Compounds and compositions as eIF4E inhibitors and their uses

Abstract

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

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 424,462, filed November 10, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Eukaryotic initiation factor 4E (eIF4E) is a limiting protein for 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 mRNA and recruits 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 then recruits additional translation initiation factors, ribosomes, and protein translation begins.

[0003] Under basal conditions, eIF4E activity is regulated by multiple mechanisms, including binding to and sequestration by the abundant negative regulatory protein 4E-binding protein (4EBP). In cancer, eIF4E activity is elevated through several mechanisms, including mutational activation of oncogenic signaling pathways, such as receptor tyrosine kinases (RTKs), RAS / RAF family members, PI3K family members, and others that converge on eIF4E (REF). Dysregulation of eIF4E expression itself promotes tumorigenesis, underscoring its critical role in cellular transformation and carcinogenesis. Furthermore, elevated expression in patients has been shown to result in poor prognosis in multiple indications, including breast, head and neck, ovarian, and colorectal cancer. Upregulation of eIF4E activity has also been reported to be important in the development of resistance to chemotherapeutic and targeted cancer drugs. Finally, genetic inhibition of eIF4E and disruption of other facets of the MNK1-eIF4E axis have demonstrated antitumor efficacy in multiple preclinical models, including melanoma, ovarian, esophageal, lung, and breast cancer.

[0004] Therefore, pharmacological inhibition of eIF4E activity may be an effective anti-cancer therapy. Summary of the Invention

[0005] In certain aspects, the present disclosure provides compounds of formula I: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, Each -L- independently represents -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 is alkyl, Each RL1 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 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, where valence allows, an integer selected from 0 to 6; R 2 are halogens, -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, 5-10 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 cS(=O)2R a , or C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 1 is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6 alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl), -(C 1-6 alkylene)-(3-12 membered heterocyclyl), -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; X is -O- or -C(R X )2- and 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 Two Germinal R X together with the carbon atom to which they are attached form oxo, m and m' are independently an integer 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, where valence allows; R B are hydrogen, halogens, -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; Each R a independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; 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 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; R c and R d together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl; Appearing R a , R b , R c , and R d Each of is independently optionally substituted.

[0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0007] In certain aspects, the present disclosure provides methods of inhibiting a protein in a subject or a biological sample comprising administering to the subject a compound disclosed herein or contacting the biological sample with a compound disclosed herein.

[0008] In certain aspects, the present disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for inhibiting a protein in a subject or biological sample.

[0009] In certain aspects, the present disclosure provides a compound disclosed herein for use in inhibiting a protein in a subject or biological sample.

[0010] In certain aspects, the present disclosure provides a method 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.

[0011] In certain aspects, the disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0012] 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.

[0013] Details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will become apparent from the description and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0014] All publications and patents mentioned herein are incorporated by reference in their entirety 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. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present disclosure relates to compounds that inhibit eIF4E activity, and pharmaceutical compositions thereof. The present disclosure further relates to a method for inhibiting proteins in a subject or a 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 a method for treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound described herein.

[0016] Compounds of the present application In certain aspects, the present disclosure provides compounds of formula I: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, Each -L- independently represents -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 is 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 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, C2-6 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, where valence allows, an integer selected from 0 to 6; R 2 are halogens, -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, 5-10 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 the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 1 is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl), -(C 1-6 alkylene)-(3-12 membered heterocyclyl), -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; X is -O- or -C(R X )2- and 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 Germinal R X together with the carbon atom to which they are attached form oxo, m and m' are independently an integer 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 3-6carbocyclyl, 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, where valence allows; R B are hydrogen, halogens, -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; Each R a independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, 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 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; 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 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; R c and R d together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl; Appearing R a , R b , R c , and R d Each of is independently optionally substituted.

[0017] In certain embodiments, the compound of Formula I has the formula I-1-i, I-1-ii, I-1-iii, or I-1-iv: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0018] In certain embodiments, the compound of Formula I has the formula I-1-i-1, I-1-i-2, I-1-i-3, I-1-iii-1, I-1-iii-2, or I-1-iii-3: [ka] [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0019] Embodiments of the variables in any of the formulas described herein, e.g., Formula I through Formula I-1-iii-3, are described below, where applicable. Any of the variables can be any moiety as described in the embodiments below. Additionally, any moiety described for any of the variables can be combined with any moiety described for any of the remaining variables, where applicable.

[0020] In certain embodiments, R 1 is hydrogen, -CN, 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)), 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 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), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), C 3-12 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-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl 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)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl), -(C 1-6 alkylene)-(3-12 membered heterocyclyl), -S(=O)Ra , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. 1-6 The alkene is selected from methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), and hexylene (-CHCHCHCHCHCHCH-). 1 optionally, one or more R u is replaced by

[0021] In certain embodiments, R 1 is hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6 alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl), -(C 1-6 alkylene)-(3-12 membered heterocyclyl), -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR cR d wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 1 is one or more R u is optionally replaced by

[0022] In certain embodiments, R 1 is hydrogen, -CN, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6 alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl), -(C 1-6 alkylene)-(3-12 membered heterocyclyl), -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 1 is one or more R u is optionally replaced by

[0023] In certain embodiments, R 1 -CN, C 1-6 Alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6alkylene)-(5-10 membered heteroaryl), -C(=O)R a wherein the alkyl, alkylene, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 1 is one or more R u is optionally replaced by

[0024] In certain embodiments, R 1 is an arbitrarily substituted C 1-6 In certain embodiments, R 1 is an arbitrarily substituted C 6-10 In certain embodiments, R 1 is an optionally substituted 5-10 membered heteroaryl containing 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 arbitrarily substituted C 3-12 In certain embodiments, R 1 is an optionally substituted 3- to 12-membered heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is -(C 1-6 alkylene)-(C 6-10 aryl), wherein the alkylene or aryl is optionally substituted. In certain embodiments, R 1 is -(C 1-6 In certain embodiments, R is an alkylene-(5- to 10-membered heteroaryl), wherein the heteroaryl contains one or two 5- or 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S, and the alkylene or heteroaryl is optionally substituted. 1 is -(C 1-6 alkylene)-(C 3-12 carbocyclyl), wherein the alkylene or carbocyclyl is optionally substituted. In certain embodiments, R 1 is -(C 1-6In certain embodiments, R is an alkylene)-(3- to 12-membered heterocyclyl) in which the heterocyclyl contains one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S, and the alkylene or heterocyclyl is optionally substituted. 1 is one or more R u is optionally replaced by

[0025] In certain embodiments, R 1 is an arbitrarily substituted C 6-10 In certain embodiments, aryl is one or more R u is optionally replaced by

[0026] In certain embodiments, R 1 is an optionally substituted 5-10 membered heteroaryl containing 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 containing one 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heteroaryl containing one five-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heteroaryl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heteroaryl containing two 5- or 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heteroaryl containing two five-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heteroaryl containing two 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1is an optionally substituted heteroaryl containing one 5-membered ring and one 6-membered ring and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, the heteroaryl is selected from one or more R u is optionally replaced by

[0027] In certain embodiments, R 1 is an arbitrarily substituted C 3-12 Carbocyclyl (e.g., cyclopropyl (C 3) , 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-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 In certain embodiments, a carbocyclyl is one or more R u is optionally replaced by

[0028] In certain embodiments, R 1 is an optionally substituted 3- to 12-membered heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing one 3-8 membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing one three-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, R1 is an optionally substituted heterocyclyl containing one four-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing one 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing one 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing one seven-membered ring and one to four heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing one 8-membered ring and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing two 3-8 membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing two five-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing two 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1 is an optionally substituted heterocyclyl containing one 5-membered ring and one 6-membered ring and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, the heterocyclyl is selected from one or more R u is optionally replaced by

[0029] In certain embodiments, R 1 is -(C 1-6 alkylene)-(C 6-10 aryl), wherein the alkylene or aryl is optionally substituted. In certain embodiments, an aryl is selected from the group consisting of one or more R uis optionally replaced by

[0030] In certain embodiments, R 1 is -(C 1-6 and alkylene)-(5-10-membered heteroaryl), wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S, and the alkylene or heteroaryl is optionally substituted. 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-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, an optionally substituted heteroaryl comprises two 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heteroaryl comprises one 5-membered ring and one 6-membered ring and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, the heteroaryl comprises one or more R u is optionally replaced by

[0031] In certain embodiments, R 1 is -(C 1-6 alkylene)-(C 3-12 carbocyclyl), and the C 3-12 Carbocyclyl is cyclopropyl (C 3), 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-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )) wherein the alkylene or carbocyclyl is optionally substituted. In certain embodiments, the carbocyclyl is selected from one or more R u is optionally replaced by

[0032] In certain embodiments, R 1 is -(C 1-6and alkylene)-(3- to 12-membered heterocyclyl), wherein the heterocyclyl comprises one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S, and the alkylene or heterocyclyl is optionally substituted. 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-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, an optionally substituted heterocyclyl comprises one 6-membered ring and one to four heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl comprises one 7-membered ring and one to four heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl comprises one 8-membered ring and one to five heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl comprises two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl comprises two 5-membered rings and one to five heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl comprises two 6-membered rings and one to five heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl contains one 5-membered ring and one 6-membered ring and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, the heterocyclyl contains one or more R u is optionally replaced by

[0033] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0034] In certain embodiments, m' is 0. In certain embodiments, m' is 1. In certain embodiments, m' is 2.

[0035] 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.

[0036] 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), 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)), C 1-6Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-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 3-6 membered heterocyclyl (e.g., a heterocyclyl containing one 3-6 membered ring and one to three 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, one or more R u is optionally replaced by

[0037] 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 and alkylamino, wherein the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R A independently, one or more R u is optionally replaced by

[0038] 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 and alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R A independently, one or more R u is optionally replaced by

[0039] 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.

[0040] 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), 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)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-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 3-6 membered heterocyclyl (e.g., a heterocyclyl containing one 3-6 membered ring and one to three 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, one or more R u is optionally replaced by

[0041] In certain embodiments, R B are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, or C 1-6 alkylamino, wherein the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R B independently, one or more R u is optionally replaced by

[0042] In certain embodiments, R B are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R B independently, one or more R u is optionally replaced by

[0043] In certain embodiments, R B is hydrogen or an optionally substituted C 1-6 In certain embodiments, R B is hydrogen. In certain embodiments, R B is an arbitrarily substituted C 1-6 In certain embodiments, R B is one or more R u is optionally replaced by

[0044] In certain embodiments, ring C is C 6-10 It is aryl or 5- to 10-membered heteroaryl.

[0045] In certain embodiments, ring C is C 6-10 aryl (eg, phenyl or naphthyl);

[0046] In certain embodiments, ring C is a 5- to 10-membered heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S. In certain embodiments, ring C is a 5- to 10-membered heteroaryl containing one 5- or 6-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, ring C is a 5- to 10-membered heteroaryl containing one 5-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, ring C is a 5- to 10-membered heteroaryl containing one 6-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, ring C is a 5- to 10-membered heteroaryl containing two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S. In certain embodiments, ring C is a 5- to 10-membered heteroaryl containing 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 containing 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 containing one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0047] In certain embodiments, Ring C is phenyl or pyridinyl.

[0048] In certain embodiments, R C1 is a 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), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6alkenyl (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), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-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 3-6 membered heterocyclyl (e.g., a heterocyclyl containing one 3-6 membered ring and one to three 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 is one or more R u is optionally replaced by

[0049] In certain embodiments, R C1 are halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R C1 is one or more R u is optionally replaced by

[0050] In certain embodiments, R C1 is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, R C1 is -Cl. In certain embodiments, R C1 is an arbitrarily substituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl). C1 is one or more R u is optionally replaced by

[0051] In certain embodiments, each R C2 are independently halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 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)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-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 3-6 membered heterocyclyl (e.g., a heterocyclyl containing one 3-6 membered ring and one to three 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, one or more R u is optionally replaced by

[0052] In certain embodiments, each R C2 are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6Alkoxy, or C 1-6 and alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R C2 independently, one or more R u is optionally replaced by

[0053] 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.

[0054] In certain embodiments, ring D is C 6-10 It is aryl or 5- to 10-membered heteroaryl.

[0055] In certain embodiments, ring D is C 6-10 aryl (eg, phenyl or naphthyl);

[0056] In certain embodiments, ring D is a 5- to 10-membered heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl containing one 5- or 6-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl containing one 5-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl containing one 6-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl containing two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S. In certain embodiments, ring D is a 5- to 10-membered heteroaryl containing 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 containing 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 containing one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0057] In certain embodiments, Ring D is phenyl, pyridinyl, pyrrolopyridazinyl, or thienopyridinyl.

[0058] 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), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6alkenyl (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), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 6-10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), C3-6 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 containing one 3- to 6-membered ring and one to three 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 the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. 2 is one or more R u is optionally replaced by

[0059] In certain embodiments, R 2 are halogens, -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, 5-10 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)ORb , -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 is optionally substituted, and in certain embodiments, R 2 is one or more R u is optionally replaced by

[0060] In certain embodiments, R 2 are halogens, -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 the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0061] In certain embodiments, R 2 are halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -NR c S(=O)2R a , -N(S(=O)2R a )2, -S(=O)2Ra , -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, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0062] In certain embodiments, R 2 is a halogen, C 1-6 Alkyl, C 6-10 Aryl, 5-10 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 the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0063] In certain embodiments, R 2 is C 1-6 Alkyl, 5-10 membered heteroaryl, -NR c S(=O)2R a , -N(S(=O)2R a )2, -C(=O)OR b , -C(=O)NR c S(=O)2Ra , or -C(=O)NR c R d wherein the alkyl or heteroaryl is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0064] In certain embodiments, R 2 is -C(=O)NR c S(=O)R a , or -C(=O)OR b In certain embodiments, R 2 is -C(=O)NHS(=O)2CH3 or -COOH.

[0065] 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), 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)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-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 3-6 membered heterocyclyl (e.g., a heterocyclyl containing one 3-6 membered ring and one to three 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, one or more R u is optionally replaced by

[0066] In certain embodiments, each R D are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6Alkoxy, or C 1-6 and alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R D independently, one or more R u is optionally replaced by

[0067] In certain embodiments, each R D are independently halogen or optionally substituted C 1-6 In certain embodiments, at least one R D is halogen. In certain embodiments, each R D are independently halogen. In certain embodiments, at least one R D is an arbitrarily substituted C 1-6 In certain embodiments, each R D are independently optionally substituted C 1-6 In certain embodiments, each R D independently, one or more R u is optionally replaced by

[0068] 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.

[0069] In certain embodiments, each -L- is independently -O-, -NR L -, -CR L1 R L2 -, -CR L1 =CR L2 In certain embodiments, each -L- is independently -O-, -CR L1 R L2 -, or -C≡C-.

[0070] In certain embodiments, [L] q teeth, [ka] and where: * indicates the bond to ring B, ** indicates the bond to ring C, p is an integer selected from 0 to 3, Y is -O-, -CR L1 R L2 -, or -C≡C-.

[0071] In certain embodiments, L is Y.

[0072] 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), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), or C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl -i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), wherein the alkyl, alkoxy, or alkylamino is optionally substituted. L1 and each R L2 independently, one or more R u is optionally replaced by

[0073] In certain embodiments, each R L1 and each R L2 is hydrogen.

[0074] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

[0075] In certain embodiments, Y is -O-. In certain embodiments, Y is -NR L In certain embodiments, Y is -CR L1 R L2In certain embodiments, Y is —C≡C—.

[0076] In certain embodiments, X is —O—. In certain embodiments, X is —C(R X )2-.

[0077] In certain embodiments, each R X 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), 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)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-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 3-6 membered heterocyclyl (e.g., a heterocyclyl containing one 3-6 membered ring and one to three heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, each R X independently, one or more R u is optionally replaced by

[0078] In certain embodiments, each R X are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6Alkoxy, or C 1-6 and alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R X independently, one or more R u is optionally replaced by

[0079] In certain embodiments, each R X is hydrogen.

[0080] In certain embodiments, each R X are independently halogen or optionally substituted C 1-6 In certain embodiments, at least one R X is halogen. In certain embodiments, each R X are independently halogen. In certain embodiments, at least one R X is an arbitrarily substituted C 1-6 In certain embodiments, each R X are independently optionally substituted C 1-6 In certain embodiments, each R X independently, one or more R u is optionally replaced by

[0081] In certain embodiments, an occurrence of R a , R b , R c , and R d Each occurrence of R is independently optionally substituted. a , R b , R c , and R d each independently represents one or more R u is optionally replaced by

[0082] In certain embodiments, each R a independently, C 1-6alkyl (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)), 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-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing 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 selected from the group consisting of one or more R u is optionally replaced by

[0083] In certain embodiments, each Ra independently, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl, or alkyny is one or more R u is optionally replaced by

[0084] In certain embodiments, each R b are 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)), 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-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing 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 selected from the group consisting of one or more R u is optionally replaced by

[0085] In certain embodiments, each R b independently, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, and the alkyl, alkenyl, or alkynyl is one or more R u is optionally replaced by

[0086] 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), 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)), C 3-12Carbocyclyl (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-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing 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 selected from the group consisting of one or more R u is optionally replaced by

[0087] 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 is selected from one or more R u is optionally replaced by

[0088] In certain embodiments, R c and R d together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is selected from one or more R uis optionally replaced by

[0089] 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), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino propylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2-6alkenyl (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), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), C 3-12 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-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a, -NR c S(=O)2OR b , -NR c S(=O)NR 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 the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is 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 It is optionally substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl.

[0090] 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 6-10 Aryl, 5-10 membered heteroaryl, C 3-12carbocyclyl, 3- to 12-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is 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 It is optionally substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl.

[0091] 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 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is 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 It is optionally substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl.

[0092] 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 3-6carbocyclyl, 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is 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 It is optionally substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl.

[0093] In certain embodiments, the compounds disclosed herein are selected from the compounds in Table 1, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0094] The compounds of the present disclosure have advantageous characteristics compared to known compounds, such as known eIF4E inhibitors. For example, the compounds of the present disclosure have more potent eIF4E inhibitory activity, more favorable pharmacokinetic properties (e.g., C max , T max and / or AUC) and / or reduced interactions with other cellular targets (e.g., hepatocyte transporters, e.g., OATP1B1), and thus improved safety (e.g., drug-drug interactions). These beneficial properties of compounds of the present disclosure can be measured according to methods generally available in the art, such as those exemplified herein.

[0095] Due to the presence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E configuration. Although one configuration may be shown in the structure of the compounds or formulas of the present disclosure, it is understood that the present disclosure also encompasses other configurations. For example, the compounds or formulas of the present disclosure may be shown in cis or trans, or Z or E configuration.

[0096] In one embodiment, the compound of the present disclosure (e.g., any compound of the formula or any individual compound disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, the compound of the present disclosure (e.g., any compound of the formula or any individual compound disclosed herein) is a solvate. In another embodiment, the compound of the present disclosure (e.g., any compound of the formula or any individual compound disclosed herein) is a hydrate.

[0097] pharmaceutically acceptable salts In certain embodiments, the compounds disclosed herein are present as their pharmaceutically acceptable salts.In certain embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts.In certain embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0098] In certain embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number 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 separately reacting the purified compound in its free form with the appropriate acid or base and isolating the salt so formed.

[0099] Examples of pharmaceutically acceptable salts include salts prepared by reaction of a compound described herein with a mineral, organic acid, or inorganic base, including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide. salt, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, 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.

[0100] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, malic acid, methylparaben ... The organic acids include, but are not limited to, organic acids such as 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.

[0101] In certain embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, 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.

[0102] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is to be understood that the compounds described herein are also intended to include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0103] solvate "Solvate" refers to a form of a compound associated with a solvent or water, usually by solvolysis (also called a "hydrate"). This physical association involves hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present disclosure may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0104] Those skilled in the art of organic chemistry will understand that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." Solvates are within the scope of the present disclosure.

[0105] It will also be understood by those skilled in the art of organic chemistry that many organic compounds can exist in multiple crystalline forms. For example, crystalline forms may vary as solvates. Accordingly, all crystalline forms or pharmaceutically acceptable solvates thereof are contemplated and within the scope of the present disclosure.

[0106] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides a method for treating a disease by administering such a solvate. The present disclosure further provides a method for treating a disease by administering such a solvate as a pharmaceutical composition.

[0107] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0108] Isomers (stereoisomers, geometric isomers, tautomers, etc.) It should be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0109] Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is assumed. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomer, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0110] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0111] As used herein, unless otherwise specified, the term "enantiomerically pure (R)-compound" refers to at least about 95% by weight of the (R)-compound and at most about 5% by weight of the (S)-compound, at least about 99% by weight of the (R)-compound and at most about 1% by weight of the (S)-compound, or at least about 99.9% by weight of the (R)-compound and at most about 0.1% by weight of the (S)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0112] As used herein, unless otherwise specified, the term "enantiomerically pure (S)-compound" refers to at least about 95% by weight of the (S)-compound and at most about 5% by weight of the (R)-compound, at least about 99% by weight of the (S)-compound and at most about 1% by weight of the (R)-compound, or at least about 99.9% by weight of the (S)-compound and at most about 0.1% by weight of the (R)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0113] In the compositions provided herein, the enantiomerically pure compound, or its pharmaceutically acceptable salt, solvate, hydrate, or prodrug, may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure (R)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such a composition may contain, for example, at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure (S)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions may comprise, for example, at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0114] 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 thereof, racemic or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0115] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein have one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. All geometric forms of the compounds disclosed herein are contemplated and within the scope of the present disclosure.

[0116] In certain embodiments, the compounds disclosed herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and within the scope of the present disclosure.

[0117] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by exploiting these differences. In certain embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In certain embodiments, the optically pure enantiomers are then recovered along with the resolving agent.

[0118] tautomers In certain embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0119] Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by switching between a single bond and an adjacent double bond. In bond configurations where tautomerization is anticipated, a chemical equilibrium of tautomers will exist. For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and within the scope of this disclosure. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0120] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In certain embodiments, the compounds described herein are administered in a manner consistent with the selected route of administration and standard pharmaceutical practice (e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 2011)). st The compound is 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 principles of the present invention (as described in Ed. Mack Pub. Co., Easton, PA (2005)).

[0121] 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.

[0122] 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 unreacted intermediates or synthetic by-products produced in one or more steps of the synthetic method.

[0123] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides a sufficient amount of the composition(s) to provide therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[0124] In certain embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, 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, intranasal administration, topical administration, or ocular 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 as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop. In certain embodiments, the pharmaceutical composition is formulated as a tablet.

[0125] Compound preparation and characterization The compounds of the present disclosure can be prepared in several ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as would be understood by one of ordinary skill in the art. The compounds of the present disclosure (i.e., compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound)) can be synthesized according to the steps outlined in the general synthetic schemes below, as well as the examples, schemes, procedures, and / or syntheses described herein (e.g., in the Examples).

[0126] General synthetic scheme [ka] Those of ordinary skill in the art will recognize whether a stereocenter exists in the compounds of the present disclosure (e.g., any compound of the formulas disclosed herein or any individual compound). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis), including not only the racemate but also the individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0127] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, using commercially available chemicals and / or compounds described in the chemical literature as starting materials. "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).

[0128] Suitable references and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing such preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992; and "Chemistry of Functional Groups," John Wiley & Sons (73 volumes in total).

[0129] Specific reactants and similar reactants are optionally identified by the index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries and online. Known but not commercially available catalog chemicals are optionally prepared by custom chemical synthesis companies, and many standard chemical suppliers (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0130] Analytical methods, materials, and instrumentation Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 MHz using a Bruker or Varian spectrometer. Spectra are reported in ppm (δ), and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as the internal standard. Liquid chromatography-mass spectrometry (LC / MS) analyses were collected using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using an Agilent 1260-6125B LCMS system equipped with a diode array detector and an Agilent G6125BA mass spectrometer, or a Waters Acquity UPLC system equipped with a diode array detector and a Waters 3100 mass detector. Purity was characterized by UV wavelengths of 214 nm, 220 nm, and 254 nm, and by ESI. Column: Poroshell 120 EC-C18 2.7 μm 4.6 x 100 mm; Flow rate: 0.8 mL / min; Solvent A (100 / 0.1 water / formic acid), Solvent B (100% acetonitrile); Gradient: 5% B ~ 0.3 min, 5-95% B, hold 0.3-2 min, 95% B ~ 4.8 min, 95-5% B, hold 4.8-5.4 min, then 5% B ~ 6.5 min. Alternatively, Column: Acquity UPLC BEH C18 1.7 μm 2.1 x 50 mm; Flow rate: 0.5 mL / min; Solvent A (0.1% formic acid in water), Solvent B (acetonitrile); Gradient: 5% B ~ 0.2 min, 5-95% B, hold 0.2-2.0 min, 95% B ~ 3.1 min, then 5% B, hold 3.5 min.

[0131] Biological assays The biological activity of the compounds of the present application can be evaluated using methods and assays known in the art.

[0132] For example, the affinity of a compound for a protein can be determined by various biophysical assay formats, including surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), mass spectrometry-based binding methods, etc. The competitive binding activity and potency of a compound for a protein can be assessed by a range of common biochemical methods, including fluorescence polarization (FP), time-resolved fluorescence energy transfer (TR-FRET), etc. The functional effects of a compound on complex biological systems can be assessed using cell-free or cell lysate-based assays, such as in vitro translation. The effects of a compound on specific target protein-related functions in cells (cellular activity and potency) can be assessed by a wide variety of methods, including reporter assays, immunoassays, e.g., Western blots, cell enzyme-linked immunosorbent assays (ELISAs), and high-content imaging. The effects of a compound on cellular phenotype can be assayed by a variety of methods, including methods measuring cell proliferation, cell cycle progression, cell viability, cell death, cell migration, cell invasion, cell metabolism, and other cellular phenotypes.

[0133] How to use In certain aspects, the present disclosure provides methods of inhibiting a protein in a subject or a biological sample comprising administering to the subject a compound disclosed herein or contacting the biological sample with a compound disclosed herein.

[0134] In certain aspects, the present disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for inhibiting a protein in a subject or biological sample.

[0135] In certain aspects, the present disclosure provides a compound disclosed herein for use in inhibiting a protein in a subject or biological sample.

[0136] In certain embodiments, the protein is eIF4E.

[0137] In certain aspects, the present disclosure provides a method 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.

[0138] In certain aspects, the disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0139] 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.

[0140] In certain embodiments, the disease or disorder is an eIF4E-mediated disease or disorder.

[0141] In certain embodiments, the disease or disorder is cancer.

[0142] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers in Table A. [Table 2-1] [Table 2-2] [Table 2-3]

[0143] 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, those 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. [Table 3]

[0144] In certain embodiments, the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, pancreatic cancer, melanoma, multiple melanoma, 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.

[0145] In certain embodiments, the disease or disorder is a non-cancer disease or disorder (e.g., an eIF4E-mediated non-cancer disease or disorder). In certain embodiments, the disease or disorder is a cytokine-associated disease, e.g., an inflammatory disease, allergy, or other condition associated with pro-inflammatory 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 the expression (or aberrant expression) and / or function (or dysfunction) of eIF4E, or a disease or disorder in which the expression (or aberrant expression) and / or function (or dysfunction) of eIF4E plays a role (e.g., in the initiation and / or development).

[0146] In certain embodiments, the subject is a mammal.

[0147] In certain embodiments, the subject is a human.

[0148] definition As used in this specification and the appended claims, unless intended to the contrary, the following terms have the meanings indicated below.

[0149] chemical definition Definitions of certain functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0150] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as 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 a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures 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 the desired isomer can 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 Optical Resolutions p. 268 (E.F. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0151] The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0152] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to 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 , C3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0153] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present disclosure. In describing the present disclosure, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise stated. As described herein, it is also understood that any of the moieties defined below can be substituted with various substituents, and that each definition is intended to include such substituted moieties within their scope as set forth below. Unless otherwise stated, the term "substituted" is defined as set forth below. It should be further understood that, as used herein, the terms "group" and "radical" can be considered interchangeable. The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. By way of example, "an analog" means one analog or more than one analog.

[0154] "Alkyl," as used herein, refers to the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("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 1-7In 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, the alkyl group has one carbon atom ("C alkyl"). 1-6 Examples 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-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 It is alkyl. Common abbreviations for alkyl include Me(-CH), Et(-CHCH), i-Pr(-CH(CH)), n-Pr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0155] As used herein, "alkylene" refers to an alkyl group in which two hydrogens have been removed to provide a divalent radical. When a range or number of carbons is provided for a particular "alkylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. An "alkenylene" group can be substituted with one or more substituents described herein or can be unsubstituted. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. For example, exemplary substituted divalent alkylene groups 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)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0156] "Alkenyl," as used herein, refers to the radical of a straight-chain or branched hydrocarbon group having 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) ("C 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 2-8In 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 two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., 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 aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0157] As used herein, "alkenylene" refers to an alkenyl group in which two hydrogens have been removed to provide a divalent radical. 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 linear divalent carbon chain. An "alkenylene" group can be substituted with one or more substituents described herein or can be unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH-, -CH-CH=CH-). For example, exemplary substituted 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.

[0158] "Alkynyl," as used herein, refers to the radical of a straight-chain or branched hydrocarbon group having 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) ("C 2-20 In certain embodiments, alkynyl groups have 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 ("C2-6 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 two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2-4 Examples 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 alkenyl groups include the aforementioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0159] As used herein, "alkynylene" refers to a straight-chain alkynyl group in which two hydrogens have been removed to provide a divalent radical. 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 a straight-chain divalent carbon chain. An "alkynylene" group can be substituted or unsubstituted with one or more substituents described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0160] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the 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 having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("C 1-10 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("C 1-9 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("C 1-8 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("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 1-6 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("C 1-5 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms ("C 1-4 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("C 1-3 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("C 1-2In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("C heteroalkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("C heteroalkyl"). 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents (a "substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted C 1-10 In certain embodiments, the heteroalkyl group is a substituted C 1-10 It is heteroalkyl.

[0161] The term "heteroalkenyl," as used herein, 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), where one or more heteroatoms are inserted between adjacent carbon atoms in a 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 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-10 In certain embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-9 In certain embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-8 In certain embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-7In certain embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("C 2-6 In certain embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2-5 In certain embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2-4 In certain embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("C 2-3 In certain embodiments, heteroalkenyl groups have 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, the heteroalkenyl group is a substituted C 2-10 It is heteroalkenyl.

[0162] The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, which further comprises 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 in 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 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-10In certain embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-9 In certain embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-8 In certain embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-7 In certain embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("C 2-6 In certain embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2-5 In certain embodiments, heteroalkynyl groups have 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 one heteroatom ("C 2-3 In certain embodiments, heteroalkynyl groups have 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 with one or more substituents (a "substituted heteroalkynyl"). In certain embodiments, a heteroalkynyl group is an unsubstituted C 2-10 In certain embodiments, the heteroalkynyl group is a substituted C 2-10 It is heteroalkynyl.

[0163] Analogous to "alkylene," "alkenylene," and "alkynylene" defined above, "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" as used herein refer to the divalent radical of a heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons 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 carbons in a linear divalent chain. "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0164] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In certain embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In certain embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl", e.g., anthracyl).

[0165] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, 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, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular 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 with one or more substituents (a "substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0166] "Fused aryl" refers to an aryl that shares two of its ring carbons with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0167] "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.

[0168] "Heteroaryl" refers to the 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 a cyclic array) having ring carbon atoms and 1 to 8 ring heteroatoms provided within the aromatic ring system, each heteroatom 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 at a carbon atom or a nitrogen atom, if valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings.

[0169] "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. In such cases, if substitution is indicated, unless otherwise specified, the substitution may occur on either the heteroaryl or one or more carbocyclyl or heterocyclyl groups. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, in which case the point of attachment is on either the aryl or heteroaryl ring, and in such cases the number of ring members refers to the total number of ring members in the fused (aryl / heteroaryl) ring system. In such cases, if substitution is indicated, unless otherwise specified, the substitution may occur on either the heteroaryl or one or more aryl groups. The point of attachment of bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.) can be at either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring that does not contain the heteroatom (e.g., 5-indolyl).

[0170] In certain embodiments, 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, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In certain embodiments, 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, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 9-membered heteroaryl"). In certain embodiments, 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, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In certain embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In certain embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0171] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0172] "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.

[0173] "Carbocyclyl" refers to a non-aromatic ring system with 3 to 12 ring carbon atoms ("C 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 3-6 Carbocyclyl includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 Carbocyclyls include the aforementioned C 3-6 Exemplary C groups include, but are not limited to, carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 Carbocyclyls include the aforementioned C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like, but are not limited to these.

[0174] In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 12 ring carbon atoms ("C 3-12 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("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 include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl include the aforementioned C 5-6 Includes cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl include the aforementioned C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 It is cycloalkyl.

[0175] As the above examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, e.g., a polycyclic system ("polycyclic carbocyclyl"), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, in which case the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. In such cases, if substitution is indicated, unless otherwise specified, the substitution can occur on either the carbocyclyl or the one or more aryl or heteroaryl groups. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 It is a carbocyclyl.

[0176] "Fused carbocyclyl" refers to a ring system in which a carbocyclyl ring, as defined above, is fused with one or more carbocyclyl rings. In such cases, the number of carbons indicates the total number of carbons in the entire fused ring system. If substitution is indicated, unless otherwise specified, the substitution can occur on the entire fused ring system. "Fused carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more heteroaryl or aryl rings, in which case the point of attachment is on the carbocyclyl ring. In such cases, the number of carbons continues to indicate the number of carbons in the carbocyclyl ring. If substitution is indicated, unless otherwise specified, the substitution can occur on either the carbocyclyl ring or one or more of the heteroaryl or aryl rings. "Fused carbocyclyl" further includes ring systems in which a fused carbocyclyl, as defined above, further forms a spiro structure with one or more heterocyclyls or carbocyclyls, in which case the point of attachment is on the fused carbocyclyl. In such cases, the number of carbons continues to indicate the number of carbons in the fused carbocyclyl. If substitution is indicated in such cases, unless otherwise specified, the substitution can occur on either the fused carbocyclyl or on one or more of the heterocyclyl or carbocyclyl.

[0177] "Heterocyclyl" refers to the radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 12-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, if valence permits. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0178] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "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 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "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 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "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 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In certain embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0179] As the above examples illustrate, in certain embodiments, heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or can be fused, bridged, or spiro ring systems, e.g., polycyclic systems ("polycyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl or the heterocyclyl ring; in such cases, the number of ring members indicates the total number of ring members in the entire ring system. In such cases, if substitution is indicated, unless otherwise specified, the substitution can occur on either the heterocyclyl or one or more carbocyclyl groups. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, in which case the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. In such cases, if substitution is indicated, unless otherwise specified, the substitution can occur on either the heterocyclyl or the one or more aryl or heteroaryl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0180] "Fused heterocyclyl" refers to a ring system in which a heterocyclyl, as defined above, is fused with one or more heterocyclyls or carbocyclyls, in which case the point of attachment is on either the heterocyclyl or one or more heterocyclyls or carbocyclyls. In such cases, the number of ring members refers to the total number of ring members throughout the ring system. In such cases, if substitution is indicated, unless otherwise specified, substitution can occur throughout the ring system. "Fused heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl rings, in which case the point of attachment is on the heterocyclyl ring, in which case the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. In such cases, if substitution is indicated, unless otherwise specified, substitution can occur on either the heterocyclyl or one or more aryl or heteroaryl rings. "Fused heterocyclyl" further includes ring systems in which the fused heterocyclyl defined above further forms a spiro structure with one or more heterocyclyls or carbocyclyls, in which case the point of attachment is on the fused heterocyclyl. In such cases, the number of ring members continues to indicate the number of members of the fused heterocyclyl. In such cases, if substitution is indicated, unless otherwise specified, the substitution can occur on either the fused heterocyclyl or one or more heterocyclyls or carbocyclyls of which the fused heterocyclyl forms a spiro structure.

[0181] "Hetero," when used to describe a compound or a group present in a compound, means that one or more carbon atoms of the compound or group are replaced, where valences allow, by nitrogen, oxygen, sulfur, boron, phosphorus, and silicon heteroatoms. Hetero can apply to any of the above hydrocarbyl groups having 1 to 5, especially 1 to 3, heteroatoms.

[0182] "Alkoxy," as used herein, refers to the group --OR, where R is alkyl as defined herein. 1-6 Alkoxy refers to the group -OR, where each R is a C as defined herein. 1-6 An exemplary C 1-6Alkyl is as defined above.

[0183] "Alkylamino," as used herein, refers to the group -NHR or -NR2, where each R is independently alkyl, as defined herein. 1-6 "Alkylamino" refers to the group -NHR or -NR, where each R is independently a C alkyl group as defined herein. 1-6 An exemplary C 1-6 Alkyl is as defined above.

[0184] "Azide" refers to the radical -N3.

[0185] "Amino" refers to the radical -NH2.

[0186] "Oxo" refers to =O. When a group or atom other than aryl or heteroaryl is substituted with oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with oxo, it is meant to indicate that a resonance / tautomeric structure with the heteroatom provides a carbon atom that can form two geminal radicals, thereby forming a double bond with an oxygen radical.

[0187] "Thioketo" refers to the group ═S.

[0188] "Carboxy" refers to the radical -C(=O)OH.

[0189] "Cyano" refers to the radical -CN.

[0190] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0191] "Hydroxy" refers to the radical --OH.

[0192] "Nitro" refers to the radical -NO2.

[0193] "Protecting group," as used herein, is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction during which the unmodified functional group does not remain or may interfere with the chemical reaction. Common functional groups that need to be protected include, but are not limited to, hydroxyl, amino, thiol, and carboxylic acid. Accordingly, protecting groups are referred to as hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

[0194] Common types of hydroxyl protecting groups include, but are not limited to, ethers (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), t-butyl, triphenylmethyl (trityl), allyl, and benzyl ethers (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-isopropylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalate (Piv) and benzoate (benzoate; Bz)).

[0195] Common types of amino-protecting groups include, but are not limited to, carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzylcarbonyl (Moz or MeOZ), 2,2,2-trichloroethoxycarbonyl (Troc), 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-alkylnitrobenzenesulfonamide (Nosyl), and 2-nitrophenylsulfenyl (Nps)).

[0196] Common types of thiol protecting groups include, but are not limited to, sulfides (e.g., p-methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (trityl)).

[0197] Common types of carboxylic acid protecting groups include, but are not limited to, esters (e.g., methyl esters, triphenylmethyl (trityl), t-butyl esters, benzyl esters (Bn), St-butyl esters, silyl esters, and orthoesters) and oxazolines.

[0198] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The present disclosure is not intended to be limited in any way by the exemplary enumeration of substituents above.

[0199] Other definitions "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of a federal or state government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0200] "Pharmaceutically acceptable salts" refers to salts of 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 can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or salts formed with 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, camphorsulfonic acid, 4-methyl or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the compound possesses basic functionality, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0201] 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)).

[0202] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the present disclosure is administered.

[0203] A "pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to yield a parent molecule of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONR, and -CHOR radicals, where R, at each occurrence, is independently selected from alkyl, trialkylsilyl, carbocyclic aryl, or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy, or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

[0204] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound.

[0205] Because prodrugs can enhance many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), compounds of the present disclosure (e.g., compounds of any of the formulas disclosed herein or any individual compound), or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, may be delivered in prodrug form. Accordingly, the present disclosure is intended to cover prodrugs of compounds of the present disclosure (e.g., compounds of any of the formulas disclosed herein or any individual compound), or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, methods of delivering the same, and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present disclosure in vivo when such prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present disclosure in which a hydroxyl or amino group is bonded to any group that is cleaved to form the free hydroxyl or free amino group, respectively, when the prodrug of the present disclosure is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of each of the formulas described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof.

[0206] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female 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, e.g., 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.

[0207] An "effective amount" means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. The "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. A "therapeutically effective amount" refers to an amount effective for therapeutic treatment. A "prophylactically effective amount" refers to an amount effective for prophylactic treatment.

[0208] "Preventing," "prevention," or "prophylactic treatment" refers to reducing the risk of contracting or developing a disease or disorder (i.e., preventing at least one clinical symptom of a disease from developing in a subject who has not yet been exposed to a pathogen, or in a subject who has not developed the disease but is predisposed to the disease).

[0209] The term "prophylaxis" is related to "prevention" and refers to a measure or procedure aimed at preventing, rather than treating or curing, a disease. Non-limiting examples of prophylactic measures include administration of a vaccine, administration of low molecular weight heparin to hospitalized patients who are at risk of thrombosis due to immobilization, and administration of an antimalarial agent such as chloroquine before visiting a geographic area where malaria is endemic or where there is an increased risk of contracting malaria.

[0210] "Treating" or "treatment" or "therapeutic treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing at least one symptom, degree, or severity of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that is not discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0211] The term "about" when referring to a numerical value or numerical range means that the stated numerical value or numerical range is approximate within experimental variability (or within statistical experimental error), and thus the numerical value or numerical range may, in some cases, vary by 1% to 15% of the stated numerical value or numerical range. In certain embodiments, a numerical value or numerical range may vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range. In certain embodiments, a numerical value or numerical range may vary by 1%, 2%, 3%, 4%, or 5% of the stated number or numerical range. In certain embodiments, a numerical value or numerical range may vary by 1%, 2%, or 3% of the stated number or numerical range.

[0212] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other particular embodiments, embodiments, such as any composition of matter, composition of matter, method, or process described herein, "consist" or "consist essentially of" the recited features.

[0213] The term "and / or," as used in the specification and claims, should be understood to mean "either or both" of the elements so conjunctivated, i.e., elements that are present conjunctively in some cases and disjunctively in other cases. Multiple elements listed with "and / or," i.e., "one or more" of the elements so conjunctivated, should be interpreted in the same manner. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or unrelated to the elements specifically identified. 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, for example, in one embodiment refer to only A (optionally including elements other than B), in another embodiment refer to only B (optionally including elements other than A), and in yet another embodiment refer to both A and B (optionally including other elements).

[0214] As used in this specification and the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when distinguishing items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one of, but also including more than one of, several elements or a list of elements, and optionally including additional unlisted items. Conversely, clearly indicated terms such as "only one of" or "exactly one of," or "consisting of," when used in the claims, only refer to the inclusion of exactly one element of several elements or a list of elements. In general, the term "or," as used herein, should be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") only when preceded by terms of exclusivity such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" should have its ordinary meaning as used in the field of patent law.

[0215] As used in this specification and claims, the phrase "at least one," in reference 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 and every element specifically listed in the list of elements, and does not exclude any combinations of elements in the list of elements. This definition also allows that elements other than the specifically identified elements in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or unrelated to the specifically 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") can refer, for example, to at least one optionally including more than one A (optionally including elements other than B) in the absence of B in one embodiment; to at least one optionally including more than one B (optionally including elements other than A) in the absence of A in another embodiment; to at least one optionally including more than one A and at least one optionally including more than one B (optionally including other elements) in yet another embodiment.

[0216] While the present teachings are described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0217] While various embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining the results and / or obtaining one or more advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the embodiments of the present invention described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application(s) for which the teachings of the present invention are used. Those skilled in the art will recognize many equivalents to the specific embodiments of the present invention described herein. Accordingly, it should be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, embodiments of the present invention may be practiced other than as specifically described and claimed. Inventive embodiments of the present disclosure relate to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the inventive scope of the present disclosure, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0218] The claims should not be construed as limited to the described order or elements unless expressly stated to that effect. It should be understood that various changes in form and detail can be made by those skilled in the art without departing from the spirit and scope of the appended claims. All embodiments within the spirit and scope of the following claims and their equivalents are claimed. [Example]

[0219] 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 are not to be construed as limiting the scope thereof in any way.

[0220] I. Synthesis and Characterization Scheme A [ka] Synthesis of 3: To a stirred solution of 1H-methyl pyrrole-2-carboxylate (1) (10 g, 79.92 mmol) in DMF (120 ml) was added sodium hydride (60%, 5.51 g, 239.76 mmol) in small portions at 0 °C, and the reaction mixture was stirred at the same temperature for 1 hour. Then, O-(2,4-dinitrophenyl)hydroxylamine (2) (23.87 g, 119.88 mmol) in DMF (30 ml) was added dropwise at 0 °C, and the reaction mixture was stirred at the same temperature for 3 hours. After completion of the reaction, 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 the crude product. The crude residue was purified by Combiflash column purification (SiO2, 120 g, 5% EtOAc / hexane) to give methyl 1-azanylpyrrole-2-carboxylate (3) (11 g, 78.49 mmol, 98.21% yield) as a pale yellow viscous liquid.

[0221] 1H NMR (400 MHz, 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.

[0222] LCMS: LC / MS was performed but the compound did not ionize and therefore is not included in the analytical trace.

[0223] Synthesis of 5: To a stirred solution of methyl 1-azanylpyrrole-2-carboxylate (3) (5 g, 35.68 mmol) in methanol (200 mL) was added ethyl 3-oxidanylidenebutanoate (4) (5.57 g, 42.81 mmol, 5.44 mL) followed by acetic acid (50 mL) at 25 °C, and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure, and the crude was diluted with saturated aqueous NaHCO. 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 give methyl 1-[[(E)-3-ethoxy-1-methyl-3-oxidanylidene-prop-1-enyl]amino]pyrrole-2-carboxylate (5) (8 g, crude) as a yellow oil, which was carried on to the next step without further purification.

[0224] 1 HNMR: Not recorded

[0225] LCMS: Column—Xbridge C18 (50×4.6 mm, 5 μm, 130 A), (Mobile phase: 90% [10 mM NHOAc / water] and 10% [CHCN] in 1.5 min to 70% [10 mM NHOAc / water] and 30% [CHCN], then 10% [10 mM NHOAc / water] and 90% [CHCN] in 3.0 min, maintaining this mobile phase composition until 4.0 min, and finally returning to initial conditions at 5.0 min). Flow rate=1.2 ml / min. Rt=3.17 and 3.40 (5 min run), MS calculated: 252.2; MS observed: 253.2 (M+H).

[0226] Synthesis of 6: To a stirred solution of methyl 1-[[(E)-3-ethoxy-1-methyl-3-oxidanylidene-prop-1-enyl]amino]pyrrole-2-carboxylate (5) (8 g, 31.71 mmol) in benzene (80 ml) was slowly added boron trifluoride diethyl 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 an additional 17 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic portions were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by Combiflash column chromatography (SiO; EtOAc:Hexanes 70%) to give methyl 2-methyl-4-oxidanyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (6) (2.5 g, 12.12 mmol, 38.23% yield) as an off-white solid.

[0227] 1H NMR (400MHz, DMSO-d6):11.72(s, 1H),7.28(d, J=4.76 Hz,1H),6.61(d, J=4.8Hz, 1H),6.19 (s,1H),3.78(s, 3H),2.39(s, 3H)ppm.

[0228] LCMS: Column—Xbridge C18 (50×4.6 mm, 5 μm, 130 A), (Mobile phase: 90% [10 mM NHOAc / water] and 10% [CHCN] in 1.5 min to 70% [10 mM NHOAc / water] and 30% [CHCN], then 10% [10 mM NHOAc / water] and 90% [CHCN] in 3.0 min, maintaining this mobile phase composition until 4.0 min, and finally returning to initial conditions at 5.0 min). Flow rate=1.2 ml / min. Rt=1.48 MS calculated: 206, MS found: 207 (M+H).

[0229] Synthesis of 7: A mixture of phosphorus oxychloride (37.18 g, 242.49 mmol, 22.7 mL) and methyl 2-methyl-4-oxidanyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (6) (2.5 g, 12.12 mmol) was heated at 70 °C for 5 h. After completion of the reaction, the volatiles were removed under reduced pressure. The crude product was purified by CombiFlash column chromatography (SiO; 40 g, 10% EtOAc:hexanes) to give methyl 4-chloranyl-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (7) (1.9 g, 8.46 mmol, 69.76% yield) as an off-white solid.

[0230] 1H NMR (400 MHz, 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.

[0231] LCMS: Column—Xbridge C18 (50×4.6 mm, 5 μm, 130 A), (Mobile phase: 90% [10 mM NHOAc / water] and 10% [CHCN] in 1.5 min to 70% [10 mM NHOAc / water] and 30% [CHCN], then 10% [10 mM NHOAc / water] and 90% [CHCN] in 3.0 min, maintaining this mobile phase composition until 4.0 min, and finally returning to initial conditions at 5.0 min). Flow rate=1.2 ml / min. Purity was 99.81%, Rt=3.38 min, MS calculated: 224; MS found: 224.8 (M+H).

[0232] Synthesis of 9: To a stirred mixture of methyl 4-chloranyl-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (1.9 g, 8.46 mmol) (7) and (5-chloranyl-2-oxidanyl-phenyl)boronic acid (8) (1.75 g, 10.15 mmol) in water (2 mL) and dioxane (20 mL), potassium carbonate (4.09 g, 29.60 mmol) was added at 25 °C, and the reaction mixture was degassed with argon for 30 minutes. Pd(dppf)Cl (1.86 g, 2.54 mmol) was added, and the reaction mixture was again degassed with argon for 10 minutes. The reaction mixture was stirred at 90 °C for 5 hours. After completion of the reaction, the reaction mixture was filtered through a Celite bed and washed with EtOAc (2 × 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by Combiflash column chromatography (SiO; 12 g, eluent 50% EtOAc / hexane) to give methyl 4-(5-chloranyl-2-oxidanyl-phenyl)-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (9) (2.1 g, 6.63 mmol, 78.39% yield) as a pale yellow solid.

[0233] 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.

[0234] LCMS: Column—Xbridge C18 (50×4.6 mm, 5 μm, 130 A), (Mobile phase: 90% [10 mM NHOAc / water] and 10% [CHCN] in 1.5 min to 70% [10 mM NHOAc / water] and 30% [CHCN], then 10% [10 mM NHOAc / water] and 90% [CHCN] in 3.0 min, maintaining this mobile phase composition until 4.0 min, and finally returning to initial conditions at 5.0 min). Flow rate=1.2 ml / min. Purity was 97.11%, Rt=3.36 min, MS calculated: 316; MS found: 315.2 (MH).

[0235] Synthesis of 10: To a stirred solution of methyl 4-(5-chloranyl-2-oxidanyl-phenyl)-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (9) (5 g, 15.79 mmol) in acetone (50 ml), 1,2-dibromoethane (29.66 g, 157.86 mmol, 13.60 ml) was added followed by potassium carbonate (7.64 g, 55.25 mmol) at 25° C. under nitrogen, followed by stirring at 70° C. for 12 hours. After completion of the reaction, the insoluble material was filtered through a sintered funnel, and the filtrate was concentrated under reduced pressure. The crude material was purified by Combiflash column chromatography (SiO; 40 g, 70% EtOAc / hexanes) to give methyl 4-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (10) (3.5 g, 8.18 mmol, 51.81% yield, 99% purity) as an off-white solid.

[0236] 1H NMR (400 MHz, 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.

[0237] LCMS: Column - Xbridge C18 (3 x 50 mm, 3.5 u), (Mobile phase: 95% [5 mM NHOAc / water] and 5% [5 mM NHOAc / ACN:water (90:10)] maintained at 0.75 min, then 70% [5 mM NHOAc / water] and 30% [5 mM NHOAc / ACN:water (90:10)] at 1.00 min, finally 2% [5 mM NHOAc / water] and 98% [5 mM NHOAc / ACN:water (90:10)] at 2.00 min, this mobile phase composition maintained until 2.50 min, finally returned to initial conditions at 2.75 min, this composition maintained until 3.0 min). Flow rate - 1.20 ml / min. The purity was 98.77%, Rt=2.17 min, MS calculated: 422; MS found: 423.1 (M+H).

[0238] Scheme B [ka] Synthesis of 3(3) (compound 26) 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 minutes. To this, methyl 4-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (2) (709 mg, 1.67 mmol) was added at the same temperature, and the reaction mixture was stirred at 50 °C for 17 hours. After completion of the reaction, 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 NaSO, 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 the impure solid (450 mg, 862.08 μmol) in a mixture of THF (8 mL), methanol (4 mL), and HO (2 mL) was added lithium hydroxide monohydrate (181 mg, 4.31 mmol) at 25°C, and the mixture was stirred at 25°C for 2 h. After completion of the reaction (as determined 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 NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give 4-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-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.

[0239] 1H NMR (400 MHz, 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).

[0240] Synthesis of 4(4) (compound 27) To a stirred solution of 4-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-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), DMAP (90 mg, 738.24 μmol) was added, followed by EDC.HCl (57 mg, 295.29 μmol) at 25° C. The reaction mixture was stirred at the same temperature for 30 minutes. Methanesulfonamide (70 mg, 738.24 μmol) was added at 25° C., and the reaction mixture was stirred at 25° C. for 16 hours. After completion of the reaction, the reaction mixture was diluted with DCM, washed with water, brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by RP preparative HPLC to give 4-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-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) (44 mg, 74.63 μmol, 50.55% yield, 99.24% purity) as a white solid.

[0241] 1H NMR (400 MHz, DMSO, at 100°C): 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.

[0242] Scheme C [ka] Synthesis of 3: 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 hours. After consumption of the starting material (as judged by TLC), the solvent was evaporated and the reaction mixture was dissolved in THF (50 mL). Methyl 4-azanylthiophene-3-carboxylate (1) (7 g, 44.53 mmol) was then added to the reaction mixture, and heating at 90° C. was continued for 2 hours. After consumption of the starting material, 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 (SiO, 120 g, 40% EtOAc / hexanes) afforded methyl 4-[1-[2,2-di(methyl)-4,6-bis(oxidanylidene)-1,3-dioxan-5-ylidene]ethylamino]thiophene-3-carboxylate (3) (2 g, 6.15 mmol, 14%) as a yellow liquid.

[0243] 1H NMR(400 MHz,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).

[0244] LCMS: LC / MS was performed but the compound did not ionize and therefore is not included in the analytical trace.

[0245] Synthesis of 4: A stirred solution of methyl 4-[1-[2,2-di(methyl)-4,6-bis(oxidanylidene)-1,3-dioxan-5-ylidene]ethylamino]thiophene-3-carboxylate (3) (20 g, 61.47 mmol) in Dowtham (19.94 g, 61.47 mmol, 40 mL) was heated at 230 °C for 2 h. After completion of the starting material (as judged by TLC), the volatiles were removed under reduced pressure. The crude material thus obtained was purified by Combiflash chromatography (SiO, 120 g, 100% ethyl acetate) to give methyl 5-methyl-7-oxidanyl-thieno[3,2-b]pyridine-3-carboxylate (4) (6 g, 26.88 mmol, 43.72% yield) as a brown solid.

[0246] 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).

[0247] LCMS: LC / MS was performed but the compound did not ionize and therefore is not included in the analytical trace.

[0248] Synthesis of 5: To a stirred solution of methyl 5-methyl-7-oxidanyl-thieno[3,2-b]pyridine-3-carboxylate (4) (3.5 g, 15.68 mmol) in toluene (50 mL) was added N,N-dimethylaniline (99%) (15.20 g, 125.42 mmol, 15.90 mL) and cooled to 0 °C. POCl (3.60 g, 23.52 mmol) was added to the reaction mixture and heated at 120 °C for 2.5 h. After completion of the starting material (as judged by TLC), the solvent was evaporated under reduced pressure and the crude material thus obtained was purified by Combiflash chromatography (SiO, 120 g, 30% ethyl acetate / hexane) to give methyl 7-chloranyl-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (5) (3.0 g, 12.41 mmol, 79.17% yield) as a white solid.

[0249] 1H NMR (400MHz, DMSO-d6) δ8.93(s,1H), 7.57(s,1H),3.86(s,3H),2.63 (s,3H).

[0250] ESI-MS: m / z calculated 241.0, observed 243.0 (M+2); retention time 3.17 min (5 min run)

[0251] Synthesis of 7: To a stirred solution of methyl 7-chloranyl-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (5) (3.0 g, 12.41 mmol) in dioxane (30 mL) and water (5 mL), (5-chloranyl-2-oxidanyl-phenyl)boronic acid (6) (2.14 g, 12.41 mmol) was added, followed by NaCO (3.95 g, 37.24 mmol) under an argon atmosphere and degassed at 25 °C for 10 minutes. To this solution, Pd(dppf)Cl (907.35 mg, 1.24 mmol) was added and degassed again for 5 minutes. The reaction mixture was then heated at 90 °C for 5 hours. After completion of the reaction (confirmed by LCMS), the reaction mixture was filtered through a Celite bed and concentrated under reduced pressure. The crude material thus obtained was purified by flash column chromatography (SiO, 40 g, 30-35% ethyl acetate / hexane) to give methyl 7-(5-chloranyl-2-oxidanyl-phenyl)-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (7) (1.5 g, 4.49 mmol, 36.20% yield) as an off-white solid.

[0252] 1H NMR (400MHz, DMSO-d6) δ10.26(s, 1H), 8.84(s,1H),7.38(t,J=8.08 Hz 3H),7.05(d,J=8.68 Hz1H),3.87 (s, 3H),2.66 (s, 3H).

[0253] ESI-MS: m / z calculated 333, observed 334 (M+H) + ; hold time 3.32 min (5 min run).

[0254] Synthesis of 9: To a stirred solution of 7-(5-chloranyl-2-oxidanyl-phenyl)-5-methyl-thieno[3,2-b]pyridine-3-pcarboxylate (7) (1.2 g, 3.60 mmol) in acetone (25 mL), anhydrous potassium carbonate (1.49 g, 10.79 mmol, 650.91 μL) was added, followed by 1,2-bis(bromanyl)ethane (8) (5.40 g, 28.76 mmol, 2.48 mL), and the reaction mixture was refluxed at 70 °C for 16 h. After completion of the reaction (as determined solely by LC / MS), the reaction mixture was cooled to 25 °C and filtered. The filtrate was evaporated under reduced pressure. The crude material thus obtained was purified by silica gel column chromatography (SiO; 40 g, 50% EtOAc / hexane) to give methyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (9) (1.3 g, 2.95 mmol, 82.05% yield) as an off-white solid.

[0255] 1H-NMR (400 MHz,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).

[0256] ESI-MS: m / z calculated 440.74; observed 441.8 (M+1); retention time 3.65 min (5 min run).

[0257] Scheme D [ka] Synthesis of 3: To a stirred solution of compound 1,1-di(methyl)ethyl 2-methyl-4-oxidanylidene-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carboxylate (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 minutes. To this was added methyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (1) (2000 mg, 4.54 mmol) at 25° C., and the reaction mixture was stirred at 25° C. for 16 hours. After completion of the reaction (as determined 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 material was purified by silica gel CombiFlash column chromatography (SiO; 40 g, 5% MeOH / DCM) to give methyl 7-[5-chloranyl-2-[2-[6-[1,1-di(methyl)ethoxycarbonyl]-2-methyl-4-oxidanylidene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (3) (1 g, 1.50 mmol, 33.14% yield) as an off-white solid.

[0258] 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),4.31 (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.

[0259] Calculated m / z 624.18, observed (M+1) = 625.0 (RT 3.86).

[0260] Synthesis of 4: To a stirred solution of the compound 7-[5-chloranyl-2-[2-[6-[1,1-di(methyl)ethoxycarbonyl]-2-methyl-4-oxidanylidene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (3) (1000 mg, 1.60 mmol) in DCM (6 mL) was added 4(N)HCl / dioxane (7 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 4 h. After completion of the reaction (as determined 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 a saturated solution of NaHCO. The aqueous layer was extracted twice with 10% MeOH / DCM. The combined organic layers were dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure to give methyl 7-[5-chloranyl-2-[2-(2-methyl-4-oxidanylidene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (4) (700 mg, 1.33 mmol, 83.35% yield) as a white solid, which was used in the next step without further purification.

[0261] Calculated m / z 524.1, observed (M+1) = 525.2 (RT 2.89).

[0262] Synthesis of 5: To a stirred solution of the compound 7-[5-chloranil-2-[2-[2-methyl-4-oxidanylidene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (1) (100 mg, 190.47 μmol) in DCM, 37% formalin (22.86 mg, 761.88 μmol, 61.77 μL) was added at 0° C. The reaction mixture was then stirred at 25° C. for 1 hour, and Na(OAc)BH (201.84 mg, 952.35 μmol) was added to the mixture at 0° C. The reaction mixture was then stirred at 25° C. for an additional 1 hour. After completion of the reaction (as determined solely by LC / MS), the solvent was evaporated under reduced pressure to give the crude material. The crude product thus obtained was purified by (Chromatorex® NH DM1020 (mesh 100-200)-amine silica gel; 12 g, 1% MeOH / DCM) to give the compound 7-[5-chloranil-2-[2-[2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (5) (80 mg, 148.41 μmol, 77.92% yield) as a pale yellow solid.

[0263] Calculated m / z 538.1, observed (M+1) = 539.0 (RT 3.37).

[0264] Synthesis of 6 (compound 29) To a stirred solution of the compound methyl 7-[5-chloranil-2-[2-[2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (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 hours. After completion of the reaction (as determined 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 give pure compound 7-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-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, yield 43.58%, purity 99.87%) as a white solid.

[0265] 1 H NMR-VT(400 MHz, DMSO-d6): δ8.77(s, 1H), 7.55(dd,J=8.80,2.80 Hz,1H),7.42(d,J=2.40 Hz, 1H),7.37(s,1H),7.31(d,J=8.80 Hz,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.

[0266] Synthesis of 7 (compound 28) To a stirred solution of compound 7-[5-chloranil-2-[2-[2,6-di(methyl)-4-oxidanylidene-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 MeSONH (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 250° C. for 20 hours. After completion of the reaction (as determined 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 give pure compound 7-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-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-tris(fluoranyl)acetic acid (7) (compound 28) (65 mg, 89.14 μmol, yield 46.80%, purity 98.21%) as a white solid.

[0267] 1 H NMR(400 MHz, DMSO-d6):δ 12.87 (brs, 1H),8.99 (s,1H),7.57(dd,J=9.2,2.80 Hz,1H),7.45(s,1H),7.43(d,J= 2.4 Hz,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.

[0268] Scheme E [ka] Synthesis of 3: To a stirred solution of methyl 7-[5-chloranil-2-[2-[2-methyl-4-oxidanylidene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (1) (100 mg, 190.47 μmol) in NMP (2 mL) was added KCO (105.14 mg, 761.88 μmol) followed by 2,2,2-tris(fluoranil)ethyl tris(fluoranil)methanesulfonate (2) (53.05 mg, 228.56 μmol, 32.93 μL) at 25 °C, 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, washed with ice-cold water, brine, dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure to afford methyl 7-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-[2,2,2-tris(fluoranyl)ethyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (3) (100 mg, 214.15 μmol, 95% yield) as a pale yellow gum, which was used in the next step without further purification.

[0269] Calculated m / z 606.1, observed (M+1) = 607 (RT 3.85).

[0270] Synthesis of 4 (compound 24) To a stirred solution of the compound methyl 7-[5-chloranil-2-[2-[2-methyl-4-oxidanylidene-6-[2,2,2-tris(fluoranyl)ethyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (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 at 25° C. for 16 hours. After completion of the reaction (as determined 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-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-[2,2,2-tris(fluoranyl)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-tris(fluoranyl)acetic acid (4) (compound 24) (25 mg, 33.15 μmol, 15.48% yield, 93.75% purity) as an off-white sticky solid.

[0271] 1 H NMR(400MHz, DMSO-d6): δ8.79 (s, 1H),7.55 (dd, J=8.80,2.80 Hz, 1H),7.42 (d, J=2.80 Hz,1H),7.39 (s,1H),7.31 (d,J=8.80 Hz, 1H),4.34 (t, J=5.2Hz, 2H),4.1 (t,J=5.2 Hz, 2H),3.45 (s,2H), 3.33(q, J=10 Hz,1H), 2.91 (t,J=5.6, 2H), 2.76(s, 3H), 2.54(s, 4H), 1.79(s, 3H)ppm.

[0272] Synthesis of 5 (compound 25) To a stirred solution of compound 7-[5-chloranil-2-[2-[2-methyl-4-oxidanylidene-6-[2,2,2-tris-(fluoranyl)ethyl]-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 μmol) and MeSONH (33.68 mg, 354.12 μmol) in DCM (4 mL) was added DMAP (34.61 mg, 283.30 μmol) followed by EDC.HCl (54.97 mg, 354.12 μmol) at 0° C., and the reaction mixture was stirred at 25° C. for 16 h. After completion of the reaction (as determined solely by LC / MS), the solvent was evaporated under reduced pressure. The crude product thus obtained was purified by reverse-phase preparative HPLC to give 7-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-[2,2,2-tris(fluoranyl)ethyl]-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-tris(fluoranyl)acetic acid (5) (compound 25) (24 mg, 29.68 μmol, 20.95% yield, 96.96% purity) as an off-white solid.

[0273] 1 H NMR(400MHz, DMSO-d6): δ13.05 (brs, 1H),8.95 (s, 1H),7.59 (dd, J=9.20,2.80 Hz, 1H),7.48 (s,1H),7.45 (d, J=2.80Hz, 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.

[0274] Calculated m / z 569.1, observed value (M+1) = 570.0 (RT 2.68).

[0275] Scheme F [ka] Synthesis of 3: To a degassed solution of methyl 7-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (1) (200 mg, 380.94 μmol) in toluene (5 mL), 4-bromanyl-2-methoxy-pyridine (2) (107.44 mg, 571.41 μmol) was added, followed by CsCO (496.74 mg, 1.52 mmol) at 25° C. To this was added RuPhos (17.75 mg, 38.09 μmol) followed by RuPhosPdG (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 completion of the reaction (as determined 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 layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by silica gel CombiFlash column chromatography (SiO2; 12 g, 4% MeOH / DCM) to give methyl 7-[5-chloranyl-2-[2-[6-(2-methoxy-4-pyridyl)-2-methyl-4-oxidanylidene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (3) (140 mg, 168.32 μmol, 44.19% yield, 76% purity) as a pale yellow solid.

[0276] Calculated m / z 631.08, observed (M+1) = 632.0 (RT 3.24).

[0277] Synthesis of 4 (compound 23) To a stirred solution of the compound 7-[5-chloranil-2-[2-[6-(2-methoxy-4-pyridyl)-2-methyl-4-oxidanylidene-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (3) (140 mg, 168.32 μmol) in a mixture of THF (4.00 mL) and water (999.77 μL) was added LiOH.HO (28.25 mg, 673.28 μmol, 18.71 μL) at 25° C., and the reaction mixture was stirred for 16 hours at 25° C. After completion of the reaction (as determined 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-chloranyl-2-[2-[6-(2-methoxy-4-pyridyl)-2-methyl-4-oxidanylidene-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-tris(fluoranyl)acetic acid (4) (compound 23) (19 mg, 25.07 μmol, 14.90% yield, 96.62% purity) as a white solid.

[0278] 1 H NMR(400MHz, DMSO-d6): δ8.71 (s, 1H),7.87(d,J=6.8 Hz, 1H),7.56 (dd,J=8.8, 2.0Hz, 1H), 7.42(d,J=2.4 Hz, 1H), 7.39(s,1H), 7.32(d,J=8.8 Hz, 1H), 6.78(d,J=6 Hz, 1H),6.38 (s, 1H),4.38 (t,J=4.8 Hz,2H), 4.25 (s,2H), 4.17(t,J=4.8 Hz,2H), 3.99(s,3H), 3.78(t,J=5.6 Hz, 2H), 2.75(s,3H), 2.64(t,J=5.6 Hz,2H), 1.79 (s,3H)ppm.

[0279] Calculated m / z 617.15, observed value (M-1) = 616.1 (RT 2.37).

[0280] Scheme G [ka] Synthesis of compound 2: To a stirred solution of 4,6-bis(chloranil)-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) at 25 °C, and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to 25 °C. Volatiles were removed under reduced pressure. The crude product was purified by CombiFlash column chromatography (SiO, 40 g, 4% EtOAc / hexane) to give 4,6-bis(chloranil)-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidine (2) (3.1 g, 13.19 mmol, 50.38% yield) as a white solid.

[0281] LC-MS: 235.1 (M+H).

[0282] 1H-NMR (400 MHz, DMSO-d6): δ6.23(s,1H), 4.16-4.22(m,2H), 4.00-4.06(m,2H), 2.60(s,3H) ppm.

[0283] Synthesis of compound 3: 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) under an argon atmosphere at 0° C., and the reaction mixture was stirred at 25° C. for 30 minutes. To this was added 4,6-bis(chloranil)-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidine (2) (3.1 g, 13.19 mmol) in THF (5 mL) at 0° C., and the reaction mixture was stirred at 25° C. for 2 hours. After completion of the reaction (as judged by LC / MS and TLC), the reaction mixture was quenched with ice-cold water, extracted with EtOAc, and the combined organics were washed with ice-cold water, brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (SiO; 230–400 mesh, 40 g, 4% EtOAc / hexanes) to give 4-chloranyl-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.

[0284] MS calculated: 306.1; MS found: 307.1 (M+H).

[0285] 1H NMR (400 MHz, 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

[0286] Synthesis of compound 4: To a stirred solution of 4-chloranyl-5-(1,3-dioxolan-2-yl)-2-methyl-6-(phenylmethoxy)pyrimidine (3) (2 g, 6.52 mmol) in acetone (8 mL) was added I2 (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 material thus obtained was purified by flash column chromatography (SiO2, 230-400 mesh, 20% EtOAc / hexanes) to give 4-chloranyl-2-methyl-6-(phenylmethoxy)pyrimidine-5-carbaldehyde (4) (1.5 g, 5.71 mmol, 87.58% yield) as a colorless sticky gum.

[0287] LC-MS: 263.3 (M+H)

[0288] 1H-NMR (400 MHz, 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

[0289] Synthesis of compound 6: To a stirred solution of 4-chloranil-2-methyl-6-(phenylmethoxy)pyrimidine-5-carbaldehyde (4) (1.7 g, 6.47 mmol) in DCM (10.40 mL) was added 2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxyethanamine (5) (1.36 g, 7.77 mmol, 1.60 mL) and a catalytic amount of AcOH at 25° C., and the reaction mixture was stirred at 25° C. for 30 minutes. To this reaction mixture was added sodium triacetoxyborohydride (5.49 g, 25.89 mmol) in small portions at 0° C., and stirring was continued at 25° C. for 16 hours. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude material thus obtained was purified by Combiflash column chromatography (SiO; 12 g, 30% EtOAc / hexane) to give N-[[4-chloranyl-2-methyl-6-(phenylmethoxy)pyrimidin-5-yl]methyl]-2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxy-ethanamine (6) (2 g, 4.74 mmol, 73.23% yield) as an off-white solid.

[0290] LC-MS: 421.3 (M+H)

[0291] 1H-NMR (400 MHz, 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)

[0292] Synthesis of compound 7: To a stirred solution of N-[[4-chloranyl-2-methyl-6-(phenylmethoxy)pyrimidin-5-yl]methyl]-2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxy-ethanamine (6) (2 g, 4.74 mmol) in DCM (10.00 mL) was added HCHO (1.61 g, 47.39 mmol, 1.98 mL) and a catalytic amount of AcOH at 25° C., and the reaction mixture was stirred at 25° C. for 30 minutes. To this reaction mixture was added sodium triacetoxyborohydride (5.02 g, 23.69 mmol) in small portions at 0° C., and stirring was continued at 25° C. for 3 hours. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude material thus obtained was purified by Combiflash column chromatography (SiO; 12 g, 30% EtOAc / hexane) to give N-[[4-chloranyl-2-methyl-6-(phenylmethoxy)pyrimidin-5-yl]methyl]-2-[1,1-di(methyl)ethyl-di(methyl)silyl]oxy-N-methyl-ethanamine (7) (980 mg, 2.25 mmol, 47.42% yield) as an off-white solid.

[0293] LC-MS: 436.3 (M+H)

[0294] 1H-NMR (400 MHz, DMSO-d6): δ7.46 (d, J= 8Hz, 2H), 7.40-7.34 (m, 3H), 5.43 (s, 2H), 3.60 (t, J= 12 Hz, 2H), 3.54 (s, 2H), 3.29 (t, J= 12 Hz, 2H), 2.50 (s, 3H), 2.16 (s, 3H), 0.85 (s, 9H), -0.034 (s, 6H).

[0295] Synthesis of compound 8: To a stirred solution of N-[[4-chloranyl-2-methyl-6-(phenylmethoxy)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) was added TBAF (2.52 g, 9.63 mmol, 2.79 mL, 1 M in THF) at 0° C., and the reaction mixture was stirred for 6 h at 25° C. 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, and the combined organics were washed with ice-cold water, brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by Combiflash column chromatography (SiO; 12 g, 40 g, 70% EtOAc / hexanes) to give 2-[[4-chloranyl-2-methyl-6-(phenylmethoxy)pyrimidin-5-yl]methyl-methyl-amino]ethanol (8) (800 mg, 2.49 mmol, 77.43% yield) as an off-white solid.

[0296] LC-MS: 321.6 (M+H)

[0297] 1H-NMR (400 MHz, DMSO-d6): δ7.48 (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).

[0298] Synthesis of compound 9: To a stirred solution of 2-[[4-chloranil-2-methyl-6-(phenylmethoxy)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 for 1 h at 25 °C. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure, and the crude material thus obtained was purified by CombiFlash column chromatography (SiO; 12 g, 40 g, 60% EtOAc / hexane) to give 2,6-di(methyl)-4-(phenylmethoxy)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepine (350 mg, 1.23 mmol, 49.34% yield) as an off-white solid.

[0299] LC-MS: 286.0 (M+H)

[0300] 1H NMR (400 MHz, 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

[0301] Synthesis of compound 10: To a stirred solution of 2,6-di(methyl)-4-(phenylmethoxy)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepane (9) (350 mg, 1.23 mmol) in MeOH (5 mL) was added 10% wet palladium on carbon (130.54 mg, 1.23 mmol), and the reaction mixture was degassed with argon for 30 minutes. The reaction mixture was stirred at 25 °C under a positive pressure of H for 3 hours. After completion of the reaction, the catalyst was filtered through a sintered funnel. The filtrate was removed under reduced pressure and the crude material thus obtained was purified by Combiflash column chromatography (SiO; 4 g, 40 g, 50% EtOAc / hexane) to give 2,6-di(methyl)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepin-4-ol (10) (210 mg, 1.08 mmol, 87.70% yield) as a white solid.

[0302] LC-MS: 196.2 (M+H)

[0303] 1H NMR (400 MHz, 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

[0304] Synthesis of compound 12: To a stirred solution of 2,6-di(methyl)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepin-4-ol (170 mg, 870.82 μmol) (10) in DMF (3 mL) was added anhydrous potassium carbonate 99% (361.07 mg, 2.61 mmol, 157.67 μL) followed by methyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (11) (460.57 mg, 1.04 mmol) at 25 °C, 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 material was purified by CombiFlash column chromatography (SiO2; 12 g, 40 g, 60% EtOAc / Hexanes) to give methyl 7-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (12) (110 mg, 19%). 8.18 μmol, 22.76% yield), and methyl 7-[5-chloranil-2-[2-[[2,6-di(methyl)-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepin-4-yl]oxy]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (13) (117 mg, 210.79 μmol, 24.21% yield) as an off-white solid.

[0305] LC-MS: 556.3 (M+H)

[0306] 1H-NMR (400 MHz, DMSO-d6):δ8.75 (s, 1H), 7.54 (d, J= 4 Hz, 1H), 7.41 (s, 1H), 7.27 (t, J= 12 Hz, 2H), 4.26 (d, J= 8 Hz, 2H), 4.17 (s, 2H), 4.03 (d, J= 8 Hz, 4H), 3.88 (s, 3H), 3.45 (s, 2H), 2.76 (s, 2H), 1.55 (s, 3H), 1.23 (s, 3H).

[0307] Synthesis of 13 (compound 30) To a stirred solution of methyl 7-[5-chloranil-2-[2-[2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (12) (110 mg, 198.18 μmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (98%) (24.95 mg, 594.55 μmol, 16.52 μL) at 25° C., and the reaction mixture was stirred for 2 hours at 25° C. After completion of the reaction (as determined 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 give 7-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-pyrimido[5,4-f][1,4]oxazepin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tris(fluorenyl)acetic acid (13) (compound 30) (42 mg, 63.83 μmol, 32.21% yield, 99.55% purity) as a white solid.

[0308] (M+H)=541.1.

[0309] 1H NMR (400 MHz, DMSO-d6) δ8.88 (s, 1H), 7.58 (dd , J= 4 Hz, 4Hz, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.31 (d, J= 8 Hz, 1H), 4.37 (d, J= 16 Hz, 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).

[0310] II. Biological Evaluation Biochemical competitive binding assay The potency of compounds binding to human eIF4E protein was measured using a 384-well time-resolved fluorescence resonance energy transfer (TR-FRET) competitive 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 (Jena Bioscience, NU-827-647N), 2.5 nM europium-conjugated anti-6xHIS antibody (PerkinElmer, AD0402), and various concentrations of compound. The final DMSO concentration was 1%.

[0311] Compounds were prepared in 11-point, 4-fold serial dilutions in DMSO, and 100 nL of diluted compound was transferred to a 384-well assay-ready plate. Recombinant human eIF4E protein at 2x final concentration (8 nM) was preincubated with Eu-anti-6xHIS antibody at 2x final concentration (5 nM) for 5 minutes, after which 5 μL of the protein solution was added to the assay-ready plate. The protein / compound mix was incubated for 15 minutes, after which 5 μL of a solution containing EDA-m7GDP-ATTO-647N probe at 2x final concentration (10 nM) was added. After the subsequent 15-minute incubation, time-resolved fluorescence of the assay plate was measured using a Clariostar Plus microplate reader (BMG Labtech), and TR-FRET values ​​were calculated by using the ratio of the 665 to 620 wavelength signals. After normalization to the mean values ​​of the DMSO control wells and the maximum inhibition control wells, concentration-response data were plotted and IC values ​​were calculated using standard 4-parameter curve fitting (PEI signal). 50 The results of the competitive binding assay are shown in Table E1. [Table 4-1] [Table 4-2]

[0312] Cellular cap-dependent translation inhibition assay The effects of compounds on cellular cap-dependent translation were assessed using a dual luciferase assay (DLA) based on stably integrated Flp-In™-293 (ThermoFisher Scientific, R75007) reporter cells. 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. pcDNA5 / FRT (Invitrogen, V601020) was used to construct the reporter plasmid. Test compounds were prepared in 11-point, 4-fold serial dilutions in DMSO, and 100 nL of diluted compound was transferred to a 384-well assay-ready plate. Reporter cells were seeded into the assay-ready plate at 10,000 cells per well in a volume of 33.5 microliters in DMEM medium supplemented with 10% FBS. After 24 hours of compound treatment, Fluc and Rluc activity were assessed sequentially using the Dual-Glo® Luciferase Assay System (Promega, E2920) according to the manufacturer's instructions. Luminescence was measured using a Clariostar Plus microplate reader (BMG Labtech) or equivalent. For each well, the ratio of Fluc luminescence to Rluc luminescence was calculated. After normalization to the mean values ​​of DMSO and maximum inhibition control wells, concentration-response data were plotted and IC values ​​were calculated using standard 4-parameter curve fitting (PEI signal). 50 The results of the cellular cap-dependent translation dual luciferase inhibition assay (DLA) are summarized in Table E2. [Table 5]

[0313] equivalent As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth.

[0314] While specific embodiments of the present disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art in light of this specification and the claims that follow. The full scope of the present 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. Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. (In the formula, 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 is alkyl, Each R Ｌ１ and each R Ｌ２ are independently hydrogen, halogen, —CN, —NO ２ , —OH, —NH ２ , C １－６ Alkyl, C １－６ Alkoxy, or C １－６ alkylamino, wherein said alkyl, alkoxy, or alkylamino 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, —NO ２ , —OH, —NH ２ , 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 said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; r and s are independently, where valences allow, integers selected from 0 to 6; R ２ is halogen, -CN, -NO ２ , —OH, —NH ２ , 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) ２ R ａ , -N(S(=O) ２ R ａ ) ２ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ NR ｃ R ｄ , -C(=O)OR ｂ , —C(═O)NR ｃ S (= O) ２ R ａ or C(═O)NR ｃ R ｄ wherein said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R １ 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 Carbocyclyl, 3- to 12-membered heterocyclyl, -(C １－６ alkylene)-(C ６－１０ aryl), -(C １－６ alkylene)-(5- to 10-membered heteroaryl), -(C １－６ alkylene)-(C ３－１２ carbocyclyl), -(C １－６ alkylene)-(3- to 12-membered heterocyclyl), —S(═O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ or —C(═O)NR ｃ R ｄ wherein said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; X is —O— or —C(R Ｘ ) ２ - and Each R Ｘ are independently hydrogen, halogen, —CN, —NO ２ , —OH, —NH ２ , 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 said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; or Two Germinal R Ｘ together with the carbon atom to which they are attached form oxo, m and m' are independently integers selected from 0 to 2; Each R Ａ are independently oxo, halogen, —CN, —NO ２ , —OH, —NH ２ , 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 said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; n is an integer selected from 0 to 10, where valences allow; R Ｂ is hydrogen, halogen, -CN, -NO ２ , —OH, —NH ２ , 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 said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; Each R ａ is independent, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Carbocyclyl, 3- to 12-membered heterocyclyl, 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 Carbocyclyl, 3- to 12-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; 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 Carbocyclyl, 3- to 12-membered heterocyclyl, C ６－１０ aryl, or 5- to 10-membered heteroaryl; R ｃ and R ｄ together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl; Appearing R ａ , R ｂ , R ｃ , and R ｄ each of which is independently optionally substituted).

2. The compound of claim 1 , wherein Ring C is phenyl or pyridinyl.

3. The compound of formula I is represented by formula I-1-i, I-1-ii, I-1-iii, or I-1-iv: 【Chemistry 2】 3. The compound of claim 1 or 2, wherein the compound is: 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, pyridinyl, pyrrolopyridazinyl, or thienopyridinyl.

5. R ２ is halogen, -CN, -NO ２ , —OH, —NH ２ , 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) ２ R ａ , -N(S(=O) ２ R ａ ) ２ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ NR ｃ R ｄ , -C(=O)OR ｂ , —C(═O)NR ｃ S (= O) ２ R ａ or —C(═O)NR ｃ R ｄ 5. The compound of claim 1, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

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

7. R ２ is —COOH or —C(═O)NR ｃ S (= O) ２ CH ３ The compound according to any one of claims 1 to 6,

8. The compound of formula I is represented by formula I-1-i-1, I-1-i-2, I-1-i-3, I-1-iii-1, I-1-iii-2, or I-1-iii-3: 【Chemistry 3-1】 【Chemistry 3-2】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

9. R Ｃ１ is halogen, -CN, -NO ２ , —OH, —NH ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C １－６ Alkylamino, C ３－６ The compound of any one of claims 1 to 8, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted.

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

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

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

13. Each R Ｄ are independently halogen, —CN, —NO ２ , —OH, —NH ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C １－６ Alkylamino, C ３－６ The compound of any one of claims 1 to 12, wherein said 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. [L] ｑ but 【Chemistry 4】 where: * indicates a bond to ring B, ** indicates a bond to ring C, p is an integer selected from 0 to 3; Y is —O—, —NR Ｌ -, -CR Ｌ１ R Ｌ２ The compound according to any one of claims 1 to 13, wherein the aryl group is -, or -C≡C-.

16. Each R Ｌ１ and each R Ｌ２ 16. The compound of claim 15, wherein is hydrogen.

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

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

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

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

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

22. R Ｂ is hydrogen, halogen, -CN, -NO ２ , —OH, —NH ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C １－６ Alkylamino, C ３－６ 22. The compound of any one of claims 1 to 21, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted.

23. R １ 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 Carbocyclyl, 3- to 12-membered heterocyclyl, -(C １－６ alkylene)-(C ６－１０ aryl), -(C １－６ alkylene)-(5- to 10-membered heteroaryl), -(C １－６ alkylene)-(C ３－１２ carbocyclyl), -(C １－６ alkylene)-(3- to 12-membered heterocyclyl), —S(═O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ or —C(═O)NR ｃ R ｄ 23. The compound of any one of claims 1 to 22, wherein said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl 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. 26. A method of inhibiting a protein in a subject or a biological sample, the method comprising administering to the subject a compound of any one of claims 1 to 24 or contacting the biological sample with a compound of any one of claims 1 to 24.

27. 25. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for inhibiting a protein in a subject or 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. 29. The method, use or compound for use of 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, said method comprising administering to said subject a compound according to any one of claims 1 to 24.

31. 25. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment or prevention of 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. 33. The method, use or compound for use of any one of claims 30 to 32, wherein the disease or disorder is an eIF4E-mediated disease or disorder.

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