterocyclyl (e.g., a heterocyclyl containing one or two 3 to 8 membered rings and 1-5 heteroatoms selected from N, O and S), wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u In certain embodiments, R 1 and R 1’ Together with the carbon atoms to which they are bonded, they form C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0177] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0178] In certain embodiments, m' is 0. In certain embodiments, m' is 1. In certain embodiments, m' is 2.

[0179] In certain embodiments, m is 0 and m' is 0. In certain embodiments, m is 0 and m' is 1. In certain embodiments, m is 0 and m' is 2. In certain embodiments, m is 1 and m' is 0. In certain embodiments, m is 1 and m' is 1. In certain embodiments, m is 1 and m' is 2. In certain embodiments, m is 2 and m' is 0. In certain embodiments, m is 2 and m' is 1. In certain embodiments, m is 2 and m' is 2.

[0180] In certain embodiments, each R A are independently oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, each R A independently optionally replaced by one or more R u replace.

[0181] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkenyl, alkynyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, each R A independently optionally replaced by one or more R u replace.

[0182] In certain embodiments, each R A are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, each R Aindependently optionally replaced by one or more R u replace.

[0183] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10.

[0184] In certain embodiments, R B is hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C3-6 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, R B independently optionally replaced by one or more R u replace.

[0185] In certain embodiments, R B It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkenyl, alkynyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R B independently optionally replaced by one or more R u replace.

[0186] In certain embodiments, R B It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R B independently optionally replaced by one or more R u replace.

[0187] In certain embodiments, R B is hydrogen or optionally substituted C 1-6 In certain embodiments, R B In certain embodiments, R B is optionally substituted C 1-6 In certain embodiments, R B Optionally, one or more R u replace.

[0188] In certain embodiments, Ring C is C 6-10 aryl or 5- to 10-membered heteroaryl.

[0189] In certain embodiments, Ring C is C 6-10 Aryl (eg, phenyl or naphthyl).

[0190] In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is a 5- to 10-membered heteroaryl group comprising one 5- and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0191] In certain embodiments, Ring C is phenyl or pyridinyl.

[0192] In certain embodiments, R C1 is halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, R C1 Optionally, one or more R u replace.

[0193] In certain embodiments, R C1 Halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R C1 Optionally, one or more R u replace.

[0194] In certain embodiments, R C1 is halogen or -OH. In certain embodiments, R C1 is halogen (e.g., -F, -Cl, -Br, or -I). In certain embodiments, R C1 In certain embodiments, R C1 In certain embodiments, R C1 is optionally substituted C 1-6In certain embodiments, R C1 Optionally, one or more R u replace.

[0195] In certain embodiments, each R C2 are independently halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, each R C2 independently optionally replaced by one or more R u replace.

[0196] In certain embodiments, each R C2 are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, each R C2 independently optionally replaced by one or more R u replace.

[0197] In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4. In certain embodiments, r is 5. In certain embodiments, r is 6.

[0198] In certain embodiments, Ring D is C 6-10 aryl or 5- to 10-membered heteroaryl.

[0199] In certain embodiments, Ring D is C 6-10 Aryl (eg, phenyl or naphthyl).

[0200] In certain embodiments, ring D is a 5- to 10-membered heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl group comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl group comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl group comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl group comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl group comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is a 5- to 10-membered heteroaryl group comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is a 5- to 10-membered heteroaryl group comprising one 5- and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0201] In certain embodiments, Ring D is phenyl, pyridinyl, pyrrolopyridazinyl, or thienopyridinyl.

[0202] In certain embodiments, R 2 is hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O and S), C 3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., a heterocyclyl comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O and S), -C(=O)NR c S(=O)2R a ,-C(=O)NR c R d ,-(CH2)C(=O)OR b or C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0203] In certain embodiments, R 2 It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NRc S(=O)2R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or -C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0204] In certain embodiments, R 2 It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)NR c S(=O)2R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0205] In certain embodiments, R 2 It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)NR c S(=O)2R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or C(=O)OR b , wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0206] In certain embodiments, R 2 It is hydrogen, halogen, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, -NR c S(=O)2R a 、-N(S(=O)2R a )2、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)OR b 、-C(=O)NR c S(=O)2R a or C(=O)NR c R d , wherein alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0207] In certain embodiments, R 2 is hydrogen, -C(=O)NR c S(=O)R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or -C(=O)OR b In certain embodiments, R 2 It is -C(=O)NHS(=O)2CH3 or -COOH.

[0208] In certain embodiments, R 2 is hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O and S), C 3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., a heterocyclyl comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O and S), -C(=O)NR c S(=O)2R a or C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0209] In certain embodiments, R 2 Halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NRc S(=O)2R a or -C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0210] In certain embodiments, R 2 Halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)NR c S(=O)2R a or C(=O)OR b , wherein alkyl, alkenyl, alkynyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0211] In certain embodiments, R 2 Halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)NR c S(=O)2R a or C(=O)OR b , wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0212] In certain embodiments, R 2 Halogen, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, -NR c S(=O)2R a 、-N(S(=O)2R a )2、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)OR b 、-C(=O)NRc S(=O)2R a or C(=O)NR c R d , wherein alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0213] In certain embodiments, R 2 is -C(=O)NR c S(=O)R a or -C(=O)OR b In certain embodiments, R 2 It is -C(=O)NHS(=O)2CH3 or -COOH.

[0214] In certain embodiments, each R D are independently halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, each R D independently optionally replaced by one or more R u replace.

[0215] In certain embodiments, each R D are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, each R D independently optionally replaced by one or more R u replace.

[0216] In certain embodiments, each R D is independently halogen or optionally substituted C 1-6 In certain embodiments, at least one R D In certain embodiments, each R D In certain embodiments, at least one R D is optionally substituted C 1-6 In certain embodiments, each R Dis independently optionally substituted C 1-6 In certain embodiments, each R D independently optionally replaced by one or more R u replace.

[0217] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6.

[0218] In certain embodiments, each -L- is independently -O-, -NR L -、-CR L1 R L2 -、-CR L1 =CR L2 - or -C≡C-. In certain embodiments, each -L- is independently -O-, -CR L1 R L2 -or-C≡C-.

[0219] In certain embodiments, [L] q yes

[0220]

[0221] in:

[0222] * indicates attachment to ring B, and ** indicates attachment to ring C;

[0223] p is an integer selected from 0 to 3; and

[0224] Y is -O-, -CR L1 R L2 -or-C≡C-.

[0225] In certain embodiments, L is Y.

[0226] In certain embodiments, each R L1 and each R L2 are independently hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl-n-butylamino, ethyl- In certain embodiments, each R L1 and each R L2 independently optionally replaced by one or more R u replace.

[0227] In certain embodiments, each R L1 and each R L2 It's hydrogen.

[0228] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

[0229] In certain embodiments, Y is -O-. In certain embodiments, Y is -NR L -. In certain embodiments, Y is -CR L1 R L2 -. In certain embodiments, Y is -C≡C-. In certain embodiments, Y is -O- or -C≡C-.

[0230] In certain embodiments, Y is -O- and p is 0, or Y is -C≡C- and p is 0.

[0231] In certain embodiments, X is -O-. In certain embodiments, X is -C(R) X )2-.

[0232] In certain embodiments, each R X are independently hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5) or hexyloxy (C6)), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, each R X independently optionally replaced by one or more R u replace.

[0233] In certain embodiments, each RX are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, each R X independently optionally replaced by one or more R u replace.

[0234] In certain embodiments, each R X are independently hydrogen or C 1-6 alkyl.

[0235] In certain embodiments, each R X Independently C 1-6 alkyl.

[0236] In certain embodiments, each R X It's hydrogen.

[0237] In certain embodiments, each R X is independently halogen or optionally substituted C 1-6 In certain embodiments, at least one R X In certain embodiments, each R X In certain embodiments, at least one R X is optionally substituted C 1-6 In certain embodiments, each R X is independently optionally substituted C 1-6 In certain embodiments, each R X independently optionally replaced by one or more R u replace.

[0238] In certain embodiments, both R X Together with the carbon atom to which they are bonded they form an oxo group.

[0239] In certain embodiments, both R X Together with the carbon atoms to which they are bonded, they form C 3-6 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, two R XTogether with the carbon atoms to which they are bonded, they form C 3-6 Carbocyclyl or 3 to 6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0240] In certain embodiments, both R X Together with the carbon atoms to which they are bonded, they form C 3-4 a carbocyclic group or a 3- to 4-membered heterocyclic group.

[0241] In certain embodiments, each R A1 are independently hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5) or hexyloxy (C6)), C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 3 to 6 membered heterocyclyl (e.g., a heterocyclyl comprising a 3 to 6 membered ring and 1-3 heteroatoms selected from N, O and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, each R A1 independently optionally replaced by one or more R u replace.

[0242] In certain embodiments, each R A1 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein alkyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, each R A1 independently optionally replaced by one or more R u replace.

[0243] In certain embodiments, each R A1 are independently hydrogen or C 1-6 alkyl.

[0244] In certain embodiments, each R A1 Independently C 1-6 alkyl.

[0245] In certain embodiments, each R A1 It's hydrogen.

[0246] In certain embodiments, each R A1 is independently halogen or optionally substituted C 1-6 In certain embodiments, at least one R A1 In certain embodiments, each R A1 In certain embodiments, at least one R A1 is optionally substituted C 1-6 In certain embodiments, each R A1 is independently optionally substituted C 1-6 In certain embodiments, each R A1 independently optionally replaced by one or more R u replace.

[0247] In certain embodiments, R X and adjacent R A1 Together with the carbon atoms to which they are bonded, they form C 3-4 In certain embodiments, the carbocyclyl or heterocyclyl is optionally substituted with one or more R u replace.

[0248] In certain embodiments, R a 、R b 、R c and R d Each occurrence of is independently and optionally substituted. In certain embodiments, R a 、R b 、R c and R d Each occurrence of is independently optionally replaced by one or more R u replace.

[0249] In certain embodiments, each R a Independently C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )), 3 to 12 membered heterocyclyl (e.g., a heterocyclyl containing one or two 3 to 8 membered rings and 1 to 5 heteroatoms selected from N, O and S), C 6-10 aryl or 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

[0250] In certain embodiments, each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl or alkynyl group is optionally substituted by one or more R u replace.

[0251] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )), 3 to 12 membered heterocyclyl (e.g., a heterocyclyl containing one or two 3 to 8 membered rings and 1 to 5 heteroatoms selected from N, O and S), C 6-10 aryl or 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

[0252] In certain embodiments, each R b Independently C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl or alkynyl group is optionally substituted by one or more R u replace.

[0253] In certain embodiments, each R c and each R d are independently hydrogen, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )), 3 to 12 membered heterocyclyl (e.g., a heterocyclyl containing one or two 3 to 8 membered rings and 1 to 5 heteroatoms selected from N, O and S), C 6-10 aryl or 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

[0254] In certain embodiments, each R c and each R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl or alkynyl group is optionally substituted by one or more R u replace.

[0255] In certain embodiments, R c and R d Together with the nitrogen atom to which they are bound, they form a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclic group is optionally substituted by one or more R u replace.

[0256] In certain embodiments, each R u are independently deuterium, oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy), C1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl- (e.g., n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O and S), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b ,-S(=O)R a, -S(=O)2R a , -S(=O)2OR b ,-S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b ,-OS(=O)2R a ,-OS(=O)2OR b ,-OS(=O)2NR c R d ,-OC(=O)R a ,-OC(=O)OR b ,-OC(=O)NR c R d ,-C(=O)R a ,-C(=O)OR b or -C(=O)NR c R d wherein alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally substituted by one or more oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The substituents of the carbocyclic group and the 3- to 6-membered heterocyclic group are substituted.

[0257] In certain embodiments, each R u are independently deuterium, oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, 3 to 12 membered heterocyclyl, wherein alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The substituents of the carbocyclic group and the 3- to 6-membered heterocyclic group are substituted.

[0258] In certain embodiments, each R u are independently deuterium, oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, 3 to 6 membered heterocyclyl, wherein alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The substituents of the carbocyclic group and the 3- to 6-membered heterocyclic group are substituted.

[0259] In certain embodiments, each R u are independently deuterium, oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclyl, 3 to 6 membered heterocyclyl, wherein alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted by one or more oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The substituents of the carbocyclic group and the 3- to 6-membered heterocyclic group are substituted.

[0260] In certain embodiments, the compounds disclosed herein are selected from the compounds in Table 1 and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof.

[0261] Table 1.

[0262] For all compounds, the specified configuration of any given chiral center

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391] Compared to known compounds such as known eIF4E inhibitors, the compounds of the present disclosure have advantageous properties. For example, the compounds of the present disclosure exhibit more potent eIF4E inhibitory activity, more favorable pharmacokinetic properties (e.g., as measured by C 最大 、T 最大 and / or AUC measurements), and / or less interaction with other cellular targets (e.g., hepatocyte transporters such as OATP1B1) and correspondingly improved safety (e.g., drug-drug interactions). These beneficial properties of the compounds of the present disclosure can be measured according to methods generally available in the art, such as those exemplified herein.

[0392] Due to the presence of double bonds, the compounds of the present disclosure may be in a cis configuration or a trans configuration or a Z configuration or an E configuration. It should be understood that while one configuration may be depicted in the structure of a compound or formula of the present disclosure, the present disclosure also encompasses another configuration. For example, a compound or formula of the present disclosure may be depicted in a cis configuration or a trans configuration or a Z configuration or an E configuration.

[0393] In one embodiment, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are pharmaceutically acceptable salts. In another embodiment, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are solvates. In another embodiment, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are hydrates.

[0394] Pharmaceutically acceptable salts

[0395] In certain embodiments, the compounds disclosed herein exist as pharmaceutically acceptable salts thereof. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0396] In certain embodiments, the compounds described herein possess acidic or basic groups and, therefore, react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compound in its free form separately with a suitable acid or base and isolating the salt thus formed.

[0397] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral acids, organic acids, or inorganic bases, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide , 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0398] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0399] In certain embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base of a pharmaceutically acceptable metal cation, such as a hydroxide, carbonate, bicarbonate, or sulfate, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0400] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0401] Solvates

[0402] "Solvate" refers to a form of a compound that is associated with a solvent or water, usually by a solvolysis reaction (also referred to as a "hydrate"). This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present disclosure can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0403] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." For example, complexes with water are referred to as "hydrates." Solvates are within the scope of this disclosure.

[0404] It will also be understood by those skilled in the art of organic chemistry that many organic compounds can exist in more than one crystalline form. For example, the crystalline form can vary with solvates. Therefore, all crystalline forms or pharmaceutically acceptable solvates thereof are contemplated and are within the scope of this disclosure.

[0405] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0406] Solvates contain stoichiometric or non-stoichiometric amounts of solvents, such as water, ethanol, etc. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Solvates of compounds described herein can be easily prepared or formed during the processes described herein. In addition, provided herein are compounds that can exist in unsolvated and solvated forms. Typically, for the purposes of compounds and methods provided herein, solvated forms are considered to be equivalent to unsolvated forms.

[0407] Isomers (stereoisomers, geometric isomers, tautomers, etc.)

[0408] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of the atoms of the compound or in the arrangement of the atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0409] Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center (e.g., it is bonded to four different groups), paired enantiomers are possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S sorting rules of Cahn and Prelog or by the way in which the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., (+) isomer or (-) isomer, respectively). Chiral compounds can exist as individual enantiomers or as their mixture. A mixture comprising equal proportions of enantiomers is referred to as a "racemic mixture".

[0410] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of the enantiomer. In certain embodiments, weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0411] As used herein, and unless otherwise indicated, the term "enantiomerically pure (R)-compound" refers to at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound, at least about 99% by weight of the (R)-compound and up to about 1% by weight of the (S)-compound, or at least about 99.9% by weight of the (R)-compound and up to about 0.1% by weight of the (S)-compound. In certain embodiments, weights are based on the total weight of the compound.

[0412] As used herein, and unless otherwise indicated, the term "enantiomerically pure (S)-compound" refers to at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound, at least about 99% by weight of the (S)-compound and up to about 1% by weight of the (R)-compound, or at least about 99.9% by weight of the (S)-compound and up to about 0.1% by weight of the (R)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0413] In the compositions provided herein, enantiomerically pure compounds or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof can be present with other active ingredients or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound can include, for example, about 90% excipients and about 10% enantiomerically pure (R)-compounds. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, include at least about 95% (R)-compounds by weight and up to about 5% (S)-compounds by weight based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound can include, for example, about 90% excipients and about 10% enantiomerically pure (S)-compounds. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, include at least about 95% (S)-compounds by weight and up to about 5% (R)-compounds by weight based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with minimal or no excipients or carriers.

[0414] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures (racemic or otherwise) thereof.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0415] In certain embodiments, compounds described herein exist as geometric isomers. In certain embodiments, compounds described herein have one or more double bonds. Compounds disclosed herein include all cis (cis) isomers, trans (trans) isomers, cis (syn) isomers, trans (anti) isomers, cis (entgegen) (E) isomers and trans (zusammen) (Z) isomers and their corresponding mixtures. All geometric forms of compounds disclosed herein are contemplated and are within the scope of the present disclosure.

[0416] In certain embodiments, the compounds disclosed herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds disclosed herein include all diastereomeric forms, enantiomeric forms, and epimeric forms, as well as their corresponding mixtures. All diastereomeric forms, enantiomeric forms, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the present disclosure.

[0417] In other embodiments of the compounds and methods provided herein, the mixture of enantiomers and / or diastereomers produced by a single preparation step, combination or mutual conversion can be used for applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by: reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and reclaiming optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by utilizing these differences. In certain embodiments, diastereomers are separated by chiral chromatography, or preferably separated by separation / splitting techniques based on solubility differences. In certain embodiments, optically pure enantiomers and resolving agents are then recovered.

[0418] Tautomers

[0419] In certain embodiments, the compounds described herein exist as tautomers.The compounds described herein include all possible tautomers within the formulae described herein.

[0420] Tautomers are compounds that are interconvertible by the migration of hydrogen atoms, accompanied by the conversion of single bonds and adjacent double bonds. In bonding arrangements where tautomerization is possible, the chemical equilibrium of the tautomers will exist. For example, enols and ketones are tautomers because they rapidly interconvert by treatment with an acid or base. Another example of tautomerism is the acid form and nitro form of phenylnitromethane, which are also formed by treatment with an acid or base. Tautomeric forms may be relevant to the optimal chemical reactivity and biological activity of the compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of this disclosure. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0421] Pharmaceutical composition

[0422] In certain embodiments, the compounds described herein are administered as the pure chemical. In certain embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)).

[0423] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0424] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthesis by-products produced in one or more of the steps of the synthetic methods.

[0425] Pharmaceutical composition is used in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration of application and frequency of application will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of active ingredient and administration method. Usually, suitable dosage and treatment regimen provide compositions in an amount sufficient to provide therapeutic benefit and / or preventive benefit (for example, improved clinical outcome, such as more frequent complete or partial relief or longer disease-free (disease-free) and / or total survival rate or the alleviating of symptom severity). Optimal dose is determined using experimental models and / or clinical trials as a whole. Optimal dose depends on the patient's body mass, weight or blood volume.

[0426] In certain embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical or ophthalmic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection. In certain embodiments, the pharmaceutical composition is formulated for tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, suspensions, solutions, emulsions, ointments, lotions, eye drops or ear drops. In certain embodiments, the pharmaceutical composition is formulated as tablets.

[0427] Preparation and characterization of compounds

[0428] The compound of the present disclosure can be prepared in a variety of ways known to those skilled in the art of organic synthesis. By way of example, the compound of the present disclosure can be synthesized using the method described below together with synthetic methods known in the field of synthetic organic chemistry or its modification as understood by those skilled in the art. The compound of the present disclosure (that is, the compound of the application (for example, the compound of any formula disclosed herein or any independent compound)) can be synthesized by following the steps outlined in the following general synthesis scheme and the embodiments described herein, scheme, program and / or synthesis (for example, embodiment).

[0429] General synthetic scheme

[0430]

[0431]

[0432] Those skilled in the art will recognize whether stereocenter exists in the compound of the present disclosure (for example, the compound of any formula disclosed herein or any independent compound).Therefore, the present disclosure includes two possible stereoisomers (unless specified in synthesis), and not only includes racemic compound but also includes independent enantiomer and / or diastereomer.When compound needs as single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by the splitting of final product or any convenient intermediate.The splitting of final product, intermediate or starting material can be affected by any suitable method known in the art.See, for example " Stereochemistry of Organic Compounds " (Wiley-Interscience, 1994) by E.L. Eliel, S.H. Wilen and L.N. Mander.

[0433] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI), including Sigma Chemical and Fluka (Pittsburgh, PA).

[0434] Suitable reference books and treatises that detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H.O. House, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992; and "Chemistry of Functional Groups," John Wiley & Sons, in Vol. 73.

[0435] Specific and similar reactants are optionally identified by indexing known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries, as well as online. Chemicals that are known in the catalog but not commercially available are optionally prepared by custom chemical synthesis facilities, many of which provide custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0436] Analytical methods, materials, and instruments

[0437] Unless otherwise noted, reagents and solvents are used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra are obtained at 400 MHz on a Bruker spectrometer or a Varian spectrometer. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) is used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) is collected using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data are measured using an Agilent 1260-6125B LCMS system (with a diode array detector and an Agilent G6125BA mass spectrometer) or using a Waters Acquity UPLC system (with a diode array detector and a Waters 3100 mass detector). Purity is characterized by UV wavelengths of 214 nm, 220 nm, 254 nm, and ESI. Column: Poroshell 120EC-C18 2.7 μm 4.6×100 mm; flow rate 0.8 mL / min; solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile); gradient: hold 5% B for 0.3 min, 5%-95% B from 0.3 min to 2 min, hold 95% B for 4.8 min, 95%-5% B from 4.8 min to 5.4 min, then hold 5% B for 6.5 min. Alternatively, column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; flow rate 0.5 mL / min; solvent A (0.1% formic acid in water), solvent B (acetonitrile); gradient: hold 5% B for 0.2 min, 5%-95% B from 0.2 min to 2.0 min, hold 95% B for 3.1 min, then hold 5% B for 3.5 min.

[0438] Biological assays

[0439] The biological activity of the compounds of the present application can be assessed using methods and assays known in the art.

[0440] For example, the affinity of a compound for a protein can be determined via a variety of biophysical assay formats, including surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), mass spectrometry-based binding methods and others. The competitive binding activity and potency of a compound for a protein can be assessed by a range of conventional biochemical methods, including fluorescence polarization (FP), time-resolved fluorescence energy transfer (TR-FRET) and others. The functional effects of a compound on a complex biological system can be assessed in a cell-free assay or a cell lysate-based assay, such as in vitro translation and others. The effects of a compound on specific target protein-related functions (cell activity and potency) in a cell can be assessed by a wide range of different methods, including reporter gene assays, immunoassays such as Western blots, cell enzyme-linked immunosorbent assays (ELISAs), high-content imaging and others. The effects of a compound on a cell phenotype can be measured by a range of methods, including methods for measuring cell proliferation, cell cycle progression, cell viability, cell death, cell migration, cell invasion, cell metabolism and other cell phenotypes.

[0441] How to use

[0442] In certain aspects, the disclosure provides methods of inhibiting a protein in a subject or a biological sample, the method comprising administering to the subject a compound disclosed herein or contacting the biological sample with a compound disclosed herein.

[0443] In certain aspects, the disclosure provides use of a compound disclosed herein in the preparation of a medicament for inhibiting a protein in a subject or biological sample.

[0444] In certain aspects, the disclosure provides compounds disclosed herein for use in inhibiting a protein in a subject or biological sample.

[0445] In certain embodiments, the protein is eIF4E.

[0446] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein.

[0447] In certain aspects, the present disclosure provides the use of a compound disclosed herein in the preparation of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0448] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0449] In certain embodiments, the disease or disorder is an eIF4E-mediated disease or disorder.

[0450] In certain embodiments, the disease or disorder is cancer.

[0451] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers of Table A.

[0452] Table A

[0453]

[0454]

[0455]

[0456] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table B. In certain embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

[0457] Table B

[0458]

[0459]

[0460] In certain embodiments, the cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, pancreatic cancer, melanoma, multiple melanomas, brain cancer, CNS cancer, kidney cancer, prostate cancer, ovarian cancer, breast cancer, liver cancer, mesothelioma, rectal cancer, esophageal cancer, head and neck cancer, pancreatic cancer, uterine cancer, cervical cancer, or bladder cancer.

[0461] In certain embodiments, the disease or disorder is a non-cancer disease or disorder (e.g., a non-cancer disease or disorder mediated by eIF4E). In certain embodiments, the disease or disorder is a cytokine-related disease, such as an inflammatory disease, an allergy, or other condition associated with a pro-inflammatory cytokine. In certain embodiments, the disease or disorder is a fibrotic disease. In certain embodiments, the disease or disorder is a disease or disorder associated with expression (or abnormal expression) and / or function (or dysfunction) of eIF4E or in which expression (or abnormal expression) and / or function (or dysfunction) of eIF4E plays a role (e.g., in initiation and / or development).

[0462] In certain embodiments, the subject is a mammal.

[0463] In certain embodiments, the subject is a human.

[0464] definition

[0465] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0466] Chemical definition

[0467] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry as well as specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0468] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and OpticalResolutions p. 268 (EF Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0469] The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0470] When a range of values ​​is listed, it is intended to encompass every value and subrange within that range. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0471] The following terms are intended to have the meanings presented below and can be used to understand the description and expected scope of the present disclosure. When describing the present disclosure that can include compounds, pharmaceutical compositions comprising such compounds, and methods using such compounds and compositions, unless otherwise indicated, the following terms (if present) have the following meanings. It should also be understood that when described herein, any portion defined below can be substituted by a variety of substituents, and the corresponding definition is intended to include such substituted portions within its scope as described below. Unless otherwise indicated, the term "substituted" is as defined below. It should be further understood that the terms "groups" and "radicals" can be considered to be interchangeable when used in this article. The articles "a" and "an" can be used to refer to one or more than one (i.e., at least one) grammatical object of the article in this article. By way of example, "analog" means an analog or more than one analog.

[0472] As used herein, "alkyl" refers to a group having from 1 to 20 carbon atoms, a straight or branched chain saturated hydrocarbon group ("C 1-20 In certain embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In certain embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In certain embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In certain embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In certain embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In certain embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butane (C5), tert-pentyl (C5) and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise stated, an alkyl group is independently optionally substituted in each case, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") by one or more substituents; such as, for example, substituted by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), i-Pr(-CH(CH3)2), n-Pr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0473] As used herein, "alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent group. When a range or number of carbons is provided for a specific "alkylene" group, it is understood that the range or number refers to the range or number of carbons in a straight carbon divalent chain. An "alkylene" group can be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-) and the like. Exemplary substituted divalent alkylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-), and the like.

[0474] As used herein, "alkenyl" refers to a group ("C") that is a straight or branched chain hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2-20 In certain embodiments, an alkenyl group does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In certain embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In certain embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In certain embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In certain embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In certain embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In certain embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 In some embodiments, an alkenyl group is an unsubstituted C 1-4, C 1-6, C 1-8, C 1-17, C 1-19, C 2-30, C 3-41, C 3-50, C 3-60, C 3-70, C 3-80, C 3-90, C 4-100, C 4-110, C 4-120, C 4-130, C 4-140, C 4-150, C 4-160, C 4-170, C 4-180, C 4-190, C 4-180, C 4-190, C 4-120, C 4-130, C 4-140, C 4-160, C 4-170, C 4-180, C 4-19 ... 2-10 In certain embodiments, an alkenyl group is a substituted C 2-10 Alkenyl.

[0475] As used herein, "alkenylene" refers to an alkenyl group in which two hydrogens are removed to provide a divalent group. When a range or number of carbons is provided for a particular "alkenylene" group, it is understood that the range or number refers to the range or number of carbons in a straight carbon divalent chain. An "alkenylene" group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups, such as divalent alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0476] As used herein, "alkynyl" refers to a group ("C") having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2-20 In certain embodiments, an alkynyl group does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In certain embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In certain embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In certain embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In certain embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkynyl group include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl groups include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, an alkynyl group is independently optionally substituted at each occurrence, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents; such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0477] As used herein, "alkynylene" refers to a straight chain alkynyl group in which two hydrogen atoms are removed to provide a divalent group. When a range or number of carbon atoms is provided for a particular "alkynylene" group, it is understood that the range or number refers to the range or number of carbon atoms in the straight chain carbon divalent chain. The "alkynylene" group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0478] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that further includes one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group ("C") having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-10 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-9 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-8 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-7 In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("C 1-6In certain embodiments, a heteroalkyl group is a saturated group ("C 1-5 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-4 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-3 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-2 In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("C1 heteroalkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("C1 heteroalkyl"). 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted C 1-10 In certain embodiments, a heteroalkyl group is a substituted C 1-10 Heteroalkyl.

[0479] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-10 In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-9 In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-8 In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-7 In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("C 2-6 In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C2-5 In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2-4 In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("C 2-3 In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted C 2-10 In certain embodiments, a heteroalkenyl group is a substituted C 2-10 Heteroalkenyl.

[0480] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-10 In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-9 In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-8 In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-7 In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("C 2-6 In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2-5 In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2-4 In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("C 2-3In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2-6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted C 2-10 In certain embodiments, a heteroalkynyl group is a substituted C 2-10 Heteroalkynyl.

[0481] Similar to the definitions of "alkylene," "alkenylene," and "alkynylene" as described above, "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" as used herein refer to divalent radicals of heteroalkyl, heteroalkenyl, and heteroalkynyl groups, respectively. When a range or number of carbon atoms is provided for a particular "heteroalkylene," "heteroalkenylene," or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbon atoms in the linear divalent chain. "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups may be substituted or unsubstituted with one or more substituents as described herein.

[0482] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) radical having 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 "Aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, Coronene, fluaranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, pyrenes, pyranthrene, rubicene, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl.

[0483] "Heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having ring carbon atoms provided in the aromatic ring system and 1-8 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0484] "Heteroaryl" also includes ring systems in which a heteroaryl group as defined above is fused to one or more aryl groups, wherein the point of attachment is on the heteroaryl group or the one or more aryl groups, and in such cases, the number of ring members represents the total number of ring members in the fused (aryl / heteroaryl) ring system. When substitution is indicated in such cases, unless otherwise stated, substitution may occur on the heteroaryl group or the one or more aryl groups. For bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring not containing heteroatoms (e.g., 5-indolyl).

[0485] In certain embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In certain embodiments, 5 to 6 yuan of heteroaryl groups have 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 yuan of heteroaryl groups have 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 yuan of heteroaryl groups have 1 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 yuan of heteroaryl groups have 1 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. Unless otherwise stated, heteroaryl groups are optionally substituted independently in each case, that is, unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") by one or more substituents. In certain embodiments, heteroaryl groups are unsubstituted 5 to 14 yuan of heteroaryl groups. In certain embodiments, heteroaryl groups are substituted 5 to 14 yuan of heteroaryl groups.

[0486] 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0487] "Carbocyclyl" refers to a non-aromatic cyclic hydrocarbon radical having from 3 to 12 ring carbon atoms and zero heteroatoms in the non-aromatic ring system ("Carbocyclyl"). 3-12 In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms ("C 5-6 Carbocyclyl”). Exemplary C 3-6Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclic groups include but are not limited to the above C 3-6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the above C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 )wait.

[0488] In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-12 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-10 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-8 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-6 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 5-6 carbocyclyl”). C 5-6 Examples of carbocyclic groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the carbocyclic group include the above-mentioned C 5-6 Carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the carbocyclic group include the above-mentioned C 3-6In some embodiments, a carbocyclyl group is an unsubstituted C or C-substituted carbocyclyl group, and a cycloheptyl (C7) and cyclooctyl (C8) group. Unless otherwise specified, a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, a carbocyclyl group is an unsubstituted C or C-substituted carbocyclyl group. 3-12 In certain embodiments, a carbocyclyl group is a substituted C 3-12 Carbocyclic group.

[0489] In certain embodiments, the carbocyclyl group is a monocyclic ("monocyclic carbocyclyl") or polycyclic ("polycyclic carbocyclyl") ring system comprising a fused ring system, a bridged ring system or a spirocyclic ring system and can be saturated or can be partially unsaturated. Unless otherwise stated, the carbocyclyl group is optionally substituted independently in each case, that is, unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3-12 In certain embodiments, a carbocyclyl group is a substituted C 3-12 Carbocyclic group.

[0490] "Fused carbocyclyl" or "fused carbocycle" refers to a ring system in which a carbocyclyl group as defined above is fused to, i.e., shares a common bond with, one or more carbocyclyl groups as defined above, wherein the point of attachment is on any of the fused rings. In such cases, the number of carbons represents the total number of carbons in the fused carbocyclyl ring system. When substitution is indicated, unless otherwise stated, the substitution may occur on any of the fused rings.

[0491] "Spirocarbocyclyl" or "spirocarbocycle" refers to a ring system in which a carbocyclyl group as defined above forms a spiro structure with one or more carbocyclyl groups as defined above, i.e., shares a common atom with one or more carbocyclyl groups as defined above, wherein the point of attachment is on any carbocyclyl ring embedded in the spiro structure. In such cases, the number of carbons represents the total number of carbons in the carbocyclyl ring in which the spiro structure is embedded. When substitution is indicated, unless otherwise stated, substitution may occur on any carbocyclyl ring embedded in the spiro structure.

[0492] "Bridged carbocyclyl" or "bridged carbocycle" refers to a carbocyclyl group as defined above that forms a bridged structure with one or more carbocyclyl groups as defined above, i.e., a ring system that shares more than one atom (and therefore, more than one bond) with one or more carbocyclyl groups as defined above, wherein the point of attachment is on any carbocyclyl ring embedded in the bridged structure. In such cases, the number of carbons represents the total number of carbons in the bridged ring. When substitution is indicated, unless otherwise stated, substitution may occur on any carbocyclyl ring embedded in the bridged structure.

[0493] "Heterocyclyl" refers to a group of a 3-12 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-12 membered heterocyclyl"). In a heterocyclyl group comprising one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom when valence permits. Exemplary 3-membered heterocyclyl groups comprising one heteroatom include, but are not limited to, azetidinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups comprising one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups comprising one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic radicals comprising two heteroatoms include but are not limited to dioxolane, oxasulfuranyl, disulfuranyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic radicals comprising three heteroatoms include but are not limited to triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic radicals comprising one heteroatom include but are not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Exemplary 6-membered heterocyclic radicals comprising two heteroatoms include but are not limited to piperazinyl, morpholinyl, dithianyl and dioxanyl. Exemplary 6-membered heterocyclic radicals comprising two heteroatoms include but are not limited to triazinyl. Exemplary 7-membered heterocyclic radicals comprising one heteroatom include but are not limited to azepanyl, oxepanyl and thienyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0494] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0495] In certain embodiments, the heterocyclyl group can be a monocycle ("monocyclic heterocyclyl") or a polycycle ("polycyclic heterocyclyl"), which includes a fused ring system, a bridged ring system or a spirocyclic ring system, and can be saturated or can be partially unsaturated. The heterocyclyl polycyclic ring system can include one or more heteroatoms in one or two rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl group as defined above is fused to one or more carbocyclyl groups, wherein the attachment point is on the carbocyclyl ring or the heterocyclyl ring, and in such cases, the number of ring members represents the total number of ring members in the entire ring system. When substitution is indicated in such cases, unless otherwise stated, substitution can occur in heterocyclyl or one or more carbocyclyl groups. Unless otherwise stated, heterocyclyl is optionally substituted independently in each case, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 12-membered heterocyclyl.

[0496] "Fused heterocyclyl" or "fused heterocycle" refers to a ring system in which a heterocyclyl group, as defined above, is fused to, i.e., shares a common bond with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any fused ring. In such cases, the number of carbons represents the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise stated, substitution may occur on any fused ring.

[0497] "Spiroheterocyclyl" or "spiroheterocycle" refers to a ring system in which a heterocyclyl group as defined above forms a spiro structure with one or more heterocyclyl or carbocyclyl groups as defined above, i.e., shares one common atom with one or more heterocyclyl or carbocyclyl groups as defined above, wherein the point of attachment is on any heterocyclyl ring or carbocyclyl ring embedded in the spiro structure. In such cases, the number of ring members represents the total number of ring members of the heterocyclyl ring or carbocyclyl ring in which the spiro structure is embedded. When substitution is indicated, unless otherwise stated, substitution may occur on any heterocyclyl ring or carbocyclyl ring embedded in the spiro structure.

[0498] "Bridged heterocyclyl" or "bridged heterocycle" refers to a ring system in which a heterocyclyl group as defined above forms a bridged structure with one or more heterocyclyl or carbocyclyl groups as defined above, i.e., a ring system that shares more than one atom (and therefore more than one bond) with one or more heterocyclyl or carbocyclyl groups as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl ring embedded in the bridged structure. In such cases, the number of ring members represents the total number of ring members of the heterocyclyl or carbocyclyl ring in which the bridged structure is embedded. When substitution is indicated, unless otherwise stated, substitution may occur on any bridged ring.

[0499] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, sulfur, boron, phosphorus or silicon heteroatoms, where valence permits. Hetero applies to any of the above-described hydrocarbon groups having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0500] As used herein, "alkoxy" refers to the group -OR, where R is alkyl, carbocyclyl, or heterocyclyl as defined herein. 1-6 Alkoxy refers to a group -OR, wherein each R is C as defined herein. 1-6 Alkyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group. Exemplary C 1-6 Alkyl, C 3-6 The carbocyclyl or 3- to 6-membered heterocyclyl is described above.

[0501] As used herein, "alkylamino" refers to the group -NHR or -NR2, wherein each R is independently alkyl, carbocyclyl, or heterocyclyl as defined herein. 1-6 Alkylamino refers to a group -NHR or -NR2, wherein each R is independently C as defined herein. 1-6 Alkyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group. Exemplary C 1-6 Alkyl, C 3-6 The carbocyclyl or 3- to 6-membered heterocyclyl is described above.

[0502] "Oxo" refers to =0. When a group or atom other than an aryl or heteroaryl group is substituted with an oxo group, it is intended to indicate that two geminal groups on the group or atom form a double bond with the oxo group. When a heteroaryl group is substituted with an oxo group, it is intended to indicate that the resonance structure / tautomer involving the heteroatom provides a carbon atom capable of forming two geminal groups, which form a double bond with the oxo group.

[0503] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, the halogen group is fluorine or chlorine.

[0504] As used herein, "protecting group" is well known in the art and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thiol, and carboxylic acid) to achieve chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that require protection include, but are not limited to, hydroxyl, amino, thiol, and carboxylic acid. Therefore, protecting groups are referred to as hydroxyl protecting groups, amino protecting groups, thiol protecting groups, and carboxylic acid protecting groups, respectively.

[0505] Common types of hydroxy protecting groups include, but are not limited to, ethers (e.g., methoxymethyl ether (MOM), β-methoxyethoxymethyl ether (MEM), tetrahydropyranyl ether (THP), p-methoxyphenyl ether (PMP), tert-butyl ether, triphenylmethyl ether (trityl ether), allyl ether, and benzyl ether (Bn)), silyl ethers (e.g., tert-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), triisopropylsilyloxymethyl (TOM), and tert-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalate (Piv) and benzoic acidester (benzoate; Bz)).

[0506] Common types of amino protecting groups include, but are not limited to, carbamates (e.g., tert-butoxycarbonyl (Boc) carbamate, 9-fluorenylmethoxycarbonyl (Fmoc) carbamate, p-methoxybenzylcarbonyl (Moz or MeOZ) carbamate, 2,2,2-trichloroethoxycarbonyl (Troc) carbamate, and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac), benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g., benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkylnitrobenzenesulfonamides (Nosyl), and 2-nitrophenylsulfinyl (Nps)).

[0507] Common types of thiol protecting groups include, but are not limited to, sulfides (eg, p-methylbenzyl (Meb), tert-butyl, acetamidomethyl (Acm), and triphenylmethyl (trityl)).

[0508] Common types of carboxylic acid protecting groups include, but are not limited to, esters (eg, methyl, triphenylmethyl (trityl), tert-butyl, benzyl (Bn), S-tert-butyl, silyl, and orthoesters) and oxazolines.

[0509] These and other exemplary substituents are described in greater detail in the Detailed Description, Examples, and Claims.This disclosure is not intended to be limited in any way by the above exemplary list of substituents.

[0510] Other definitions

[0511] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or corresponding agency in countries outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0512] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid. (i) acid addition salts formed with 1,2-dimethyl-2-nitropropionic acid, ...

[0513] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0514] "Effective amount" means the amount of a compound that, when administered to a subject for the treatment or prevention of a disease, is sufficient to effect such treatment or prevention. "Effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. "Therapeutically effective amount" refers to an amount effective for therapeutic treatment. "Prophylactically effective amount" refers to an amount effective for preventative treatment.

[0515] "Preventing," "prevention," or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., causing at least one clinical symptom of a disease to not develop in a subject who has not been exposed to the disease-causing agent or in a subject who is susceptible to the disease before the onset of the disease).

[0516] The term "prophylaxis" is related to "prevention" and refers to measures or procedures whose purpose is to prevent rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospitalized patients who are at risk of thrombosis, for example, due to their residence, and the administration of antimalarial agents such as chloroquine before visiting geographical areas where malaria is prevalent or where the risk of contracting malaria is high.

[0517] In one embodiment, "treating" or "treatment" or "therapeutic treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent, or severity of at least one clinical symptom thereof). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In additional embodiments, "treating" or "treatment" involves slowing the progression of the disease.

[0518] The term "about" when referring to a number or numerical range, means that the number or numerical range referred to is an approximate value within experimental variability (experimental variability) or within statistical experimental error, and therefore in some cases, the number or numerical range will change between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range changes 1% of the stated number or numerical range, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%. In certain embodiments, the number or numerical range changes 1% of the stated number or numerical range, 2%, 3%, 4% or 5%. In certain embodiments, the number or numerical range changes 1% of the stated number or numerical range, 2% or 3%.

[0519] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in certain other embodiments, e.g., any composition of matter embodiments, a composition, method or process described herein, or the like, "consists of" or "consists essentially of" the described features.

[0520] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so connected, i.e., elements that are present in conjunction in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so connected. In addition to the elements explicitly identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those explicitly identified elements. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising" may refer in one embodiment to only A (optionally including elements other than B); in another embodiment to only B (optionally including elements other than A); in yet another embodiment to both A and B (optionally including other elements); and so on.

[0521] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, that is, including at least one of a plurality of elements or a list of elements but also including more than one, and optionally including additional unlisted items. Only when the term clearly indicates the opposite, such as "only one of..." or "exactly one of...", or, when used in the claims, "consisting of...", will mean including exactly one element of a plurality of elements or a list of elements. Generally, as used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when followed by exclusive terms such as "any one of...", "one of...", "only one of..." or "exactly one of...". "Consisting essentially of...", when used in the claims, should have the ordinary meaning as used in the field of patent law.

[0522] As used herein in the specification and in the claims, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements and does not exclude any combination of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements explicitly identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those explicitly identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and / or B") may refer in one embodiment to at least one A, optionally including more than one A, wherein B is absent (and optionally including elements other than B); in another embodiment to at least one B, optionally including more than one B, wherein A is absent (and optionally including elements other than A); in yet another embodiment to at least one A, optionally including more than one A, and at least one B, optionally including more than one B (and optionally including other elements); and so on.

[0523] Although the teaching of the present invention has been described in conjunction with various embodiments and examples, it is not intended that the teaching of the present invention be limited to such embodiments or examples. On the contrary, as will be appreciated by those skilled in the art, the teaching of the present invention encompasses various alternatives, modifications and equivalents.

[0524] Although various inventive embodiments have been described and illustrated herein, a person of ordinary skill in the art will readily conceive of various other means and / or structures for performing the functions and / or obtaining the results and / or one or more advantages described herein, and each of such variations and / or modifications is considered to be within the scope of the inventive embodiments described herein. More generally, a person skilled in the art will readily understand that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on one or more specific applications in which the teachings of the present invention are used. A person skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. Therefore, it should be understood that the foregoing embodiments are presented by way of example only, and within the scope of the appended claims and their equivalents, embodiments of the present invention may be practiced in a manner different from that specifically described and claimed. The inventive embodiments of the present disclosure relate to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0525] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and details may be made by one skilled in the art without departing from the spirit and scope of the appended claims. Protection is claimed for all embodiments and equivalents thereof that come within the spirit and scope of the following claims. Example

[0526] In order that the disclosure described herein may be more fully understood, the following examples are set forth.The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be interpreted in any way as limiting the scope thereof.

[0527] I. Synthesis and Characterization

[0528] Plan A

[0529]

[0530] Synthesis of 103:

[0531] To a suspension of sodium hydride (60% dispersion in mineral oil) (1.92 g, 48.02 mmol, 60% purity) in THF (50 mL) was added 1,4-dioxaspiro [4.5] decane-8-one (101) (5 g, 32.01 mmol) at 25 ° C, followed by dimethyl carbonate (102) (8.65 g, 96.04 mmol, 8.09 mL, 99% purity). The reaction mixture was then heated at 70 ° C for 16 hours. After the reaction was complete (as judged by LC / MS and TLC), the reaction mixture was cooled to 25 ° C and quenched with water (100 ml). The aqueous phase was extracted with EtOAc (2 × 100 ml). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude material. The crude product thus obtained was purified by silica gel column chromatography (SiO2; 100-200 mesh, 15% EtOAc / hexane) to give methyl 8-oxidanylidene-1,4-dioxaspiro[4.5]decane-7-carboxylate (103) (5 g, 23.34 mmol, 72.91% yield) as an off-white solid.

[0532] 1 H NMR (400MHz, DMSO-d6): δ12.05(s,1H),3.92(s,4H),3.86(s,3H),2.39(t,J=6.76Hz,1H),2.34(s,2H),1.76(t,J=6.72Hz,1H)ppm.

[0533] m / z calculated: 214.08, found (M+1) = 215.0.

[0534] Synthesis of 105:

[0535] To a stirred solution of 8-oxomethylene-1,4-dioxaspiro[4.5]decane-7-formic acid methyl ester (103) (5 g, 23.34 mmol) in MeOH (50 mL) was added NaOMe (25 mL, 4 M) at 25 ° C, and the reaction mixture was stirred for 10 minutes. To the reaction mixture was added acetamidine HCl (104) (3.31 g, 35.01 mmol) at 25 ° C, and the reaction was stirred at the same temperature for 16 h. The solvent was removed under reduced pressure to obtain a crude material. The crude product was dissolved in 1N HCl (40 mL) (pH ~ 7). The aqueous layer was extracted with 10% MeOH / DCM (50 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO 2 ; 100-200 mesh, 10% MeOH / DCM) to afford 2′-methylspiro[1,3-dioxolane-2,6′-3,5,7,8-tetrahydroquinazolin]-4′-one (105) (3.25 g, 14.62 mmol, 62.65% yield) as an off-white solid.

[0536] 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),3.91(s,4H),2.62(t,J=6.6Hz,2H),2.46(s,2H),2.23(s,3H),1.81(t,J=6.6Hz,2H)ppm.

[0537] MS calculated value: 222.2; MS found value: 222.8 (M+H).

[0538] Plan B

[0539]

[0540] 3-[2-(2-Bromoethoxy)-5-chloro-phenyl]benzoic acid ethyl ester (106)

[0541] To a stirred solution of ethyl 3-(5-chloro-2-hydroxyphenyl)benzoate (4.5 g, 16.26 mmol) in acetone (50 mL) was added KCO (8.98 g, 65.05 mmol), and the mixture was stirred for 30 min. 1,2-dibromoethane (13.75 g, 73.18 mmol, 6.31 mL) was slowly added, and the reaction mixture was stirred at 60 ° C for 16 h. The reaction mixture was passed through a pad of celite, concentrated under reduced pressure, and subjected to flash column chromatography (silica gel, 30% EtOAc / hexane) to give 106 (4.0 g, 10.43 mmol, 64.11% yield). 1H NMR (400MHz, DMSO-d6-L): 8.186 (s, J = 8.4, 1H), 7.959 (t, J = 15.8, 1H), 7.663 (t, J = 7.76Hz, 1H), 7.566 (m ,1H),7.42(m,2H),7.17(d,J=3.92,1H),4.32(m,J=9.04Hz,4H),3.73(t,J=5.4Hz,2H),1.335(m,3H)ppm.

[0542] Synthesis of 107:

[0543] To a stirred solution of 2'-methylspiro[1,3-dioxolane-2,6'-3,5,7,8-tetrahydroquinazoline]-4'-one (105) (400 mg, 1.80 mmol) in DMF (10 mL) was added potassium carbonate (746.25 mg, 5.40 mmol) at 25 ° C., followed by addition of 3-[2-(2-bromoethoxy)-5-chloro-phenyl] ethyl benzoate (106) (690.54 mg, 1.80 mmol), and the reaction mixture was stirred at 25 ° C. for 16 h. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by combi flash column chromatography (SiO2; 12 g, 80% EtOAc) to afford off-white 3-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazoline]-3'-yl)ethoxy]phenyl]benzoic acid ethyl ester (107) (360 mg, 685.73 μmol, 38.10% yield).

[0544] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=7.2Hz,1H),7.88(s,1H),7.57-7.51(m,2H),7.40(d,J=6.4Hz,1H),7.31(s,1H),7.18(d,J=12Hz,1H),4.35-4.30 (m,2H),4.24(d,J=8Hz,2H),4.18(d,J=4Hz,2H),3.90(s,4H),2.59(s,2H ), 2.49-2.45 (m, 2H), 2.05 (s, 3H), 1.82-1.80 (m, 2H), 1.32 (t, J = 8Hz, 3H).

[0545] LC-MS: 525.0 (M+H).

[0546] Synthesis of 108:

[0547] To a stirred solution of ethyl 3-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazoline]-3'-yl)ethoxy]phenyl]benzoate (107) (500 mg, 952.40 μmol) in acetone (10 mL) was added 10% HCl in HO (10 mL) at 25 °C, and the reaction mixture was stirred at 55 °C for 16 h. After the reaction was complete, the volatiles were removed under reduced pressure. The crude product was dissolved in HO and neutralized with saturated NaHCO solution (50 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by combi flash column chromatography (SiO; 12 g, 70% EtOAc) to afford ethyl 3-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]benzoate (108) (290 mg, 602.99 μmol, 63.31% yield) as an off-white solid.

[0548] 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=8Hz,1H),7.88(s,1H),7.58-7.50(m,2H),7.41-7.39(m,1H),7.30(d,J=2.8Hz,1H),7.19(d,J=8.8Hz,1H ), 4.32 (t, J = 7.4Hz, 2H), 4.27-4.22 (m, 4H), 3.11 (s, 2H), 2.84 (t, J = 6.8Hz, 2H), 2.53 (t, J = 6.8Hz, 2H), 2.07 (s, 3H), 1.33 (t, J = 6.8Hz, 3H).

[0549] LC-MS: 481.02 (M+H).

[0550] Plan C

[0551]

[0552] Synthesis of 109:

[0553] To a stirred solution of ethyl 3-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]benzoate (108) (100 mg, 207.93 μmol) in MeOH (5 mL) was added AcOH (12.49 mg, 207.93 μmol) at 25 ° C., followed by NaBH CN (78.40 mg, 1.25 mmol), and the reaction mixture was stirred at this temperature for 15 min. N-methylmethylamine (46.87 mg, 1.04 mmol, 60.48 μL) was added to the reaction mixture at 0 ° C., and the reaction mixture was stirred at 25 ° C. for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product thus obtained was diluted with saturated NH Cl solution (30 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (SiO2; 12 g, 5% MeOH / DCM) to afford ethyl 3-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]benzoate (109) (100 mg, 196.07 μmol, 94.30% yield) as an off-white solid.

[0554] 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=7.2Hz,1H),7.88(s,1H),7.56-7.49(m,2H ),7.39(t,J=8Hz,1H),7.31(s,1H),7.19(d,J=9.2Hz,1H),4.35-4.30(m,2H) ,4.09-4.07(m,2H),3.16(d,J=4.8Hz,4H),2.50(s,3H),2.41(s,4H),2.04(s ,3H),1.90(s,1H),1.53(d,J=6.8Hz,1H),1.33(t,J=6.8Hz,3H),1.23(s,3H).

[0555] LC-MS: 510.1 (M+H).

[0556] Synthesis of 110 (Compound 1):

[0557] To a stirred solution of ethyl 3-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]benzoate (109) (100 mg, 196.07 μmol) in THF:HO (7:3) (5 mL) was added LiOH.HO (24.68 mg, 588.21 μmol, 16.35 μL) at 0° C., and the reaction mixture was stirred at 25° C. for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure. The crude product thus obtained was purified by reverse phase preparative HPLC to give 3-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]benzoic acid (110) (Compound 1) (30 mg, 61.71 μmol, 31.47% yield, 99.14% purity) as a white solid.

[0558] 1 H NMR (400MHz, MeOD): δ7.94(d,J=7.6Hz,1H),7.75(s,1H),7.41-7.34(m,2H),7.32-7.29(m,1H),7.20(d,J=2.8Hz,1H),7.13-7.11(m ,1H),4.38-4.23(m,4H),3.49(t,J=7.6Hz,1H),2.90(s,7H),2.78-2.74(m,2H),2.70-2.68(m,1H),2.17-2.15(m.2H),2.06(s,3H).

[0559] MS calculated value: 481.97; MS found value: 482.2 (M+H).

[0560] Plan D

[0561]

[0562] Synthesis of 113:

[0563] A stirred solution of 2,2-di(methyl)-1,3-dioxane-4,6-dione (112) (7.06 g, 48.99 mmol) in 1,1,1-triethoxyethane (7.22 g, 44.53 mmol, 50 mL) was heated at 90 ° C for 3 h. After the starting material was consumed (judged by TLC), the solvent was evaporated and the reaction mixture was dissolved in THF (50 mL). Then, 4-aminothiophene-3-methyl formate (111) (7 g, 44.53 mmol) was added to the reaction mixture and continued to heat at 90 ° C for 2 h. After the starting material was consumed, the reaction mixture was quenched with water and extracted with ethyl acetate (150 mL). The organic layer was washed with saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Combiflash chromatography (SiO2, 120 g, 40% EtOAc / hexanes) gave methyl 4-[1-[2,2-di(methyl)-4,6-bis(oxymethylene)-1,3-dioxan-5-ylidene]ethylamino]thiophene-3-carboxylate (113) (2 g, 6.15 mmol, 14%) as a yellow liquid.

[0564] 1 H NMR(400MHz,DMSO-d6)δ1.20(m,2H),1.65(s,3H),2.53(m,1H),3.30(s,3H),3.96 (m, 2H), 4.1 (m, 1H), 7.78 (d, J = 12.3Hz, 1H), 8.48 (d, J = 3.28Hz, 1H), 12.68 (s, 1H).

[0565] Synthesis of 114:

[0566] A stirred solution of methyl 4-[1-[2,2-di(methyl)-4,6-bis(oxymethylene)-1,3-dioxane-5-ylidene]ethylamino]thiophene-3-carboxylate (113) (20 g, 61.47 mmol) in a Dowtherm (19.94 g, 61.47 mmol, 40 mL) was heated at 230° C. for 2 h. After consumption of the starting material (judged by TLC), the volatiles were removed under reduced pressure. The crude product thus obtained was purified by combiflash chromatography (SiO , 120 g, 100% ethyl acetate) to give methyl 5-methyl-7-hydroxy-thieno[3,2-b]pyridine-3-carboxylate (114) (6 g, 26.88 mmol, 43.72% yield) as a brown solid.

[0567] 1H NMR (400MHz, DMSO-d6) δ2.43(s,3H),2.54(s,1H),2.56(s,1H),3.85(s,1H),3.91(s,3H),5.99(s,1H),8.78(s,1H),10.95(s,1H).

[0568] Synthesis of 115

[0569] To a stirred solution of 5-methyl-7-hydroxy-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (114) (3.5 g, 15.68 mmol) in toluene (50 mL) was added N,N-dimethylaniline 99% (15.20 g, 125.42 mmol, 15.90 mL) and cooled to 0° C. POCl 3 (3.60 g, 23.52 mmol) was added to the reaction mixture and heated at 120° C. for 2.5 h. After consumption of the starting material (judged by TLC), the solvent was evaporated under reduced pressure and the crude product thus obtained was purified by combiflash chromatography (SiO 2, 120 g, 30% ethyl acetate / hexane) to afford 7-chloro-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (115) (3.0 g, 12.41 mmol, 79.17% yield) as a white solid.

[0570] 1H NMR (400MHz, DMSO-d6) δ8.93(s,1H),7.57(s,1H),3.86(s,3H),2.63(s,3H).

[0571] ESI-MS: m / z calculated: 241.0, found: 243.0 (M+2)+.

[0572] Synthesis of 117

[0573] To a stirred solution of 7-chloro-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (115) (3.0 g, 12.41 mmol) in dioxane (30 mL) and water (5 mL) was added (5-chloro-2-hydroxy-phenyl)boronic acid (116) (2.14 g, 12.41 mmol) under an argon atmosphere, followed by addition of Na2CO3 (3.95 g, 37.24 mmol) and degassed at 25°C for 10 min. Pd(dppf)2Cl2 (907.35 mg, 1.24 mmol) was added thereto and degassed again for 5 min. The reaction mixture was then heated at 90°C for 5 h. After the reaction was complete (confirmed by LCMS), the reaction mixture was filtered through a bed of celite and concentrated under reduced pressure. The crude product thus obtained was purified by flash column chromatography (SiO2, 40 g, 30%-35%: ethyl acetate / hexanes) to give 7-(5-chloro-2-hydroxy-phenyl)-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (117) (1.5 g, 4.49 mmol, 36.20% yield) as an off-white solid.

[0574] 1H NMR (400MHz, DMSO-d6) δ 10.26 (s, 1H), 8.84 (s, 1H), 7.38 (t, J = 8.08Hz 3H), 7.05 (d, J = 8.68Hz 1H), 3.87 (s, 3H), 2.66 (s, 3H).

[0575] ESI-MS: m / z calculated: 333, found: 334 (M+H) +

[0576] Synthesis of 118:

[0577] To a stirred solution of 7-(5-chloro-2-hydroxy-phenyl)-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (117) (1.2 g, 3.60 mmol) in acetone (25 mL) was added anhydrous potassium carbonate (1.49 g, 10.79 mmol, 650.91 μL) followed by 1,2-bis(bromo)ethane (5.40 g, 28.76 mmol, 2.48 mL) and the reaction mixture was refluxed at 70° C. for 16 h. After completion of the reaction (as determined by LC / MS only), the reaction mixture was cooled to 25° C. and filtered. The filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography (SiO2; 40 g, 50% EtOAc / hexanes) to give 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (118) (1.3 g, 2.95 mmol, 82.05% yield) as an off-white solid.

[0578] 1H-NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.57(m,2H),7.42(s,1H),7.30(m,1H),4.36(m,2H),3.93(s,3H),3.62(m,2H),2.66(s,3H).

[0579] ESI-MS: m / z calculated value: 440.74; found value: 441.8 (M+1)-.

[0580] Plan E

[0581]

[0582] Synthesis of 119:

[0583] To a stirred solution of 2'-methylspiro[1,3-dioxolane-2,6'-3,5,7,8-tetrahydroquinazoline]-4'-one (105) (1.5 g, 6.75 mmol) in DMF (15 mL) was added potassium carbonate (anhydrous) (2.79 g, 20.25 mmol) and the reaction was stirred for 10 min. To the reaction was added 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (118) (2.97 g, 6.75 mmol) and the reaction was stirred at 25 °C for 16 h. After completion of the reaction (checked by TLC and LC / MS), the reaction mixture was evaporated to dryness and then purified by combi flash column chromatography (SiO2; 40 g, 4% MeOH / DCM) to give 7-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazoline]-3'-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (119) (1.6 g, 2.75 mmol, 40.73% yield) as an off-white solid.

[0584] 1 H-NMR (400MHz, DMSO-d6) δ8.68(d,J=5.08Hz 1H),7.55-7.53(m,1H),7.39(d,J=2.16Hz 1H),7.31-7.24(m,2H),4.06(s,2H),3.88(t,J=16.92Hz 1H), 7.42 (d, J = 2.6Hz10H), 2.76 (s, 3H), 2.68 (s, 2H), 1.88-1.82 (m, 2H), 1.57 (s, 3H) ppm.

[0585] MS calculated value: 581; MS found value: 582 (M+H)

[0586] Synthesis of 120

[0587] A solution of 7-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazoline]-3'-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (119) (1.6 g, 2.75 mmol) in HCl (15 mL, 6N) was allowed to stir at 50 ° C for 4 hours. The reaction mixture was poured into a cold saturated sodium bicarbonate solution (100 mL). The aqueous layer was extracted with 10% MeOH / DCM (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography (SiO2; 12 g, 15% MeOH / DCM) to give 7-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (120) as a white solid (890 mg, 1.65 mmol, 60.18% yield).

[0588] 1 H-NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 7.55 (dd, J = 2.6Hz, 8.96Hz, 1H), 7.40 (dJ = 2.6Hz, 1H), 7.31-7.23 (m, 2H), 4.3 7(m,2H),4.10(m,2H),3.88(s,3H),3.11(s,2H),2.79(t,J=6.16Hz,2H),2.71(s,3H),2.58(m,1H),1.60(s,3H)ppm.

[0589] m / z calculated: 537.11; found: 538.2 (M+H)

[0590] Plan F

[0591]

[0592] Synthesis of 121

[0593] To a stirred solution of compound 7-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (120) (100 mg, 185.87 μmol) and N-methylmethylamine (12.57 mg, 278.81 μmol) in DCM (4 mL) was added catalytic AcOH at 0° C. The reaction mixture was then allowed to stir at 25° C. for 2 h. Na(OAc)3BH (157.57 mg, 743.48 μmol) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at 25° C. for 5 h. After completion of the reaction (as judged by TLC and LCMS), excess solvent was evaporated under reduced pressure to give the crude material, which was purified by silica gel column chromatography (SiO; 12 g, 15% MeOH / DCM) to give 7-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (121) (81 mg, 142.83 μmol, 76.85% yield) as an off-white solid.

[0594] m / z calculated: 566.2, found: (M+1) = 567.1

[0595] Synthesis of 122 (Compound 3)

[0596] To a stirred solution of compound 7-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (121) (78 mg, 137.54 μmol) in a mixture of THF (4 mL) and HO (1 mL) was added LiOH.HO (17.31 mg, 412.63 μmol) at 0° C. The reaction mixture was then stirred at 25° C. for 16 h. After the reaction was complete (as judged by TLC and LC / MS), the crude material was purified by reverse phase preparative HPLC purification to give 7-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (Compound 3) (0.032 g, 47.75 μmol, 34.72% yield, 99.54% purity) as a white solid.

[0597] 1 H NMR (400MHz, DMSO-d6): δ9.68(brs,1H),8.82(brs,1H),7.59(d,J=8Hz,1H),7.45(s,2H),7.33(d,J=8Hz,1H),4.34(brs,2H ),4.09(brs,2H),3.49(brs,1H),2.85(s,6H),2.78(s,2H),2.55(brs,2H),2.07(brs,1H),1.78(brs,1H),1.56(s,3H)ppm.

[0598] m / z calculated: 552.1, found: (M+1)=553.1

[0599] Plan G

[0600]

[0601] Synthesis of 9a and 9b:

[0602] This compound was synthesized similarly to 7-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (121) from 7-[5-chloro-2-[2-[2-methyl-4,6-bis(oxomethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (120) (400 mg, 743.48 μmol) and N-methylmethanamine (50.28 mg, 1.12 mmol). Off-white solid (340 mg, 76.85%).

[0603] The racemic compound was separated by chiral preparative HPLC to give 7-[5-chloro-2-[2-[(3R,6S)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (121a, tentative) as an off-white solid (140 mg, 246.87 μmol, 33.21% yield, 100% ee) and 7-[5-chloro-2-[2-[(3S,6R)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (121b, tentative) (105 mg, 185.15 μmol, 24.90% yield, 99.56% ee) as an off-white solid.

[0604] Synthesis of 123a (Compound 13)

[0605] To a solution of 7-[5-chloro-2-[2-[(3R,6S)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (121a) (140 mg, 246.87 μmol) in a mixture of THF (5 ml) and water (1 ml) was added lithium hydroxide monohydrate (200 mg, 250 μmol), and the mixture was stirred at 25° C. for 16 h. The solvent was concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC to give 7-[5-chloro-2-[2-[(3R,6S)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-trifluoroacetic acid (123a) (Compound 13) (83 mg, 123.92 μmol, 50.20% yield, 99.60% purity, 100% ee) as a white solid.

[0606] 1 H NMR (400MHz, DMSO-d6): δ9.70(brs,1H),8.82(s,1H),7.59(d,J=8Hz,1H),7.45(s,2H),7.33(d,J=8Hz,1H),4.34(brs,2H), 4.09(brs,2H),3.49(brs,1H),2.85(s,6H),2.78(s,3H),2.55(brs,2H),2.07(brs,1H),1.78-1.74(m,1H),1.56(s,3H)ppm.

[0607] m / z calculated: 552.1, found: (M+1)=553.1

[0608] Synthesis of 123b (Compound 14)

[0609] To a solution of 7-[5-chloro-2-[2-[(3S,6R)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (121b) (105 mg, 185.15 μmol) in a mixture of THF (5 ml) and water (1 ml) was added lithium hydroxide monohydrate (200 mg, 250 μmol), and the mixture was stirred at 25° C. for 16 h. The solvent was concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC to give 7-[5-chloro-2-[2-[(3S,6R)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-trifluoroacetic acid (123b) (Compound 14) (57 mg, 85.25 μmol, 46.04% yield, 99.77% purity, 100% ee) as a white solid.

[0610] 1 H NMR (400MHz, DMSO-d6): δ9.69(brs,1H),8.82(s,1H),7.59(d,J=8Hz,1H),7.45(s,2H),7.33(d,J=8Hz,1H),4.34(brs,2H), 4.09(brs,2H),3.49(brs,1H),2.85(s,6H),2.74(s,3H),2.55(brs,2H),2.18(brs,1H),1.78-1.74(m,1H),1.56(s,3H)ppm.

[0611] m / z calculated: 552.1, found: (M+1)=553.1

[0612] Plan H

[0613]

[0614] Synthesis of 124 (Compound 39)

[0615] To a stirred solution of compound 7-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (122) (75 mg, 135.61 μmol) and MeSO2NH2 (32.25 mg, 339.02 μmol) in DCM (4 mL) was added EDCI.HCl (51.99 mg, 271.21 μmol) at 0°C followed by DMAP (41.42 mg, 339.02 μmol) and the reaction mixture was stirred at 25°C for 20 h. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure and the crude product thus obtained was purified by reverse phase preparative HPLC to afford 7-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-N-methylsulfonyl-thieno[3,2-b]pyridine-3-carboxamide; 2,2,2-tri(fluoro)acetic acid (124) (Compound 39) (18 mg, 23.93 μmol, 17.64% yield, 98.92% purity) as an off-white solid.

[0616] 1 H NMR (400MHz, DMSO-d6): δ13.00(brs,1H),9.51(brs,1H),8.96(s,1H),7.57(dd,J=9.2 ,2.4Hz,1H),7.43(s,1H),7.42(d,J=4.4Hz,1H),7.32(d,J=8.8Hz,1H),4.36(d,J=5.2 Hz,2H),4.14(d,J=5.2Hz,2H),3.49(s,3H),2.86(s,6H),2.83(m,1H),2.77(s,3H),2. 58(brs,2H),2.47-2.39(m,2H),2.24-2.21(m,1H),1.83-1.78(m,1H),1.75(s,3H)ppm.

[0617] m / z calcd: 629.15, found (M+1) = 630.1 at RT 2.21.

[0618] Plan I

[0619]

[0620] Synthesis of 125:

[0621] To a stirred solution of 7-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (120) (100 mg, 185.87 μmol) in DCM (5 mL) was added 3,3-bis(fluoro)cyclobutanamine (39.81 mg, 371.74 μmol) and the reaction mixture was stirred at 25° C. for 3 h. Sodium triacetoxyborohydride (196.97 mg, 929.34 μmol) was added portionwise to the reaction mixture at 0° C. and stirring was continued at 25° C. for 3 h. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude product was purified by combi flash column chromatography (SiO; 12 g, 15% MeOH in DCM) to afford 7-[2-[2-[6-[[3,3-bis(fluoro)cyclobutyl]amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (125) (100 mg, 158.95 μmol, 85.52% yield) as an off-white solid.

[0622] 1H NMR(400MHz,DMSO-d6):8.70(s,1H),7.55-7.53(m,1H),7.39(s,1H),7.31-7.26(m,2H),4.32-4.30(m,2 H),4.05(s,2H),3.88(s,3H),2.78-2.72(m,3H),2.66(s,3H),1.59-1.57(m,4H),1.23-1.21(m,4H)ppm.

[0623] m / z calculated value 628, found value 629.2 (M+1).

[0624] Synthesis of 126:

[0625] To a stirred solution of 7-[2-[2-[6-[[3,3-bis(fluoro)cyclobutyl]amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (125) (100 mg, 158.95 μmol) in dichloromethane (5 ml) at 0° C. was added catalytic acetic acid followed by formalin (36 mg, 476.86 μmol, 33.05 μL, 40% purity) and the reaction mixture was stirred at 25° C. for 3 h. Sodium triacetoxyborohydride (135 mg, 635.81 μmol) was added portionwise to the reaction mixture at 0° C. and stirring was continued at 25° C. for 3 h. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude product was purified by combi flash column chromatography (SiO; 12 g, 15% MeOH in DCM) to afford 7-[2-[2-[6-[[3,3-bis(fluoro)cyclobutyl]-methyl-amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (126) (90 mg, 100.76 μmol, 63.39% yield, 72% purity) as an off-white gum.

[0626] m / z calculated: 642, found: 643.4 (M+1)

[0627] Synthesis of 127 (Compound 40)

[0628] To a stirred solution of 7-[2-[2-[6-[[3,3-bis(fluoro)cyclobutyl]-methyl-amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (126) (90 mg, 139.94 μmol) in THF (1.5 ml), water (0.3 ml) and methanol (0.3 ml) was added lithium hydroxide monohydrate (34 mg, 1.40 mmol) and the reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, the volatiles were removed in vacuo and the crude product was purified by reverse phase preparative HPLC to afford 7-[2-[2-[6-[[3,3-bis(fluoro)cyclobutyl]-methyl-amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (Compound 40) (23.18 mg, 30.42 μmol, 21.74% yield, 97.53% purity) as a white sticky solid.

[0629] 1 H NMR (400MHz, DMSO-d6): 8.81 (s, 1H), 7.59 (dd, J = 8.8Hz, 1H), 7.45 (m, 2H), 7.33 (d, J = 8.8Hz, 1H),4.36(m,2H),4.09(m,4H),3.01(m,4H),2.77-2.74(m,7H),2.55(s,3H),1.5(s,3H)ppm.

[0630] MS calculated value: 628; MS found value: 629.2 (M+H).

[0631] Plan J

[0632]

[0633] Synthesis of 130:

[0634] To a degassed solution of 7-[5-chloro-2-[2-[2-methyl-6-(methylamino)-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (125) (150 mg, 271.21 μmol) in toluene (5 mL) at 25° C., 4-iodopyridine (4) (83.40 mg, 406.82 μmol) and Cs 2 CO 3 (353.66 mg, 1.08 mmol) were added. RuPhos (12.64 mg, 27.12 μmol) was added thereto at 25° C., followed by RuPhosPdG 4 (23.09 mg, 27.12 μmol), and the reaction mixture was degassed with argon for 10 min. The reaction mixture was heated at 90° C. for 16 h. After the reaction was complete (as judged by TLC and LC / MS), the reaction mixture was cooled to 25° C. and filtered through a pad of celite. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by silica gel combi flash column chromatography (SiO2; 12 g, 4% MeOH / DCM) to obtain 7-[5-chloro-2-[2-[2-methyl-6-[methyl(4-pyridyl)amino]-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (130) (110 mg, 174.56 μmol, 64.36% yield) as a brown solid.

[0635] m / z calculated: 629.2, found: (M+1)=630.3

[0636] Synthesis of 131 (Compound 47):

[0637] To a stirred solution of compound 7-[5-chloro-2-[2-[2-methyl-6-[methyl(4-pyridinyl)amino]-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (130) (100 mg, 158.69 μmol) in a mixture of THF (2 mL) and water (500.00 μL) was added LiOH.HO (26.63 mg, 634.76 μmol, 17.64 μL) at 25° C., and the reaction mixture was stirred at the same temperature for 4 h. After completion of the reaction (as judged by TLC and LC / MS), the reaction mixture was evaporated under reduced pressure. The crude product thus obtained was purified by reverse phase preparative HPLC to afford 7-[5-chloro-2-[2-[2-methyl-6-[methyl(4-pyridinyl)amino]-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (Compound 47) (35 mg, 47.48 μmol, 29.92% yield, 99.06% purity) as a white sticky solid.

[0638] 1 H NMR (400MHz, DMSO-d6): δ13.28(brs,1H),8.85(s,1H),8.20(d,J=7.6,2H), 7.57(dd,J=8.8,2.4Hz,1H),7.44(d,J=2.0Hz,1H),7.41(s,1H),7.32(d,J=8 .8Hz,1H),7.16(d,J=6.8Hz,1H),4.34(m,3H),4.14(brs,2H),3.10(s,3H),2 .77(s,3H),2.55(s,3H),2.16-2.05(m,1H),1.93-1.88(m,1H),1.77(s,3H).

[0639] m / z calcd: 615.17, found: (M+1) = 616.1 at RT 2.15.

[0640] Plan K

[0641]

[0642] Synthesis of 133:

[0643] To a stirred solution of methyl 7-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (120) (300 mg, 555 μmol) in DCM (4 mL) was added catalytic acetic acid followed by 1,1-di(methyl)ethyl 3-(methylamino)azetidine-1-carboxylate (132) (150 mg, 832 μmol) at 0°C and the reaction mixture was stirred at 25°C for 30 min. Sodium triacetoxyborohydride (176 mg, 832 μmol) was added portionwise at 0°C and stirring was continued at 25°C for 16 h. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude product thus obtained was purified by combi flash column chromatography (SiO2; 4 g, 15% MeOH-DCM) to afford 7-[5-chloro-2-[2-[6-[[1-[1,1-di(methyl)ethoxycarbonyl]azetidin-3-yl]-methyl-amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (133) (0.220 g, 310.62 μmol, 60% yield) as a white solid.

[0644] MS calculated value: 707; MS found value: 708 (M+H).

[0645] Synthesis of 134:

[0646] To a stirred solution of 7-[5-chloro-2-[2-[6-[[1-[1,1-di(methyl)ethoxycarbonyl]azetidin-3-yl]-methyl-amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (133) (0.220 g, 310.62 μmol) in DCM (2 mL) was added HCl (4 M) in dioxane (2.0 mL, 8 mmol) at 0° C., and the reaction mixture was stirred for 2 h at 25° C. After completion of the reaction (as judged by LC / MS only), the reaction mixture was evaporated under reduced pressure. The crude product thus obtained was purified by trituration with EtO to give 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester hydrochloride (chlorane) (134) (150 mg, 232.70 μmol, 74.91% yield) as an off-white solid which was used in the next step without further purification.

[0647] MS calculated value: 607; MS found value: 608 (M+H).

[0648] Synthesis of 135 (Compound 66):

[0649] To a stirred solution of 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (134) (0.060 g, 98.66 μmol) in a mixture of THF (5 mL) and water (1 mL) was added LiOH.HO (4.14 mg, 98.66 μmol, 2.74 μL) at 25° C., and the reaction mixture was stirred for 4 h at 25° C. After completion of the reaction (as judged by TLC and LCMS), the solvent was evaporated in vacuo. The crude product thus obtained was purified by reverse phase preparative HPLC to give 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (21 mg, 29.43 μmol, 29.83% yield, 99.25% purity) (Compound 66) as a white solid.

[0650] 1H NMR (400MHz, DMSO-d6): 8.78 (s, 1H), 8.7-8.2 (m, 3H), 7.57-7.54 (m, 1H), 7.42 (d, J = 2.4Hz 1H), 7.38 (s, 1H), 7.31 (t, J = 9.2Hz 1H),4.35-3.5(m,10H),2.75(s,5H),2.35(s,3H),2.1(s,1H),1.9(bs,1H),1.7(s,3H),1.6(bs,1H)ppm.

[0651] m / z calculated: 593, found: 594 (M+H).

[0652] Synthesis of 137:

[0653] To a stirred solution of compound 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester HCl (134) (0.210 g, 325.78 μmol) in NMP (4.0 mL) at 25° C. was added K CO (134.87 mg, 977.33 μmol) followed by 2,2,2-tri(fluoro)ethyl tri(fluoro)methanesulfonate (136) (90.74 mg, 390.93 μmol, 56.32 μL) and the reaction mixture was stirred at 60° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to 25° C. The reaction mixture was quenched with NH4Cl and the aqueous solution was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by grinding with Et2O to give 7-[5-chloro-2-[2-[2-methyl-6-[methyl-[1-[2,2,2-tri(fluoro)ethyl]azetidin-3-yl]amino]-4-oxomethylene-5,6,7,8-tetrahydroquinazoline-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (137) (130 mg, 188.36 μmol, 57.82% yield) as a brown gum.

[0654] MS calculated value: 689; MS found value: 690 (M+H).

[0655] Synthesis of 138 (Compound 64)

[0656] To a stirred solution of compound 7-[5-chloro-2-[2-[2-methyl-6-[methyl-[1-[2,2,2-tri(fluoro)ethyl]azetidin-3-yl]amino]-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (137) (0.100 g, 144.89 μmol) in a mixture of THF (5 mL) and water (1 mL) was added LiOH.HO (6.08 mg, 144.89 μmol, 4.03 μL) at 25°C. The reaction mixture was stirred at 25°C for 4 h. After completion of the reaction (as judged by TLC and LCMS), the solvent was evaporated in vacuo. The crude product thus obtained was purified by reverse phase preparative HPLC to give 7-[5-chloro-2-[2-[2-methyl-6-[methyl-[1-[2,2,2-tri(fluoro)ethyl]azetidin-3-yl]amino]-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (Compound 64) (8 mg, 9.28 μmol, 6.40% yield, 91.63% purity) as a white solid.

[0657] 1H NMR (400MHz, DMSO-d6): 7.56(d,J=8.8Hz 1H), 7.41(d,J=14.4Hz 2H), 7.31(d,J=8.8Hz 1H),7.16(bs,1H),7.02(bs,1H),6.90(bs,1H),4.35(bs,2H),4.12(bs,2H),3.74(t,2H),3.50(bs,2H),3.27(d,J=10Hz 2H),2.76(s,3H),2.66(s,4H),2.55(s,2H),2.08-2.04(m,2H),1.74(s,3H)ppm.

[0658] m / z calculated: 675, found: 674 (MH).

[0659] Plan L

[0660]

[0661] Synthesis of 141:

[0662] To a stirred solution of 1H-pyrrole-2-carboxylic acid methyl ester (139) (10 g, 79.92 mmol) in DMF (120 mL) was added sodium hydride (60%, 5.51 g, 239.76 mmol) in portions at 0 ° C., and the reaction mixture was stirred at the same temperature for 1 h. O-(2,4-dinitrophenyl)hydroxylamine (140) (23.87 g, 119.88 mmol) in DMF (30 mL) was then added dropwise at 0 ° C., and the reaction mixture was stirred at the same temperature for 3 h. After the reaction was complete, the reaction mixture was diluted with saturated aqueous sodium thiosulfate solution (1000 ml) and extracted with EtOAc (4 × 1000 ml). The combined organic layers were washed with brine (2 × 1000 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude residue was purified by combiflash column purification (SiO2, 120 g, 5% EtOAc in hexanes) to afford methyl 1-aminopyrrole-2-carboxylate (141) (11 g, 78.49 mmol, 98.21% yield) as a light yellow viscous liquid.

[0663] 1H NMR (400MHz, DMSO-d6): 7.02-7.01(m,1H),6.71-6.70(m,1H),6.25(s,2H),5.98-5.96(m,1H),3.74(s,3H)ppm.

[0664] Synthesis of 143:

[0665] To a stirred solution of 1-aminopyrrole-2-formic acid methyl ester (141) (5 g, 35.68 mmol) in methanol (200 ml) was added 3-oxomethylenebutanoic acid ethyl ester (142) (5.57 g, 42.81 mmol, 5.44 mL) at 25 ° C., acetic acid (50 ml) was then added, and the reaction mixture was stirred at 25 ° C. for 16 h. After the reaction was complete, volatiles were removed under reduced pressure, and the crude product was diluted with saturated NaHCO aqueous solution. The aqueous layer was extracted with EtOAc, the combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1- [[(E) -3- ethoxy -1- methyl -3- oxomethylene -prop- 1- enyl] amino] pyrrole -2-formic acid methyl ester (143) (8 g, crude product) as a yellow oil, which was then purified to the next step without further purification.

[0666] MS calculated value: 252.2; MS found value: 253.2 (M+H).

[0667] Synthesis of 144:

[0668] To a stirred solution of 1-[[(E)-3-ethoxy-1-methyl-3-oxomethylene-prop-1-enyl]amino]pyrrole-2-carboxylic acid methyl ester (143) (8 g, 31.71 mmol) in benzene (80 mL) was slowly added boron trifluoride etherate (13.50 g, 95.14 mmol, 11.7 ml) at 25 ° C, and the reaction mixture was stirred at 90 ° C for 5 h. The reaction mixture was cooled to 25 ° C and stirred at the same temperature for another 17 h. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic portions were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified in combiflash column chromatography (SiO 2 ; EtOAc:hexanes 70%) to afford 2-methyl-4-hydroxy-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (144) (2.5 g, 12.12 mmol, 38.23% yield) as an off-white solid.

[0669] 1H NMR (400MHz, DMSO-d6): 11.72 (s, 1H), 7.28 (d, J = 4.76Hz, 1H), 6.61 (d, J = 4.8Hz, 1H), 6.19 (s, 1H), 3.78 (s, 3H), 2.39 (s, 3H) ppm.

[0670] MS calculated value: 206; MS found value: 207 (M+H).

[0671] Synthesis of 145:

[0672] A mixture of phosphorus oxychloride (37.18 g, 242.49 mmol, 22.7 mL) and 2-methyl-4-hydroxy-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (144) (2.5 g, 12.12 mmol) was heated at 70 ° C for 5 h. After the reaction was complete, the volatiles were removed under reduced pressure. The crude product was purified in combiflash column chromatography (SiO2; 40 g, 10% EtOAc: Hexane) to provide 4-chloro-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (145) (1.9 g, 8.46 mmol, 69.76% yield) as an off-white solid.

[0673] 1H NMR (400MHz, DMSO-d6): 7.48 (d, J = 4.6 Hz, 1H), 7.27 (s, 1H), 6.74 (d, J = 4.6 Hz, 1H), 3.82 (s, 3H), 2.5 (s, 3H) ppm.

[0674] MS calculated value: 224; MS found value: 224.8 (M+H).

[0675] Synthesis of 147:

[0676] To a stirred solution of 4-chloro-2-methyl-pyrrolo[1,2-b]pyridazine-7-formic acid methyl ester (1.9 g, 8.46 mmol) (145) and (5-chloro-2-hydroxy-phenyl)boronic acid (146) (1.75 g, 10.15 mmol) in water (2 mL) and dioxane (20 mL) was added potassium carbonate (4.09 g, 29.60 mmol) at 25 ° C, and the reaction mixture was degassed with argon for 30 min. Pd (dppf) Cl2 (1.86 g, 2.54 mmol) was added thereto, and the reaction mixture was degassed with argon again for 10 min. The reaction mixture was stirred at 90 ° C for 5 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite and washed with EtOAc (2 × 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (SiO; 12 g, 50% EtOAc / hexanes as eluent) to afford 4-(5-chloro-2-hydroxy-phenyl)-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (147) (2.1 g, 6.63 mmol, 78.39% yield) as a light yellow solid.

[0677] 1H NMR (400MHz, DMSO-d6): 10.14 (s, 1H), 7.41-7.37 (m, 3H), 6.95 (s, 1H), 6.32 (d, 1H, J = 4.4), 3.82 (s, 3H), 2.53 (s, 3H) ppm.

[0678] MS calculated value: 316; MS found value: 315.2 (MH).

[0679] Synthesis of 148:

[0680] To a stirred solution of 4-(5-chloro-2-hydroxy-phenyl)-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (147) (5 g, 15.79 mmol) in acetone (50 mL) at 25° C. under nitrogen was added 1,2-dibromoethane (29.66 g, 157.86 mmol, 13.60 ml), followed by potassium carbonate (7.64 g, 55.25 mmol), and then stirred at 70° C. for 12 h. After the reaction was complete, the insoluble material was filtered through a sintered funnel, and the filtrate was concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (SiO; 40 g, 70% EtOAc / hexanes) to afford 4-[2-(2-bromoethoxy)-5-chloro-phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (148) (3.5 g, 8.18 mmol, 51.81% yield, 99% purity) as an off-white solid.

[0681] 1H NMR(400MHz, DMSO-d6):7.56-7.53(m,2H),7.41(d,1H,J=4.68),7.27(d,1H,J=8.52),7.02(s ,1H),6.36(d,1H,J=4.4),4.37-4.36(m,2H),3.82(s,3H),3.64-3.63(m,2H),2.54(s,3H)ppm.

[0682] MS calcd: 422; MS found: 423.1 (M+H).

[0683] Plan M(R 1 =H)

[0684]

[0685] Synthesis of 150a:

[0686] To a stirred solution of 4-[2-(2-bromoethoxy)-5-chloro-phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (149a) (737 mg, 1.80 mmol) in DMF (10 ml) at 25 ° C under a nitrogen atmosphere was added 2'-methylspiro[1,3-dioxolane-2,6'-3,5,7,8-tetrahydroquinazoline]-4'-one (105) (400 mg, 1.80 mmol), followed by addition of K2CO3 (746 mg, 5.40 mmol), and the reaction mixture was stirred at 45 ° C for 16 h. After the reaction was complete (as judged by LCMS and TLC), the reaction mixture was cooled to 25 ° C and quenched with water. The aqueous phase was extracted with EtOAc (twice). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (SiO2; 12 g; 90% EtOAc / hexanes) to give 4-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazoline]-3'-yl)ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (150a) (410 mg, 744.12 μmol, 41.34% yield) as a yellow solid.

[0687] 1 H NMR (400MHz, DMSO-d6): 8.49 (d, J=4.44Hz, 1H), 7.55-7.52 (m, 1H), 7.42 (d, J= 2.52Hz,1H),7.34(d,J=4.64Hz,1H),7.27(d,J=8.52Hz,1H),6.91(d,J=4.64H z,1H),6.09(d,J=4.68Hz,1H),4.28-4.24(m,2H),4.06-4.01(m,2H),3.96(s, 4H), 3.84 (s, 3H), 2.49-2.44 (m, 6H), 1.79 (t, J = 6.36Hz, 2H), 1.71 (s, 3H) ppm.

[0688] MS calculated value: 550.16; MS found value: 551.5 (M+H).

[0689] Synthesis of 151a:

[0690] To a stirred solution of methyl 4-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazoline]-3'-yl)ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (150a) (200 mg, 362.98 μmol) was added 6(N)HCl (2 mL) at 25 °C, and the reaction mixture was stirred at 50 °C for 1 h. After the reaction was complete, the reaction mixture was quenched with a NaHCO3 aqueous solution. The aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (SiO2, 4 g, 5% MeOH-DCM) to give methyl 4-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (151a) (116 mg, 228.83 μmol, 63.04% yield) as a yellow solid.

[0691] 1 H NMR(400MHz,DMSO-d6):8.50(d,J=4.56Hz,1H),7.54(dd,J=2.56Hz,1H),7.42(d, J=2.6Hz,1H),7.35(d,J=4.76Hz,1H),7.28(d,J=8.92Hz,1H),6.91(d,J=4.56Hz, 1H),6.08(d,J=4.76Hz,1H),4.29(t,J=4.52Hz,2H),4.10(d,J=4.64Hz,2H),3.84 (s,3H),3.09(s,2H),2.79(t,J=6.84Hz,2H),2.56-2.53(m,2H),1.76(s,3H)ppm.

[0692] MS calculated value: 506.14; MS found value: 507.4 (M+H).

[0693] Synthesis of 152a:

[0694] To a stirred solution of methyl 4-[5-chloro-2-[2-[2-methyl-4,6-bis(oxomethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (151a) (80 mg, 157.81 μmol) in DCE (6 mL) was added catalytic acetic acid at 0°C, followed by N-methylmethylamine (36 mg, 789.05 μmol, 45.90 μL) (2M solution 0.4 ml), and the reaction mixture was stirred at 25°C for 2 h. Sodium triacetoxyborohydride (201 mg, 946.86 μmol) was added portionwise at 0°C, and stirring was continued at 25°C for 2 h. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude product was purified by combi flash column chromatography (amine functionalized; 4 g, 5% MeOH in DCM) to afford methyl 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (152a) (65 mg, 121.26 μmol, 76.84% yield) as a light yellow solid.

[0695] 1 H NMR (400MHz, DMSO-d6): δ8.50(d,J=4.6Hz,1H),7.56-7.53(m,1H),7.42(d,J=2.6Hz, 1H),7.35(d,J=4.8Hz,1H),7.28(d,J=8.9Hz,1H),6.91(d,J=4.6Hz,1H),6.91(d,J=4 .8Hz,1H),4.29(t,J=4.7Hz,2H),4.07(t,J=4.6Hz,2H),3.84(s,3H),2.23(s,6H),2. 17-2.13(m,1H),1.92-1.89(m,1H),1.73(s,3H),1.53-1.50(m,1H),1.23(s,4H)ppm.

[0696] MS calculated value: 535.20; MS found value: 536.0 (M+H).

[0697] Synthesis of 153a (Compound 30):

[0698] To a stirred solution of methyl 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (152a) (65 mg, 121.26 μmol) in THF (1.2 ml), methanol (0.3 ml) and water (0.3 ml) was added 98% lithium hydroxide monohydrate (15 mg, 363.79 μmol, 10.11 μL) at 25 °C, and the reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction, the volatiles were removed under reduced pressure and the crude product was purified by reverse phase preparative HPLC to give 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylic acid (Compound 30) (30 mg, 57.44 μmol, 47.37% yield, 99.94% purity) as a light green solid.

[0699] 1 H NMR (400MHz, DMSO-d6): δ8.45(d,J=4.5Hz,1H),7.56-7.53(m,1H),7.42(d,J=2.7Hz,1H),7.32-7.26(m,2H),6.86(d,J=4.5Hz,1H),6.11(d,J=4.8Hz ,1H),4.28(t,J=4.9Hz,2H),4.07(t,J=4.9Hz,2H),2.46(s,2H),2.24(s,6 H),2.17-2.13(m,1H),1.92-1.89(m,1H),1.75(s,3H),1.51(brs,1H)ppm.

[0700] MS calculated value: 521.18; MS found value: 522.2 (M+H).

[0701] Plan M(R 1 =CH3)

[0702]

[0703] Synthesis of 150b:

[0704] To a stirred solution of 2′-methylspiro[1,3-dioxolane-2,6′-3,5,7,8-tetrahydroquinazoline]-4′-one (105) (200 mg, 899.93 μmol) in DMF (10 mL) was added potassium carbonate particles (249 mg, 1.80 mmol) at 25°C, followed by addition of 4-[2-(2-bromoethoxy)-5-chloro-phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (149b) (381 mg, 899.93 μmol), and the reaction mixture was stirred at 45°C for 17 h. After the reaction was complete, the reaction mixture was poured into cold water and extracted with EtOAc. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (SiO2, 12 g, 5% MeOH / DCM) to give 4-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (150b) (250 mg, 442.47 μmol, 49.17% yield) as a white solid.

[0705] 1 H NMR (400MHz, DMSO-d6): δ7.54-7.52(m,1H),7.41(d,J=2.5Hz,1H),7.27-7.25(m,2H),6.85(s,1H),6.04(d,J=4.5Hz,1 H),4.27(s,2H),4.07(s,2H),3.91(s,4H),3.83(s,3H),2.53(s,4H),2.44(s,4H),1.90-1.87(m,2H),1.74(s,3H)ppm.

[0706] MS calculated value: 564.18; MS found value: 565.0 (M+H).

[0707] Synthesis of 151b:

[0708] A mixture of 4-[5-chloro-2-[2-(2'-methyl-4'-oxomethylene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazoline]-3'-yl)ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (150b) (560 mg, 991.12 μmol) and 6(N) aqueous HCl (25 mL) was heated at 60° C. for 1.5 h. After the reaction was complete, the reaction mixture was slowly quenched with solid NaHCO 3 under cooling conditions (pH ˜8). The aqueous solution was extracted with EtOAc, and the combined organic fractions were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (SiO2, 12 g, 2% MeOH / DCM) to give 4-[5-chloro-2-[2-[2-methyl-4,6-bis(oxomethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (151b) (405 mg, 777.41 μmol, 78.44% yield) as a yellow solid.

[0709] 1 H NMR (400MHz, DMSO-d6): δ7.55-7.52(m,1H),7.41(d,J=2.6Hz,1H),7.28-7.26(m,2H),6.86(s,1H),6.03(d,J=4.8Hz,1H),4. 29(t,J=4.5Hz,2H),4.11(t,J=4.6Hz,2H),3.83(s,3H),3.08(s,2H),2.81-2.78(m,2H),2.56-2.50(m,5H),1.80(s,3H)ppm.

[0710] MS calculated value: 520.15; MS found value: 521.2 (M+H).

[0711] Synthesis of 152b:

[0712] To a stirred solution of methyl 4-[5-chloro-2-[2-[2-methyl-4,6-bis(oxomethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (151b) (150 mg, 287.93 μmol) in 1,2-dichloroethane (8 mL) was added acetic acid (2 mg, 28.79 μmol, 1.65 μL) followed by N,N-dimethylamine (65 mg, 1.44 mmol, 83.75 μL, 0.35 mL, 2(M) solution in THF) at 25° C. The reaction mixture was stirred for 2 h at 25° C. Sodium triacetoxyborohydride (305 mg, 1.44 mmol) was added thereto at 0° C. The reaction mixture was stirred for 2 h at 25° C. The volatiles were removed under reduced pressure and the crude product was purified by amine functionalized combiflash column chromatography (4 g, 0.2% methanol / DCM) to give 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (152b) (130 mg, 236.34 μmol, 82.08% yield) as a light yellow solid.

[0713] 1H NMR (400MHz, DMSO-d6): δ7.55-7.52(m,1H),7.41(d,J=2.4Hz,1H),7.28-7.26(m,2H),6.85(s,1H),6.05(d,J=4.7Hz,1H),4.28 -4.27(m,2H),4.09-4.07(m,2H),3.83(s,3H),2.54(s,3H),2.45-2.33(m,2H),2.21(s,6H),1.76(s,3H),1.48-1.46(m,1H)ppm.

[0714] MS calculated value: 549.21; MS found value: 550.4 (M+H).

[0715] Synthesis of 153b

[0716] To a stirred solution of 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (13) (65 mg, 118.17 μmol) in a mixture of THF (1.2 ml), water (0.3 ml) and methanol (0.3 ml) at 25 °C was added lithium hydroxide monohydrate (25 mg, 590.86 μmol) and the reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction, the volatiles were removed under reduced pressure and the crude product was purified by reverse phase preparative HPLC to give 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (153b) (26 mg, 48.19 μmol, 40.78% yield, 99.34% purity) as an off-white solid.

[0717] 1H NMR (400MHz, DMSO-d6): δ7.55-7.52(m,1H),7.41(d,J=2.7Hz,1H),7.28-7.24(m,2H),6.83(s,1H),6.06(d,J=4.8Hz,1H),4.28(t,J=4.8Hz,2H) ,4.08(t,J=4.8Hz,2H),2.54(s,3H),2.48-2.36(m,3H),2.21(s,6H),2. 15-2.07(m,1H),1.91-1.88(m,1H),1.77(s,3H),1.54-1.47(m,1H)ppm.

[0718] MS calculated value: 535.20; MS found value: 536.30 (M+H).

[0719] Synthesis of compound 59

[0720] To a stirred solution of 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (Compound 36) (60 mg, 111.94 μmol) in dichloromethane (1.5 ml) was added N,N-di(methyl)pyridin-4-amine (68 mg, 559.68 μmol) followed by 3-(ethyliminomethyleneamino)-N,N-di(methyl)propan-1-amine hydrochloride (43 mg, 223.87 μmol) at 25° C., and the reaction mixture was stirred for 0.5 h at 25° C. Methanesulfonamide (53.24 mg, 559.68 μmol) was added thereto at 25° C., and the reaction mixture was stirred for 17 h at 25° C. After completion of the reaction, the reaction mixture was diluted with DCM and washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 4-[5-chloro-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-N-methylsulfonyl-pyrrolo[1,2-b]pyridazine-7-carboxamide (Compound 59) (29 mg, 45.96 μmol, 41.06% yield, 97.18% purity) as a light yellow solid.

[0721] 1H NMR (400MHz, MeOD): δ7.56-7.53(m,1H),7.39(d,J=2.3Hz,1H),7.30-7.25(m,2H),6.78(s,1H),6.06(d,J=4.7Hz,1H),4.27-4.25(m ,2H),4.11(s,2H),3.24(s,5H),2.83(s,1H),2.54(s,4H),2.20-2.13(m,1H),2.02-2.00(m,1H),1.91(s,3H),1.58-1.55(m,1H)ppm.

[0722] MS calculated value: 612.19; MS found value: 613.2 (M+H).

[0723] Synthesis of 152c

[0724] To a stirred solution of methyl 4-[5-chloro-2-[2-[2-methyl-4,6-bis(oxomethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (151b) (100 mg, 191.95 μmol) in 1,2-dichloroethane (3 mL) was added AcOH (6 mg, 95.98 μmol, 5.49 μl) followed by piperidine (33 mg, 383.90 μmol, 37.92 μl) at 25° C. The reaction mixture was stirred for 5 h at this temperature. Sodium triacetoxyborohydride (142 mg, 671.83 μmol) was added at 0° C. and the reaction mixture was stirred for 3 h at 25° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude product thus obtained was purified by combi flash column chromatography (SiO2; 12 g, 8% MeOH / DCM) to afford 4-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-(1-piperidinyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (152c) (90 mg, 152.51 μmol, 79.45% yield) as a yellow solid.

[0725] 1H NMR (400MHz, DMSO-d6): δ7.54-7.52(m,1H),7.44-7.41(m,1H),7.28-7.26(m,2H),6.84(s,1H),6.04(d,J =5Hz,1H),4.28(s,2H),4.07(s,2H),3.83(s,3H),2.41(s,6H),1.75(s,3H),1.49(s,4H),1.39(s,3H)ppm.

[0726] MS calculated value: 589.25; MS found value: 590.1 (M+H).

[0727] Synthesis of 153c (Compound 45)

[0728] To a stirred solution of methyl 4-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-(1-piperidinyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (152c) (90 mg, 152.51 μmol) in a mixture of THF (2 ml):HO (0.4 ml):MeOH (0.4 mL) was added LiOH.HO (26 mg, 610.05 μmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse phase preparative HPLC to give 4-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-(1-piperidinyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (153c) (Compound 45) (23 mg, 39.47 μmol, 25.88% yield, 98.87% purity) as a light yellow solid.

[0729] MS calculated value: 575.23; MS found value: 576.3 (M+H).

[0730] 1H NMR (400MHz, MeOD): δ7.47-7.43(m,1H),7.26-7.23(m,2H),7.18(d,J=2.3Hz,1H),6.51(s,1H),5.91(d,J=4. 5Hz,1H),4.24(s,4H),2.78-2.66(m,4H),2.56(s,3H),2.26-2.23(m,5H),1.93-1.91(m,6H),1.68(s,2H)ppm.

[0731] Synthesis of compound 62

[0732] To a stirred solution of 4-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-(1-piperidinyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (Compound 45) (120 mg, 208.30 μmol) in dichloromethane (6 ml) was added DMAP (127 mg, 1.04 mmol) followed by EDC-HCl (79.86 mg, 416.61 μmol) and the reaction mixture was stirred at 25° C. for 0.5 h. Methanesulfonamide (99 mg, 1.04 mmol) was added thereto at 25° C. and the reaction mixture was stirred at 25° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with DCM and washed with water, brine, dried over anhydrous Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 4-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-(1-piperidinyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-N-methylsulfonyl-pyrrolo[1,2-b]pyridazine-7-carboxamide (Compound 62) (24 mg, 36.46 μmol, 17.51% yield, 99.24% purity) as a light yellow solid.

[0733] MS calculated value: 652.22; MS found value: 653.3 (M+H).

[0734] 1H NMR (400MHz, DMSO): δ7.56-7.53(m,1H),7.39(d,J=2.6Hz,1H),7.30-7.25(m,2H),6.79(s,1H),6.04(d,J=4.7Hz,1H),4.31-4.25(m,2H) ,4.11(s,2H),3.25(s,4H),2.81(brs,4H),2.54(s,3H),2.20-2.13(m,1H),2.02-2.00(m,1H),1.91(s,3H),1.63(s,4H),1.47(s,2H)ppm.

[0735] Plan N

[0736]

[0737] Synthesis of compound 135

[0738] To a stirred solution of 4-[tri(fluoro)methoxy]piperidine (18.86 g, 111.52 mmol, 2.0 eq) in dichloroethane (300 mL, 10 V) was added triethylamine (8.46 g, 83.64 mmol, 11.66 mL, 1.5 eq) at room temperature and stirred for 10 minutes, followed by the addition of methyl 7-[5-chloro-2-[2-[2-methyl-4,6-bis(oxomethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (30 g, 55.76 mmol, 1 eq) at the same temperature and continued for 4 hours. Afterwards, sodium cyanoborohydride (3.50 g, 55.76 mmol, 5.0 eq) was added to the above reaction mixture and continued at the same temperature for 36 hours. The reaction was monitored by TLC and LCMS. After the reaction was complete, water (10 volumes) was added to the reaction mass and extracted with 10% MeOH in DCM (10 volumes). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by reverse phase column chromatography (using diatomaceous earth, eluting with a gradient of 45%-50% acetonitrile in 0.1% ammonium bicarbonate in water) to provide 7- (5- chloro-2- (2- (2- methyl -4- oxo -6- (4- (trifluoromethoxy) piperidin-1-yl) -5,6,7,8- tetrahydroquinazoline -3 (4H) -yl) ethoxy) phenyl) -5- methyl-thieno [3,2-b] pyridine -3- carboxylic acid methyl esters (16 g, 41.57%) as a white solid. LCMS: 691.43 [M+1]

[0739] To a stirred solution of 7-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-[4-[tri(fluoro)methoxy]-1-piperidinyl]-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (13g, 18.81mmol) in tetrahydrofuran (130mL) and water (20mL) was added lithium hydroxide (450.48mg, 18.81mmol) at 0°C, and the resulting reaction was stirred at 25°C for 2 hours. The reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated to completely remove volatiles. The pH of the reaction mixture was adjusted to neutral with saturated citric acid, and then extracted with 10% methanol in dichloromethane (3×200mL). The combined organics were washed with water and brine and dried over sodium sulfate. The dried organics were filtered and concentrated under reduced pressure to give racemic 7-(5-chloro-2-(2-(2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (13.4 g, 85.48%) as a brown solid. The chiral isomers were separated by SFC to afford (S)-7-(5-chloro-2-(2-(2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (Compound 135) (4.5 g, 34.66%) as an off-white solid and (R)-7-(5-chloro-2-(2-(2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (Compound 136) (4.39 g, 33.81%) as an off-white solid.

[0740] Plan O

[0741]

[0742] Synthesis of 2

[0743] To a stirred solution of 1-chloro-2-methylsulfanyl-ethane (25 g, 226.03 mmol) was added MeI (160.41 g, 1130 mmol) dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 36 h. All volatiles were concentrated under reduced pressure to provide a crude compound. The crude compound was stirred in ether, the formed solid was filtered through a Buckner funnel, and the residue was washed with ether and dried under reduced pressure to provide the desired compound 2-chloroethyl-di(methyl)sulfonium iodide (2) (45 g, 78%) as a brown solid.

[0744] 1H NMR (DMSO-d6, 400MHz): δ4.16 (t, J=8.0Hz, 2H), 3.01 (s, 6H).

[0745] Synthesis of 4:

[0746] To a stirred solution of potassium tert-butoxide (9.34 g, 83.24 mmol) in t-BuOH (50 mL) was added 1,4-dioxaspiro[4.5]decane-8-one (10 g, 64.03 mmol). The reaction mixture was stirred at room temperature for 15 min. (Chloromethyl)dimethylsulfonium iodide (12.22 g, 51.22 mmol) was added thereto in batches at room temperature. The reaction mixture was stirred at room temperature for 15 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (2 × 200 mL), the two organic layers were combined and washed with water, brine solution and dried over Na2SO4 and concentrated under reduced pressure to give a crude compound. The crude compound was purified by combi flash column chromatography, eluting with 15%-20% ethyl acetate in petroleum ether as a light yellow oily liquid (3.5 g, 30%).

[0747] 1H NMR (DMSO-d6, 400MHz): δ0.68 (t, J = 4.0 Hz, 2H), 1.26 (t, J = 4.0 Hz, 2H), 1.99 (s, 2H), 2.11 (t, J = 8.0 Hz, 2H), 2.574 (t, J = 8.0 Hz, 2H), 4.01 (m, 6H).

[0748] Synthesis of 6:

[0749] To a stirred solution of 6,9-dioxadispiro[2.1.45.33]dodecan-12-one (1.2 g, 6.59 mmol) in dimethyl carbonate (3 mL) was added sodium hydride (60% dispersion in mineral oil) (757.01 mg, 32.93 mmol) in dimethyl carbonate (2 mL). The reaction mixture was stirred at room temperature for 5 min and then stirred at 90 ° C for 4 h. The reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was diluted with a saturated solution of ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were thoroughly washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to provide a crude compound (1.2 g) as a brown oily liquid, which was further used without purification. LCMS: [M+H] +: 241.1.

[0750] Synthesis of 8:

[0751] To a stirred solution of 12-oxo-6,9-dioxadispiro[2.1.45.33]dodecane-11-methylformate (1.2g, 4.55mmol) in sodium methoxide 25% in methanol (2.46g, 45.45mmol, 2.53mL) was added 97% acetamidine hydrochloride (644.56mg, 6.82mmol). The reaction mixture was stirred at 60 ° C for 6 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was acidified to pH (5-6) with 2N citric acid (10mL) and extracted with ethyl acetate (3×20mL). The combined organic layer was washed with water, then washed with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by column chromatography eluting with MeOH:DCM (1%-10%) to afford the desired compound (500 g, 44.31%) as a pale yellow solid, LCMS: [M+H]+: 249.17

[0752] Synthesis of 10:

[0753] To a stirred solution of 8 in DMSO (5 mL) was added 99% anhydrous potassium carbonate (949.83 mg, 6.87 mmol) and then 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (1.594 g, 3.6 mmol), and the reaction mixture was heated to 60 ° C for 4 h. The reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water, then with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography eluting with MeOH:DCM (1%-5%) (650 mg, 38%), LCMS: [M+H]+: 608.48.

[0754] Synthesis of 11:

[0755] To a stirred solution of 10 (650 mg, 1.06 mmol) in THF (2 mL) was added 4 M HCl (3 mL) at room temperature. The reaction mixture was stirred at 60 ° C for 6 h. The reaction was monitored by TLC and LCMS. After the reaction was complete, the mixture was alkalized with saturated NaHCO solution (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material (450 mg, 30%) as a yellow solid, which was further used without purification. LCMS: [M+H] +: 564.22.

[0756] Synthesis of 13:

[0757] To a solution of 12 (150.mg, 732.58 μmol) in DCE (1 mL) was added triethylamine (4.40 mg, 43.48 μmol) at room temperature. The reaction mixture was stirred for 10 minutes, followed by the addition of 4-[5-chloro-2-[2-[2-methyl-4,6-bis(oxymethylene)spiro[5,7-dihydroquinazoline-8,1′-cyclopropane]-3-yl]ethoxy]phenyl]-2-methyl-5H-cyclopenta[b]pyridine-7-carboxylic acid methyl ester (200 mg, 366.29 μmol), and the resulting mixture was stirred at room temperature for 16 h. NaCNBH was added to the reaction mixture at room temperature (1.45 g, 23.01 mmol) and stirred at the same temperature for 2 h. After the reaction was complete (monitored by TLC and LCMS), the reaction was quenched with water (5 mL) and extracted with 10% MeOH:DCM (2×20 mL), then washed with brine. The combined organic layers were dried over sodium sulfate and concentrated to provide 7-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-[4-[tri(fluoro)methoxy]-1-piperidinyl]spiro[6,7-dihydro-5H-quinazoline-8,1′-cyclopropane]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (200 mg, 25.68%) as a gray solid. LCMS: [M+H]+: 717.80.

[0758] Synthesis of Compound 379 and Compound 380

[0759] To a solution of 7-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-[4-[tri(fluoro)methoxy]-1-piperidinyl]spiro[6,7-dihydro-5H-quinazoline-8,1′-cyclopropane]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (200 mg, 278.86 μmol) in THF (0.7 mL) and water (0.3 ml) was added lithium hydroxide monohydrate (29.26 mg, 697.16 μmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 4 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was acidified with 2N citric acid (pH 5-6) and extracted with 10% MeOH:DCM (2×30 mL), then washed with brine. The combined organic layers were dried over sodium sulfate and concentrated to provide 7-(5-chloro-2-(2-(2'-methyl-4'-oxo-6'-(4-(trifluoromethoxy)piperidin-1-yl)-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-quinazolin]-3'(5'H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid as a racemic mixture. This was purified by preparative chromatography, and the pure fractions were concentrated to provide a racemate and subjected to SFC purification to separate enantiomers 379 and 380 (29 mg, 14.69%). LCMS: 717.80 [M+1] (NMR data in the table).

[0760] The following compounds in Table E1 were synthesized according to the above scheme:

[0761] Table E1.

[0762]

[0763]

[0764]

[0765] Reductive amination reaction:

[0766] Condition A1: (Titanium isopropoxide / room temperature):

[0767] Titanium isopropoxide (5.0 equivalents) is added to a mixture of amine (1.5 equivalents) and triethylamine (1.5 equivalents) in 1,2-dichloromethane (10V) at room temperature. A ketone compound (1.0 equivalents) is added and the resulting reaction mixture is stirred at room temperature for 16 hours. It is then cooled to 0°C and sodium cyanoborohydride (5.0 equivalents) is added in batches. The resulting reaction mixture is stirred for 2 hours. The reaction progress is monitored by TLC and LCMS. The reaction mixture is poured into ice-cold water and filtered through a celite bed, then washed with 10% methanol in dichloromethane. The organic layer is separated, and the aqueous layer is washed again with 10% methanol in dichloromethane. The combined organic layers are concentrated under reduced pressure to obtain a crude material sample. It is purified by flash column chromatography using 60-120 mesh silica gel, and the desired product is eluted with 0-10% methanol in dichloromethane as eluent. Pure fractions (as determined by TLC) were combined and evaporated under reduced pressure to afford the desired product.

[0768] Condition A2: (Titanium isopropoxide / 80°C):

[0769] Titanium isopropoxide (5.0 equivalents) is added to a mixture of amine (1.5 equivalents) and triethylamine (1.5 equivalents) in 1,2-dichloromethane (10V) at room temperature. A ketone compound (1.0 equivalents) is added and the resulting reaction mixture is stirred at 80°C for 16h. It is then cooled to 0°C and sodium cyanoborohydride (5.0 equivalents) is added in batches. The resulting reaction mixture is stirred for 2h. The reaction progress is monitored by TLC and LCMS. The reaction mixture is poured into ice-cold water and filtered through a celite bed, then washed with 10% methanol in dichloromethane. The organic layer is separated, and the aqueous layer is washed again with 10% methanol in dichloromethane. The combined organic layers are concentrated under reduced pressure to obtain a crude material sample. It is purified by flash column chromatography using 60-120 mesh silica gel, and the desired product is eluted with 0-10% methanol in dichloromethane as eluent. Pure fractions (as determined by TLC) were combined and evaporated under reduced pressure to afford the desired product.

[0770] Condition A3: (titanium isopropoxide / 60°C)

[0771] Titanium isopropoxide (5.0 equivalents) is added to a mixture of amine (1.5 equivalents) and triethylamine (1.5 equivalents) in 1,2-dichloroethane (10V) at room temperature. A ketone compound (1.0 equivalents) is added and the resulting reaction mixture is stirred at 60°C for 16h. It is then cooled to 0°C and sodium cyanoborohydride (5.0 equivalents) is added in batches. The resulting reaction mixture is stirred for 2h. The reaction progress is monitored by TLC and LCMS. The reaction mixture is poured into ice-cold water and filtered through a bed of celite, then washed with 10% methanol in dichloromethane. The organic layer is separated, and the aqueous layer is washed again with 10% methanol in dichloromethane. The combined organic layers are concentrated under reduced pressure to obtain a crude material sample. It is purified by flash column chromatography using 60-120 mesh silica gel, and the desired product is eluted with 0-10% methanol in dichloromethane as eluent. Pure fractions (as determined by TLC) were combined and evaporated under reduced pressure to afford the desired product.

[0772] Condition A4: (sodium acetate / toluene or methanol / room temperature)

[0773] At room temperature, sodium acetate (5.0 equivalents) is added to a mixture of amine (1.5 equivalents) and triethylamine (1.5 equivalents) in toluene or methanol (10V). Ketone compound (1.0 equivalents) is added and the resulting reaction mixture is stirred at room temperature for 16h. It is then cooled to 0°C and sodium cyanoborohydride (5.0 equivalents) is added in batches. The resulting reaction mixture is stirred for 2h. The reaction process is monitored by TLC and LCMS. The reaction mixture is poured into ice-cold water and filtered through a diatomaceous earth bed, then washed with 10% methanol in dichloromethane. The organic layer is separated, and the water layer is washed with 10% methanol in dichloromethane again. The combined organic layer is concentrated under reduced pressure to obtain a crude material sample. It is purified by flash column chromatography using 60-120 mesh silica gel, and the desired product is eluted with 0-10% methanol in dichloromethane as eluent. Pure fractions (determined by TLC) are merged and evaporated under reduced pressure to provide the desired product.

[0774] Condition A5: (sodium acetate / 60°C):

[0775] At room temperature, sodium acetate (5.0 equivalents) is added to a mixture of amine (1.5 equivalents) and triethylamine (1.5 equivalents) in 1,2-dichloroethane (10V). A ketone compound (1.0 equivalents) is added and the resulting reaction mixture is stirred at 60°C for 16h. It is then cooled to 0°C and sodium cyanoborohydride (5.0 equivalents) is added in batches. The resulting reaction mixture is stirred for 2h. The reaction progress is monitored by TLC and LCMS. The reaction mixture is poured into ice-cold water and filtered through a celite bed, then washed with 10% methanol in dichloromethane. The organic layer is separated, and the aqueous layer is washed again with 10% methanol in dichloromethane. The combined organic layers are concentrated under reduced pressure to obtain a crude material sample. It is purified by flash column chromatography using 60-120 mesh silica gel, and the desired product is eluted with 0-10% methanol in dichloromethane as eluent. Pure fractions (as determined by TLC) were combined and evaporated under reduced pressure to afford the desired product.

[0776] Condition A6: (TEA / DCE or methanol / room temperature):

[0777] At room temperature, triethylamine (5.0 equivalents) is added to a solution of amine (1.5 equivalents) in 1,2-dichloroethane or methanol (10V). A ketone compound (1.0 equivalents) is added and the resulting reaction mixture is stirred at room temperature for 16h. It is then cooled to 0°C and sodium cyanoborohydride (5.0 equivalents) is added in batches. The resulting reaction mixture is stirred for 2h. The reaction progress is monitored by TLC and LCMS. The reaction mixture is poured into ice-cold water and filtered through a diatomaceous earth bed, then washed with 10% methanol in dichloromethane. The organic layer is separated, and the aqueous layer is washed again with 10% methanol in dichloromethane. The combined organic layers are concentrated under reduced pressure to obtain a crude material sample. It is purified by flash column chromatography using 60-120 mesh silica gel, and the desired product is eluted with 0-10% methanol in dichloromethane as eluent. Pure fractions (determined by TLC) are combined and evaporated under reduced pressure to provide the desired product.

[0778] Condition A7: (titanium isopropoxide / methanol / 80°C)

[0779] At room temperature, titanium isopropoxide (5.0 equivalents) is added to a mixture of amine (1.5 equivalents) and triethylamine (1.5 equivalents) in methanol (10V). Ketone compound (1.0 equivalents) is added and the resulting reaction mixture is stirred at 60°C for 16h. It is then cooled to 0°C and sodium cyanoborohydride (5.0 equivalents) is added in batches. The resulting reaction mixture is stirred for 2h. The reaction process is monitored by TLC and LCMS. The reaction mixture is poured into ice-cold water and filtered through a diatomaceous earth bed, then washed with 10% methanol in dichloromethane. The organic layer is separated, and the water layer is washed with 10% methanol in dichloromethane again. The combined organic layer is concentrated under reduced pressure to obtain a crude material sample. It is purified by flash column chromatography using 60-120 mesh silica gel, and the desired product is eluted with 0-10% methanol in dichloromethane as eluent. Pure fractions (as determined by TLC) were combined and evaporated under reduced pressure to afford the desired product.

[0780] Condition A8: (methanol / acetic acid):

[0781] At room temperature, acetic acid (catalysis) is added to a stirred solution of amine (1.0 equivalents) and ketone compound (1.1 equivalents) in methanol (10V) and stirring continues for 5h. After adding sodium cyanoborohydride (2 equivalents) at 0 ℃, then allow it to reach room temperature and stir and continue for 16h. Monitor the reaction process by TLC. After the reaction is complete, quench with water and wash with 10% methanol in dichloromethane (50mL×3). The organic layer merged is through anhydrous Na2SO4 drying, filter and the filtrate is evaporated under reduced pressure, to obtain crude product. The crude product is purified by reversed-phase flash chromatography (using the gradient of 0-100% acetonitrile in 0.1% ammonium hydroxide in water, 230-400 mesh silica gel). Collect pure fractions and concentrate under reduced pressure to provide the desired product.

[0782] Ester hydrolysis (using lithium hydroxide monohydrate):

[0783] At room temperature, lithium hydroxide monohydrate (5 equivalents) is added to a solution of the ester analogue (1 equivalent) in a mixture of THF:H2O (3:1). The resulting mixture is stirred at room temperature for xx hours. The reaction progress is monitored by TLC and LCMS. The reaction mass is acidified to pH 4-6 with 1N HCl / saturated citric acid solution. Volatiles are removed under reduced pressure and washed with 10%-15% methanol in dichloromethane. The combined organic layers are concentrated under reduced pressure to obtain the desired product.

[0784] Boc deprotection:

[0785] The Boc derivative (1 equivalent) is dissolved in dichloromethane (10V), and then the 4.0M hydrochloric acid in 1,4-dioxane (6 equivalents) is added at 0°C. The reaction mixture is stirred at room temperature for another 2h. The reaction is monitored by TLC. After the reaction is complete, the excess solvent is evaporated under reduced pressure to obtain a crude material. The crude material is further washed with ether (30V). The solid obtained is further dried to provide the desired product.

[0786] Alkylation using 2,2,2-tri(fluoro)ethyl tri(fluoro)methanesulfonate

[0787] In room temperature, will be in acetone (2mL) and K cO (7 equivalents) in the amine compound (1 equivalent) is packed in 25mL three-necked round-bottom flask.The resulting reaction mixture is stirred for 5 minutes, and then tri(fluoro) methanesulfonic acid-2,2,2-tri(fluoro) ethyl ester (11 equivalents) is added to the above mixture.The resulting mixture is stirred at 80 DEG C for 4h.After the reaction is completed, excess solvent is evaporated under reduced pressure, to obtain crude material.Crude material is further purified by flash chromatography to provide desired product.

[0788] Alkylation of quinazolin-4-one:

[0789] Potassium carbonate granules (1 equivalent) is added in the stirred solution of quinazoline-4-one analogue (1 equivalent) in DMSO (10V), and resulting mixture is continued 15 minutes at stirring at room temperature.Then, add bromo compound (0.7 equivalent), then reaction mixture is continued 3h at 75 ℃ of heating.Monitor the reaction by TLC.After reaction is completed, add ice-cold water, and filter the precipitate formed.The solid obtained washs with n-pentane, so that the product of expectation is provided.

[0790] Sulfonamide formation:

[0791] Condition F1: At 0 ° C, methanesulfonamide (10 equivalents), 4-dimethylaminopyridine (1.5 equivalents) and EDC (3 equivalents), DIPEA (3.5 equivalents) were added to a stirred solution of the acid compound (1 equivalent) in DCM (10V). The resulting mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LC-MS. After the reaction was complete, the reaction mixture was diluted with water and washed with DCM (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by preparative HPLC, and the desired pure fractions were collected and concentrated to the desired product.

[0792] Condition F2: At 0 ° C, methanesulfonamide (5 equivalents), CDI (3.5 equivalents) and DBU (3.5 equivalents) were added to a stirred solution of the acid compound (1 equivalent) in DMF (10V). The resulting mixture was stirred at 80 ° C for 16 h. The reaction progress was monitored by LC-MS. After the reaction was complete, the reaction mixture was diluted with water and washed with DCM (2 × 100 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC, and the required pure fractions were collected and concentrated into the desired product.

[0793] Condition F3: At 0 ° C, methanesulfonamide (10 equivalents), HATU (3 equivalents) and DIPEA (3.5 equivalents) were added to a stirred solution of the acid compound (1 equivalent) in THF (10V). The resulting mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LC-MS. After the reaction was complete, the reaction mixture was diluted with water and washed with DCM (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC, and the required pure fractions were collected and concentrated to the desired product.

[0794] N-Methylation via reductive amination:

[0795] 37% formaldehyde solution and sodium cyanoborohydride (337.75mg, 5.37mmol) are added to the stirred solution of amine (700mg, 1.07mmol) in methanol (10V).Afterwards, the reaction mixture is stirred at room temperature for 16h. The reaction process is monitored by LC-MS. The reaction mixture is quenched with water and washed with 10% methanol in dichloromethane (2×100mL), and the organic layer combined is through anhydrous Na2SO4 drying, filtered and concentrated to obtain crude product. The crude product is by flash column chromatography, by using 100-200 mesh silica gel, eluted with 0-10% methanol in dichloromethane to purify, merges required pure fractions and is concentrated into the desired product.

[0796] Compound 532. (S)-7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid

[0797] Compound 533. (R)-7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-methylhydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid

[0798]

[0799] Step-1: Synthesis of isopropyl 7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (3)

[0800] Step 1 was synthesized using General Procedure A2 starting from 7-[5-chloro-2-[2-[2-methyl-4,6-bis(oxomethylene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (350 mg, 650.54 μmol) and 5,6-bis(fluoro)isoindoline hydrochloride (186.97 mg, 975.81 μmol) to provide isopropyl 7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (400 mg, crude material) as a light yellow solid. LCMS: 705.20 [M+1].

[0801] Step-2: Synthesis of 7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid

[0802] Step 2 was synthesized using General Procedure B starting from 7-[2-[2-[6-[5,6-bis(fluoro)isoindolin-2-yl]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid-1-methylethyl ester (400 mg, 567.21 μmol) and lithium hydroxide (67.92 mg, 2.84 mmol): to provide (S)-7-(5-chloro-2-( 2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid and (R)-7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid. LCMS: 663.22 [M+1], 660.81 [M-1].

[0803] 2. Experimental procedures for Examples 1-88: These were prepared from Int-A (the bulky ketone) and the appropriate amine according to the general procedure described for Synthesis Example 01:

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812] 3. Experimental procedures for compounds 512 and 511.

[0813]

[0814] Step-1: Synthesis of methyl 7-(2-(2-(6-(7-(tert-butoxycarbonyl)-9,9-difluoro-2,7-diazaspiro[4.5]dec-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (3)

[0815] This compound was synthesized by General Procedure A1 to afford methyl 7-(2-(2-(6-(7-(tert-butoxycarbonyl)-9,9-difluoro-2,7-diazaspiro[4.5]dec-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate as a light yellow solid (400 mg, crude material). LCMS: 826.2 [M+1].

[0816] Step-2: Synthesis of 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]dec-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid isopropyl ester (4)

[0817] This compound was synthesized by General Procedure C from methyl 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]dec-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate to give isopropyl 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]dec-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate as a light yellow solid. LCMS: 726.36 [M+1].

[0818] Step 3: Synthesis of 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]quinazolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid isopropyl ester (5)

[0819] This compound was synthesized using General Procedure D from 7-[2-[2-[6-[7,7-bis(fluoro)-2,9-diazaspiro[4.5]dec-2-yl]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-benzothiophene-3-carboxylic acid-1-methylethyl ester (180 mg, 248.18 μmol) to provide 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]dec-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid isopropyl ester.

[0820] Step-4: Synthesis of 7-(5-chloro-2-(2-((6S)-6-(9,9-difluoro-7-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]dec-2-yl)-2-methyl-4-oxo-5,6,7,8-methylhydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (Compound 512)

[0821] This compound was synthesized by General Procedure B using 7-[2-[2-[6-[9,9-bis(fluoro)-7-[2,2,2-tri(fluoro)ethyl]-2,7-diazaspiro[4.5]dec-2-yl]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (200 mg, 256.33 μmol) to provide 7-[5-chloro-2-[2-[(6S)-6-[(7R)-9,9-difluoro-7-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]dec-2-yl]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester [Methyl-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (6 mg, 7.54 μmol, 2.94% yield, 96.29% purity) and 7-[5-chloro-2-[2-[(6R)-6-[(7S)-9,9-difluoro-7-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]dec-2-yl]-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (9 mg, 11.46 μmol, 4.47% yield, 97.57% purity). LCMS: 766.32 [M+1].

[0822] The following ester derivatives were prepared using the above scheme. The corresponding esters were further hydrolyzed to the final compounds.

[0823]

[0824]

[0825] 4. Experimental Procedures for Compounds 496 and 497

[0826]

[0827] Step-1: Synthesis of 4-methoxy-1-(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)piperidine (3)

[0828] The three-necked flask equipped with a mechanical stirrer, a Dean-Stark trap, a condenser with a nitrogen inlet-outlet is equipped with 4-methoxypiperidine (5g, 43.41mmol), 1,4-dioxaspiro [4.5] decane-8-one (6.78g, 43.41mmol), 1,2,3-triazole (2.21g, 32.01mmol) and 50mL toluene. Reactant mixture is heated to 108 DEG C-114 DEG C to realize reflux and stir for 6h-8h, while collecting water via the Dean-Stark trap. Reactant mixture is cooled to room temperature and, when effectively stirred, is added to methylmagnesium bromide (200mmol, 3.0M in THF) within the time period of 30min, while internal temperature is maintained at <24 DEG C. Reactant mixture is stirred at room temperature for another 1h. After completing, reactant mixture is added to 20% ammonium chloride solution within the time period of 30 minutes, while internal temperature is maintained at <30 DEG C. Separate organic layer. The aqueous layer was washed with ethyl acetate (200 mL). The combined organic layers were washed with water (100 mL) and concentrated. The crude material was purified by silica gel chromatography to provide 4-methoxy-1-(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)piperidine (2.5 g, 22% yield) as a colorless oil. LCMS: 270.21 [M+1].

[0829] Step-2: Synthesis of 4-(4-methoxy-1-piperidinyl)-4-methyl-cyclohexanone (4)

[0830] To a stirred solution of 4-methoxy-1-(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)piperidine (2.0 g, 7.42 mmol) in tetrahydrofuran (20 mL) was added 6 M HCl (20 mL) at 25 ° C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 6 h. The reaction progress was monitored by LCMS. After completion, all volatiles were removed from the reaction mixture in a vacuum. The crude material obtained was alkalized (until pH ~ 7) using saturated NaHCO 3 and washed with 15% methanol in dichloromethane (1000 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated in a vacuum. The obtained gum was ground with ether and dried to provide 4-(4-methoxy-1-piperidinyl)-4-methyl-cyclohexanone (1.67 g, 39% yield) as a light yellow oil. LCMS: 226.19 [M+1].

[0831] Step-3: Synthesis of 5-(4-methoxy-1-piperidinyl)-5-methyl-2-oxomethylene-cyclohexanecarboxylic acid methyl ester (6)

[0832] To a stirred solution of 4-(4-methoxy-1-piperidinyl)-4-methyl-cyclohexanone (1.0 g, 4.43 mmol) in THF (25 mL) at 0° C. under a nitrogen atmosphere was added sodium hydride (in oil dispersion) 60% dispersion (510 mg, 22.18 mmol) in mineral oil. Dimethyl carbonate (20 mL) was added to the mixture, and the resulting mixture was allowed to stir at 80° C. for 6 h. After completion, the reaction mixture was quenched with ice-cold water and washed with 10% methanol-DCM. The combined organic layers were dried over Na 2 SO 4 and concentrated in a vacuum. The crude material obtained was purified by column chromatography using 0-10% methanol-DCM as eluent to provide 5-(4-methoxy-1-piperidinyl)-5-methyl-2-oxomethylene-cyclohexanecarboxylic acid methyl esters (0.51 g, 40% yield) as yellow gum. LCMS: 284.2[M+1].

[0833] Step-4: Synthesis of 6-(4-methoxy-1-piperidinyl)-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (8)

[0834] To a stirred solution of 5-(4-methoxy-1-piperidinyl)-5-methyl-2-oxomethylene-cyclohexanecarboxylic acid methyl esters (0.5g, 1.76mmol) in methanol (5mL) was added sodium methoxide solution (476.69mg, 8.82mmol), followed by addition of acetamidine hydrochloride (166.82mg, 1.76mmol), and the resulting mixture was allowed to stir at 80°C for 6h. After completion, the reaction mixture was concentrated to completely remove volatiles. The pH of the reaction mixture was adjusted to neutral with saturated citric acid, and then washed with 10% methanol in dichloromethane (3 × 20mL). The organic layer was dried over NaSO and concentrated in a vacuum to provide 6-(4-methoxy-1-piperidinyl)-2,6-bis(methyl)-3,5,7,8-tetrahydroquinazoline-4-one (0.2g, 39% yield), and the solid obtained was used directly in the next step. LCMS: 292.26 [M+1].

[0835] Step 5: Synthesis of 7-[5-chloro-2-[2-[6-(4-methoxy-1-piperidinyl)-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (10)

[0836] To a stirred solution of 6-(4-methoxy-1-piperidinyl)-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (0.5 g, 1.72 mmol) and 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (605.02 mg, 1.37 mmol) in N,N'-dimethylformamide (5 mL) was added potassium carbonate powder (711.45 mg, 5.15 mmol) and the reaction mixture was stirred at 80° C. for 16 h. Upon completion, the reaction mixture was poured into ice-cold water and the obtained solid was filtered. The obtained crude material was purified by reverse phase column chromatography using ACN-water as eluent to afford 7-[5-chloro-2-[2-[6-(4-methoxy-1-piperidinyl)-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (0.125 g, 11.2% yield) as a white solid. LCMS: 651.31 [M+1].

[0837] Step-6: Synthesis of 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2,6-dimethyl-4-oxo-5,6,7,8-methylhydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (11)

[0838] To a stirred solution of 7-[5-chloro-2-[2-[6-(4-methoxy-1-piperidinyl)-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (100.00 mg, 153.56 μmol) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide (19.33 mg, 460.68 μmol) at 0 ° C, and the resulting reaction was stirred at 25 ° C for 2 h. The reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated to completely remove volatiles. The pH of the reaction mixture was adjusted to neutral with 1N HCl, and then washed with 10% methanol in dichloromethane (3 × 20 mL). The combined organics were washed with water and brine and dried over sodium sulfate. The dried organics were filtered and concentrated under reduced pressure to give racemic 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2,6-dimethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid as an off-white solid. The chiral isomers were separated by SFC to provide 7-[5-chloro-2-[2-[(6S)-6-(4-methoxy-1-piperidinyl)-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (21 mg, 32.23 μmol) as an off-white solid. , 21% yield) and 7-[5-chloro-2-[2-[(6R)-6-(4-methoxy-1-piperidinyl)-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (15 mg, 22.72 μmol, 15% yield) as an off-white solid. LCMS: 637.34 [M+1].

[0839] The following ester analogs were prepared using the above protocol. The corresponding esters were hydrolyzed to the final compounds.

[0840]

[0841] 5. Experimental Procedures for Compounds 565, 559, and 558

[0842] Synthesis scheme:

[0843]

[0844] Step-1: Synthesis of 6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2-methyl-4-oxomethylene-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (3)

[0845] To the stirred solution of 4-methoxy-3,3-di(methyl)piperidines (1.21g, 6.73mmol) in DCE (8.93mL) was added triethylamine (851.83mg, 8.42mmol, 1.17mL) in room temperature. Stirring continued for 15min. Then 2-methyl-3,5,7,8-tetrahydroquinazoline-4,6-dione (1g, 5.61mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 12h. Then potassium cyanide (548.15mg, 8.42mmol) and methanol (893.33 μL) were slowly added at room temperature. Then the reaction mixture was stirred for 4h and monitored by LCMS. After the reaction was completed, it was quenched with water (50mL) and washed with DCM. The organics were collected, dried over sodium sulfate, and concentrated under reduced pressure to give 6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2-methyl-4-oxomethylene-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (1.2 g, 907.93 μmol, 16.18% yield, 25% purity). LCMS: 331.35 [M+1].

[0846] Step-2: Synthesis of 6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (4)

[0847] To a stirred solution of 6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2-methyl-4-oxomethylene-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (1.2 g, 3.63 mmol) in THF (12 mL) was added methylmagnesium bromide (3 M in Et2O, 1.69 g, 14.53 mmol, 1.63 mL) at -75 ° C under N2 atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. After the reaction was complete, cold water (20 mL) was slowly added and washed with ethyl acetate (20 mL × 3). Organic matter was collected, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material. The crude material was purified by reverse phase column using 50% ACN and 1% ammonium bicarbonate solution to provide 6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (400 mg, 713.75 μmol, 19.65% yield, 57% purity). LCMS: 320.22 [M+1].

[0848] Step-3: Synthesis of 7-[5-chloro-2-[2-[6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (6):

[0849] To a stirred solution of 6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (800mg, 2.50mmol) in DMF (546.56 μL) was added potassium carbonate (1.04g, 7.51mmol, 453.43 μL) and 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-methyl carboxylate (1.10g, 2.50mmol). The resulting mixture was heated at 80°C for 4h. The reaction was monitored by LCMS. After the reaction was complete, the reaction was quenched with cold water (20mL) and then washed with ethyl acetate (20mL × 3). Organic matter was collected, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. The crude material was purified by reverse phase column with 50% ACN and 1% ammonium bicarbonate solution to provide 7-[5-chloro-2-[2-[6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (120 mg, 713.75 μmol, 19.65% yield, 52% purity). LCMS: 679.38 [M+1].

[0850] Step-4: Synthesis of 7-[5-chloro-2-[2-[(6R)-6-[(4S)-4-methoxy-3,3-dimethyl-1-piperidinyl]-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]piperidine-3-carboxylic acid (7):

[0851] To a stirred solution of methyl 7-[5-chloro-2-[2-[6-[4-methoxy-3,3-di(methyl)-1-piperidinyl]-2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]thieno[3,2-b]pyridine-3-carboxylate (120 mg, 180.39 μmol) in THF (5 mL) and water (3 mL) was added lithium hydroxide (12.96 mg, 541.16 μmol). The reaction mixture was stirred at 25 ° C for 2 h. The reaction progress was monitored by LCMS. After completion, the volatiles were evaporated under reduced pressure, and the crude material obtained was acidified with 1 M citric acid and washed with 10% methanol-DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material compound obtained was purified by preparative HPLC and room temperature isomer separation was performed by SFC purification to provide each isomer. LCMS: 665.33 [M+1].

[0852] 6. Experimental Procedures for Compounds 516 and 515

[0853]

[0854] Step-1: Synthesis of 2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile (3):

[0855] Triethylamine (2.92 g, 28.81 mmol, 4.02 mL) was added to a solution of 2-methyl-3,5,7,8-tetrahydroquinazoline-4,6-dione (3.5 g, 19.21 mmol) and 4-[tri(fluoro)methoxy]piperidine (4.87 g, 28.81 mmol) in DCE (100 mL) at room temperature and stirred for 3 h. The reaction mixture was cooled to 0 ° C and KCN (1.99 g, 28.81 mmol) was added portionwise and allowed to warm at room temperature for 5 h. The reaction mixture was cooled to 0 ° C and quenched with water and extracted with DCM (100 mL × 3). The combined organic layer was washed with cold water (100 mL) and brine solution (100 mL), and the organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile (3.5 g, 50%) as a brown gummy solid. LCMS: 357.27 [M+1].

[0856] Step-2: Synthesis of 2,6-dimethyl-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (4)

[0857] Methylmagnesium bromide (1.30 g, 11.23 mmol, 1.26 mL) was slowly added dropwise to a solution of 2-methyl-4-oxomethylene-6-[4-[tri(fluoro)methoxy]-1-piperidinyl]-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (800 mg, 2.25 mmol) in THF (10 mL) at -78 ° C, and the resulting reaction mixture was allowed to reach room temperature and stirred for 2 h. The reaction mixture was cooled to 0 ° C and quenched with saturated aqueous ammonium chloride solution. It was then extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with cold water (100 mL) and brine solution (100 mL), and the organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to provide a crude product. The crude product was purified by combi-flash column chromatography using 230-400 mesh silica gel and the desired product was eluted with 0-10% MeOH in DCM as eluent. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to provide 2,6-dimethyl-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (180 mg, 46%) as a brown solid. LCMS: 346.18 [M+1].

[0858] Step 3: Synthesis of methyl 7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (6):

[0859] At room temperature, potassium carbonate (180 mg, 1.30 mmol, 78.64 μL) was added to a solution of 2,6-di(methyl)-6-[4-[tri(fluoro)methoxy]-1-piperidinyl]-3,5,7,8-tetrahydroquinazolin-4-one (180 mg, 521.20 μmol) in DMF (5 mL) and slowly heated to 75 ° C and stirred for 15 min. 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid-1,1-di(methyl)ethyl ester (252 mg, 521.20 μmol) was then slowly added to the reaction mixture in portions at 75 ° C, and the resulting reaction mixture was stirred at the same temperature for another 4 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with cold water (100 mL) and brine solution (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to provide a crude product as a brown liquid. The crude product was purified by combi-flash column chromatography using 230-400 mesh silica gel and the desired product was eluted with 0-10% MeOH in DCM as eluent. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to provide 7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazoline-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid methyl ester (120 mg, 35%) as a brown solid. LCMS: 705.23 [M+1].

[0860] Step 4: Synthesis of (S)-7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid and (R)-7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid

[0861] At room temperature, lithium hydroxide monohydrate (36 mg, 850.84 μmol, 23.65 μL) is added to a solution of 7- [5- chloro -2- [2- [2,6- di (methyl) -4- oxomethylene -6- [4- [tri (fluoro) methoxy] -1- piperidinyl] -7,8- dihydro -5H- quinazolin -3- base] ethoxy] phenyl] -5- methyl -thieno [3,2-b] pyridine -3- carboxylic acid methyl ester (120 mg, 170.17 μmol) in a mixture of solvent THF and H2O (2mL and 0.5mL). The resulting mixture is stirred at room temperature for 2h. The resulting reaction mixture is concentrated under reduced pressure at 45 ° C. The reaction mass is diluted in water and acidified to pH 4-6 with saturated aqueous citric acid solution. It is then washed with 10% MeOH in dichloromethane (30mL × 2). The combined organic layers were concentrated under reduced pressure to give a crude material. The crude product was purified by preparative HPLC (column name X-BRIDGE-C18 (150*19mm), 5μ column number # MCL-PREP-COL-2022-068 mobile phase-A, 10mM ammonium bicarbonate in water, mobile phase-B, acetonitrile gradient program (T / %B) 0 / 15, 12 / 50, 12.1 / 98, 14 / 98, 14.1 / 15, 16 / 15, flow rate (mL / min), 16 samples loaded (mg / injection)) to provide the desired product as an off-white solid. The isomers were separated by SFC to provide the two desired isomers as off-white solids. LCMS: 691.25 [M+1].

[0862] The following ester analogs were prepared using the above protocol and hydrolyzed to the final compounds.

[0863]

[0864] 7. Experimental Procedures for Compounds 239 and 240

[0865]

[0866] Step-1: Synthesis of methyl 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-methylhydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (3)

[0867] This compound was synthesized by General Procedure E from 6-(4-methoxy-1-piperidinyl)-2-methyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (1.4 g, 5.05 mmol) to afford methyl 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate. LCMS: 637.25.

[0868] Step-2: Synthesis of 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (4)

[0869] This compound was synthesized by General Procedure B from 7-[5-chloro-2-[2-[6-(4-methoxy-1-piperidinyl)-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (650 mg, 1.02 mmol) to provide 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid. LCMS: 623.16.

[0870] Step 3: Synthesis of (R)-7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-methylhydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methyl-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide and (S)-7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methyl-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide.

[0871] These intermediates were synthesized using Procedure F1 from 7-[5-chloro-2-[2-[6-(4-methoxy-1-piperidinyl)-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid to afford 7-[5-chloro-2-[2-[(6R)-6-(4-methoxy-1-piperidinyl)-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-N-methylthieno[3,2-b]pyridine-3-carboxylic acid as an off-white solid. Sulfonyl-thieno[3,2-b]pyridine-3-carboxamide (42.46 mg, 60.33 μmol, 6.27% yield, 99.50% purity) and 7-[5-chloro-2-[2-[(6S)-6-(4-methoxy-1-piperidinyl)-2-methyl-4-oxomethylene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-N-methylsulfonyl-thieno[3,2-b]pyridine-3-carboxamide (38.23 mg, 53.69 μmol, 5.58% yield, 98.34% purity). LCMS: 700.27 ...

Claims

1. A compound of formula I": or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, in: Each -L- is independently -O-, -NR L -、-CR L1 R L2 -、-CR L1 =CR L2 -or-C≡C-; Each R L are independently hydrogen or optionally substituted C 1-6 alkyl; Each R L1 and each R L2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, wherein the alkyl, alkoxy or alkylamino group is optionally substituted; q is an integer selected from 1 to 5; Ring C and Ring D are independently C 6-10 aryl or 5- to 10-membered heteroaryl; R C1 , each R C2 and each R D are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; r and s are independently integers selected from 0 to 6 when valence permits; R 2 It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or -C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted, R 1 Yes-NR 1a R 1b OR 1c ; R 1’ It is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; or R 1 and R 1’ Together with the carbon atoms to which they are bonded, they form C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted; R 1a and R 1b are independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 Carbocyclic), -(C 1-6 alkylene)-(3 to 12 membered heterocyclic group), -S(=O)R a 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted; or R 1a and R 1b Together with the nitrogen atom to which they are bound, they form a 3- to 12-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by one or more R ab replace; Each R ab are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, or -S(=O)R a wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted; or Two adjacent R ab Together with the atoms to which they are bound, they form a C6 aryl or a 5- to 6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; R 1c It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; X is -O- or -C(R X )2-; Each R X are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; Two R's X Together with the carbon atom to which they are bonded, they form an oxo group; or Two R's X Together with the carbon atoms to which they are bonded, they form C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted; Each R A1 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; or R A1 and adjacent R X Together with the carbon atoms to which they are bonded, they form C 3-4 carbocyclyl or 3- to 4-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted; m and m' are independently integers selected from 0 to 2; Each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; n is an integer selected from 0 to 10 when valence permits; R B It is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; in: Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and Each R c and each R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or R c and R d together with the nitrogen atom to which they are bound, form a 3- to 12-membered heterocyclic group; where R a 、R b 、R c and R d Each occurrence of is independently and optionally substituted. The compound according to claim 1 , wherein Ring C is phenyl or pyridyl.

3. The compound according to claim 1 or 2, wherein the compound of formula I" is a compound of formula I"-1-i, formula I"-1-ii, formula I"-1-iii or formula I"-1-iv: or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

4. The compound according to any one of claims 1 to 3, wherein ring D is phenyl, pyridyl, pyrrolopyridazinyl or thienopyridinyl.

5. The compound according to any one of claims 1 to 4, wherein R 2 is hydrogen, -C(=O)NR c S(=O)2R a 、-C(=O)NR c R d 、-(CH2)C(=O)OR b or -C(=O)OR b .

6. The compound according to claim 5, wherein R 2 It is -C(=O)NHS(=O)2CH3 or -COOH.

7. The compound according to claim 1, wherein the compound of formula I″ is a compound of formula I″-1-i-1, I″-1-i-2, I″-1-i-3, I″-1-iii-1, I″-1-iii-2 or I″-1-iii-3: or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

8. A compound according to any one of claims 1 to 7, wherein R C1 is a halogen or -OH.

9. The compound according to claim 8, wherein R C1 It is -Cl.

10. The compound according to any one of claims 1 to 9, wherein r is 0 or 1.

11. The compound according to any one of claims 1 to 10, wherein at least one R D It is C 1-6 Alkyl or R D Each of C 1-6 alkyl.

12. The compound according to any one of claims 1 to 11, wherein s is 0, 1 or 2.

13. The compound according to any one of claims 1 to 12, wherein [L] q yes in: * indicates attachment to ring B, and ** indicates attachment to ring C; p is an integer selected from 0 to 3; and Y is -O-, -NR L -、-CR L1 R L2 -or-C≡C-.

14. The compound according to claim 13, wherein each R L1 and each R L2 It's hydrogen.

15. The compound according to claim 13 or 14, wherein p is 0 or 1.

16. The compound according to any one of claims 13 to 15, wherein Y is -O- or -C≡C-.

17. The compound of any one of claims 1-16, wherein each of m and m' is 1.

18. A compound according to any one of claims 1 to 17, wherein at least one R A It is C 1-6 alkyl.

19. The compound of any one of claims 1 to 18, wherein n is 0, 1 or 2.

20. The compound according to any one of claims 1 to 19, wherein R B is optionally substituted C 1-6 alkyl.

21. A compound according to any one of claims 1 to 20, wherein X is -C(R X )2-.

22. The compound of claim 21, wherein each R X are independently hydrogen or C 1-6 alkyl.

23. The compound according to claim 21, wherein two R X Together with the carbon atoms to which they are bonded, they form C 3-4 a carbocyclic group or a 3- to 4-membered heterocyclic group.

24. A compound according to any one of claims 1 to 21, wherein R X and adjacent R A1 Together with the carbon atoms to which they are bonded, they form C 3-4 a carbocyclic group or a 3- to 4-membered heterocyclic group.

25. A compound according to any one of claims 1 to 21, wherein each R A1 It's hydrogen.

26. A compound according to any one of claims 1 to 25, wherein R 1 Yes-NR 1a R 1b .

27. The compound according to claim 26, wherein R 1a and R 1b are independently hydrogen, -CN, C 1-6 Alkyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl) or -(C 1-6 alkylene)-(3 to 12 membered heterocyclyl), wherein the alkyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

28. The compound according to claim 26, wherein R 1a and R 1b At least one of them is not hydrogen.

29. The compound according to claim 26, wherein R 1a and R 1b Together with the nitrogen atom to which they are bound, they form a 3- to 12-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by one or more R ab replace.

30. The compound of claim 27, wherein each R ab are independently oxo, halogen, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, or -S(=O)R a wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted.

31. The compound according to claim 27, wherein the two adjacent R ab Together with the atoms to which they are bonded, they form a C6 aryl or a 5- to 6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted.

32. A compound according to any one of claims 1 to 31, wherein R 1 Yes-OR 1c .

33. The compound according to claim 32, wherein R 1c It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted.

34. A compound according to any one of claims 1 to 33, wherein R 1’ is hydrogen, deuterium or optionally substituted C 1-6 alkyl.

35. A compound according to any one of claims 1 to 25, wherein R 1 and R 1’ Together with the carbon atoms to which they are bonded, they form C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted.

36. A compound selected from Table 1 or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 and a pharmaceutically acceptable excipient.

38. A method of inhibiting a protein in a subject or a biological sample comprising administering to the subject a compound according to any one of claims 1-36 or contacting the biological sample with a compound according to any one of claims 1-36.

39. Use of a compound according to any one of claims 1 to 36 in the preparation of a medicament for inhibiting a protein in a subject or biological sample.

40. A compound according to any one of claims 1 to 36 for use in inhibiting a protein in a subject or biological sample.

41. The method, use or compound for use according to any one of claims 38 to 40, wherein the protein is eIF4E.

42. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-36.

43. Use of a compound according to any one of claims 1 to 36 in the preparation of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

44. A compound according to any one of claims 1-36 for use in treating or preventing a disease or disorder in a subject in need thereof.

45. The method, use or compound for use according to any one of claims 42 to 44, wherein the disease or disorder is an eIF4E-mediated disease or disorder.

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