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 / 424,462, 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:

[0009]

[0010] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof,

[0011] in:

[0012] each -L- is independently -O-, -NR L -CR L1 R L2 -CR L1 =CR L2 - or -C≡C-;

[0013] each R L is independently hydrogen or optionally substituted C 1-6 alkyl;

[0014] each R L1 and each R L2 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 6-10 alkoxy, C C1 alkylamino, C C2 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted;

[0015] q is an integer selected from 1 to 5;

[0016] Ring C and Ring D are independently C 6-10 aryl or 5- to 10-membered heteroaryl;

[0017] R C1 , each R C2 , and each R D is 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 alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted;

[0018] r and s are independently integers selected from 0 to 6, as valence allows;

[0019] R 2 is 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, -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, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0020] R 1 It is 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 group is optionally substituted;

[0021] X is -O- or -C(R X )2-;

[0022] 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 3-6carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted; or

[0023] Two R X Together with the carbon atom to which they are attached, they form an oxo group;

[0024] m and m' are independently integers selected from 0 to 2;

[0025] 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;

[0026] n is an integer selected from 0 to 10 when valence permits;

[0027] 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;

[0028] in:

[0029] 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;

[0030] 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

[0031] Each R cand 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

[0032] R c and R d together with the nitrogen atom to which they are attached, form a 3- to 12-membered heterocyclic group;

[0033] where R a 、R b 、R c and R d Each occurrence of is independently and optionally substituted.

[0034] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0035] 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.

[0036] 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.

[0037] In certain aspects, the disclosure provides compounds disclosed herein for use in inhibiting a protein in a subject or biological sample.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] Details

[0044] 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.

[0045] Compounds of the present application

[0046] In certain aspects, the present disclosure provides compounds of Formula I:

[0047]

[0048] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof,

[0049] in:

[0050] Each -L- is independently -O-, -NR L -、-CR L1 R L2 -、-CR L1 =CR L2 -or-C≡C-;

[0051] Each R L are independently hydrogen or optionally substituted C 1-6 alkyl;

[0052] Each R L1 and each R L2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, wherein alkyl, alkoxy or alkylamino are optionally substituted;

[0053] q is an integer selected from 1 to 5;

[0054] ring C and ring D are independently C 6-10 aryl or 5- to 10-membered heteroaryl;

[0055] R C1 , each R C2 and each R D is 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 alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl are optionally substituted;

[0056] r and s are independently at valence allows an integer selected from 0 to 6;

[0057] R 2 is 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, -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, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl are optionally substituted;

[0058] R 1 is hydrogen, -CN, C1-6 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;

[0059] X is -O- or -C(R X )2-;

[0060] 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

[0061] Two R X Together with the carbon atom to which they are attached, they form an oxo group;

[0062] m and m' are independently integers selected from 0 to 2;

[0063] 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, C3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted;

[0064] n is an integer selected from 0 to 10 when valence permits;

[0065] 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;

[0066] in:

[0067] 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;

[0068] 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

[0069] 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

[0070] R c and R d together with the nitrogen atom to which they are attached, form a 3- to 12-membered heterocyclic group;

[0071] where R a 、R b 、R c and R d Each occurrence of is independently and optionally substituted.

[0072] 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:

[0073]

[0074] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0075] 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:

[0076]

[0077] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0078] 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.

[0079] In certain embodiments, R 1 is hydrogen, -CN, 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 heterocyclic group (e.g., a heterocyclic group containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), -(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 alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, C 1-6 The olefin is selected from methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). In certain embodiments, R 1 Optionally, one or more R u replace.

[0080] In certain embodiments, R 1 It is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C6-10 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 alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 1 Optionally, one or more R u replace.

[0081] In certain embodiments, R 1 It is hydrogen, -CN, C 1-6 Alkyl, 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 alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 1 Optionally, one or more R ureplace.

[0082] In certain embodiments, R 1 Yes -CN, C 1-6 Alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclic group, -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -C(=O)R a , wherein alkyl, alkylene, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 1 Optionally, one or more R u replace.

[0083] In certain embodiments, R 1 is optionally substituted C 1-6 In certain embodiments, R 1 is optionally substituted C 6-10 In certain embodiments, R 1 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 1 is optionally substituted C 3-12 In certain embodiments, R 1 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 1 Yes-(C 1-6 alkylene)-(C 6-10 In certain embodiments, R 1 Yes-(C 1-6 In certain embodiments, R 1 Yes-(C 1-6 alkylene)-(C 3-12 In certain embodiments, R 1 Yes-(C 1-6 In certain embodiments, R 1 Optionally, one or more Ru replace.

[0084] In certain embodiments, R 1 is optionally substituted C 6-10 In certain embodiments, the aryl group is optionally replaced by one or more R u replace.

[0085] In certain embodiments, R 1 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 1 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 1 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 1 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 1 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 1 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 1 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 1 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.

[0086] In certain embodiments, R 1 is optionally substituted 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 In certain embodiments, the carbocyclyl group is optionally replaced by one or more R u replace.

[0087] In certain embodiments, R 1 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 1 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 1 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 1 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 1 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 1 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 1 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 1 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 1 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 1 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 1 is an optionally substituted heterocyclyl group comprising two 6-membered rings and 1-5 heteroatoms selected from N, O and S. In certain embodiments, R 1 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.

[0088] In certain embodiments, R 1 Yes-(C 1-6 alkylene)-(C 6-10In certain embodiments, aryl is optionally substituted with one or more R u replace.

[0089] In certain embodiments, R 1 Yes-(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.

[0090] In certain embodiments, R 1 Yes-(C 1-6 alkylene)-(C 3-12 carbocyclic group), wherein C 3-12 The carbocyclic group is selected from 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 ) 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.

[0091] In certain embodiments, R 1 Yes-(C 1-6 In certain embodiments, the optionally substituted heterocyclyl comprises one 3 to 8-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 3 to 8-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 3 to 8-membered ring and 1-3 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 4-membered ring and 1-3 heteroatoms selected from N, O and S. In certain 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 one 6-membered ring and 1-4 heteroatoms selected from N, O and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 8-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 3 to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 5-membered ring and one 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.

[0092] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0093] In certain embodiments, m' is 0. In certain embodiments, m' is 1. In certain embodiments, m' is 2.

[0094] 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.

[0095] 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 (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 3-6Carbocyclyl (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 A independently optionally replaced by one or more R u replace.

[0096] 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.

[0097] 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 A independently optionally replaced by one or more R u replace.

[0098] 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.

[0099] In certain embodiments, R B is 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 B independently optionally replaced by one or more R u replace.

[0100] In certain embodiments, RB 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 is independently optionally substituted with one or more R u substituents.

[0101] In certain embodiments, R B 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 is independently optionally substituted with one or more R u substituents.

[0102] In certain embodiments, R B is hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, R B is hydrogen. In certain embodiments, R B is optionally substituted C 1-6 alkyl. In certain embodiments, R B is optionally substituted with one or more R u substituents.

[0103] In certain embodiments, ring C is C 6-10 aryl or 5- to 10-membered heteroaryl.

[0104] In certain embodiments, ring C is C 6-10 aryl (e.g., phenyl or naphthyl).

[0105] 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.

[0106] In certain embodiments, Ring C is phenyl or pyridinyl.

[0107] 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 (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, R C1 Optionally, one or more R u replace.

[0108] 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.

[0109] In certain embodiments, R C1 is halogen (e.g., -F, -Cl, -Br, or -I). In certain embodiments, R C1 In certain embodiments, R C1 is optionally substituted C 1-6 In certain embodiments, R C1 Optionally, one or more R u replace.

[0110] 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 (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 3-6Carbocyclyl (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.

[0111] 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.

[0112] 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.

[0113] In certain embodiments, Ring D is C 6-10 aryl or 5- to 10-membered heteroaryl.

[0114] In certain embodiments, Ring D is C 6-10 Aryl (eg, phenyl or naphthyl).

[0115] 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.

[0116] In certain embodiments, Ring D is phenyl, pyridinyl, pyrrolopyridazinyl, or thienopyridinyl.

[0117] 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 (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 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), -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, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0118] In certain embodiments, R 2 Halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, 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)NR c S(=O)2R a or C(=O)NR c R d , 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.

[0119] 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, -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, alkenyl, alkynyl, alkoxy or alkylamino is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0120] In certain embodiments, R 2 Halogen, -CN, -NO2, -OH, -NH2, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -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, alkoxy or alkylamino is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0121] 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)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.

[0122] In certain embodiments, R 2 It is C 1-6 alkyl, 5- to 10-membered heteroaryl, -NR c S(=O)2R a 、-N(S(=O)2R a )2, -C(=O)OR b 、-C(=O)NR c S(=O)2R aor -C(=O)NR c R d , wherein alkyl or heteroaryl is optionally substituted. In certain embodiments, R 2 Optionally, one or more R u replace.

[0123] 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.

[0124] 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 (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 D independently optionally replaced by one or more R u replace.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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-.

[0129] In certain embodiments, [L] q yes

[0130]

[0131] in:

[0132] * indicates attachment to ring B, and ** indicates attachment to ring C;

[0133] p is an integer selected from 0 to 3; and

[0134] Y is -O-, -CR L1 R L2 -or-C≡C-.

[0135] In certain embodiments, L is Y.

[0136] 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 1-6Alkoxy (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-n-butylamino, ethyl- In certain embodiments, each R L1 and each R L2 independently optionally replaced by one or more R u replace.

[0137] In certain embodiments, each R L1 and each R L2 It's hydrogen.

[0138] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

[0139] 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-.

[0140] In certain embodiments, X is -O-. In certain embodiments, X is -C(R) X )2-.

[0141] 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 (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), amyl (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), amylkynyl (C5), or hexynyl (C6)), C 1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), amyloxy (C5), or hexyloxy (C6)), C 1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butyiamino, di-i-butyiamino, di-s-butyiamino, di-t-butyiamino, diamylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butyiamino, methyl-i-butyiamino, methyl-s-butyiamino, methyl-t-butyiamino, methylamylamino, methyhaxylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butyiamino, ethyl-s-butyiamino, ethyl-i-butyiamino, ethyl-t-butyiamino, ethylamylamino, ethylhexylamino, propyl-n-butyiamino, propyl-i-butyiamino, propyl-s-butyiamino, propyl-t-butyiamino, propylamylamino, propylhexylamino, n-butyiamylamino, i-butyiamylamino, s-butyiamylamino, t-butyiamylamino, n-butyihexylamino, i-butyihexylamino, s-butyihexylamino, t-butyihexylamino, or amylhexylamino), 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 one 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 is independently optionally substituted with one or more R u substituents.

[0142] 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.

[0143] In certain embodiments, each R X It's hydrogen.

[0144] 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.

[0145] 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.

[0146] 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)), C2-6 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 3-12 carbocyclyl (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]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., a heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u substituents.

[0147] In certain embodiments, each R a is independently C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R u substituents.

[0148] In certain embodiments, each R b is independently hydrogen, C 1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] In certain embodiments, R c and R d Together with the nitrogen atom to which they are attached, they form a 3- to 12-membered heterocyclyl (e.g., a heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted by one or more R u replace.

[0153] In certain embodiments, each R u are independently oxo, halogen, -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 1-6Alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butyiamino, diisobutylamino, di-sec-butyiamino, di-t-butyiamino, dipentylamino, dihexylamino, methyl ethyl amino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butyiamino, methyl-isobutyiamino, methyl-sec-butyiamino, methyl-t-butyiamino, methylpentoxy, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino, ethyl-n-butyiamino, ethyl-sec-butyiamino, ethyl-isobutyiamino, ethyl-t-butyiamino, ethylpentoxy, ethylhexylamino, propyl-n-butyiamino, propyl-isobutyiamino, propyl-sec-butyiamino, propyl-t-butyiamino, propylpentoxy, propylhexylamino, n-butyipentoxy, isobutyipentoxy, sec-butyipentoxy, t-butyipentoxy, n-butyihexylamino, isobutyihexylamino, sec-butyihexylamino, t-butyihexylamino, or pentoxyhexylamino), 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., a heteroaryl 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., 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]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthyl (C 10 ), or spiro[4.5]decanyl (C10 ))3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising 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 is optionally substituted with one or more substituents selected from the group consisting of oxo, halo, -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, and 3- to 6-membered heterocyclyl.

[0154] In certain embodiments, each R u is independently oxo, halo, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C1-6 Alkoxy, C 1-6 Alkylamino, 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, 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.

[0155] In certain embodiments, each R u are independently 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 12 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.

[0156] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclyl, 3 to 12 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, C3-6 The substituents of the carbocyclic group and the 3- to 6-membered heterocyclic group are substituted.

[0157] In certain embodiments, the compounds disclosed herein are selected from the compounds in Table 1 and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof.

[0158] Table 1.

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] 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.

[0168] 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.

[0169] 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.

[0170] Pharmaceutically acceptable salts

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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, benzenesulfonic acid, benzoic ... Formic 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.

[0175] 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.

[0176] 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.

[0177] Solvent compounds

[0178] "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.

[0179] 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.

[0180] Those skilled in the art of organic chemistry will also appreciate 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.

[0181] 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.

[0182] 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.

[0183] Isomers (stereoisomers, geometric isomers, tautomers, etc.)

[0184] 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."

[0185] 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".

[0186] As used herein, an enantiomerically pure compound is substantially free of the other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the 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, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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 / resolving techniques based on solubility differences. In certain embodiments, optically pure enantiomers and resolving agents are then recovered.

[0194] Tautomers

[0195] In certain embodiments, the compounds described herein exist as tautomers.The compounds described herein include all possible tautomers within the formulae described herein.

[0196] 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.

[0197] Pharmaceutical composition

[0198] 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)).

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] Preparation and characterization of compounds

[0204] 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).

[0205] General synthetic scheme

[0206]

[0207] 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.

[0208] 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).

[0209] 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.

[0210] 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.

[0211] Analytical methods, materials, and instruments

[0212] 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.

[0213] Biological assays

[0214] The biological activity of the compounds of the present application can be assessed using methods and assays known in the art.

[0215] 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.

[0216] How to use

[0217] 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.

[0218] 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.

[0219] In certain aspects, the present disclosure provides compounds disclosed herein for use in inhibiting the expression of a protein in a subject or biological sample.

[0220] In certain embodiments, the protein is eIF4E.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] In certain embodiments, the disease or disorder is an eIF4E-mediated disease or disorder.

[0225] In certain embodiments, the disease or disorder is cancer.

[0226] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers of Table A.

[0227] Table A

[0228]

[0229]

[0230]

[0231] 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.

[0232] Table B

[0233]

[0234]

[0235] 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.

[0236] 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 proinflammatory cytokines. 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).

[0237] In certain embodiments, the subject is a mammal.

[0238] In certain embodiments, the subject is a human.

[0239] Definitions

[0240] As used in the specification and the appended claims, the following terms have the indicated meanings, unless otherwise indicated.

[0241] Chemical Definitions

[0242] The definitions for certain functional groups and chemical terms used herein are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEd., 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, 3rdEd., Cambridge University Press, Cambridge, 1987.

[0243] 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).

[0244] The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0245] 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.

[0246] 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 may 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 may 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 interchangeable when used herein. 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.

[0247] 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), etc. 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).

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] "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 certain embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In certain embodiments, an aryl group has ten ring carbon atoms ("C 10 In certain embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "aryl"; for example, anthracenyl).

[0258] 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.

[0259] "Fused aryl" refers to an aryl group that has two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0260] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0261] "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.

[0262] "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl groups or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases the number of ring members represents the number of ring members in the fused (heteroaryl / carbocyclyl or heterocyclyl) ring system. When substitution is indicated in such cases, unless otherwise specified, substitution can occur on the heteroaryl or the one or more carbocyclyl groups or heterocyclyl groups. Bi-cyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl).

[0263] In certain embodiments, the heteroaryl 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, the heteroaryl 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, the heteroaryl 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, the 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, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, the heteroaryl group is independently in each instance optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0264] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, 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.

[0265] "Heteroaralkyl" is a subset of alkyl and heteroaryl as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0266] "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 6 ring carbon atoms ("C 5-6 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 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.

[0267] 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 cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl”). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the cycloalkyl group include the above-mentioned C 5-6 Cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the cycloalkyl group include the above-mentioned C 3-6 Cycloalkyl groups and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10In certain embodiments, a cycloalkyl group is a substituted C 3-10 Cycloalkyl.

[0268] As shown in the aforementioned examples, in certain embodiments, carbocyclyl group is monocyclic (" monocyclic carbocyclyl ") or comprises fused ring system, bridged ring system or spirocyclic ring system, such as polycyclic system (" polycyclic carbocyclyl "), and can be saturated or can be partially undersaturated." carbocyclyl " also includes the ring system that carbocyclyl ring as defined above is fused with one or more aryl groups or heteroaryl groups, wherein attachment point is on carbocyclyl ring, and in such cases, the number of carbon continues to represent the number of carbon in carbocyclyl ring system. When indicating substitution in such cases, unless otherwise stated, substitution can occur in carbocyclyl or one or more aryl groups or heteroaryl groups. Unless otherwise stated, 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, carbocyclyl group is unsubstituted C 3-10 In certain embodiments, a carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0269] "Fused carbocyclyl" refers to a ring system in which a carbocyclyl ring as defined above is fused to one or more carbocyclyl rings. In such cases, the number of carbons represents the total number of carbons in the entire fused ring system. When substitution is indicated, unless otherwise stated, substitution may occur on the entire fused ring system. "Fused carbocyclyl" also includes a ring system in which a carbocyclyl ring as defined above is fused to one or more heteroaryl rings or aryl rings, wherein the point of attachment is on the carbocyclyl ring. In such cases, the number of carbons continues to represent the number of carbons in the carbocyclyl ring. When substitution is indicated, unless otherwise stated, substitution may occur on the carbocyclyl ring or on one or more heteroaryl rings or aryl rings. "Fused carbocyclyl" also includes a ring system in which a fused carbocyclyl as defined above further forms a spiro structure with one or more heterocyclyl or carbocyclyl rings, wherein the point of attachment is on the fused carbocyclyl. In such cases, the number of carbons continues to represent the number of carbons in the fused carbocyclyl. When substitution is indicated in such cases, unless otherwise stated, the substitution may be on the fused carbocyclyl or one or more heterocyclyl or carbocyclyl groups.

[0270] "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.

[0271] 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.

[0272] As shown in the foregoing examples, in certain embodiments, the heterocyclyl group can be a monocyclic ("monocyclic heterocyclyl") or a fused ring system, a bridged ring system or a spirocyclic system, such as a polycyclic system ("polycyclic heterocyclyl"), and can be saturated or can be partially unsaturated. The heterocyclyl polycyclic ring system can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment 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 on a heterocyclyl or one or more carbocyclyl groups. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl groups or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. When substitution is indicated in such cases, unless otherwise stated, substitution may occur on a heterocyclyl or one or more aryl groups or heteroaryl groups. Unless otherwise stated, a heterocyclyl is independently optionally substituted in each case, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0273] "Fused heterocyclyl" refers to a ring system in which a heterocyclyl as defined above is fused to one or more heterocyclyl or carbocyclyl groups, wherein the point of attachment is on the heterocyclyl group or on one or more heterocyclyl or carbocyclyl groups. 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 may occur on the entire ring system. "Fused heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. When substitution is indicated in such cases, unless otherwise stated, substitution may occur on the heterocyclyl group or on one or more aryl or heteroaryl rings. "Fused heterocyclyl" also includes ring systems in which the fused heterocyclyl as defined above further forms a spiro structure with one or more heterocyclyls or carbocyclyls, wherein the point of attachment is on the fused heterocyclyl. In such cases, the number of ring members continues to represent the number of ring members in the fused heterocyclyl. When substitution is indicated in such cases, unless otherwise indicated, substitution may occur on the fused heterocyclyl or on one or more heterocyclyls or carbocyclyls with which the fused heterocyclyl forms a spiro structure.

[0274] 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 and 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.

[0275] As used herein, "alkoxy" refers to a group -OR, wherein R is an alkyl group as defined herein. 1-6 Alkoxy refers to a group -OR, wherein each R is C as defined herein. 1-6 Alkyl. Exemplary C 1-6 The alkyl group is described above.

[0276] As used herein, "alkylamino" refers to the group -NHR or -NR2, wherein each R is independently an alkyl group 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. Exemplary C 1-6 The alkyl group is described above.

[0277] "Azide" refers to the group -N3.

[0278] "Amino" refers to the group -NH2.

[0279] "Oxycarbonyl" refers to the group -C(=O)O-.

[0280] "Sulfonyl" refers to the group -S(O)2-.

[0281] "Carboxyl" refers to the group -C(=O)OH.

[0282] "Cyano" refers to the group -CN.

[0283] "Halo" or "halogen" refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I). In certain embodiments, the halo group is fluoro or chloro.

[0284] "Hydroxyl" refers to the group -OH.

[0285] "Nitro" refers to the group -NO2.

[0286] As used herein, "protecting group" is well known in the art and refers to a chemical moiety that is introduced into a molecule by chemical modification of a functional group to obtain chemical selectivity in subsequent chemical reactions during which the unmodified functional group can not survive or can interfere with the chemical reaction. Common functional groups that require protection include, but are not limited to, hydroxyl, amino, thiol, and carboxylic acid. Thus, protecting groups are referred to as hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

[0287] Common types of hydroxyl-protecting groups include, but are not limited to, ethers (e.g., methoxymethyl ether (MOM), beta-methoxyethoxymethyl ether (MEM), tetrahydropyranyl ether (THP), p-methoxyphenyl ether (PMP), t-butyl ether, triphenylmethyl ether (trityl ether), allyl ether, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), triisopropylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivaloate (Piv) and benzoic acid ester (benzoate; Bz)).

[0288] 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)).

[0289] Common types of thiol protecting groups include, but are not limited to, sulfides (eg, p-methylbenzyl (Meb), tert-butyl, acetamidomethyl (Acm), and triphenylmethyl (trityl)).

[0290] 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.

[0291] 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.

[0292] Other definitions

[0293] "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.

[0294] "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-ethane-disulfonic 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, ...

[0295] The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge et al., J. Pharm. Sci. 66(1): 1-79 (January 77).

[0296] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the disclosure is administered.

[0297] A "pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to produce the parent molecule of the formula indicated herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONR2, and -CH2OR groups, wherein R, at each occurrence, is independently selected from an alkyl group, a trialkylsilyl group, a carbocyclic aryl group, or a carbocyclic aryl group substituted with one or more of an alkyl group, a halogen group, a hydroxyl group, or an alkoxy group. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

[0298] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0299] Because prodrugs can enhance many desirable qualities of drugs (e.g., solubility, bioavailability, manufacturing, etc.), compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any independent compound) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof can be delivered in prodrug form. Therefore, the present disclosure is intended to encompass prodrugs of compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any independent compound) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, methods for delivering them, and compositions comprising them." prodrugs" are intended to include any covalently bonded carriers that, when such prodrugs are administered to mammalian subjects, release the active parent drug of the present disclosure in vivo. Prodrugs are prepared by modifying the functional groups present in the compound in such a way that the modification is cleaved into the parent compound in conventional manipulations or in vivo. Prodrugs include compounds of the present disclosure wherein a hydroxyl group or an amino group is bonded to any group that, when the prodrug of the present disclosure is administered to a mammalian subject, cleaves to form a free hydroxyl group or a free amino group, respectively. Examples of prodrugs include, but are not limited to, acetate derivatives, formate derivatives, and benzoate derivatives of alcohol and amine functional groups in the compounds of each formula described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof.

[0300] "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.

[0301] "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.

[0302] "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).

[0303] 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.

[0304] 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.

[0305] 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%.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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

[0313] 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.

[0314] I. Synthesis and Characterization

[0315] Plan A

[0316]

[0317] Synthesis of 3:

[0318] To a stirred solution of 1H-pyrrole-2-carboxylic acid methyl ester (1) (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 (2) (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 provide methyl 1-aminopyrrole-2-carboxylate (3) (11 g, 78.49 mmol, 98.21% yield) as a light yellow viscous liquid.

[0319] 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.

[0320] LCMS: LC / MS was performed, but the compound was not ionized and therefore not included in the analytical trace.

[0321] Synthesis of 5:

[0322] To a stirred solution of 1-aminopyrrole-2-carboxylic acid methyl ester (3) (5 g, 35.68 mmol) in methanol (200 ml) was added ethyl 3-oxomethylenebutanoate (4) (5.57 g, 42.81 mmol, 5.44 mL) at 25° C., followed by acetic acid (50 ml), 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 a saturated aqueous NaHCO solution. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-[[(E)-3-ethoxy-1-methyl-3-oxomethylene-prop-1-enyl]amino]pyrrole-2-carboxylic acid methyl ester (5) (8 g, crude) as a yellow oil, which was carried to the next step without further purification.

[0323] 1 HNMR: Not recorded

[0324] LCMS: Column - Xbridge C18 (50×4.6 mm, 5u, 130A), (Mobile phase: from 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min, this mobile phase composition was maintained until 4.0 min, and finally returned to the initial conditions in 5.0 min). Flow rate = 1.2 ml / min. Rt = 3.17 and 3.40 (5 min run), MS calculated value: 252.2; MS found value: 253.2 (M+H).

[0325] Synthesis of 6:

[0326] To a stirred solution of 1-[[(E)-3-ethoxy-1-methyl-3-oxomethylene-prop-1-enyl]amino]pyrrole-2-carboxylic acid methyl ester (5) (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 fractions 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 (SiO2; EtOAc:hexanes 70%) to afford 2-methyl-4-hydroxy-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (6) (2.5 g, 12.12 mmol, 38.23% yield) as an off-white solid.

[0327] 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.

[0328] LCMS: Column - Xbridge C18 (50×4.6 mm, 5u, 130A), (Mobile phase: from 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min, this mobile phase composition was maintained until 4.0 min, and finally returned to the initial conditions in 5.0 min). Flow rate = 1.2 ml / min. Rt = 1.48. MS calculated value: 206; MS found value: 207 (M+H).

[0329] Synthesis of 7:

[0330] 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 (6) (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 (7) (1.9 g, 8.46 mmol, 69.76% yield) as an off-white solid.

[0331] 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.

[0332] LCMS: Column: Xbridge C18 (50×4.6 mm, 5u, 130A), (Mobile phase: from 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min, this mobile phase composition was maintained until 4.0 min, and finally returned to the initial conditions in 5.0 min). Flow rate = 1.2 ml / min. Purity: 99.81%, Rt = 3.38 min, MS calculated value: 224; MS found value: 224.8 (M+H).

[0333] Synthesis of 9:

[0334] To a stirred solution of 4-chloro-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (1.9 g, 8.46 mmol) (7) and (5-chloro-2-hydroxy-phenyl)boronic acid (8) (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 (SiO2; 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 (9) (2.1 g, 6.63 mmol, 78.39% yield) as a light yellow solid.

[0335] 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.

[0336] LCMS: Column: Xbridge C18 (50×4.6 mm, 5u, 130A), (Mobile phase: from 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min, this mobile phase composition was maintained until 4.0 min, and finally returned to the initial conditions in 5.0 min). Flow rate = 1.2 ml / min. Purity: 97.11%, Rt = 3.36 min, MS calculated value: 316; MS found value: 315.2 (MH).

[0337] Synthesis of 10:

[0338] To a stirred solution of 4-(5-chloro-2-hydroxy-phenyl)-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (9) (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 (10) (3.5 g, 8.18 mmol, 51.81% yield, 99% purity) as an off-white solid.

[0339] 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.

[0340] LCMS: Column - Xbridge C18 (3×50 mm, 3.5 u) (mobile phase: 95% [5 mM NH4OAc in water] and 5% [5 mM NH4OA in ACN: water (90:10)] for 0.75 min, then to 70% [5 mM NH4OAc in water] and 30% [5 mM NH4OA in ACN: water (90:10)] within 1.00 min, and finally to 2% [5 mM NH4OAc in water] and 98% [5 mM NH4OA in ACN: water (90:10)] within 2.00 min, the mobile phase composition was maintained until 2.50 min, and finally returned to the initial conditions within 2.75 min, and the composition was maintained until 3.0 min). Flow rate - 1.20 ml / min. The purity was 98.77%, Rt=2.17 min, MS calculated value: 422; MS found value: 423.1 (M+H).

[0341] Plan B

[0342]

[0343] Synthesis of 3(3) (Compound 26)

[0344] To a stirred solution of 2,6-di(methyl)-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-one (1) (300 mg, 1.67 mmol) in DMF (10 mL) was added potassium carbonate granules (694 mg, 5.02 mmol) at 10 ° C under argon, and the reaction mixture was stirred at 10 ° C for 20 min. 4-[2-(2-bromoethoxy)-5-chloro-phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid methyl ester (2) (709 mg, 1.67 mmol) was added thereto at this temperature, and the reaction was stirred at 50 ° C for 17 h. After the reaction was complete, the reaction mixture was quenched with water. The aqueous phase 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 subjected to flash column chromatography. To a stirred solution of impure solid (450 mg, 862.08 μmol) in a mixture of THF (8 mL), methanol (4 mL) and H o (2 mL) at 25 ° C, lithium hydroxide monohydrate (181 mg, 4.31 mmol) was added, and the mixture was stirred at 25 ° C for 2 h. After the reaction was complete (as judged by LC / MS and TLC), the solvent was removed under reduced pressure, and the residue was diluted with water. The aqueous portion was acidified to pH ~ 2-3 with aqueous HCl (1 M) and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous Na sO , filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford 4-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (3) (Compound 26) (130 mg, 231.48 μmol, 26.85% yield, 90.45% purity) as a white solid.

[0345] 1H NMR(400MHz, DMSO-d6):7.55-7.52(m,1H),7.41(d,J=2.5Hz,1H),7.28-7.23(m,2H),6.83(s,1H),6.07(d ,J=4.8Hz,1H),4.29-4.27(m,2H),4.11-4.09(m,2H),3.08(s,2H),2.55(s,3H),2.32(s,3H),1.77(s,3H).

[0346] Synthesis of 4(4) (Compound 27)

[0347] To a stirred solution of 4-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (3) (Compound 26) (75 mg, 147.65 μmol) in dichloromethane (7 ml) was added DMAP (90 mg, 738.24 μmol) followed by EDC.HCl (57 mg, 295.29 μmol) at 25° C., and the reaction mixture was stirred at the same temperature for 30 min. Methanesulfonamide (70 mg, 738.24 μmol) 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 was concentrated under reduced pressure. The crude product was purified by RP preparative HPLC to give 4-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-2-methyl-N-methylsulfonyl-pyrrolo[1,2-b]pyridazine-7-carboxamide (4) (Compound 27) as a white solid (44 mg, 74.63 μmol, 50.55% yield, 99.24% purity).

[0348] 1H NMR (400MHz, DMSO, at 100℃): δ7.55-7.52(m,1H),7.43-7.39(m,1H),7.28(d,J=9.2Hz,1H),6.91(s,1H),6.22(d,J=4.4Hz ,1H),4.32-4.30(m,2H),4.15-4.12(m,2H),3.43(s,3H),3.12(s,3H),2.61-2.58(m,5H),2.37(s,3H),1.94(s,3H)ppm.

[0349] Plan C

[0350]

[0351] Synthesis of 3:

[0352] A stirred solution of 2,2-di(methyl)-1,3-dioxane-4,6-dione (2) (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-carboxylic acid methyl ester (1) (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 brine 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 (3) (2 g, 6.15 mmol, 14%) as a yellow liquid.

[0353] 1H 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).

[0354] LCMS: LC / MS was performed, but the compound was not ionized and therefore not included in the analytical trace.

[0355] Synthesis of 4:

[0356] A stirred solution of methyl 4-[1-[2,2-di(methyl)-4,6-bis(oxymethylene)-1,3-dioxane-5-ylidene]ethylamino]thiophene-3-carboxylate (3) (20 g, 61.47 mmol) in 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 (4) (6 g, 26.88 mmol, 43.72% yield) as a brown solid.

[0357] 1H NMR (400 MHz, DMSO-d6) δ 2.43 (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).

[0358] LCMS: LC / MS was performed but the compound did not ionize. Therefore not included in the analytical trace.

[0359] Synthesis of 5:

[0360] To a stirred solution of methyl 5-methyl-7-hydroxy-thieno[3,2-b]pyridine-3-carboxylate (4) (3.5 g, 15.68 mmol) in toluene (50 mL) was added 99% N,N-dimethylaniline (15.20 g, 125.42 mmol, 15.90 mL) and cooled to 0 °C. POCl3(3.60 g, 23.52 mmol) was added to the reaction mixture and heated at 120 °C for 2.5 h. After consumption of starting material (judged by TLC), the solvent was evaporated under reduced pressure and the crude thus obtained was purified by combiflash chromatography (SiO2, 120 g, 30% ethyl acetate / hexane) to afford methyl 7-chloro-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (5) (3.0 g, 12.41 mmol, 79.17% yield) as a white solid.

[0361] 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.57 (s, 1H), 3.86 (s, 3H), 2.63 (s, 3H).

[0362] ESI-MS: m / z calculated 241.0, found 243.0 (M+2)+; retention time 3.17 min (run 5 min)

[0363] Synthesis of 7:

[0364] To a stirred solution of 7-chloro-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (5) (3.0 g, 12.41 mmol) in dioxane (30 mL) and water (5 mL) was added (5-chloro-2-hydroxy-phenyl)boronic acid (6) (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 to the solution and degassed again for 5 min. The reaction mixture was then heated at 90°C for 5 h. After completion of the reaction (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 (7) (1.5 g, 4.49 mmol, 36.20% yield) as an off-white solid.

[0365] 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).

[0366] ESI-MS: m / z calculated 333, found 334 (M+H) + ; Retention time 3.32 min (running time 5 min).

[0367] Synthesis of 9:

[0368] To a stirred solution of 7-(5-chloro-2-hydroxy-phenyl)-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (7) (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 (8) (5.40 g, 28.76 mmol, 2.48 mL) and the reaction mixture was refluxed at 70° C. for 16 h. After the reaction was complete (judged only by LC / MS), 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 (9) (1.3 g, 2.95 mmol, 82.05% yield) as an off-white solid.

[0369] 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).

[0370] ESI-MS: m / z calculated value 440.74; found value 441.8 (M+1)-; retention time 3.65 min (run time 5 min).

[0371] Plan D

[0372]

[0373] Synthesis of 3:

[0374] To a stirred solution of compound 2-methyl-4-oxomethylene-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carboxylic acid-1,1-di(methyl)ethyl ester (1.44 g, 5.45 mmol) (2) in DMF (15 mL) was added dry KCO (1.88 g, 13.61 mmol) and the reaction mixture was stirred at 25° C. for 20 min. To this was added 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (1) (2000 mg, 4.54 mmol) at 25° C. and the reaction mixture was stirred at 25° C. for 16 h. After completion of the reaction (as judged by TLC and LC / MS), the reaction mixture was passed through a pad of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the crude product was purified by silica gel combi flash column chromatography (SiO2; 40 g, 5% MeOH / DCM) to afford 7-[5-chloro-2-[2-[6-[1,1-di(methyl)ethoxycarbonyl]-2-methyl-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (3) (1 g, 1.50 mmol, 33.14% yield) as an off-white solid.

[0375] 1 H-NMR (400MHz, DMSO-d6): 8.66 (s, 1H), 7.54 (d, J = 5.9Hz, 1H), 7.40 (m, 1H), 7.31-7.26 (m, 2H), 4.3 1(s,2H),4.08(s,4H),3.88(s,3H),3.55-3.50(m,2H),2.66(s,3H),1.60(s,3H),1.42(s,9H)ppm.

[0376] m / z calculated 624.18, found (M+1) = 625.0, RT 3.86.

[0377] Synthesis of 4:

[0378] To a stirred solution of compound 7-[5-chloro-2-[2-[6-[1,1-di(methyl)ethoxycarbonyl]-2-methyl-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (3) (1000 mg, 1.60 mmol) in DCM (6 mL) at 0° C. was added 4(N)HCl in dioxane (7 mL) and the reaction mixture was stirred at 25° C. for 4 h. After completion of the reaction (as judged by TLC and LC / MS), the solvent was evaporated under reduced pressure to give the HCl salt of the desired product, which was basified with saturated NaHCO 3 solution. The aqueous layer was extracted twice with 10% MeOH / DCM. The combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to afford 7-[5-chloro-2-[2-(2-methyl-4-oxomethylene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (4) (700 mg, 1.33 mmol, 83.35% yield) as a white solid which was used in the next step without further purification.

[0379] m / z calculated 524.1, found (M+1) = 525.2, RT 2.89.

[0380] Synthesis of 5:

[0381] To a stirred solution of compound 7-[5-chloro-2-[2-(2-methyl-4-oxomethylene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (1) (100 mg, 190.47 μmol) in DCM was added 37% formalin (22.86 mg, 761.88 μmol, 61.77 μL) at 0°C. The reaction mixture was then stirred at 25°C for 1 h, and Na(OAc)3BH (201.84 mg, 952.35 μmol) was added to the mixture at 0°C. The reaction mixture was then stirred at 25°C for another 1 h. After completion of the reaction (as judged by LC / MS alone), the solvent was evaporated under reduced pressure to give the crude material. The crude product thus obtained was purified by (Chromatorex(R)NH DM1020 (100-200 mesh)-amine silica gel; 12 g, 1% MeOH / DCM) to obtain compound 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (5) (80 mg, 148.41 μmol, 77.92% yield) as a pale yellow solid.

[0382] m / z calculated 538.1, found (M+1) = 539.0, RT 3.37.

[0383] Synthesis of 6 (Compound 29)

[0384] To a stirred solution of compound 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (5) (80 mg, 148.41 μmol) in a mixture of THF (2.00 mL) and water (0.5 mL) was added LiOH.HO (24.91 mg, 593.64 μmol, 16.50 μL). The reaction mixture was then stirred at 25°C for 6 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 reverse phase preparative HPLC to afford pure compound 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (6) (Compound 29) (34 mg, 64.68 μmol, 43.58% yield, 99.87% purity) as a white solid.

[0385] 1 H NMR-VT (400MHz, DMSO-d6): δ8.77(s,1H),7.55(dd,J=8.80,2.80Hz,1H),7.42(d,J=2.40Hz,1H),7.37(s,1H),7.31(d,J=8.80Hz,1H),4 .33(t,J=5.2Hz,2H),4.13(t,J=5.2Hz,2H),3.09(s,2H),2.75(s,3H),2.67(s,1H),2.58(t,J=5.2Hz,2H),2.35(s,3H),1.80(s,3H)ppm.

[0386] Synthesis of 7 (Compound 28)

[0387] To a stirred solution of compound 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (6) (Compound 29) (100 mg, 190.47 μmol) and MeSO 2 NH 2 (54.35 mg, 571.41 μmol) in DCM (7 mL) was added EDC.HCl (59.14 mg, 380.94 μmol) and DMAP (81.44 mg, 666.64 μmol) at 0° C. The reaction mixture was then 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. The crude product thus obtained was purified by reverse phase preparative HPLC to afford pure compound 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-N-methylsulfonyl-thieno[3,2-b]pyridine-3-carboxamide; 2,2,2-tri(fluoro)acetic acid (7) (Compound 28) (65 mg, 89.14 μmol, 46.80% yield, 98.21% purity) as a white solid.

[0388] 1 H NMR (400MHz, DMSO-d6): δ12.87(brs,1H),8.99(s,1H),7.57(dd,J=9.2,2.80Hz,1H),7.45(s,1H),7.43(d,J=2.4Hz,1H),7.31(d, J=9.2Hz,1H),4.36(t,J=4.8Hz,2H),4.15(t,J=4.8Hz,2H),4.01(s,2H),3.49(s,5H),2.96(s,3H),2.77(s,5H),1.72(s,3H)ppm.

[0389] Plan E

[0390]

[0391] Synthesis of 3:

[0392] To a stirred solution of 7-[5-chloro-2-[2-(2-methyl-4-oxomethylene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (1) (100 mg, 190.47 μmol) in NMP (2 mL) at 25° C. was added KCO (105.14 mg, 761.88 μmol) followed by 2,2,2-tri(fluoro)ethyl tri(fluoro)methanesulfonate (2) (53.05 mg, 228.56 μmol, 32.93 μL) and the reaction mixture was stirred at 40° C. for 16 h. After completion of the reaction (as judged by LCMS and TLC analysis), the reaction mixture was diluted with ethyl acetate and washed with ice-cold water, brine, dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to afford 7-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-[2,2,2-tri(fluoro)ethyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (3) (100 mg, 214.15 μmol, 95% yield) as a light yellow gum which was used in the next step without any further purification.

[0393] m / z calculated 606.1, found (M+1) = 607, RT 3.85.

[0394] Synthesis of 4 (Compound 24)

[0395] To a stirred solution of compound 7-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-[2,2,2-tri(fluoro)ethyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (3) (100 mg, 165 μmol) in a mixture of THF (2 mL) and water (0.5 mL) was added LiOH.HO (35.94 mg, 856.61 μmol, 23.80 μL) at 25° C., and the reaction mixture was stirred for 16 h at 25° C. 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 give 7-[5-chloro-2-[2-[2-methyl-4-oxomethylene-6-[2,2,2-tri(fluoro)ethyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (4) (Compound 24) (25 mg, 33.15 μmol, 15.48% yield, 93.75% purity) as an off-white sticky solid.

[0396] 1 H NMR (400MHz, DMSO-d6): δ8.79(s,1H),7.55(dd,J=8.80,2.80Hz,1H),7.42(d,J=2.80Hz,1H),7.39(s,1H),7.31(d,J=8.80Hz,1H),4.34( t,J=5.2Hz,2H),4.1(t,J=5.2Hz,2H),3.45(s,2H),3.33(q,J=10Hz,1H),2.91(t,J=5.6,2H),2.76(s,3H),2.54(s,4H),1.79(s,3H)ppm.

[0397] Synthesis of 5 (Compound 25)

[0398] To a stirred solution of compound 7-[5-chloro-2-[2-[2-methyl-4-oxo-methylene-6-[2,2,2- trifluoroethyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl- thieno[3,2-b]pyridine-3-carboxylic acid (4) (compound 24) (140 mg, 141.65 pmol) and MeSO2NH2(33.68 mg, 354.12 pmol) in DCM (4 mL) at 0 °C was added DMAP (34.61 mg, 283.30 pmol) followed by EDC.HC1 (54.97 mg, 354.12 pmol) and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction (as judged by LC / MS only), the solvent was evaporated under reduced pressure. The crude thus obtained was purified by reverse phase preparative HPLC to give 7-[5-chloro-2-[2-[2-methyl-4-oxo-methylene-6-[2,2,2-trifluoroethyl]-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-N-methylsulfonyl-thieno[3,2-b]pyridine- 3-carboxamide; 2,2,2-trifluoroacetic acid (5) (compound 25) (24 mg, 29.68 pmol, 20.95% yield, 96.96% purity) as off-white solid.

[0399] 1 H NMR (400 MHz, DMSO-d6): δ 13.05 (br s, 1H), 8.95 (s, 1H), 7.59 (dd, J = 9.20, 2.80 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J = 2.80 Hz, 1H), 7.34 (d, J = 8.80 Hz, 1H), 4.33 (t, J = 4.8 Hz, 2H), 4.09 (t, J = 4.8 Hz, 2H), 3.50 (s, 3H), 3.39 (s, 2H), 3.33 (q, J = 10 Hz, 2H), 2.91 (t, J = 5.2, 2H), 2.74 (s, 3H), 2.54 (s, 2H), 1.64 (s, 3H) ppm.

[0400] m / z calcd 569.1, found (M+l) = 570.0, RT 2.68.

[0401] Scheme F

[0402]

[0403] Synthesis of 3:

[0404] To a degassed solution of 7-[5-chloro-2-[2-(2-methyl-4-oxomethylene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (1) (200 mg, 380.94 μmol) in toluene (5 mL) was added 4-bromo-2-methoxy-pyridine (2) (107.44 mg, 571.41 μmol) followed by Cs2CO3 (496.74 mg, 1.52 mmol) at 25° C. RuPhos (17.75 mg, 38.09 μmol) was added followed by RuPhosPdG3 (32.43 mg, 38.09 μmol) at 25° C., 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 celite pad. The filtrate was diluted with water and extracted with EtOAc. The combined organic layer was washed with salt water, dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by silica gel combiflash column chromatography (SiO2; 12 g, 4% MeOH / DCM) to afford 7-[5-chloro-2-[2-[6-(2-methoxy-4-pyridinyl)-2-methyl-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (3) (140 mg, 168.32 μmol, 44.19% yield, 76% purity) as a light yellow solid.

[0405] m / z calculated 631.08, found (M+1) = 632.0, RT 3.24.

[0406] Synthesis of 4 (Compound 23):

[0407] To a stirred solution of compound 7-[5-chloro-2-[2-[6-(2-methoxy-4-pyridinyl)-2-methyl-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (3) (140 mg, 168.32 μmol) in a mixture of THF (4.00 mL) and water (999.77 μL) at 25° C. was added LiOH.HO (28.25 mg, 673.28 μmol, 18.71 μL) and the reaction mixture was stirred at 25° C. for 16 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-[6-(2-methoxy-4-pyridinyl)-2-methyl-4-oxomethylene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (4) (Compound 23) (19 mg, 25.07 μmol, 14.90% yield, 96.62% purity) as a white solid.

[0408] 1 H NMR (400MHz, DMSO-d6): δ8.71(s,1H),7.87(d,J=6.8Hz,1H),7.56(dd,J=8.8,2.0H z,1H),7.42(d,J=2.4Hz,1H),7.39(s,1H),7.32(d,J=8.8Hz,1H),6.78(d,J=6Hz,1 H),6.38(s,1H),4.38(t,J=4.8Hz,2H),4.25(s,2H),4.17(t,J=4.8Hz,2H),3.99(s ,3H),3.78(t,J=5.6Hz,2H),2.75(s,3H),2.64(t,J=5.6Hz,2H),1.79(s,3H)ppm.

[0409] m / z calculated 617.15, found (M-1) = 616.1, RT 2.37.

[0410] Plan G

[0411]

[0412] Synthesis of compound 2:

[0413] At 25 ° C, to a stirred solution of 4,6-bis(chloro)-2-methyl-pyrimidine-5-carbaldehyde (5 g, 26.18 mmol) in 1,4-dioxane (20 mL) was added PTSA (450.75 mg, 2.62 mmol) followed by ethane-1,2-diol (4.06 g, 65.44 mmol, 3.65 mL) and the reaction mixture was stirred at 100 ° C for 16 h. After the reaction was complete, the reaction mixture was cooled to 25 ° C. Volatiles were removed under reduced pressure. The crude product was purified by combi flash column chromatography (SiO2, 40 g, 4% EtOAc / hexane) to provide 4,6-bis(chloro)-5-(1,3-dioxolane-2-yl)-2-methyl-pyrimidine (2) (3.1 g, 13.19 mmol, 50.38% yield) as a white solid.

[0414] LC-MS: 235.1 (M+H).

[0415] 1H-NMR (400MHz, DMSO-d6): δ6.23 (s, 1H), 4.16-4.22 (m, 2H), 4.00-4.06 (m, 2H), 2.60 (s, 3H) ppm.

[0416] Synthesis of compound 3:

[0417] To a stirred solution of benzyl alcohol (1.71 g, 15.83 mmol, 1.64 mL) in THF (9.73 mL) was added NaH (454.78 mg, 19.78 mmol, 60% in oil) at 0°C under argon atmosphere, and the reaction mixture was stirred at 25°C for 30 min. 4,6-bis(chloro)-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidine (2) (3.1 g, 13.19 mmol) in THF (5 ml) was added at 0°C, and the reaction mixture was stirred at 25°C for 2 h. After the reaction was complete (as judged by LC / MS and TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc, the combined organics were washed with ice-cold water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO2; 230-400 mesh, 40 g, 4% EtOAc / hexanes) to afford 4-chloro-5-(1,3-dioxolan-2-yl)-2-methyl-6-(phenylmethoxy)pyrimidine (3) (3.5 g, 11.41 mmol, 86.52% yield) as an off-white solid.

[0418] MS calculated value: 306.1; MS found value: 307.1 (M+H).

[0419] 1H NMR (400MHz, DMSO-d6): 7.35-7.52(m,5H),6.15(s,1H),5.46(s,2H),4.20(s,2H),3.89(s,2H),2.52(s,3H)ppm.

[0420] Synthesis of compound 4:

[0421] To a stirred solution of 4-chloro-5-(1,3-dioxolan-2-yl)-2-methyl-6-(phenylmethoxy)pyrimidine (3) (2 g, 6.52 mmol) in acetone (8 mL) was added I (166.91 mg, 652.01 μmol) at 25° C. and the reaction mixture was stirred at 60° C. for 1 h. After completion of the reaction, the volatiles were removed under reduced pressure and the crude product thus obtained was purified by flash column chromatography (SiO, 230-400 mesh, 20% EtOAc / hexane) to afford 4-chloro-2-methyl-6-(phenylmethoxy)pyrimidine-5-carbaldehyde (4) (1.5 g, 5.71 mmol, 87.58% yield) as a colorless viscous gum.

[0422] LC-MS: 263.3 (M+H)

[0423] 1H-NMR (400MHz, DMSO-d6): δ10.33(s,1H),7.51(d,J=6.64Hz,2H),7.40-7.30(m,3H),5.54(s,2H),3.64(s,3H)ppm

[0424] Synthesis of compound 6:

[0425] To a stirred solution of 4-chloro-2-methyl-6-(phenylmethoxy)pyrimidine-5-carbaldehyde (4) (1.7 g, 6.47 mmol) in DCM (10.40 mL) at 25° C. was added 2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxyethylamine (5) (1.36 g, 7.77 mmol, 1.60 mL) and a catalytic amount of AcOH, and the reaction mixture was stirred at 25° C. for 30 min. Sodium triacetoxyborohydride (5.49 g, 25.89 mmol) was added portionwise to the reaction mixture 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; 12 g, 30% EtOAc / hexanes) to afford N-[[4-chloro-2-methyl-6-(phenylmethoxy)pyrimidin-5-yl]methyl]-2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxy-ethylamine (6) (2 g, 4.74 mmol, 73.23% yield) as an off-white solid.

[0426] LC-MS: 421.3 (M+H)

[0427] 1H-NMR (400MHz, DMSO-d6): δ7.46(d,J=8Hz,2H),7.40-7.34(m,3H),5.43(s,2H),3.94(s,2H),3.77(s,3H),2.16(s,3H),0.85(s,9H),-0.03(s,6H)

[0428] Synthesis of compound 7:

[0429] To a stirred solution of N-[[4-chloro-2-methyl-6-(phenylmethoxy)pyrimidin-5-yl]methyl]-2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxy-ethylamine (6) (2 g, 4.74 mmol) in DCM (10.00 mL) at 25° C. was added HCHO (1.61 g, 47.39 mmol, 1.98 mL) and a catalytic amount of AcOH, and the reaction mixture was stirred at 25° C. for 30 min. Sodium triacetoxyborohydride (5.02 g, 23.69 mmol) 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 thus obtained was purified by combi flash column chromatography (SiO2; 12 g, 30% EtOAc / hexanes) to afford N-[[4-chloro-2-methyl-6-(phenylmethoxy)pyrimidin-5-yl]methyl]-2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxy-N-methyl-ethylamine (7) (980 mg, 2.25 mmol, 47.42% yield) as an off-white solid.

[0430] LC-MS: 436.3 (M+H)

[0431] 1H-NMR (400MHz, DMSO-d6): δ7.46(d,J=8Hz,2H),7.40-7.34(m,3H),5.43(s,2H),3.60(t,J=12H z,2H),3.54(s,2H),3.29(t,J=12Hz,2H),2.50(s,3H),2.16(s,3H),0.85(s,9H),-0.034(s,6H).

[0432] Synthesis of compound 8:

[0433] To a stirred solution of N-[[4-chloro-2-methyl-6-(phenylmethyloxy)pyrimidin-5-yl]methyl]-2-[1,1 -di(methyl)ethyl-di(methyl)silyl]oxy-N-methyl-ethanamine (7) (1.4 g, 3.21 mmol) in THF (10 mL) at 0 °C was added TBAF (2.52 g, 9.63 mmol, 2.79 mL, 1 M in THF) and the reaction mixture was stirred at 25 °C for 6 h. After completion of the reaction (as judged by LC / MS and TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc, the combined organics were washed with ice-cold water, brine, dried over Na2S04, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by combi flash column chromatography (Si02; 12 g, 40 g, 70% EtOAc / hexane) to give 2-[[4-chloro-2-methyl-6-(phenylmethyloxy)pyrimidin-5-yl]methyl-methyl- amino]ethanol (8) (800 mg, 2.49 mmol, 77.43% yield) as off-white solid.

[0434] LC-MS: 321.6 (M+H)

[0435] 1H-NMR (400 MHz, DMSO-d6): d 7.48 (d, J = 8 Hz, 2H), 7.41 - 7.32 (m, 3H), 5.44 (s, 2H), 4.27 (s, 1H), 3.53 (s, 2H), 3.45 (s, 2H), 3.30 (s, 3H), 2.07 (s, 3H).

[0436] Synthesis of compound 9:

[0437] To a stirred solution of 2-[[4-chloro-2-methyl-6-(phenylmethyloxy)pyrimidin-5-yl]methyl- methyl-amino]ethanol (8) (800 mg, 2.49 mmol) in THF (5 mL) was added potassium tert- butoxide (278.95 mg, 2.49 mmol) and the reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure and the crude thus obtained was purified by combi flash column chromatography (Si02; 12 g, 40 g, 60% EtOAc / hexane) to give 2,6-di(methyl)-4-(phenylmethyloxy)-7,8-dihydro-5H-pyrimido[5,4- f][1,4]oxazepine (9) (350 mg, 1.23 mmol, 49.34% yield) as off-white solid. (350 mg, 1.23 mmol, 49.34% yield).

[0438] LC-MS: 286.0 (M+H) LC-MS: 286.0 (M+H)

[0439] 1H NMR (400MHz, DMSO-d6) δ7.45-7.31(m,5H),5.39(s,2H),4.23-4.17(m,3H),3.63(s,3H),2.86-2.83(m,3H),1.56(s,3H)ppm.

[0440] Synthesis of compound 10:

[0441] 2,6-di(methyl)-4-(phenylmethoxy)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine To a stirred solution of (9) (350 mg, 1.23 mmol) in MeOH (5 mL) was added wet 10% palladium on carbon (130.54 mg, 1.23 mmol) and the reaction mixture was degassed with argon for 30 min. The reaction mixture was stirred at 25 °C under a positive pressure of H2 for 3 h. After completion of the reaction, the catalyst was filtered through a sinter funnel. The filtrate was removed under reduced pressure and the crude product thus obtained was purified by combi flash column chromatography (SiO2; 4 g, 40 g, 50% EtOAc / hexane) to afford 2,6-di(methyl)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine as a white solid. -4-ol (10) (210 mg, 1.08 mmol, 87.70% yield).

[0442] LC-MS: 196.2 (M+H)

[0443] 1H NMR(400MHz,DMSO-d6)δ12.28-12.25(m,1H),4.16-4.14(m,2H),3.58(s,1H ),3.45(s,1H),2.77-2.74(m,2H),2.28(s,3H),2.18(s,2H),1.55(s,2H)ppm

[0444] Synthesis of compound 12:

[0445] At 25 °C, 2,6-di(methyl)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine To a stirred solution of -4-ol (170 mg, 870.82 μmol) (10) in DMF (3 mL) was added 99% anhydrous potassium carbonate (361.07 mg, 2.61 mmol, 157.67 μL) followed by 7-[2-(2-bromoethoxy)-5-chloro-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (11) (460.57 mg, 1.04 mmol) and the reaction mixture was stirred at 50° C. for 16 h. After completion of the reaction (as judged by LC / MS and TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc, the combined organics were washed with ice-cold water, brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by combi flash column chromatography (SiO2; 12 g, 40 g, 60% EtOAc / hexanes) to afford 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine] as an off-white solid. [3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (12) (110 mg, 198.18 μmol, 22.76% yield) and 7-[5-chloro-2-[2-[[2,6-di(methyl)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine] as an off-white solid [4-amino]oxy]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester (13) (117 mg, 210.79 μmol, 24.21% yield).

[0446] LC-MS: 556.3 (M+H)

[0447] 1H-NMR (400MHz, DMSO-d6): δ8.75(s,1H),7.54(d,J=4Hz,1H),7.41(s,1H),7.27(t,J=12Hz,2H),4.26(d,J= 8Hz,2H),4.17(s,2H),4.03(d,J=8Hz,4H),3.88(s,3H),3.45(s,2H),2.76(s,2H),1.55(s,3H),1.23(s,3H).

[0448] Synthesis of 13 (Compound 30)

[0449] At 25 ° C, 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine To a stirred solution of THF (3 mL) and water (1 mL) was added 98% lithium hydroxide monohydrate (24.95 mg, 594.55 μmol, 16.52 μL) and the reaction mixture was stirred 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 thus obtained was purified by reverse phase preparative HPLC to afford 7-[5-chloro-2-[2-[2,6-di(methyl)-4-oxomethylene-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine as a white solid. -3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tri(fluoro)acetic acid (13) (Compound 30) (42 mg, 63.83 μmol, 32.21% yield, 99.55% purity).

[0450] (M+H)=541.1.

[0451] 1H NMR (400MHz, DMSO-d6) δ8.88(s,1H),7.58(dd,J=4Hz,4Hz,1H),7.47(s,1H),7.41(s,1H),7.31(d,J=8Hz,1H),4 .37(d,J=16Hz,1H),4.29(s,2H),4.10(s,3H),4.07(s,2H),3.69(s,1H),2.89(s,3H),2.73(s,3H),1.60(s,3H).

[0452] II. Biological Assessment

[0453] Biochemical competitive binding assay

[0454] The potency of compound binding to human eIF4E protein was measured using a 384-well time-resolved fluorescence resonance energy transfer (TR-FRET) competition assay. The assay was performed in an assay buffer containing 50 mM HEPES pH 7.5, 100 mM KCl, 0.02% Tween-20, and 0.1 mg / mL bovine serum albumin (BSA). The reaction volume was 10 μL, and each reaction contained 4 nM recombinant 6xHIS-tagged human eIF4E protein (Novus, NBP-45314), 5 nM EDA-m7GDP-ATTO-647N (JenaBioscience, NU-827-647N), 2.5 nM europium-conjugated anti-6xHIS antibody (PerkinElmer, AD0402), and various concentrations of compound. The final DMSO concentration was 1%.

[0455] Compounds were prepared using an 11-point, 4-fold serial dilution in DMSO, and 100 nL of the diluted compounds were transferred to a 384-well assay-ready plate. Recombinant human eIF4E protein at 2X final concentration (8 nM) was pre-incubated with Eu-anti-6xHIS antibody at 2X final concentration (5 nM) for 5 minutes, and then 5 μL of protein solution was added to the assay-ready plate. The protein / compound mixture was incubated for 15 minutes, after which 5 μL of a solution containing 2X final concentration (10 nM) of EDA-m7GDP-ATTO-647N probe was added. After the subsequent 15-minute incubation, the time-resolved fluorescence of the assay plate was measured using a Clariostar Plus microplate reader (BMG Labtech), and TR-FRET values ​​were calculated by taking the ratio of the 665 to 620 wavelength signals. After normalization to the average of the DMSO control wells and the maximum inhibition control wells, the concentration-response data were plotted, and the IC was determined using a standard 4-parameter curve fit (PEI signal). 50 The results of the competitive binding assay are presented in Table E1.

[0456] Table E1

[0457]

[0458]

[0459] A=(IC 50 <400nM); B=(400nM <IC 50 <10 μM); C = (10 μM <IC 50 <100 μM)

[0460] Cellular cap-dependent translation inhibition assay

[0461] Using stable integration-based Flp-In TM The effects of compounds on cellular cap-dependent translation were assessed using a dual luciferase assay (DLA) of WT-293 (ThermoFisher Scientific, R75007) reporter cells, where cap-dependent translation of unstable firefly luciferase (Fluc-PEST) and cap-independent poliovirus IRES-mediated translation of Renilla luciferase (Rluc) were measured 24 hours after compound treatment. Reporter plasmids were constructed using pcDNA5 / FRT (Invitrogen, V601020). Test compounds were prepared using 11-point, 4-fold serial dilutions in DMSO, and 100 nL of the diluted compounds were transferred to 384-well assay-ready plates. Reporter cells were seeded at 10,000 cells per well in DMEM supplemented with 10% FBS in assay-ready plates. After 24 hours of compound treatment, the cells were plated using a 4-well plate according to the manufacturer's instructions. Luciferase assay system (Promega, E2920) is used to evaluate Fluc activity and Rluc activity in turn. Luminescence is measured using a Clariostar Plus microplate reader (BMG Labtech) or equivalent. For each well, the ratio of Fluc luminescence to Rluc luminescence is calculated. After being normalized to the mean value of the DMSO control wells and the maximum inhibition control wells, concentration-response data are plotted, and standard 4-parameter curve fitting (PEI signal) is utilized to determine IC 50 The results of the cellular cap-dependent translation dual-luciferase inhibition assay (DLA) are summarized in Table E2.

[0462] Table E2

[0463]

[0464]

[0465] A=(IC 50 <10 μM); B = (10 μM <IC 50 <20 μM); C = (IC 50 >20μM)

[0466] Equivalent

[0467] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents and reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth.

[0468] Although specific embodiments of the subject disclosure have been discussed, the foregoing description is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art after reading this specification and the appended claims. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

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 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 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 the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; R 1 It is 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 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; or Two R X Together with the carbon atom to which they are attached, they form an oxo group; 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 attached, 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 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 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 the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl group is optionally substituted.

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

7. The compound according to any one of claims 1 to 6, wherein R 2 is -COOH or -C(=O)NR c S(=O)2CH3.

8. The compound according to claim 1, wherein 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: or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

9. The compound according to any one of claims 1 to 8, wherein R C1 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.

10. The compound according to any one of claims 1 to 9, wherein R C1 Is a halogen or C 1-6 alkyl.

11. The compound according to any one of claims 1 to 10, wherein R C1 It is -Cl, -F or methyl.

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

13. The compound according to any one of claims 1 to 12, wherein 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.

14. The compound according to any one of claims 1 to 13, wherein s is 0 or 1.

15. The compound according to any one of claims 1 to 13, 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-.

16. The compound according to claim 15, wherein each R L1 and each R L2 It's hydrogen.

17. The compound according to claim 15 or 16, wherein p is 1.

18. The compound of any one of claims 15-17, wherein Y is -O-.

19. A compound according to any one of claims 1 to 18, wherein X is -C(R X )2-.

20. The compound of any one of claims 1-19, wherein each of m and m' is 1.

21. The compound of any one of claims 1-20, wherein n is 0.

22. A compound according to any one of claims 1 to 21, wherein 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.

23. A compound according to any one of claims 1 to 22, wherein R 1 It is 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 group is optionally substituted.

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

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable excipient.

26. 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 1-24 or contacting the biological sample with a compound according to any one of claims 1-24.

27. Use of a compound according to any one of claims 1 to 24 in the preparation of a medicament for inhibiting a protein in a subject or a biological sample.

28. A compound according to any one of claims 1 to 24 for use in inhibiting a protein in a subject or biological sample.

29. The method, use or compound for use according to any one of claims 26 to 28, wherein the protein is eIF4E.

30. 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 1-24.

31. Use of a compound according to any one of claims 1 to 24 in the preparation of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

32. A compound according to any one of claims 1 to 24 for use in treating or preventing a disease or disorder in a subject in need thereof.

33. The method, use or compound for use according to any one of claims 30 to 32, wherein the disease or disorder is an eIF4E-mediated disease or disorder.

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