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 / 424,463, filed November 10, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Eukaryotic translation initiation factor 4E (eIF4E) is a limiting protein factor 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, I', or I'': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein each of the variables of formulas I and I' are described, embodied, and exemplified herein.

[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 to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. 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 a compound 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 1-6alkylamino, 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 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 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a , -C(=O)NR c R d , -(CH2)C(=O)OR b , or -C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 1 is -NR 1a R 1b -OR 1c and R 1’ are hydrogen, deuterium, 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 or R 1 and R 1’ along with the carbon atoms to which they are attached, C 3-12 forming a carbocyclyl or a 3- to 12-membered heterocyclyl, the carbocyclyl or heterocyclyl being optionally substituted; R 1a and R 1b are each independently hydrogen, -CN, or 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 or R 1a and R 1b together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclic ring, and the heterocyclic ring is ab optionally replaced by Each R ab are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, or -S(=O)R a wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted or Two adjacent R ab together with the atom to which they are attached form a C6 aryl or 5-6 membered heteroaryl, the aryl or heteroaryl being optionally substituted; R 1c is hydrogen, 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(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, 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, C2-6 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; The Two R's X together with the carbon atom to which they are attached form an oxo, or The Two R's X along with the carbon atoms to which they are attached, C 3-6 forming a carbocyclyl or a 3- to 6-membered heterocyclyl, the carbocyclyl or heterocyclyl being optionally substituted; Each R A1 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted or R X and adjacent R A1 along with the carbon atoms to which they are attached, C 3-4 forming a carbocyclyl or a 3- to 4-membered heterocyclyl, the carbocyclyl or heterocyclyl being optionally substituted; 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 present disclosure provides a compound 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, 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; r and s are independently, where valence allows, an integer selected from 0 to 6; R 2 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 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a , -C(=O)NR c R d , -(CH2)C(=O)OR b , or -C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 1 is -NR 1a R 1b -OR 1c and R 1’ are hydrogen, deuterium, 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 or R 1 and R 1’ along with the carbon atoms to which they are attached, C 3-12forming a carbocyclyl or a 3- to 12-membered heterocyclyl, the carbocyclyl or heterocyclyl being optionally substituted; R 1a and R 1b are each independently hydrogen, -CN, or 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 or R 1a and R 1b together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclic ring, and the heterocyclic ring is ab optionally replaced by Each R ab are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, C 6-10Aryl, 5-10 membered heteroaryl, or -S(=O)R a wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted or Two adjacent R ab together with the atom to which they are attached form a C6 aryl or 5-6 membered heteroaryl, the aryl or heteroaryl being optionally substituted; R 1c is hydrogen, 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(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, 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; The Two R's X together with the carbon atom to which they are attached form an oxo, or The Two R's X along with the carbon atoms to which they are attached, C 3-6forming a carbocyclyl or a 3- to 6-membered heterocyclyl, the carbocyclyl or heterocyclyl being optionally substituted; 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, 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.

[0018] In certain embodiments, 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 6-10aryl 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 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 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a , or -C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 1 is -NR 1a R 1b -OR 1c and R 1a and R 1b are each independently hydrogen, 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, -(C1-6 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 or R 1a and R 1b together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle, which heterocycle is optionally substituted; R 1c is hydrogen, 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(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, 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, C1-6 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 3-6 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, C1-6 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.

[0019] In certain embodiments, the compound of formula I" has 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.

[0020] In certain embodiments, the compound of formula I' has 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.

[0021] 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.

[0022] In certain embodiments, the compound of formula I" has 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.

[0023] In certain embodiments, the compound of formula I′ has 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.

[0024] 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.

[0025] 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.

[0026] In certain embodiments, R 1 is -NR 1a R 1b -OR 1c In certain embodiments, R 1 is -NR 1a R 1b In certain embodiments, R 1 -OR 1c is.

[0027] In certain embodiments, R 1 is -NR 1a R 1b is.

[0028] In certain embodiments, R 1a and R 1b are each independently hydrogen, C 1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), 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 2-6Alkynyl (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., monocyclic or polycyclic (e.g., spiro, bridged, or fused) 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., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl containing one or two 3- to 8-membered rings and one to five 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 (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), -(C 1-6alkylene)-(3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl), -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein 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-). 1a and R 1b each optionally independently represents one or more R u is replaced by

[0029] In certain embodiments, R 1a and R 1b are each independently hydrogen, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), 3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl), -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6 alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), -(C 1-6alkylene)-(3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl)), -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 1a and R 1b each optionally independently represents one or more R u is replaced by

[0030] In certain embodiments, R 1a and R 1b are each independently hydrogen, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), 3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl), -(C 1-6 alkylene)-(5-10 membered heteroaryl), -(C 6-10 alkylene), -(C 1-6 aryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), -(C 1-6 alkylene)-(3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl)), -S(=O)R a , or -C(=O)R awherein the alkyl, alkylene, carbocyclyl, heterocyclyl, or heteroaryl is optionally substituted. In certain embodiments, R 1a and R 1bは , each optionally independently, one or more R u is replaced by

[0031] In certain embodiments, R 1a and R 1b are each independently hydrogen, -CN, or C 1-6 Alkyl, C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), 3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl), -(C 1-6 alkylene)-(C 1-6 aryl), -(C 6-10 alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), or -(C 1-6 alkylene)-(3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl)), wherein the alkyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0032] In certain embodiments, R 1a and R 1b are each independently hydrogen, optionally substituted C 1-6 Alkyl, -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d is.

[0033] In certain embodiments, R 1a and R 1b At least one of R is hydrogen. 1a and R 1b At least one of R is not hydrogen. 1a and R 1b At least one of the 1-6 In certain embodiments, R 1a and R 1b At least one of the 6-10 In certain embodiments, R 1a and R 1b At least one of R 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 1a and R 1b At least one of the 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl). In certain embodiments, R 1a and R 1b At least one of R is an optionally substituted 3- to 12-membered heterocyclyl (e.g., a monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of the 1-6 alkylene)-(C 6-10 aryl), wherein the alkylene or aryl is optionally substituted. In certain embodiments, R 1a and R 1b At least one of the 1-6In 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. 1a and R 1b At least one of the 1-6 alkylene)-(C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), wherein the alkylene or carbocyclyl is optionally substituted. In certain embodiments, R 1a and R 1b At least one of the 1-6 alkylene)-(3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl)), wherein 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. In certain embodiments, R 1a and R 1b At least one of the groups is -S(=O)R a In certain embodiments, R 1a and R 1b At least one of the groups is -C(=O)R a In certain embodiments, R 1a and R 1b is one or more R u is optionally replaced by

[0034] In certain embodiments, R 1a and R 1b At least one of the 6-10 In certain embodiments, aryl is one or more R u is optionally replaced by

[0035] In certain embodiments, R 1a and R 1bAt least one of R 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 1a and R 1b At least one of R 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 1a and R 1b At least one of R 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 1a and R 1b At least one of R 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 1a and R 1b At least one of R 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 1a and R 1b At least one of R 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 1a and R 1b At least one of R is an optionally substituted heteroaryl containing two six-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of R is 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

[0036] In certain embodiments, R1a and R 1b At least one of the 3-12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C 7) , 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 ), e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl). In certain embodiments, a carbocyclyl is a ring structure containing one or more R u is optionally replaced by

[0037] In certain embodiments, R 1a and R 1b At least one of R is an optionally substituted 3- to 12-membered heterocyclyl (e.g., a monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of R 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 1a and R 1bAt least one of R is an optionally substituted heterocyclyl containing one three-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of R 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 1a and R 1b At least one of R is an optionally substituted heterocyclyl containing one five-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of R 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 1a and R 1b At least one of R is an optionally substituted heterocyclyl containing one seven-membered ring and 1 to 4 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of R 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 1a and R 1b At least one of R is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) containing two 3-8 membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of R is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) containing two five-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1bAt least one of R is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) containing two 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1a and R 1b At least one of R is an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) 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

[0038] In certain embodiments, R 1a and R 1b At least one of the 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 u is optionally replaced by

[0039] In certain embodiments, R 1a and R 1b At least one of the 1-6and 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

[0040] In certain embodiments, R 1a and R 1b At least one of the 1-6 alkylene)-(C 3-12 carbocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl), C 3-12Carbocyclyl, for example, a monocyclic or polycyclic (e.g., spiro, bridged, or fused) carbocyclyl, is 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 ), and spiro[4.5]decanyl (C 10 ), wherein the alkylene or carbocyclyl is optionally substituted. In certain embodiments, the carbocyclyl is selected from the group consisting of one or more R u is optionally replaced by

[0041] In certain embodiments, R 1a and R 1b At least one of the 1-6alkylene)-(3- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocyclyl)), wherein the heterocyclyl (e.g., monocyclic or polycyclic (e.g., spiro, bridged, or fused) 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, an optionally substituted heterocyclyl comprises one 5-membered ring and one to three 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 (e.g., a polycyclic (e.g., spiro, bridged, or fused) 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 (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 5-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S.In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) 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

[0042] In certain embodiments, R 1a and R 1b At least one of the is -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d In certain embodiments, R 1a and R 1b At least one of the groups is -S(=O)R a In certain embodiments, R 1a and R 1b At least one of the groups is -C(=O)R a is.

[0043] In certain embodiments, R 1a and R 1b together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 12-membered heterocycle (e.g., a monocyclic or polycyclic (e.g., spiro, bridged, or fused) heterocycle containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S). In certain embodiments, R 1a and R 1b together with the nitrogen atom to which they are attached, one or more R u In certain embodiments, R 1a and R 1b together with the nitrogen atom to which they are attached, one or more R abIn certain embodiments, the optionally substituted heterocyclyl comprises one 3- to 8-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 3-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 4-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 5-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 6-membered ring and one to four heteroatoms selected from N, O, and S. In certain embodiments, the 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 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 3- to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 5-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) comprises two 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, an optionally substituted heterocyclyl (e.g., a polycyclic (e.g., spiro, bridged, or fused) heterocyclyl) contains one 5-membered ring and one 6-membered ring and 1 to 5 heteroatoms selected from N, O, and S.

[0044] In certain embodiments, each R abare 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 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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 n-butylhexylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, 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)), 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), C 6-10 aryl (i.e., phenyl or naphathalenyl), or 5-10 membered heteroaryl (e.g., heteroaryl containing one or two rings and one to five heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R ab is one or more Ru is optionally replaced by

[0045] In certain embodiments, each R ab are independently oxo, halogen, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, or -S(=O)R a and the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u is optionally replaced by

[0046] In certain embodiments, each R ab are independently oxo, halogen, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, or -S(=O)R a and the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u is optionally replaced by

[0047] In certain embodiments, two adjacent R ab together with the atoms to which they are attached form a C6 aryl (i.e., phenyl) or a 5- to 6-membered heteroaryl (e.g., a heteroaryl containing one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S), which aryl or heteroaryl is optionally substituted. In certain embodiments, two adjacent R ab together with the atom to which they are attached form a C6 aryl or a 5- to 6-membered heteroaryl, and the aryl or heteroaryl may be joined by one or more R u is optionally replaced by

[0048] In certain embodiments, R 1 -OR 1c is.

[0049] In certain embodiments, R 1c is 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 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(═O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 1c is one or more R u is optionally replaced by

[0050] In certain embodiments, R 1c is hydrogen, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 1c is one or more R u is optionally replaced by

[0051] In certain embodiments, R 1c is C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. 1c is one or more R u is optionally replaced by

[0052] In certain embodiments, R 1c is C 1-6alkyl or 3- to 12-membered heterocyclyl, wherein the alkyl or heterocyclyl is optionally substituted. 1c is an arbitrarily substituted C 1-6 In certain embodiments, R 1c is an optionally substituted 3- to 12-membered heterocyclyl. In certain embodiments, R 1c is one or more R u is optionally replaced by

[0053] In certain embodiments, R 1c is an arbitrarily substituted C 6-10 In certain embodiments, aryl is one or more R u is optionally replaced by

[0054] In certain embodiments, R 1c 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 1c 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 1c 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 1c 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 1c 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 1c 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 1cis an optionally substituted heteroaryl containing two 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments, R 1c is 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

[0055] In certain embodiments, R 1c is an arbitrarily substituted 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 In certain embodiments, a carbocyclyl is one or more R u is optionally replaced by

[0056] In certain embodiments, R 1c 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 1c 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 1cis an optionally substituted heterocyclyl containing one three-membered ring and one to three heteroatoms selected from N, O, and S. In certain embodiments, R 1c 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 1c 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 1c 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 1c 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 1c 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 1c 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 1c 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 1c 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 1c 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

[0057] In certain embodiments, R 1’is hydrogen, deuterium, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), 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, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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, R 1’ is one or more R u is optionally replaced by

[0058] In certain embodiments, R 1’ is hydrogen, deuterium, or an optionally substituted C 1-6 It is alkyl.

[0059] In certain embodiments, R 1 and R 1’ along with the carbon atoms to which they are attached, 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 )), or a 3- to 12-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is selected from one or more R u In certain embodiments, R 1 and R 1’ along with the carbon atoms to which they are attached, C 3-12 Form a carbocyclyl or a 3- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u is optionally replaced by

[0060] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0061] In certain embodiments, m' is 0. In certain embodiments, m' is 1. In certain embodiments, m' is 2.

[0062] 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.

[0063] 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 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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 A independently, one or more R u is optionally replaced by

[0064] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6Alkenyl, 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

[0065] 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

[0066] 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.

[0067] In certain embodiments, R B is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), 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, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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 B independently, one or more R u is optionally replaced by

[0068] In certain embodiments, 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, 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

[0069] 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

[0070] In certain embodiments, R B is hydrogen or an optionally substituted C 1-6 In certain embodiments, RB 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

[0071] In certain embodiments, ring C is C 6-10 It is aryl or 5- to 10-membered heteroaryl.

[0072] In certain embodiments, ring C is C 6-10 aryl (eg, phenyl or naphthyl);

[0073] 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.

[0074] In certain embodiments, Ring C is phenyl or pyridinyl.

[0075] 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 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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, R C1 is one or more R u is optionally replaced by

[0076] In certain embodiments, R C1 are halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, or C1-6 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

[0077] In certain embodiments, R C1 is halogen or —OH. In certain embodiments, R C1 is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, R C1 is -Cl. In certain embodiments, R C1 is —OH. 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

[0078] In certain embodiments, each R C2 are independently halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), 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, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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 C2 independently, one or more R u is optionally replaced by

[0079] In certain embodiments, each R C2 are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 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

[0080] 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.

[0081] In certain embodiments, ring D is C 6-10 It is aryl or 5- to 10-membered heteroaryl.

[0082] In certain embodiments, ring D is C 6-10 aryl (eg, phenyl or naphthyl);

[0083] 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.

[0084] In certain embodiments, Ring D is phenyl, pyridinyl, pyrrolopyridazinyl, or thienopyridinyl.

[0085] 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, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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), C 3-6carbocyclyl (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), -C(=O)NR c S(=O)2R a , -C(=O)NR c R d , -(CH2)C(=O)OR b , or C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. 2 is one or more R u is optionally replaced by

[0086] In certain embodiments, R 2 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 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR c S(=O)2R a , -C(=O)NR c R d , -(CH2)C(=O)OR b , or C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0087] In certain embodiments, R 2 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(=O)NR c S(=O)2R a , -C(=O)NR c R d , -(CH2)C(=O)OR b , or C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0088] In certain embodiments, R 2 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)NR c S(=O)2R a , -C(=O)NR c R d , -(CH2)C(=O)OR b , or C(=O)OR b wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0089] In certain embodiments, R 2 is hydrogen, 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)2Ra )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

[0090] In certain embodiments, R 2 is hydrogen, -C(=O)NR c S(=O)R a , -C(=O)NR c R d , -(CH2)C(=O)OR b , or -C(=O)OR b In certain embodiments, R 2 is -C(=O)NHS(=O)2CH3 or -COOH.

[0091] 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 2-6 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 2-6Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 1-6 Alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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), C 3-6carbocyclyl (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), -C(=O)NR c S(=O)2R a , or C(=O)OR b 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

[0092] 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, -C(=O)NR c S(=O)2R a , or C(=O)OR b wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0093] In certain embodiments, R 2 are halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)NR c S(=O)2R a , or C(=O)OR b 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

[0094] In certain embodiments, R 2 are halogens, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)NR c S(=O)2R a , or C(=O)OR b wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R 2 is one or more R u is optionally replaced by

[0095] 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, R2 is one or more R u is optionally replaced by

[0096] 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.

[0097] 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, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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

[0098] 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

[0099] 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

[0100] 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.

[0101] 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-.

[0102] In certain embodiments, [L] q teeth, [ka] and During the ceremony, * 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-.

[0103] In certain embodiments, L is Y.

[0104] 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, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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

[0105] In certain embodiments, each R L1 and each R L2 is hydrogen.

[0106] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

[0107] 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-. In certain embodiments, Y is -O- or -C≡C-.

[0108] In certain embodiments, Y is —O— and p is 0, or Y is —C≡C— and p is 0.

[0109] In certain embodiments, X is —O—. In certain embodiments, X is —C(R X )2-.

[0110] 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

[0111] 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

[0112] In certain embodiments, each R X are independently hydrogen or C 1-6 It is alkyl.

[0113] In certain embodiments, each R X independently, C 1-6 It is alkyl.

[0114] In certain embodiments, each R X is hydrogen.

[0115] 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

[0116] In certain embodiments, two R X together with the carbon atom to which they are attached form an oxo.

[0117] In certain embodiments, two R X along with the carbon atoms to which they are attached, C 3-6forming a carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or a 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), wherein the carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, two R X along with the carbon atoms to which they are attached, C 3-6 A carbocyclyl or a 3- to 6-membered heterocyclyl is formed, and the carbocyclyl or heterocyclyl is one or more R u is optionally replaced by

[0118] In certain embodiments, two R X along with the carbon atoms to which they are attached, C 3-4 Forms a carbocyclyl or a 3- or 4-membered heterocyclyl.

[0119] In certain embodiments, each R A1 are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), 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 A1 independently, one or more R u is optionally replaced by

[0120] In certain embodiments, each R A1 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 and alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R A1 independently, one or more R u is optionally replaced by

[0121] In certain embodiments, each R A1 are independently hydrogen or C 1-6 It is alkyl.

[0122] In certain embodiments, each R A1 independently, C 1-6 It is alkyl.

[0123] In certain embodiments, each R A1 is hydrogen.

[0124] In certain embodiments, each R A1 are independently halogen or optionally substituted C 1-6 In certain embodiments, at least one R A1 is halogen. In certain embodiments, each R A1 are independently halogen. In certain embodiments, at least one R A1 is an arbitrarily substituted C 1-6 In certain embodiments, each R A1 are independently optionally substituted C 1-6 In certain embodiments, each R A1 independently, one or more R u is optionally replaced by

[0125] In certain embodiments, R X and adjacent R A1along with the carbon atoms to which they are attached, C 3-4 In certain embodiments, the carbocyclyl or heterocyclyl is optionally substituted, forming a carbocyclyl or a 3- to 4-membered heterocyclyl. In certain embodiments, the carbocyclyl or heterocyclyl is optionally substituted, forming one or more R u is optionally replaced by

[0126] 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

[0127] In certain embodiments, each R a independently, 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

[0128] In certain embodiments, each R a independently, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is selected from one or more R u is optionally replaced by

[0129] 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 2-6Alkenyl (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 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

[0130] In certain embodiments, each R b independently, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is selected from one or more R uis optionally replaced by

[0131] 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 3-12 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 6-10aryl, 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

[0132] In certain embodiments, each R c and each R d are independently hydrogen, 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

[0133] 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 u is optionally replaced by

[0134] In certain embodiments, each R u are independently deuterium, oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), 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, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), 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 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 6-10 aryl (e.g., phenyl or naphthyl), 5-10 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 3-12Carbocyclyl (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), -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)ORb , -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.

[0135] In certain embodiments, each R u are independently deuterium, oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl, 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.

[0136] In certain embodiments, each R uare independently deuterium, oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, 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.

[0137] In certain embodiments, each R u are independently deuterium, oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, 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.

[0138] 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 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83 Table 1-84 Table 1-85 Table 1-86 Table 1-87 Table 1-88 Table 1-89

Table 1-90

Table 1-97

Table 1-110

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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."

[0154] 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."

[0155] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The 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.

[0156] 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.

[0157] 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.

[0158] 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 at most 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 at most 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] tautomers In certain embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0164] 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.

[0165] 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)).

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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). General synthetic scheme [ka]

[0171] 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).

[0172] 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).

[0173] 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).

[0174] 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.

[0175] 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.

[0176] Biological assays The biological activity of the compounds of the present application can be evaluated using methods and assays known in the art.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] In certain aspects, the present disclosure provides a compound disclosed herein for use in inhibiting a protein in a subject or biological sample.

[0181] In certain embodiments, the protein is eIF4E.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] In certain embodiments, the disease or disorder is an eIF4E-mediated disease or disorder.

[0186] In certain embodiments, the disease or disorder is cancer.

[0187] 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]

[0188] 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]

[0189] In certain embodiments, the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, 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.

[0190] 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).

[0191] In certain embodiments, the subject is a mammal.

[0192] In certain embodiments, the subject is a human.

[0193] definition As used in this specification and the appended claims, unless intended to the contrary, the following terms have the meanings indicated below.

[0194] 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, 75 th 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.

[0195] 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).

[0196] The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0197] 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.

[0198] 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.

[0199] "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)).

[0200] "Alkylene," as used herein, 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 "alkylene" 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.

[0201] "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 a triple bond. 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.

[0202] 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.

[0203] "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, an alkynyl group does not contain a double bond. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In certain embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In certain embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] "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 some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl," e.g., anthracyl). 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.

[0210] "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.

[0211] "Heteroaryl" also includes ring systems in which a heteroaryl group, as defined above, is fused to one or more aryl groups, and the point of attachment is at either the heteroaryl or one or more aryl groups; 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, the substitution may occur at either the heteroaryl or one or more aryl groups, unless otherwise specified. The point of attachment of bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) may be at either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0212] 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.

[0213] 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.

[0214] "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 ("C3-10 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms ("C 5-6 carbocyclyl). Exemplary C 3-6 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.

[0215] In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 12 ring carbon atoms ("C 3-12 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 8 ring carbon atoms ("C 3-8 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 6 ring carbon atoms ("C 3-6 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 5 to 12 ring carbon atoms ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 5 or 6 ring carbon atoms ("C 5-6 Carbocyclyl). C 5-6 Examples of carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of carbocyclyls include the aforementioned C 5-6 Includes carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of carbocyclyls include the aforementioned C 3-6 Carbocyclyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-12 In certain embodiments, the carbocyclyl group is a substituted C3-12 It is a carbocyclyl.

[0216] In certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic ("polycyclic carbocyclyl"), contains fused, bridged, or spiro ring systems, and can be saturated or partially unsaturated. 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, a carbocyclyl group is an unsubstituted C 3-12 In certain embodiments, the carbocyclyl group is a substituted C 3-12 It is a carbocyclyl.

[0217] "Fused carbocyclyl" or "fused carbocycle" refers to a ring system in which a carbocyclyl group, as defined above, is fused, i.e., shares a common bond with, one or more carbocyclyl groups, as defined above, in which case the point of attachment is on either of the fused rings. In such cases, the number of carbons refers to the total number of carbons in the fused carbocyclyl ring system. If substitution is indicated, unless otherwise specified, the substitution may occur on any of the fused rings.

[0218] "Spirocarbocyclyl" or "spirocarbocycle" refers to a ring system in which a carbocyclyl group, as defined above, forms a spiro structure, i.e., shares one common atom with one or more carbocyclyl groups, as defined above, and in which case the point of attachment is on either carbocyclyl ring in which the spiro structure is incorporated. In such cases, the number of carbons indicates the total number of carbons in the carbocyclyl ring in which the spiro structure is incorporated. If substitution is indicated, unless otherwise specified, the substitution may occur on either of the carbocyclyl rings in which the spiro structure is incorporated.

[0219] "Bridged carbocyclyl" or "bridged carbocycle" refers to a ring system in which a carbocyclyl group, as defined above, forms a bridged structure, i.e., shares more than one atom (e.g., more than one bond) with one or more carbocyclyl groups, as defined above, in which case the point of attachment is on either carbocyclyl ring incorporating the bridged structure. In such cases, the number of carbons refers to the total number of carbons in the bridged ring. Where substitution is indicated, unless otherwise specified, the substitution may occur on either of the carbocyclyl rings incorporating the bridged structure.

[0220] "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.

[0221] 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.

[0222] In certain embodiments, heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic ("polycyclic heterocyclyl"), contain fused, bridged, or spiro ring systems, 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 group, as defined above, is fused to one or more carbocyclyl groups, where 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. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 12-membered heterocyclyl.

[0223] "Fused heterocyclyl" or "fused heterocycle" refers to a ring system in which a heterocyclyl group, as defined above, is fused, i.e., shares a common bond with, one or more heterocyclyl or carbocyclyl groups, as defined above, in which case the point of attachment is on either of the fused rings. In such cases, the number of carbons indicates the total number of ring members of the fused ring system. If substitution is indicated, unless otherwise specified, the substitution may occur on any of the fused rings.

[0224] "Spiroheterocyclyl" or "spiroheterocycle" refers to a ring system in which a heterocyclyl group, as defined above, forms a spiro structure, i.e., shares one common atom with one or more heterocyclyl or carbocyclyl groups, as defined above, where the point of attachment is on the heterocyclyl or carbocyclyl ring in which the spiro structure is incorporated. In such cases, the number of ring members indicates the total number of ring members of the heterocyclyl or carbocyclyl ring in which the spiro structure is incorporated. If substitution is indicated, unless otherwise specified, the substitution may occur on either the heterocyclyl or carbocyclyl ring in which the spiro structure is incorporated.

[0225] "Bridged heterocyclyl" or "bridged heterocycle" refers to a ring system in which a heterocyclyl group, as defined above, forms a bridged structure, i.e., shares more than one atom (e.g., more than one bond) with one or more heterocyclyl or carbocyclyl groups, as defined above, where the point of attachment is on the heterocyclyl or carbocyclyl ring into which the bridged structure is incorporated. In such cases, the number of ring members refers to the total number of ring members of the heterocyclyl or carbocyclyl ring into which the bridged structure is incorporated. If substitution is indicated, unless otherwise specified, the substitution can occur on either of the bridged rings.

[0226] "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 a nitrogen, oxygen, sulfur, boron, phosphorus, or silicon heteroatom. Hetero can apply to any of the above hydrocarbyl groups having 1 to 5, especially 1 to 3, heteroatoms.

[0227] "Alkoxy," as used herein, refers to the group -OR, where R is alkyl, carbocyclyl, or heterocyclyl, as defined herein. 1-6 Alkoxy refers to the group -OR, where each R is a C as defined herein. 1-6 Alkyl, C 3-6carbocyclyl, or 3- to 6-membered heterocyclyl. 1-6 Alkyl, C 3-6 The carbocyclyl or 3- to 6-membered heterocyclyl is as defined above.

[0228] "Alkylamino," as used herein, refers to the group -NHR or -NR2, where each R is independently alkyl, carbocyclyl, or heterocyclyl, as defined herein. 1-6 Alkylamino refers to the group -NHR or -NR, where each R is independently a C as defined herein. 1-6 Alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. 1-6 Alkyl, C 3-6 The carbocyclyl or 3- to 6-membered heterocyclyl is as defined above.

[0229] "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 structure / tautomer with the heteroatom provides a carbon atom that can form two geminal radicals, thereby forming a double bond with an oxygen radical.

[0230] "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.

[0231] As used herein, the term "protecting group" is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction. During this subsequent chemical reaction, the unmodified functional group will not survive 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.

[0232] 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)).

[0233] 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)).

[0234] 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)).

[0235] 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.

[0236] 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.

[0237] 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.

[0238] "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.

[0239] "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.

[0240] An "effective amount" refers to 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" will 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.

[0241] "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).

[0242] 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.

[0243] "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), or 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.

[0244] 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 statistical experimental error, and thus the numerical value or numerical range may vary, in some cases, 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.

[0245] 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.

[0246] 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).

[0247] 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" shall be interpreted as inclusive, i.e., including at least one of the elements or listed elements, but also including more than one, 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 of the elements or listed elements. In general, the term "or," as used herein, shall 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" shall have its ordinary meaning as used in the field of patent law.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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]

[0252] 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.

[0253] I. Synthesis and Characterization Scheme A [ka] Synthesis of 103: To a suspension of sodium hydride (60% dispersion in mineral oil) (1.92 g, 48.02 mmol, 60% purity) in THF (50 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (101) (5 g, 32.01 mmol), followed by dimethyl carbonate (102) (8.65 g, 96.04 mmol, 8.09 mL, 99% purity) at 25 °C. The reaction mixture was then heated at 70 °C for 16 h. After completion of the reaction (as judged by LC / MS and TLC), the reaction mixture was cooled to 25 °C and quenched with water (100 ml). The aqueous phase was extracted with EtOAc (2 × 100 ml). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure to give the crude material. The crude product thus obtained was purified by silica gel column chromatography (SiO; 100–200 mesh, 15% EtOAc / hexane) to give methyl 8-oxidanylidene-1,4-dioxaspiro[4.5]decane-7-carboxylate (103) (5 g, 23.34 mmol, 72.91% yield) as an off-white solid.

[0254] 1 H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 3.92 (s, 4H), 3.86 (s, 3H), 2.39 (t, J= 6.76 Hz, 1H), 2.34 (s, 2H), 1.76 (t, J= 6.72 Hz, 1H) ppm.

[0255] Calculated m / z 214.08, observed (M+1) = 215.0.

[0256] Synthesis of 105: To a stirred solution of methyl 8-oxidanylidene-1,4-dioxaspiro[4.5]decane-7-carboxylate (103) (5 g, 23.34 mmol) in MeOH (50 mL), NaOMe (25 mL, 4 M) was added at 25°C, and the reaction mixture was stirred for 10 min. Acetamidine HCl (104) (3.31 g, 35.01 mmol) was added at 25°C, and the reaction mixture was stirred at the same temperature for 16 h. The solvent was removed under reduced pressure to give the crude material. The crude product was dissolved in 1 N HCl (40 mL) (pH ∼7). The aqueous layer was extracted with 10% MeOH / DCM (50 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO; 100–200 mesh, 10% MeOH / DCM) to give 2′-methylspiro[1,3-dioxolane-2,6′-3,5,7,8-tetrahydroquinazolin]-4′-one (105) (3.25 g, 14.62 mmol, 62.65% yield) as an off-white solid.

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 3.91 (s, 4H), 2.62 (t, J= 6.6 Hz, 2H), 2.46 (s, 2H), 2.23 (s, 3H), 1.81 (t, J = 6.6 Hz, 2H) ppm.

[0258] MS calculated: 222.2, MS found: 222.8 (M+H).

[0259] Scheme B [ka] Ethyl 3-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]benzoate (106) To a stirred solution of ethyl 3-(5-chloranyl-2-oxidanyl-phenyl)benzoate (4.5 g, 16.26 mmol) in acetone (50 mL) was added KCO (8.98 g, 65.05 mmol) and the mixture was stirred for 30 min. 1,2-Dibromoethane (13.75 g, 73.18 mmol, 6.31 mL) was added slowly and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was passed through a Celite pad, concentrated under reduced pressure, and subjected to flash column chromatography (silica gel, 30% EtOAc / hexanes) to give 106 (4.0 g, 10.43 mmol, 64.11% yield). 1 H NMR (400 MHz, DMSO-d6-L): 8.186 (s, J=8.4, 1H), 7.959 (t, J=15.8, 1H), 7.663 (t, J=7.76 Hz, 1H), 7.566 (m, 1H), 7.42 (m, 2H), 7.17 (d, J=3.92, 1H), 4.32(m, J=9.04Hz, 4H), 3.73 (t, J=5.4 Hz, 2H), 1.335 (m, 3H) ppm.

[0260] Synthesis of 107: To a stirred solution of 2'-methylspiro[1,3-dioxolane-2,6'-3,5,7,8-tetrahydroquinazolin]-4'-one (105) (400 mg, 1.80 mmol) in DMF (10 mL) was added potassium carbonate (746.25 mg, 5.40 mmol) followed by ethyl 3-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]benzoate (106) (690.54 mg, 1.80 mmol) at 25 °C, and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by Combiflash column chromatography (SiO; 12 g, 80% EtOAc) to give off-white ethyl 3-[5-chloranyl-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]benzoate (107) (360 mg, 685.73 μmol, 38.10% yield).

[0261] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.2 Hz, 1H), 7.88 (s,1H), 7.57-7.51 (m, 2H), 7.40 (d, J = 6.4 Hz, 1H), 7.31 (s, 1H), 7.18 (d, J = 12 Hz, 1H ), 4.35-4.30 (m, 2H), 4.24 (d, J = 8 Hz, 2H), 4.18 (d, J = 4 Hz, 2H), 3.90 (s, 4H ), 2.59 (s, 2H), 2.49-2.45 (m, 2H), 2.05 (s, 3H), 1.82-1.80(m, 2H), 1.32 (t, J = 8 Hz, 3H).

[0262] LC-MS: 525.0 (M+H).

[0263] Synthesis of 108: To a stirred solution of ethyl 3-[5-chloranyl-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]benzoate (107) (500 mg, 952.40 μmol) in acetone (10 mL) was added 10% HCl in HO (10 mL) at 25 °C, and the reaction mixture was stirred at 55 °C for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure. The crude product was dissolved in HO and neutralized with saturated NaHCO solution (50 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure. The crude material thus obtained was purified by Combiflash column chromatography (SiO; 12 g, 70% EtOAc) to give ethyl 3-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]benzoate (108) (290 mg, 602.99 μmol, 63.31% yield) as an off-white solid.

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8 Hz, 1H), 7.88 (s, 1H), 7.58-7.50 (m, 2H), 7.41-7.39 (m, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H ), 4.32 (t, J = 7.4 Hz, 2H), 4.27-4.22 (m, 4H), 3.11 (s, 2H), 2.84 (t, J = 6.8 Hz, 2H ), 2.53 (t, J = 6.8 Hz, 2H), 2.07 (s, 3H), 1.33 (t, J = 6.8 Hz, 3H).

[0265] LC-MS: 481.02 (M+H).

[0266] Scheme C [ka] Synthesis of 109: To a stirred solution of ethyl 3-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]benzoate (108) (100 mg, 207.93 μmol) in MeOH (5 mL) was added AcOH (12.49 mg, 207.93 μmol) followed by NaBHCN (78.40 mg, 1.25 mmol) at 25 °C, and the reaction mixture was stirred at that temperature for 15 minutes. To this was added N-methylmethanamine (46.87 mg, 1.04 mmol, 60.48 μL) at 0 °C, and the reaction mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product thus obtained was diluted with saturated NH Cl solution (30 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by CombiFlash column chromatography (SiO2; 12 g, 5% MeOH / DCM) to give ethyl 3-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]benzoate (109) (100 mg, 196.07 μmol, 94.30% yield) as an off-white solid.

[0267] 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H), 7.56-7.49 (m, 2H), 7.39 (t, J = 8Hz, 1H), 7.31 (s, 1H), 7.19 (d, J = 9.2 Hz, 1H), 4.35-4.30 (m, 2H ), 4.09-4.07 (m, 2H), 3.16 (d, J = 4.8 Hz, 4H), 2.50 (s, 3H), 2.41(s, 4H ), 2.04 (s, 3H), 1.90 (s, 1H), 1.53(d, J = 6.8 Hz, 1H), 1.33 (t, J = 6.8 Hz, 3H), 1.23 (s, 3H).

[0268] LC-MS: 510.1 (M+H).

[0269] Synthesis of 110: (Compound 1) To a stirred solution (5 mL) of ethyl 3-[5-chloranil-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]benzoate (109) (100 mg, 196.07 μmol) in THF:HO (7:3), LiOH.HO (24.68 mg, 588.21 μmol, 16.35 μL) was added at 0° C., and the reaction mixture was stirred at 25° C. for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure. The crude product thus obtained was purified by reverse-phase preparative HPLC to give 3-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]benzoic acid (110) (Compound 1) (30 mg, 61.71 μmol, 31.47% yield, 99.14% purity) as a white solid.

[0270] 1H NMR(400 MHz,MeOD):δ 7.94 (d, J = 7.6 Hz, 1H), 7.75 (s, 1H), 7.41-7.34 (m, 2H), 7.32-7.29 (m, 1H), 7.20 (d, J = 2.8 Hz, 1H), 7.13-7.11(m, 1H), 4.38-4.23 (m, 4H), 3.49 (t,J = 7.6 Hz, 1H), 2.90 (s, 7H), 2.78-2.74(m, 2H), 2.70-2.68 (m, 1H), 2.17-2.15 (m. 2H), 2.06 (s, 3H).

[0271] MS calculated: 481.97, MS found: 482.2 (M+H).

[0272] Scheme D [ka] Synthesis of 113: A stirred solution of 2,2-di(methyl)-1,3-dioxane-4,6-dione (112) (7.06 g, 48.99 mmol) in 1,1,1-triethoxyethane (7.22 g, 44.53 mmol, 50 mL) was heated at 90 °C for 3 h. After 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 (111) (7 g, 44.53 mmol) was then added to the reaction mixture, and heating at 90 °C was continued for 2 h. 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 (113) (2 g, 6.15 mmol, 14%) as a yellow liquid.

[0273] 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).

[0274] Synthesis of 114: A stirred solution of methyl 4-[1-[2,2-di(methyl)-4,6-bis(oxidanylidene)-1,3-dioxan-5-ylidene]ethylamino]thiophene-3-carboxylate (113) (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 (114) (6 g, 26.88 mmol, 43.72% yield) as a brown solid.

[0275] 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).

[0276] Synthesis of 115: To a stirred solution of methyl 5-methyl-7-oxidanyl-thieno[3,2-b]pyridine-3-carboxylate (114) (3.5 g, 15.68 mmol) in toluene (50 mL) was added N,N-dimethylaniline (99%) (15.20 g, 125.42 mmol, 15.90 mL) and cooled to 0° C. POCl (3.60 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 (115) (3.0 g, 12.41 mmol, 79.17% yield) as a white solid.

[0277] 1H NMR (400 MHz, DMSO-d6) δ 8.93(s,1H), 7.57 (s,1H), 3.86( s, 3H),2.63 (s,3H).

[0278] ESI-MS: m / z calculated 241.0, observed 243.0 (M+2)+;

[0279] Synthesis of 117: To a stirred solution of methyl 7-chloranyl-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (115) (3.0 g, 12.41 mmol) in dioxane (30 mL) and water (5 mL), (5-chloranyl-2-oxidanyl-phenyl)boronic acid (116) (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 min. To this solution was added Pd(dppf)Cl (907.35 mg, 1.24 mmol) and degassed again for 5 min. The reaction mixture was then heated at 90 °C for 5 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was passed 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 (117) (1.5 g, 4.49 mmol, 36.20% yield) as an off-white solid.

[0280] 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.84 (s, 1H), 7.38 (t,J=8.08 Hz 3H), 7.05 (d,J=8.68 Hz 1H),3.87 (s, 3H), 2.66 (s, 3H).

[0281] ESI-MS: m / z calculated 333, observed 334 (M+H) +

[0282] Synthesis of 118: To a stirred solution of methyl 7-(5-chloranyl-2-oxidanyl-phenyl)-5-methyl-thieno[3,2-b]pyridine-3-pcarboxylate (117) (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 (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 (118) (1.3 g, 2.95 mmol, 82.05% yield) as an off-white solid.

[0283] 1H-NMR (400 MHz, DMSO-d6) δ 8.84(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).

[0284] ESI-MS: m / z calculated 440.74; found 441.8 (M+1)

[0285] Scheme E [ka] Synthesis of 119: To a stirred solution of 2'-methylspiro[1,3-dioxolane-2,6'-3,5,7,8-tetrahydroquinazolin]-4'-one (105) (1.5 g, 6.75 mmol) in DMF (15 mL) was added anhydrous potassium carbonate (2.79 g, 20.25 mmol) and the reaction was stirred for 10 min. To this was added methyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (118) (2.97 g, 6.75 mmol) and the reaction was stirred at 25 °C for 16 h. After completion of the reaction (confirmed by TLC and LC / MS), the reaction mixture was evaporated to dryness and then purified by CombiFlash column chromatography (SiO; 40 g, 4% MeOH / DCM) to give methyl 7-[5-chloranyl-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (119) (1.6 g, 2.75 mmol, 40.73% yield) as an off-white solid.

[0286] 1 H-NMR (400 MHz, DMSO-d6) δ 8.68 (d, J=5.08 Hz 1H), 7.55-7.53 (m, 1H), 7.39 (d, J=2.16 Hz 1H), 7.31-7.24 (m, 2H),4.06 (s, 2H), 3.88 (t, J=16.92 Hz 1H), 7.42 (d, J=2.6 Hz 10H), 2.76 (s, 3H), 2.68 (s, 2H),1.88-1.82 (m, 2H), 1.57 (s, 3H) ppm.

[0287] MS calculated: 581; MS found: 582 (M+H)

[0288] 120 Synthesis: A solution of 7-[5-chloranyl-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (119) (1.6 g, 2.75 mmol) in HCl (15 mL, 6N) was stirred at 50°C for 4 hours. The reaction mixture was poured into cold saturated sodium bicarbonate solution (100 mL). The aqueous layer was extracted with 10% MeOH / DCM (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by Combiflash column chromatography (SiO; 12 g, 15% MeOH / DCM) to give methyl 7-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (120) (890 mg, 1.65 mmol, 60.18% yield) as a white solid.

[0289] 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.55 (dd, J= 2.6 Hz, 8.96 Hz, 1H), 7.40 (d J= 2.6Hz, 1H), 7.31-7.23 (m, 2H), 4.37 (m, 2H), 4.10 (m, 2H), 3.88 (s, 3H), 3.11 (s, 2H), 2.79 (t, J= 6.16 Hz, 2H), 2.71 (s, 3H), 2.58 (m, 1H), 1.60 (s, 3H) ppm.

[0290] m / z calculated: 537.11; found: 538.2 (M+H)

[0291] Scheme F [ka] Synthesis of 121: To a stirred solution of compound 7-[5-chloranil-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (120) (100 mg, 185.87 μmol) and N-methylmethanamine (12.57 mg, 278.81 μmol) in DCM (4 mL) was added catalytic AcOH at 0° C. The reaction mixture was then stirred at 25° C. for 2 hours. To this was added Na(OAc)BH (157.57 mg, 743.48 μmol) at 0° C., and the reaction mixture was stirred at 25° C. for 5 hours. After completion of the reaction (as judged by TLC and LCMS), excess solvent was evaporated under reduced pressure to give the crude material, which was purified by silica gel column chromatography (SiO; 12 g, 15% MeOH / DCM) to give methyl 7-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (121) (81 mg, 142.83 μmol, 76.85% yield) as an off-white solid.

[0292] Calculated m / z 566.2, observed (M+1) = 567.1

[0293] Synthesis of 122: (Compound 3) To a stirred solution of compound methyl 7-[5-chloranil-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (121) (78 mg, 137.54 μmol) in a mixture of THF (4 mL) and HO (1 mL) was added LiOH.HO (17.31 mg, 412.63 μmol) at 0° C. The reaction mixture was then stirred at 25° C. for 16 h. After completion of the reaction (as judged by TLC and LC / MS), the crude material was purified by reverse-phase preparative HPLC purification to give 7-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tris(fluoranyl)acetic acid (compound 3) (0.032 g, 47.75 μmol, 34.72% yield, 99.54% purity) as a white solid.

[0294] 1 H NMR (400 MHz, DMSO-d6): δ 9.68 (brs, 1H), 8.82 (brs, 1H), 7.59 (d, J=8 Hz, 1H), 7.45 (s, 2H), 7.33 (d, J=8 Hz, 1H), 4.34 (brs, 2H), 4.09 (brs, 2H), 3.49 (brs, 1H), 2.85 (s, 6H), 2.78 (s, 2H), 2.55 (brs, 2H), 2.07 (brs, 1H), 1.78 (brs, 1H), 1.56 (s, 3H) ppm.

[0295] Calculated m / z 552.1, observed (M+1) = 553.1

[0296] Scheme G [ka] Synthesis of 9a and 9b: This compound was synthesized from 7-[5-chloranil-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (121) (400 mg, 743.48 μmol) and N-methylmethanamine (50.28 mg, 1.12 mmol) as an off-white solid (340 mg, 76.85%).

[0297] The racemic compound was separated by chiral preparative HPLC to give methyl 7-[5-chloro-2-[2-[(3R,6S)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (121a, tentatively assigned) (140 mg, 246.87 μmol, 33.21% yield, 100% ee) off-white. The resulting solid was 105 mg, 185.15 μmol, 24.90% yield, 99.56% ee, of methyl 7-[5-chloro-2-[2-[(3S,6R)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (121b, tentatively assigned) (105 mg, 185.15 μmol, 24.90% yield, 99.56% ee) as an off-white solid.

[0298] Synthesis of 123a (compound 13) To a solution of 7-[5-chloro-2-[2-[(3R,6S)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (121a) (140 mg, 246.87 μmol) in a mixture of THF (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (200 mg, 250 μmol), and the mixture was stirred at 25° C. for 16 hours. The solvent was concentrated in vacuo. The resulting residue was purified by reverse-phase preparative HPLC to give 7-[5-chloro-2-[2-[(3R,6S)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-trifluoroacetic acid (123a) (Compound 13) (83 mg, 123.92 μmol, 50.20% yield, 99.60% purity, 100% ee) as a white solid.

[0299] 1 H NMR (400 MHz, DMSO-d6): δ 9.70 (brs, 1H), 8.82 (s, 1H), 7.59 (d, J=8 Hz, 1H), 7.45 (s, 2H), 7.33 (d, J=8 Hz, 1H), 4.34 (brs, 2H), 4.09 (brs, 2H), 3.49 (brs, 1H), 2.85 (s, 6H), 2.78 (s, 3H), 2.55 (brs, 2H), 2.07 (brs, 1H), 1.78-1.74 (m, 1H), 1.56 (s, 3H) ppm.

[0300] Calculated m / z 552.1, observed (M+1) = 553.1

[0301] Synthesis of 123b (compound 14) To a solution of 7-[5-chloro-2-[2-[(3S,6R)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (121b) (105 mg, 185.15 μmol) in a mixture of THF (5 ml) and water (1 ml) was added lithium hydroxide monohydrate (200 mg, 250 μmol), and the mixture was stirred at 25° C. for 16 h. The solvent was concentrated in vacuo. The resulting residue was purified by reverse-phase preparative HPLC to give 7-[5-chloro-2-[2-[(3S,6R)-6-(dimethylamino)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-trifluoroacetic acid (123b) (Compound 14) (57 mg, 85.25 μmol, 46.04% yield, 99.77% purity, 100% ee) as a white solid.

[0302] 1 H NMR (400 MHz, DMSO-d6): δ 9.69 (brs, 1H), 8.82 (s, 1H), 7.59 (d, J=8 Hz, 1H), 7.45 (s, 2H), 7.33 (d, J=8 Hz, 1H), 4.34 (brs, 2H), 4.09 (brs, 2H), 3.49 (brs, 1H), 2.85 (s, 6H), 2.74 (s, 3H), 2.55 (brs, 2H), 2.18 (brs, 1H), 1.78-1.74 (m, 1H), 1.56 (s, 3H) ppm.

[0303] Calculated m / z 552.1, observed (M+1) = 553.1

[0304] Scheme H [ka] Synthesis of 124 (compound 39) To a stirred solution of compound 7-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (122) (75 mg, 135.61 μmol) and MeSONH (32.25 mg, 339.02 μmol) in DCM (4 mL) was added EDCI.HCl (51.99 mg, 271.21 μmol) followed by DMAP (41.42 mg, 339.02 μmol) at 0 °C, and the reaction mixture was stirred at 25 °C for 20 h. After completion of the reaction (as judged by TLC and LC / MS), the volatiles were removed under reduced pressure, and the crude material thus obtained was purified by reverse-phase preparative HPLC to give 7-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-N-methylsulfonyl-thieno[3,2-b]pyridine-3-carboxamide; 2,2,2-tris(fluoranyl)acetic acid (124) (compound 39) (18 mg, 23.93 μmol, 17.64% yield, 98.92% purity) as an off-white solid.

[0305] 1 H NMR (400 MHz, DMSO-d6): δ 13.00 (brs, 1H), 9.51 (brs, 1H), 8.96 (s, 1H), 7.57 (dd, J=9.2, 2.4 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.36 (d, J=5.2 Hz, 2H), 4.14 (d, J=5.2 Hz, 2H), 3.49 (s, 3H), 2.86 (s, 6H), 2.83 (m, 1H), 2.77 (s, 3H), 2.58 (brs, 2H), 2.47-2.39 (m, 2H), 2.24-2.21 (m, 1H), 1.83-1.78 (m, 1H), 1.75 (s, 3H) ppm.

[0306] Calculated m / z 629.15, observed (M+1) = 630.1 (RT 2.21).

[0307] Scheme I [ka] 125 Synthesis: To a stirred solution of methyl 7-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (120) (100 mg, 185.87 μmol) in DCM (5 mL) was added 3,3-bis(fluoranyl)cyclobutanamine (39.81 mg, 371.74 μmol), and the reaction mixture was stirred at 25° C. for 3 hours. To this was added sodium triacetoxyborohydride (196.97 mg, 929.34 μmol) in small portions at 0° C., and stirring was continued at 25° C. for 3 hours. After completion of the reaction (as determined by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude material was purified by Combi-Flash column chromatography (SiO; 12 g, 15% MeOH / DCM) to give methyl 7-[2-[2-[6-[[3,3-bis(fluoranyl)cyclobutyl]amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (125) (100 mg, 158.95 μmol, 85.52% yield) as an off-white solid.

[0308] 1H NMR (400 MHz, DMSO-d6):8.70 (s,1H), 7.55-7.53 (m,1H ), 7.39 (s, 1H), 7.31-7.26 (m, 2H), 4.32-4.30 (m, 2H), 4.05 (s, 2H), 3.88 (s, 3H), 2.78-2.72 (m, 3H), 2.66 (s, 3H), 1.59-1.57 (m, 4H), 1.23-1.21(m, 4H) ppm.

[0309] m / z calculated 628, observed 629.2 (M+1);

[0310] Synthesis of 126: To a stirred solution of methyl 7-[2-[2-[6-[[3,3-bis(fluoranyl)cyclobutyl]amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (125) (100 mg, 158.95 μmol) in dichloromethane (5 mL) was added catalytic acetic acid followed by formalin (36 mg, 476.86 μmol, 33.05 μL, 40% purity) at 0° C. The reaction mixture was stirred for 3 hours at 25° C. To this was added sodium triacetoxyborohydride (135 mg, 635.81 μmol) 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 was purified by CombiFlash column chromatography (SiO; 12 g, 15% MeOH / DCM) to give methyl 7-[2-[2-[6-[[3,3-bis(fluoranyl)cyclobutyl]-methyl-amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (126) (90 mg, 100.76 μmol, 63.39% yield, 72% purity) as an off-white gum.

[0311] Calculated m / z 642, observed 643.4 (M+1)

[0312] Synthesis of 127 (compound 40) To a stirred solution of methyl 7-[2-[2-[6-[[3,3-bis(fluoranyl)cyclobutyl]-methyl-amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (126) (90 mg, 139.94 μmol) in THF (1.5 mL), water (0.3 mL), and methanol (0.3 mL) was added lithium hydroxide (monohydrate) (34 mg, 1.40 mmol), and the reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, the volatiles were removed in vacuo and the crude material was purified by reverse-phase preparative HPLC to give 7-[2-[2-[6-[[3,3-bis(fluoranyl)cyclobutyl]-methyl-amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tris(fluoranyl)acetic acid (compound 40) (23.18 mg, 30.42 μmol, 21.74% yield, 97.53% purity) as a white sticky solid.

[0313] 1 H NMR (400 MHz, DMSO-d6):8.81 (s,1H), 7.59 (dd, J=8.8 Hz,1H), 7.45 (m, 2H), 7.33 (d, J=8.8 Hz, 1H), 4.36 (m, 2H), 4.09 (m, 4H), 3.01 (m, 4H), 2.77-2.74 (m, 7H), 2.55 (s, 3H), 1.5 (s, 3H) ppm.

[0314] MS calculated: 628, MS found: 629.2 (M+H).

[0315] Scheme J [ka] 130 Synthesis: To a degassed solution of methyl 7-[5-chloranyl-2-[2-[2-methyl-6-(methylamino)-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (125) (150 mg, 271.21 μmol) in toluene (5 mL), 4-iodanylpyridine (4) (83.40 mg, 406.82 μmol) and CsCO (353.66 mg, 1.08 mmol) were added at 25° C. To this was added RuPhos (12.64 mg, 27.12 μmol) followed by RuPhosPdG (23.09 mg, 27.12 μmol) at 25° C. 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-[2-methyl-6-[methyl(4-pyridyl)amino]-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (130) (110 mg, 174.56 μmol, 64.36% yield) as a brown solid.

[0316] Calculated m / z 629.2, observed (M+1) = 630.3

[0317] Synthesis of 131 (compound 47) To a stirred solution of compound 7-[5-chloranyl-2-[2-[2-methyl-6-[methyl(4-pyridyl)amino]-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (130) (100 mg, 158.69 μmol) in a mixture of THF (2 mL) and water (500.00 μL) was added LiOH.HO (26.63 mg, 634.76 μmol, 17.64 μL) at 25 °C, and the reaction mixture was stirred at the same temperature for 4 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-6-[methyl(4-pyridyl)amino]-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tris(fluoranyl)acetic acid (compound 47) (35 mg, 47.48 μmol, yield 29.92%, purity 99.06%) as a white sticky solid.

[0318] 1 H NMR (400 MHz, DMSO-d6): δ 13.28 (brs, 1H), 8.85 (s, 1H), 8.20 (d, J=7.6, 2H), 7.57 (dd, J=8.8, 2.4 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.16 (d, J=6.8 Hz, 1H), 4.34 (m, 3H), 4.14 (brs, 2H), 3.10 (s, 3H), 2.77 (s, 3H), 2.55 (s, 3H), 2.16-2.05 (m, 1H), 1.93-1.88 (m, 1H), 1.77 (s, 3H).

[0319] Calculated m / z 615.17, observed (M+1) = 616.1 (RT 2.15).

[0320] Scheme K [ka] Synthesis of 133: To a stirred solution of methyl 7-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (120) (300 mg, 555 μmol) in DCM (4 mL) was added catalytic acetic acid followed by 1,1-di(methyl)ethyl 3-(methylamino)azetidine-1-carboxylate (132) (150 mg, 832 μmol) at 0° C., and the reaction mixture was stirred at 25° C. for 30 minutes. To this was added sodium triacetoxyborohydride (176 mg, 832 μmol) in portions at 0° C., and stirring was continued at 25° C. for 16 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 Combiflash column chromatography (SiO; 4 g, 15% MeOH-DCM) to give methyl 7-[5-chloranyl-2-[2-[6-[[1-[1,1-di(methyl)ethoxycarbonyl]azetidin-3-yl]-methyl-amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (133) (0.220 g, 310.62 μmol, 60% yield) as a white solid.

[0321] MS calculated: 707, MS found: 708 (M+H).

[0322] Synthesis of 134: To a stirred solution of methyl 7-[5-chloranyl-2-[2-[6-[[1-[1,1-di(methyl)ethoxycarbonyl]azetidin-3-yl]-methyl-amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (133) (0.220 g, 310.62 μmol) in DCM (2 mL) was added HCl-4 (M) in dioxane (2.0 mL, 8 mmol) at 0° C., and the reaction mixture was stirred for 2 hours at 25° C. After completion of the reaction (as judged solely by LC / MS), the reaction mixture was evaporated under reduced pressure. The crude material thus obtained was purified by trituration with EtO to give chloran; methyl 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (134) (150 mg, 232.70 μmol, 74.91% yield) as an off-white solid, which was used in the next step without further purification.

[0323] MS calculated: 607, MS found: 608 (M+H).

[0324] Synthesis of 135: (Compound 66) To a stirred solution of methyl 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (134) (0.060 g, 98.66 μmol) in a mixture of THF (5 mL) and water (1 mL) was added LiOH.HO (4.14 mg, 98.66 μmol, 2.74 μL) at 25° C., and the reaction mixture was stirred at 25° C. for 4 hours. After completion of the reaction (as judged by TLC and LCMS), the solvent was evaporated in vacuo. The crude product thus obtained was purified by reverse-phase preparative HPLC to give 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tris(fluoranyl)acetic acid (21 mg, 29.43 μmol, 29.83% yield, 99.25% purity) (Compound 66) as a white solid.

[0325] 1H NMR (400 MHz, DMSO-d6): 8.78 (s, 1H), 8.7-8.2 (m, 3H), 7.57-7.54 (m, 1H), 7.42 (d, J=2.4 Hz 1H), 7.38 (s, 1H), 7.31 (t, J=9.2 Hz 1H), 4.35-3.5 (m, 10H), 2.75 (s, 5H),2.35 (s, 3H),2.1 (s, 1H), 1.9 (bs, 1H), 1.7 (s, 3H), 1.6 (bs, 1H) ppm.

[0326] m / z calculated 593, observed 594 (M+H).

[0327] Synthesis of 137: To a stirred solution of the compound 7-[2-[2-[6-[azetidin-3-yl(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate HCl (134) (0.210 g, 325.78 μmol) in NMP (4.0 mL) was added KCO (134.87 mg, 977.33 μmol) followed by 2,2,2-tris(fluoranil)ethyl tris(fluoranil)methanesulfonate (136) (90.74 mg, 390.93 μmol, 56.32 μL) at 25 °C, and the reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to 25 °C. The reaction mixture was quenched with aqueous NH4Cl 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 trituration with Et2O to give methyl 7-[5-chloranyl-2-[2-[2-methyl-6-[methyl-[1-[2,2,2-tris(fluoranyl)ethyl]azetidin-3-yl]amino]-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (137) (130 mg, 188.36 μmol, 57.82% yield) as a brown gum.

[0328] MS calculated: 689, MS found: 690 (M+H).

[0329] Synthesis of 138 (compound 64) To a stirred solution of the compound 7-[5-chloranyl-2-[2-[2-methyl-6-[methyl-[1-[2,2,2-tris(fluoranyl)ethyl]azetidin-3-yl]amino]-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (137) (0.100 g, 144.89 μmol) in a mixture of THF (5 mL) and water (1 mL) was added LiOH.HO (6.08 mg, 144.89 μmol, 4.03 μL) at 25° C. The reaction mixture was stirred at 25° C. for 4 hours. After completion of the reaction (as determined by TLC and LCMS), the solvent was evaporated in vacuo. The crude product thus obtained was purified by reverse-phase preparative HPLC to give 7-[5-chloranyl-2-[2-[2-methyl-6-[methyl-[1-[2,2,2-tris(fluoranyl)ethyl]azetidin-3-yl]amino]-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid; 2,2,2-tris(fluoranyl)acetic acid (Compound 64) (8 mg, 9.28 μmol, yield 6.40%, purity 91.63%) as a white solid.

[0330] 1H NMR (400 MHz, DMSO-d6): 7.56 (d, J=8.8 Hz 1H), 7.41 (d, J=14.4 Hz 2H), 7.31 (d, J=8.8 Hz 1H), 7.16 (bs, 1H), 7.02 (bs, 1H), 6.90 (bs, 1H), 4.35 (bs, 2H), 4.12 (bs, 2H),3.74 (t, 2H),3.50 (bs, 2H), 3.27 (d, J=10 Hz 2H), 2.76 (s, 3H), 2.66 (s, 4H), 2.55 (s, 2H), 2.08-2.04 (m, 2H), 1.74 (s, 3H) ppm.

[0331] Calculated m / z 675, observed 674 (M−H).

[0332] Scheme L [ka] Synthesis of 141: To a stirred solution of 1H-methyl pyrrole-2-carboxylate (139) (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 (140) (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 in hexanes) to give methyl 1-azanylpyrrole-2-carboxylate (141) (11 g, 78.49 mmol, 98.21% yield) as a pale yellow viscous liquid.

[0333] 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.

[0334] Synthesis of 143: To a stirred solution of methyl 1-azanylpyrrole-2-carboxylate (141) (5 g, 35.68 mmol) in methanol (200 mL) was added ethyl 3-oxidanylidenebutanoate (142) (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 (143) (8 g, crude) as a yellow oil, which was carried on to the next step without further purification.

[0335] MS calculated: 252.2, MS found: 253.2 (M+H).

[0336] Synthesis of 144: To a stirred solution of methyl 1-[[(E)-3-ethoxy-1-methyl-3-oxidanylidene-prop-1-enyl]amino]pyrrole-2-carboxylate (143) (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 (144) (2.5 g, 12.12 mmol, 38.23% yield) as an off-white solid.

[0337] 1H NMR (400 MHz, DMSO-d6): 11.72 (s, 1H), 7.28 (d, J=4.76 Hz, 1H), 6.61 (d, J=4.8 Hz, 1H), 6.19 (s, 1H), 3.78 (s, 3H), 2.39 (s, 3H) ppm.

[0338] MS calculated: 206, MS found: 207 (M+H).

[0339] Synthesis of 145: 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 (144) (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 (145) (1.9 g, 8.46 mmol, 69.76% yield) as an off-white solid.

[0340] 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.

[0341] MS calculated: 224, MS found: 224.8 (M+H).

[0342] Synthesis of 147: To a stirred mixture of methyl 4-chloranyl-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (1.9 g, 8.46 mmol) (145) and (5-chloranyl-2-oxidanyl-phenyl)boronic acid (146) (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. To this was added Pd(dppf)Cl (1.86 g, 2.54 mmol), 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, 50% EtOAc / hexane as eluent) to give methyl 4-(5-chloranyl-2-oxidanyl-phenyl)-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (147) (2.1 g, 6.63 mmol, 78.39% yield) as a pale yellow solid.

[0343] 1H NMR (400 MHz, 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.

[0344] MS calculated: 316, MS observed: 315.2 (MH).

[0345] Synthesis of 148: To a stirred solution of methyl 4-(5-chloranyl-2-oxidanyl-phenyl)-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (147) (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 (148) (3.5 g, 8.18 mmol, 51.81% yield, 99% purity) as an off-white solid.

[0346] 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.

[0347] MS calculated: 422, MS found: 423.1 (M+H).

[0348] Scheme M(R 1 =H) [ka] Synthesis of 150a: To a stirred solution of methyl 4-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (149a) (737 mg, 1.80 mmol) in DMF (10 mL) was added 2'-methylspiro[1,3-dioxolane-2,6'-3,5,7,8-tetrahydroquinazolin]-4'-one (105) (400 mg, 1.80 mmol) followed by K2CO3 (746 mg, 5.40 mmol) at 25 °C under a nitrogen atmosphere, and the reaction mixture was stirred at 45 °C for 16 h. After completion of the reaction (as judged by LCMS and TLC), the reaction mixture was cooled to 25 °C and quenched with water. The aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by Combiflash column chromatography (SiO; 12 g; 90% EtOAc / hexane) to give methyl 4-[5-chloranyl-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (150a) (410 mg, 744.12 μmol, 41.34% yield) as a yellow solid.

[0349] 1 H NMR (400 MHz, DMSO-d6): 8.49(d,J=4.44Hz,1H), 7.55-7.52(m,1H), 7.42(d,J=2.52Hz,1H), 7.34(d,J=4.64Hz,1H), 7.27(d,J=8.52Hz,1H), 6.91(d,J=4.64Hz,1H), 6.09(d,J=4.68Hz,1H), 4.28-4.24(m,2H), 4.06-4.01(m,2H), 3.96(s,4H), 3.84(s,3H), 2.49-2.44(m,6H), 1.79(t,J=6.36Hz,2H), 1.71(s,3H) ppm.

[0350] MS calculated: 550.16, MS found: 551.5 (M+H).

[0351] Synthesis of 151a: To a stirred solution of methyl 4-[5-chloranyl-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (150a) (200 mg, 362.98 μmol), 6(N)HCl (2 ml) was added at 25°C, and the reaction mixture was stirred at 50°C for 1 hour. After completion of the reaction, the reaction mixture was quenched with aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude material thus obtained was purified by Combiflash column chromatography (SiO, 4 g, 5% MeOH-DCM) to give methyl 4-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (151a) (116 mg, 228.83 μmol, 63.04% yield) as a yellow solid.

[0352] 1 H NMR (400 MHz, DMSO-d6): 8.50(d,J=4.56Hz,1H), 7.54(dd, J=2.56Hz,1H), 7.42(d,J=2.6Hz,1H), 7.35(d,J=4.76Hz,1H), 7.28(d,J=8.92Hz,1H), 6.91(d,J=4.56Hz,1H), 6.08(d,J=4.76Hz,1H), 4.29(t,J=4.52Hz,2H), 4.10(d,J=4.64Hz,2H), 3.84(s,3H), 3.09(s,2H), 2.79(t,J=6.84Hz,2H), 2.56-2.53(m,2H), 1.76(s,3H) ppm.

[0353] MS calculated: 506.14, MS found: 507.4 (M+H).

[0354] Synthesis of 152a: To a stirred solution of 4-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (151a) (80 mg, 157.81 μmol) in DCE (6 mL) was added catalytic acetic acid followed by N-methylmethanamine (36 mg, 789.05 μmol, 45.90 μL) (0.4 mL of a 2 M solution) at 0° C., and the reaction mixture was stirred at 25° C. for 2 hours. To this was added sodium triacetoxyborohydride (201 mg, 946.86 μmol) in small portions at 0° C., and stirring was continued at 25° C. for 2 hours. After completion of the reaction (as determined by TLC and LC / MS), the volatiles were removed under reduced pressure. The crude was purified by Combiflash column chromatography (amine functionalized; 4 g, 5% MeOH in DCM) to give 4-[5-chloranil-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (152a) (65 mg, 121.26 μmol, 76.84% yield) as a pale yellow solid.

[0355] 1 H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J=4.6Hz, 1H), 7.56-7.53 (m, 1H), 7.42 (d, J=2.6Hz, 1H), 7.35 (d, J=4.8Hz, 1H), 7.28 (d, J=8.9Hz, 1H), 6.91 (d, J=4.6Hz, 1H), 6.91 (d, J=4.8Hz, 1H), 4.29 (t, J=4.7Hz, 2H), 4.07 (t, J=4.6Hz, 2H), 3.84 (s, 3H), 2.23(s, 6H), 2.17-2.13 (m, 1H), 1.92-1.89 (m, 1H), 1.73 (s, 3H), 1.53-1.50 (m, 1H), 1.23 (s, 4H) ppm.

[0356] MS calculated: 535.20, MS observed: 536.0 (M+H)

[0357] Synthesis of 153a: (Compound 30) To a stirred solution of methyl 4-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylate (152a) (65 mg, 121.26 μmol) in THF (1.2 mL), methanol (0.3 mL), and water (0.3 mL) was added lithium hydroxide monohydrate (98%) (15 mg, 363.79 μmol, 10.11 μL) at 25° C., and the reaction mixture was stirred at 25° C. for 1 hour. After completion of the reaction, the volatiles were removed under reduced pressure and the crude was purified by reverse-phase preparative HPLC to give 4-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-7-carboxylic acid (Compound 30) (30 mg, 57.44 μmol, 47.37% yield, 99.94% purity) as a pale green solid.

[0358] 1 H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J=4.5Hz, 1H), 7.56-7.53 (m, 1H), 7.42 (d, J=2.7Hz, 1H), 7.32-7.26 (m, 2H), 6.86 (d, J=4.5Hz, 1H), 6.11 (d, J=4.8Hz, 1H), 4.28 (t, J=4.9Hz, 2H), 4.07 (t, J=4.9Hz, 2H), 2.46 (s, 2H), 2.24 (s, 6H), 2.17-2.13 (m, 1H), 1.92-1.89 (m, 1H), 1.75 (s, 3H), 1.51 (brs, 1H) ppm.

[0359] MS calculated: 521.18, MS observed: 522.2 (M+H)

[0360] Scheme M(R 1 =CH3) [ka] Synthesis of 150b: To a stirred solution of 2'-methylspiro[1,3-dioxolane-2,6'-3,5,7,8-tetrahydroquinazolin]-4'-one (105) (200 mg, 899.93 μmol) in DMF (10 mL), potassium carbonate (granules) (249 mg, 1.80 mmol) was added, followed by methyl 4-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (149b) (381 mg, 899.93 μmol) at 25 °C, and the reaction mixture was stirred at 45 °C for 17 h. After completion of the reaction, the reaction mixture was poured into cold water and extracted with EtOAc. The combined organic portions were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by Combiflash column chromatography (SiO, 12 g, 5% MeOH / DCM) to give methyl 4-[5-chloranyl-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (150b) (250 mg, 442.47 μmol, 49.17% yield) as a white solid.

[0361] 1 H NMR (400 MHz, DMSO-d6): δ 7.54-7.52 (m, 1H), 7.41 (d, J=2.5Hz, 1H), 7.27-7.25 (m, 2H), 6.85 (s, 1H), 6.04 (d, J=4.5Hz, 1H), 4.27 (s, 2H), 4.07 (s, 2H), 3.91 (s, 4H), 3.83 (s, 3H), 2.53 (s, 4H), 2.44 (s, 4H), 1.90-1.87 (m, 2H), 1.74 (s, 3H)ppm.

[0362] MS calculated: 564.18; MS found: 565.0 (M+H).

[0363] Synthesis of 151b: A mixture of 4-[5-chloranil-2-[2-(2'-methyl-4'-oxidanylidene-spiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinazolin]-3'-yl)ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (150b) (560 mg, 991.12 μmol) and 6(N) aqueous HCl (25 mL) was heated at 60 °C for 1.5 h. After completion of the reaction, the reaction mixture was slowly quenched with solid NaHCO under cooled conditions (pH ∼8). The aqueous layer was extracted with EtOAc, and the combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by Combiflash column chromatography (SiO, 12 g, 2% MeOH / DCM) to give methyl 4-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin]-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (151b) (405 mg, 777.41 μmol, 78.44% yield) as a yellow solid.

[0364] 1 H NMR (400 MHz, DMSO-d6): δ 7.55-7.52 (m, 1H), 7.41 (d, J=2.6Hz, 1H), 7.28-7.26 (m, 2H), 6.86 (s, 1H), 6.03 (d, J=4.8Hz, 1H), 4.29 (t, J=4.5Hz, 2H), 4.11 (t, J=4.6Hz, 2H), 3.83 (s, 3H), 3.08 (s, 2H), 2.81-2.78 (m, 2H), 2.56-2.50 (m, 5H), 1.80 (s, 3H) ppm.

[0365] MS calculated: 520.15, MS found: 521.2 (M+H).

[0366] Synthesis of 152b: To a stirred solution of methyl 4-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin]-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (151b) (150 mg, 287.93 μmol) in 1,2-dichloroethane (8 mL) was added acetic acid (2 mg, 28.79 μmol, 1.65 μL) followed by N,N-dimethylamine (65 mg, 1.44 mmol, 83.75 μL, 0.35 mL, 2 (M) solution in THF) at 25° C., and the reaction mixture was stirred for 2 hours at 25° C. To this, sodium triacetoxyborohydride (305 mg, 1.44 mmol) was added at 0° C., and the reaction mixture was stirred for 2 hours at 25° C. The volatiles were removed under reduced pressure and the crude was purified by amine-functionalized Combiflash column chromatography (4 g, 0.2% methanol / DCM) to afford methyl 4-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (152b) (130 mg, 236.34 μmol, 82.08% yield) as a pale yellow solid.

[0367] 1H NMR (400 MHz, DMSO-d6): δ 7.55-7.52 (m, 1H), 7.41 (d, J=2.4Hz, 1H), 7.28-7.26 (m, 2H), 6.85 (s, 1H), 6.05 (d, J=4.7Hz, 1H), 4.28-4.27 (m, 2H), 4.09-4.07 (m, 2H), 3.83 (s, 3H), 2.54 (s, 3H), 2.45-2.33 (m, 2H), 2.21 (s, 6H), 1.76 (s, 3H), 1.48-1.46 (m, 1H) ppm.

[0368] MS calculated: 549.21, MS found: 550.4 (M+H).

[0369] Synthesis of 153b To a stirred solution of methyl 4-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (13) (65 mg, 118.17 μmol) in a mixture of THF (1.2 mL), water (0.3 mL), and methanol (0.3 mL) was added lithium hydroxide monohydrate (25 mg, 590.86 μmol) at 25° C., and the reaction mixture was stirred at 25° C. for 1 hour. After completion of the reaction, the volatiles were removed under reduced pressure and the crude was purified by reverse-phase preparative HPLC to give 4-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (153b) (26 mg, 48.19 μmol, 40.78% yield, 99.34% purity) as an off-white solid.

[0370] 1H NMR (400 MHz, DMSO-d6): δ 7.55-7.52 (m, 1H), 7.41 (d, J=2.7Hz, 1H), 7.28-7.24 (m, 2H), 6.83 (s, 1H), 6.06 (d, J=4.8Hz, 1H), 4.28 (t, J=4.8Hz, 2H), 4.08 (t, J=4.8Hz, 2H), 2.54 (s, 3H), 2.48-2.36 (m, 3H), 2.21 (s, 6H), 2.15-2.07 (m, 1H), 1.91-1.88 (m, 1H), 1.77 (s, 3H), 1.54-1.47 (m, 1H) ppm.

[0371] MS calculated: 535.20, MS observed: 536.30 (M+H)

[0372] Synthesis of compound 59 To a stirred solution of 4-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (compound 36) (60 mg, 111.94 μmol) in dichloromethane (1.5 ml) was added N,N-di(methyl)pyridin-4-amine (68 mg, 559.68 μmol) followed by chloran; 3-(ethyliminomethyleneamino)-N,N-di(methyl)propan-1-amine (43 mg, 223.87 μmol) at 25° C., and the reaction mixture was stirred at 25° C. for 0.5 h. To this was added methanesulfonamide (53.24 mg, 559.68 μmol) at 25° C., and the reaction mixture was stirred at 25° C. for 17 hours. After completion of the reaction, the reaction mixture was diluted with DCM, washed with water, brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to give 4-[5-chloranyl-2-[2-[6-[di(methyl)amino]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-N-methylsulfonyl-pyrrolo[1,2-b]pyridazine-7-carboxamide (Compound 59) (29 mg, 45.96 μmol, 41.06% yield, 97.18% purity) as a pale yellow solid.

[0373] 1H NMR (400 MHz, MeOD): δ 7.56-7.53 (m, 1H), 7.39 (d, J=2.3Hz, 1H), 7.30-7.25 (m, 2H), 6.78 (s, 1H), 6.06 (d, J=4.7Hz, 1H), 4.27-4.25 (m, 2H), 4.11 (s, 2H), 3.24 (s, 5H), 2.83 (s, 1H), 2.54 (s, 4H), 2.20-2.13 (m, 1H), 2.02-2.00 (m, 1H), 1.91 (s, 3H), 1.58-1.55 (m, 1H) ppm.

[0374] MS calculated: 612.19, MS observed: 613.2 (M+H)

[0375] Synthesis of 152c: To a stirred solution of methyl 4-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (151b) (100 mg, 191.95 μmol) in 1,2-dichloroethane (3 mL), AcOH (6 mg, 95.98 μmol, 5.49 μL) was added followed by piperidine (33 mg, 383.90 μmol, 37.92 μL) at 25° C., and the reaction mixture was stirred at that temperature for 5 hours. To this, sodium triacetoxyborohydride (142 mg, 671.83 μmol) was added at 0° C., and the reaction mixture was stirred at 25° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude material thus obtained was purified by CombiFlash column chromatography (SiO; 12 g, 8% MeOH / DCM) to give methyl 4-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-(1-piperidyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (152c) (90 mg, 152.51 μmol, 79.45% yield) as a yellow solid.

[0376] 1H NMR (400 MHz, DMSO-d6): δ 7.54-7.52 (m, 1H), 7.44-7.41 (m, 1H), 7.28-7.26 (m, 2H), 6.84 (s, 1H), 6.04 (d, J=5Hz, 1H), 4.28 (s, 2H),4.07 (s, 2H), 3.83 (s, 3H), 2.41 (s, 6H), 1.75 (s, 3H), 1.49 (s, 4H), 1.39 (s, 3H) ppm.

[0377] MS calculated: 589.25, MS found: 590.1 (M+H).

[0378] Synthesis of 153c (compound 45) To a stirred solution of 4-[5-chloranil-2-[2-[2-methyl-4-oxidanylidene-6-(1-piperidyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylate (152c) (90 mg, 152.51 μmol) in a mixture of THF (2 mL):HO (0.4 mL):MeOH (0.4 mL) was added LiOH.HO (26 mg, 610.05 μmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude was purified by reverse-phase preparative HPLC to give 4-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-(1-piperidyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (153c) (Compound 45) (23 mg, 39.47 μmol, 25.88% yield, 98.87% purity) as a pale yellow solid.

[0379] MS calculated: 575.23, MS observed: 576.3 (M+H)

[0380] 1H NMR (400 MHz, MeOD): δ 7.47-7.43 (m, 1H), 7.26-7.23 (m, 2H), 7.18 (d, J=2.3Hz, 1H), 6.51 (s, 1H), 5.91 (d, J=4.5Hz, 1H), 4.24 (s, 4H), 2.78-2.66 (m, 4H), 2.56 (s, 3H), 2.26-2.23 (m, 5H), 1.93-1.91 (m, 6H), 1.68 (s, 2H)ppm.

[0381] Synthesis of compound 62 To a stirred solution of 4-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-(1-piperidyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-pyrrolo[1,2-b]pyridazine-7-carboxylic acid (Compound 45) (120 mg, 208.30 μmol) in dichloromethane (6 ml), DMAP (127 mg, 1.04 mmol) was added, followed by EDC-HCl (79.86 mg, 416.61 μmol), and the reaction mixture was stirred at 25° C. for 0.5 hours. To this was added methanesulfonamide (99 mg, 1.04 mmol) 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 material was purified by reverse-phase preparative HPLC to give 4-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-(1-piperidyl)-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-2-methyl-N-methylsulfonyl-pyrrolo[1,2-b]pyridazine-7-carboxamide (Compound 62) (24 mg, 36.46 μmol, 17.51% yield, 99.24% purity) as a pale yellow solid.

[0382] MS calculated: 652.22, MS observed: 653.3 (M+H)

[0383] 1H NMR (400 MHz, DMSO): δ 7.56-7.53 (m, 1H), 7.39 (d, J=2.6Hz, 1H), 7.30-7.25 (m, 2H), 6.79 (s, 1H), 6.04 (d, J=4.7Hz, 1H), 4.31-4.25 (m, 2H), 4.11 (s, 2H), 3.25 (s, 4H), 2.81 (brs, 4H), 2.54 (s, 3H), 2.20-2.13 (m, 1H), 2.02-2.00 (m, 1H), 1.91 (s, 3H), 1.63 (s, 4H), 1.47 (s, 2H)ppm.

[0384] Scheme N [ka] Synthesis of compound 135 To a stirred solution of 4-[tris(fluoranyl)methoxy]piperidine (18.86 g, 111.52 mmol, 2.0 equiv.) in dichloroethane (300 mL, 10 V) at room temperature, triethylamine (8.46 g, 83.64 mmol, 11.66 mL, 1.5 equiv.) was added and stirred for 10 min, followed by methyl 7-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (30 g, 55.76 mmol, 1 equiv.) at the same temperature and continued for 4 h. Then, sodium cyanoborohydride (3.50 g, 55.76 mmol, 5.0 equiv.) was added to the reaction mixture, which was continued at the same temperature for 36 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water (10 vol.) was added to the reaction mass and extracted with 10% MeOH / DCM (10 vol.). The organics were collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude compound was purified by reverse-phase column chromatography (using Celite and eluting with a gradient of 45-50% acetonitrile / 0.1% aqueous ammonium bicarbonate) to give methyl 7-(5-chloro-2-(2-(2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (16 g, 41.57%) as a white solid. LCMS: 691.43 [M+1]

[0385] To a stirred solution of methyl 7-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-[4-[tris(fluoranyl)methoxy]-1-piperidyl]-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (13 g, 18.81 mmol) in tetrahydrofuran (130 mL) and water (20 mL) was added lithium hydroxide (450.48 mg, 18.81 mmol) at 0° C., and the resulting reaction was stirred at 25° C. for 2 hours. The reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated to completely remove volatiles. The pH of the reaction mixture was adjusted to neutral with saturated citric acid and then extracted with 10% methanol / dichloromethane (3×200 mL). The combined organics were washed with water and brine and dried over sodium sulfate. The dried organics were filtered and concentrated under reduced pressure to give racemic 7-(5-chloro-2-(2-(2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (13.4 g, 85.48%) as a brown solid. The chiral isomers were separated by SFC, and (S)-7-(5-chloro-2-(2-(2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (compound 135) was obtained as an off-white solid (4.5 g, 34. (R)-7-(5-chloro-2-(2-(2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (Compound 136) (4.39 g, 33.81%) as an off-white solid.

[0386] Scheme O [ka] Synthesis of 2: To a stirred solution of 1-chloranyl-2-methylsulfanyl-ethane (25 g, 226.03 mmol), MeI (160.41 g, 1130 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 36 h. All volatiles were concentrated under reduced pressure to give the crude compound. The crude compound was stirred with diethyl ether, and the solid formed was filtered through a Buckner funnel. The residue was washed with diethyl ether and dried under reduced pressure to give the required compound, 2-chloroethyl-di(methyl)sulfonium iodide (2), as a brown solid (45 g, 78%).

[0387] 1H NMR (DMSO-d6, 400 MHz): δ 4.16 (t, J = 8.0 Hz, 2H), 3.01 (s, 6H).

[0388] Synthesis of 4: To a stirred solution of potassium tert-butoxide (9.34 g, 83.24 mmol) in t-BuOH (50 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64.03 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and (chloromethyl)dimethylsulfonium iodide (12.22 g, 51.22 mmol) was added in small portions at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2 × 200 mL). Both organic layers were combined, washed with water, brine solution, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound (3.5 g, 30%) (light yellow oily liquid). The crude compound was purified by CombiFlash column chromatography (eluting with 15–20% ethyl acetate / petroleum ether) (3.5 g, 30%) (pale yellow oily liquid).

[0389] 1H NMR (DMSO-d6, 400 MHz): δ 0.68 (t, J = 4.0 Hz, 2H), 1.26 (t, J = 4.0 Hz, 2H), 1.99 (s, 2H), 2.11 (t, J = 8.0 Hz, 2H), 2.574 (t, J = 8.0 Hz, 2H), 4.01 (m, 6H).

[0390] Synthesis of 6 To a stirred solution of 6,9-dioxadispiro[2.1.45.33]dodecan-12-one (1.2 g, 6.59 mmol) in dimethyl carbonate (3 mL) was added a 60% dispersion of sodium hydride in mineral oil (757.01 mg, 32.93 mmol) in dimethyl carbonate (2 mL). The reaction mixture was stirred at room temperature for 5 minutes and then at 90 °C for 4 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with a saturated solution of ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed thoroughly with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound as a brown oily liquid (1.2 g), which was used without further purification. LCMS; [M+H]: 241.1.

[0391] Synthesis of 8 To a stirred solution of methyl 12-oxo-6,9-dioxadispiro[2.1.45.33]dodecane-11-carboxylate (1.2 g, 4.55 mmol) in 25% sodium methoxide (2.46 g, 45.45 mmol, 2.53 mL) in methanol was added acetamidine hydrochloride 97% (644.56 mg, 6.82 mmol). The reaction mixture was stirred at 60 °C for 6 h. The reaction was monitored by TLC and LCMS. The reaction mixture was acidified to pH (5-6) with 2 N citric acid (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water followed by brine solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (eluting with MeOH:DCM (1-10%)) to give the desired compound as a pale yellow solid (500 g, 44.31%). LCMS; [M+H]+: 249.17

[0392] Synthesis of 10 To a stirred solution of 8 in DMSO (5 mL) was added anhydrous potassium carbonate 99% (949.83 mg, 6.87 mmol), followed by methyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (1.594 g, 3.6 mmol), and the reaction mixture was heated at 60 °C for 4 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water, followed by brine solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (eluted with MeOH:DCM (1–5%)) (650 mg, 38%). LCMS [M+H]: 608.48.

[0393] Synthesis of 11 To a stirred solution of 10 (650 mg, 1.06 mmol) in THF (2 mL) was added 4 M HCl (3 mL) at room temperature. The reaction mixture was stirred at 60 °C for 6 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was basified with saturated NaHCO solution (10 ml) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water, brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material as a yellow solid (450 mg, 30%), which was used without further purification. LCMS; [M+H]: 564.22.

[0394] Synthesis of 13 To a solution of 12 (150 mg, 732.58 μmol) in DCE (1 mL), triethylamine (4.40 mg, 43.48 μmol) was added at room temperature. The reaction mixture was stirred for 10 min, followed by the addition of methyl 4-[5-chloranyl-2-[2-[2-methyl-4,6-bis(oxidanylidene)spiro[5,7-ihydroquinazoline-8,1'-cyclopropan]-3-yl]ethoxy]phenyl]-2-methyl-5H-cyclopenta[b]pyridine-7-carboxylate (200 mg, 366.29 μmol). The resulting mixture was stirred at room temperature for 16 h. NaCNBH (1.45 g, 23.01 mmol) was added to the reaction mixture at room temperature and stirred at the same temperature for 2 h. After completion of the reaction (monitored by TLC and LCMS), the reaction was quenched with water (5 mL), extracted with 10% MeOH:DCM (2 × 20 mL), and then washed with brine. The combined organic layers were dried over sodium sulfate and concentrated to give methyl 7-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-[4-[tris(fluoranyl)methoxy]-1-piperidyl]spiro[6,7-dihydro-5H-quinazoline-8,1′-cyclopropan]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (200 mg, 25.68%) as a gray solid. LCMS; [M+H]: 717.80.

[0395] Synthesis of Compounds 379 and 380 To a solution of methyl 7-[5-chloranyl-2-[2-[2-methyl-4-oxidanylidene-6-[4-[tris(fluoranyl)methoxy]-1-piperidyl]spiro[6,7-dihydro-5H-quinazoline-8,1'-cyclopropan]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (200 mg, 278.86 μmol) in THF (0.7 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (29.26 mg, 697.16 μmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was acidified with 2N citric acid (pH 5-6), extracted with 10% MeOH:DCM (2 × 30 mL), and then washed with brine. The combined organic layers were dried over sodium sulfate and concentrated to give 7-(5-chloro-2-(2-(2'-methyl-4'-oxo-6'-(4-(trifluoromethoxy)piperidin-1-yl)-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-quinazoline]-3'(5'H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid as a racemic mixture, which was purified by preparative separation, and the pure fractions were concentrated to give the racemate, which was subjected to SFC purification for the separation of enantiomers 379 and 380 (29 mg, 14.69%). LCMS: 717.80 [M+1] (NMR data in the table).

[0396] The following compounds in Table E1 are synthesized according to the above scheme: [Table 4-1] [Table 4-2] [Table 4-3]

[0397] Reductive amination: Condition A1: (Titanium isopropoxide / room temperature): Titanium isopropoxide (5.0 equiv.) was added to a mixture of amine (1.5 equiv.) and triethylamine (1.5 equiv.) in 1,2-dichloromethane (10 V) at room temperature. The keto compound (1.0 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. It was then cooled to 0°C, and sodium cyanoborohydride (5.0 equiv.) was added portionwise. The resulting reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and filtered through a Celite bed, followed by washing with 10% methanol / dichloromethane. The organic layer was separated, and the aqueous layer was washed again with 10% methanol / dichloromethane. The combined organic layers were concentrated under reduced pressure to give a crude sample. This was purified by flash column chromatography using 60-120 mesh silica gel. The desired product was eluted with 0-10% methanol / dichloromethane. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give the desired product.

[0398] Condition A2: (Titanium isopropoxide / 80°C): Titanium isopropoxide (5.0 equiv.) was added to a mixture of amine (1.5 equiv.) and triethylamine (1.5 equiv.) in 1,2-dichloromethane (10 V) at room temperature. The keto compound (1.0 equiv.) was added, and the resulting reaction mixture was stirred at 80°C for 16 hours. It was then cooled to 0°C, and sodium cyanoborohydride (5.0 equiv.) was added portionwise. The resulting reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and filtered through a Celite bed, followed by washing with 10% methanol / dichloromethane. The organic layer was separated, and the aqueous layer was washed again with 10% methanol / dichloromethane. The combined organic layers were concentrated under reduced pressure to give a crude sample. This was purified by flash column chromatography using 60-120 mesh silica gel. The desired product was eluted with 0-10% 10% methanol / dichloromethane as eluent. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give the desired product.

[0399] Condition A3: (Titanium isopropoxide / 60°C) Titanium isopropoxide (5.0 equiv.) was added to a mixture of amine (1.5 equiv.) and triethylamine (1.5 equiv.) in 1,2-dichloroethane (10 V) at room temperature. The keto compound (1.0 equiv.) was added, and the resulting reaction mixture was stirred at 60°C for 16 hours. It was then cooled to 0°C, and sodium cyanoborohydride (5.0 equiv.) was added portionwise. The resulting reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and filtered through a Celite bed, followed by washing with 10% methanol / dichloromethane. The organic layer was separated, and the aqueous layer was washed again with 10% methanol / dichloromethane. The combined organic layers were concentrated under reduced pressure to give a crude sample. This was purified by flash column chromatography using 60-120 mesh silica gel. The desired product was eluted with 0-10% 10% methanol / dichloromethane as eluent. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give the desired product.

[0400] Condition A4: (sodium acetate / toluene or methanol / room temperature) Sodium acetate (5.0 equiv.) was added to a mixture of an amine (1.5 equiv.) and triethylamine (1.5 equiv.) in toluene or methanol (10 V) at room temperature. The keto compound (1.0 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. It was then cooled to 0°C, and sodium cyanoborohydride (5.0 equiv.) was added in small portions. The resulting reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and filtered through a Celite bed, followed by washing with 10% methanol / dichloromethane. The organic layer was separated, and the aqueous layer was washed again with 10% methanol / dichloromethane. The combined organic layers were concentrated under reduced pressure to give a crude sample. This was purified by flash column chromatography using 60-120 mesh silica gel. The desired product was eluted with 0-10% methanol / dichloromethane. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give the desired product.

[0401] Condition A5: (Sodium acetate / 60°C): Sodium acetate (5.0 equiv.) was added to a mixture of amine (1.5 equiv.) and triethylamine (1.5 equiv.) in 1,2-dichloroethane (10 V) at room temperature. The keto compound (1.0 equiv.) was added, and the resulting reaction mixture was stirred at 60°C for 16 hours. It was then cooled to 0°C, and sodium cyanoborohydride (5.0 equiv.) was added portionwise. The resulting reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and filtered through a Celite bed, followed by washing with 10% methanol / dichloromethane. The organic layer was separated, and the aqueous layer was washed again with 10% methanol / dichloromethane. The combined organic layers were concentrated under reduced pressure to give a crude sample. This was purified by flash column chromatography using 60-120 mesh silica gel. The desired product was eluted with 0-10% methanol / dichloromethane. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give the desired product.

[0402] Condition A6: (TEA / DCE or methanol / room temperature): Triethylamine (5.0 equiv.) was added to a solution of the amine (1.5 equiv.) in 1,2-dichloroethane or methanol (10 V) at room temperature. The keto compound (1.0 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. It was then cooled to 0°C, and sodium cyanoborohydride (5.0 equiv.) was added in small portions. The resulting reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and filtered through a Celite bed, followed by washing with 10% methanol / dichloromethane. The organic layer was separated, and the aqueous layer was washed again with 10% methanol / dichloromethane. The combined organic layers were concentrated under reduced pressure to give a crude sample. This was purified by flash column chromatography using 60-120 mesh silica gel, and the desired product was eluted with 0-10% methanol / dichloromethane as eluent. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give the desired product.

[0403] Condition A7: (Titanium isopropoxide / methanol / 80°C) Titanium isopropoxide (5.0 equiv.) was added to a mixture of amine (1.5 equiv.) and triethylamine (1.5 equiv.) in methanol (10 V) at room temperature. The keto compound (1.0 equiv.) was added, and the resulting reaction mixture was stirred at 60°C for 16 hours. It was then cooled to 0°C, and sodium cyanoborohydride (5.0 equiv.) was added portionwise. The resulting reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and filtered through a Celite bed, followed by washing with 10% methanol / dichloromethane. The organic layer was separated, and the aqueous layer was washed again with 10% methanol / dichloromethane. The combined organic layers were concentrated under reduced pressure to give a crude sample. This was purified by flash column chromatography using 60-120 mesh silica gel. The desired product was eluted with 0-10% methanol / dichloromethane as eluent. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give the desired product.

[0404] Condition A8: (methanol / acetic acid): Acetic acid (catalyst) was added to a stirred solution of the amine (1.0 equiv.) and keto compound (1.1 equiv.) in methanol (10 V) at room temperature and stirred for 5 hours. Sodium cyanoborohydride (2 equiv.) was added at 0°C, then the mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, it was quenched with water and washed with 10% methanol / dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by reverse-phase flash chromatography (0-100% gradient of acetonitrile / 0.1% aqueous ammonium hydroxide, 230-400 mesh silica gel). The pure fractions were collected and concentrated under reduced pressure to give the desired product.

[0405] Ester hydrolysis (using lithium hydroxide monohydrate): Lithium hydroxide monohydrate (5 equiv.) was added to a solution of the ester analog (1 equiv.) in a THF:HO (3:1) mixture at room temperature. The resulting mixture was stirred at room temperature for 20 (xx) hours. The reaction progress was monitored by TLC and LCMS. The reaction mass was acidified to pH 4-6 with 1N HCl / saturated citric acid solution. The volatiles were removed under reduced pressure and washed with 10-15% methanol in dichloromethane. The combined organic layers were concentrated under reduced pressure to give the desired product.

[0406] Boc deprotection: The Boc derivative (1 equivalent) was dissolved in dichloromethane (10 V), followed by the addition of 4.0 M hydrochloric acid in 1,4-dioxane (6 equivalents) at 0° C. The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by TLC. After completion of the reaction, excess solvent was evaporated under reduced pressure to give the crude material. The crude material was further washed with diethyl ether (30 V). The resulting solid was further dried to give the desired product.

[0407] Alkylation using 2,2,2-tris(fluoranil)ethyl tris(fluoranil)methanesulfonate: The amine compound (1 equivalent) and K2CO3 (7 equivalents) in acetone (2 mL) were charged into a 25 mL three-necked round-bottom flask at room temperature. The resulting reaction mixture was stirred for 5 minutes, and then 2,2,2-tris(fluoranil)ethyl tris(fluoranil)methanesulfonate (11 equivalents) was added to the mixture. The resulting mixture was stirred at 80 °C for 4 hours. After completion of the reaction, excess solvent was evaporated under reduced pressure to obtain the crude material. The crude material was further purified by flash chromatography to obtain the desired product.

[0408] Alkylation of quinazolin-4-one: Potassium carbonate (granules) (1 equivalent) was added to a stirred solution of quinazolin-4-one analog (1 equivalent) in DMSO (10 V), and the resulting mixture was stirred at room temperature for 15 minutes. The bromo compound (0.7 equivalents) was then added, and the reaction mixture was then heated at 75°C for 3 hours. The reaction was monitored by TLC. After completion of the reaction, ice-cold water was added, and the precipitate formed was filtered. The resulting solid was washed with n-pentane to give the desired product.

[0409] Sulfonamide formation: Condition F1: Methanesulfonamide (10 eq.), 4-dimethylaminopyridine (1.5 eq.), EDC (3 eq.), and DIPEA (3.5 eq.) were added to a stirred solution of the acidic compound (1 eq.) in DCM (10 V) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with water and washed with DCM (2×100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC, and the required pure fractions were collected and concentrated to give the desired product.

[0410] Condition F2: Methanesulfonamide (5 eq.), CDI (3.5 eq.), and DBU (3.5 eq.) were added to a stirred solution of the acidic compound (1 eq.) in DMF (10 V) at 0 °C. The resulting mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with water and washed with DCM (2 × 100 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC, and the required pure fractions were collected and concentrated to give the desired product.

[0411] Condition F3: Methanesulfonamide (10 eq.), HATU (3 eq.), and DIPEA (3.5 eq.) were added to a stirred solution of the acidic compound (1 eq.) in THF (10 V) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with water and washed with DCM (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC, and the required pure fractions were collected and concentrated to give the desired product.

[0412] N-Methylation by reductive amination: Formaldehyde (37% solution) and sodium cyanoborohydride (337.75 mg, 5.37 mmol) were added to a stirred solution of the amine (700 mg, 1.07 mmol) in methanol (10 V). The reaction mixture was then stirred at room temperature for 16 h. The reaction progress was monitored by LC-MS. The reaction mixture was quenched with water and washed with 10% methanol / dichloromethane (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography using 100-200 mesh silica gel eluting with 0-10% methanol / dichloromethane. The required pure fractions were combined and concentrated to give the desired product.

[0413] Compound 532. (S)-7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid Compound 533. (R)-7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid [ka] Step-1: Synthesis of isopropyl 7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (3) In step 1, general procedure A2 was used to prepare 7-[5-chloranil-2-[2-[2-methyl-4,6-bis(oxidanylidene)-7,8-dihydro-5H-quinazolin]-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (350 mg, 650.54 μmol) and 5,6-bis(fluoranyl)isoindoline; hydrochloride (186. Synthesis from 97 mg, 975.81 μmol) gave isopropyl 7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (400 mg, crude) as a pale yellow solid. LCMS: 705.20 [M+1].

[0414] Step-2: Synthesis of 7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid In step 2, general procedure B was used to synthesize (S)-7-(5-chloro-2-(2-(6-[5,6-bis(fluoranyl)isoindolin-2-yl]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (400 mg, 567.21 μmol) and lithium hydroxide (67.92 mg, 2.84 mmol) to give (S)-7-(5-chloro-2-(2-(6 -(5,6-Difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid and (R)-7-(5-chloro-2-(2-(6-(5,6-difluoroisoindolin-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid were obtained. LCMS: 663.22 [M+1], 660.81 [M-1]. 2. Experimental procedures for examples 1-88: These were prepared from intermediate A (large keto) and the appropriate amine following the general procedure described for the synthesis of example 01: [ka] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8]

[0415] 3. Experimental procedures for compound 512 and compound 511. [ka] Step-1: Synthesis of methyl 7-(2-(2-(6-(7-(tert-butoxycarbonyl)-9,9-difluoro-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (3) This compound was synthesized by general procedure A1 to give methyl 7-(2-(2-(6-(7-(tert-butoxycarbonyl)-9,9-difluoro-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (400 mg, crude) as a pale yellow solid. LCMS: 826.2 [M+1].

[0416] Step-2: Synthesis of isopropyl 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (4) This compound was synthesized from methyl 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate by general procedure C to give isopropyl 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate as a pale yellow solid. LCMS:726.36[M+1].

[0417] Step 3: Synthesis of isopropyl 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (5) This compound was synthesized from 1-methylethyl 7-[2-[2-[6-[7,7-bis(fluoranyl)-2,9-diazaspiro[4.5]decan-2-yl]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-benzothiophene-3-carboxylate (180 mg, 248.18 μmol) using general procedure D to give isopropyl 7-(5-chloro-2-(2-(6-(9,9-difluoro-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate.

[0418] Step-4: Synthesis of 7-(5-chloro-2-(2-((6S)-6-(9,9-difluoro-7-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decan-2-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (compound 512). This compound was synthesized by general procedure B using methyl 7-[2-[2-[6-[9,9-bis(fluoranyl)-7-[2,2,2-tris(fluoranyl)ethyl]-2,7-diazaspiro[4.5]decan-2-yl]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (200 mg, 256.33 μmol) to give 7-[5-chloranyl-2-[2-[(6S)-6-[(7R)-9,9-difluoro-7-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decan-2-yl]-2-methyl-4- Oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (6 mg, 7.54 μmol, yield 2.94%, purity 96.29%) and 7-[5-chloranyl-2-[2-[(6R)-6-[(7S)-9,9-difluoro-7-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decan-2-yl]-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (9 mg, 11.46 μmol, yield 4.47%, purity 97.57%) were obtained. LCMS:766.32[M+1].

[0419] The following ester derivatives are prepared using the above protocol: Each ester is further hydrolyzed to give the final compound. [Table 6]

[0420] 4. Experimental Procedure for Compound 496 and Compound 497 [ka] Step-1: Synthesis of 4-methoxy-1-(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)piperidine (3) A three-neck flask equipped with a mechanical stirrer, Dean-Stark trap, and nitrogen inlet / outlet condenser was charged with 4-methoxypiperidine (5 g, 43.41 mmol), 1,4-dioxaspiro[4.5]decan-8-one (6.78 g, 43.41 mmol), 1,2,3-triazole (2.21 g, 32.01 mmol), and 50 mL of toluene. The reaction mixture was heated to reflux at 108-114 °C and stirred for 6-8 h while collecting water via the Dean-Stark trap. The reaction mixture was cooled to room temperature and methylmagnesium bromide (200 mmol, 3.0 M in THF) was added over 30 min, maintaining the internal temperature at <24 °C with efficient stirring. The reaction mixture was stirred at room temperature for an additional 1 h. Upon completion, the reaction mixture was added to 20% ammonium chloride solution over 30 min while maintaining the internal temperature at <30 °C. The organic layer was separated. The aqueous layer was washed with ethyl acetate (200 mL). The combined organic layers were washed with water (100 mL) and concentrated. The crude material was purified by silica gel chromatography to give 4-methoxy-1-(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)piperidine as a colorless oil (2.5 g, 22% yield). LCMS: 270.21 [M+1].

[0421] Step-2: Synthesis of 4-(4-methoxy-1-piperidyl)-4-methyl-cyclohexanone (4) To a stirred solution of 4-methoxy-1-(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)piperidine (2.0 g, 7.42 mmol) in tetrahydrofuran (20 mL) was added 6 M HCl (20 mL) at 25 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 6 hours. The reaction progress was monitored by LCMS. Upon completion, all volatiles were removed from the reaction mixture in vacuo. The resulting crude material was basified (to pH 7) using saturated NaHCO3 and washed with 15% methanol / dichloromethane (1000 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting gum was triturated with diethyl ether and dried to give 4-(4-methoxy-1-piperidyl)-4-methyl-cyclohexanone as a pale yellow oil (1.67 g, 39% yield). LCMS: 226.19 [M+1].

[0422] Step-3: Synthesis of methyl 5-(4-methoxy-1-piperidyl)-5-methyl-2-oxidanylidene-cyclohexanecarboxylate (6) To a stirred solution of 4-(4-methoxy-1-piperidyl)-4-methyl-cyclohexanone (1.0 g, 4.43 mmol) in THF (25 mL) was added sodium hydride (oil dispersion) 60% mineral oil dispersion (510 mg, 22.18 mmol) at 0 °C under a nitrogen atmosphere. Dimethyl carbonate (20 mL) was added to the mixture, and the resulting mixture was stirred at 80 °C for 6 h. Upon completion, the reaction mixture was quenched with ice-cold water and washed with 10% methanol-DCM. The combined organic layers were dried over Na SO and concentrated in vacuo. The resulting crude material was purified by column chromatography using 0-10% methanol-DCM as the eluent to afford methyl 5-(4-methoxy-1-piperidyl)-5-methyl-2-oxidanylidene-cyclohexanecarboxylate as a yellow gum (0.51 g, 40% yield). LCMS: 284.2 [M+1].

[0423] Step-4: Synthesis of 6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (8) To a stirred solution of methyl 5-(4-methoxy-1-piperidyl)-5-methyl-2-oxidanylidene-cyclohexanecarboxylate (0.5 g, 1.76 mmol) in methanol (5 mL), sodium methoxide solution (476.69 mg, 8.82 mmol) was added, followed by acetamidine hydrochloride (166.82 mg, 1.76 mmol), and the resulting mixture was stirred at 80 °C for 6 hours. Upon completion, the reaction mixture was concentrated to completely remove volatiles. The pH of the reaction mixture was adjusted to neutral with saturated citric acid and then washed with 10% methanol / dichloromethane (3 × 20 mL). The organic layer was dried over Na SO and concentrated in vacuo to give 6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (0.2 g, 39% yield), which was used directly in the next step. LCMS: 292.26 [M+1].

[0424] Step 5: Synthesis of methyl 7-[5-chloranyl-2-[2-[6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (10) To a stirred solution of 6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (0.5 g, 1.72 mmol) and methyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (605.02 mg, 1.37 mmol) in N,N'-dimethylformamide (5 mL) was added potassium carbonate powder (711.45 mg, 5.15 mmol), and the reaction mixture was stirred at 80° C. for 16 hours. After completion, the reaction mixture was poured into ice-cold water, and the resulting solid was filtered. The resulting crude material was purified by reverse-phase column chromatography using ACN-water as eluent to give methyl 7-[5-chloranyl-2-[2-[6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate as a white solid (0.125 g, 11.2% yield). LCMS: 651.31 [M+1].

[0425] Step-6: Synthesis of 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2,6-dimethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (11) To a stirred solution of methyl 7-[5-chloranyl-2-[2-[6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (100.00 mg, 153.56 μmol) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide (19.33 mg, 460.68 μmol) at 0° C., and the resulting reaction was stirred at 25° C. for 2 hours. The reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated to completely remove volatiles. The pH of the reaction mixture was adjusted to neutral with 1N HCl and then washed with 10% methanol / dichloromethane (3×20 mL). The combined organics were washed with water and brine and dried over sodium sulfate. The dried organics were filtered and concentrated under reduced pressure to give racemic 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2,6-dimethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid as an off-white solid. Chiral isomers were separated by SFC to give 7-[5-chloranil-2-[2-[(6S)-6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid as an off-white solid (21 mg, 32.23 μmol, yield: 21%) and 7-[5-chloranyl-2-[2-[(6R)-6-(4-methoxy-1-piperidyl)-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid as an off-white solid (15 mg, 22.72 μmol, 15% yield). LCMS: 637.34 [M+1].

[0426] The following ester analogs are prepared using the above protocol: Each ester is hydrolyzed to give the final compound. [Table 7]

[0427] 5. Experimental Procedures for Compound 565, Compound 559, and Compound 558 Synthesis scheme: [ka] Step-1: Synthesis of 6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2-methyl-4-oxidanylidene-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (3) To a stirred solution of 4-methoxy-3,3-di(methyl)piperidine (1.21 g, 6.73 mmol) in DCE (8.93 mL) was added triethylamine (851.83 mg, 8.42 mmol, 1.17 mL) at room temperature. Stirring was continued for 15 minutes. 2-Methyl-3,5,7,8-tetrahydroquinazoline-4,6-dione (1 g, 5.61 mmol) was then added at room temperature. The resulting reaction mixture was stirred at room temperature for 12 hours. Potassium cyanide (548.15 mg, 8.42 mmol) and methanol (893.33 μL) were then slowly added at room temperature. The reaction mixture was then stirred for 4 hours and monitored by LCMS. After completion of the reaction, it was quenched with water (50 mL) and washed with DCM. The organics were collected, dried over sodium sulfate, and concentrated under reduced pressure to give 6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2-methyl-4-oxidanylidene-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (1.2 g, 907.93 μmol, 16.18% yield, 25% purity). LCMS: 331.35 [M+1].

[0428] Step-2: Synthesis of 6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (4): To a stirred solution of 6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2-methyl-4-oxidanylidene-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (1.2 g, 3.63 mmol) in THF (12 mL) was added methylmagnesium bromide (3 M in EtO, 1.69 g, 14.53 mmol, 1.63 mL) at −75° C. under a N atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, cold water (20 mL) was added slowly and washed with ethyl acetate (20 mL×3). The organics were collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. The crude material was purified by reverse-phase column chromatography using 50% ACN and 1% ammonium bicarbonate solution to give 6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (400 mg, 713.75 μmol, 19.65% yield, 57% purity). LCMS: 320.22 [M+1].

[0429] Step-3: Synthesis of methyl 7-[5-chloranyl-2-[2-[6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (6) To a stirred solution of 6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2,6-di(methyl)-3,5,7,8-tetrahydroquinazolin-4-one (800 mg, 2.50 mmol) in DMF (546.56 μL) was added potassium carbonate (1.04 g, 7.51 mmol, 453.43 μL) and methyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (1.10 g, 2.50 mmol). The resulting mixture was heated at 80° C. for 4 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction was quenched with cold water (20 mL) and then washed with ethyl acetate (20 mL×3). The organics were collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. The crude material was purified by reverse-phase column chromatography using 50% ACN and 1% ammonium bicarbonate solution to give methyl 7-[5-chloranyl-2-[2-[6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (120 mg, 713.75 μmol, 19.65% yield, 52% purity). LCMS: 679.38 [M+1].

[0430] Step-4: Synthesis of 7-[5-chloranyl-2-[2-[(6R)-6-[(4S)-4-methoxy-3,3-dimethyl-1-piperidyl]-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylic acid (7): To a stirred solution of methyl 7-[5-chloranil-2-[2-[6-[4-methoxy-3,3-di(methyl)-1-piperidyl]-2,6-di(methyl)-4-oxidanylidene-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]thieno[3,2-b]pyridine-3-carboxylate (120 mg, 180.39 μmol) in THF (5 mL) and water (3 mL) was added lithium hydroxide (12.96 mg, 541.16 μmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction progress was monitored by LCMS. Upon completion, the volatiles were evaporated under reduced pressure, and the resulting crude material was acidified with 1 M citric acid and washed with 10% methanol-DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude compound obtained was purified by preparative HPLC, and the isomers were separated by SFC purification at room temperature to give each isomer. LCMS: 665.33 [M+1].

[0431] 6. Experimental Procedures for Compounds 516 and 515 [ka] Step-1: Synthesis of 2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile (3):

[0432] Triethylamine (2.92 g, 28.81 mmol, 4.02 mL) was added to a solution of 2-methyl-3,5,7,8-tetrahydroquinazoline-4,6-dione (3.5 g, 19.21 mmol) and 4-[tris(fluoranyl)methoxy]piperidine (4.87 g, 28.81 mmol) in DCE (100 mL) at room temperature and stirred for 3 hours. The reaction mixture was cooled to 0 °C, and KCN (1.99 g, 28.81 mmol) was added portionwise and warmed to room temperature for 5 hours. The reaction mixture was cooled to 0 °C, quenched with water, and extracted with DCM (100 mL × 3). The combined organic layer was washed with cold water (100 mL) and brine solution (100 mL). The organic layer was dried over Na SO and filtered. The filtrate was concentrated under reduced pressure to give 2-methyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile (3.5 g, 50%) as a brown gummy solid. LCMS: 357.27 [M+1].

[0433] Step-2: Synthesis of 2,6-dimethyl-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (4): Methylmagnesium bromide (1.30 g, 11.23 mmol, 1.26 mL) was slowly added dropwise to a solution of 2-methyl-4-oxidanylidene-6-[4-[tris(fluoranyl)methoxy]-1-piperidyl]-3,5,7,8-tetrahydroquinazoline-6-carbonitrile (800 mg, 2.25 mmol) in THF (10 mL) at −78° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution. Extraction with ethyl acetate (100 mL × 3) was then performed. The combined organic layers were washed with cold water (100 mL) and brine solution (100 mL). The organic layer was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified by Combi-Flash column chromatography using 230-400 mesh silica gel, and the desired product was eluted with 0-10% MeOH / DCM. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give 2,6-dimethyl-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (180 mg, 46%) as a brown solid. LCMS: 346.18 [M+1].

[0434] Step 3: Synthesis of methyl 7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (6): Potassium carbonate (180 mg, 1.30 mmol, 78.64 μL) was dissolved in 2,6-di(methyl)-6-[4-[tris(fluoranyl)methoxy]-1-piperidyl]-3,5,7,8-tetrahydroquinazolin-4-one (180 mg, 521.20 μmol).

[0435] The mixture was added to a DMF solution (5 mL) at room temperature, slowly heated to 75 °C, and stirred for 15 minutes. Then, 1,1-di(methyl)ethyl 7-[2-(2-bromanylethoxy)-5-chloranyl-phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (252 mg, 521.20 μmol) was slowly added in small portions to the reaction mixture at 75 °C, and the resulting reaction mixture was stirred at the same temperature for another 4 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with cold water (100 mL) and brine solution (100 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product as a brown liquid. The crude material was purified by CombiFlash column chromatography using 230-400 mesh silica gel. The desired product was eluted with 0-10% MeOH / DCM. Pure fractions (determined by TLC) were combined and evaporated under reduced pressure to give methyl 7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (120 mg, 35%) as a brown solid. LCMS: 705.23 [M+1].

[0436] Step 4: Synthesis of (S)-7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid and (R)-7-(5-chloro-2-(2-(2,6-dimethyl-4-oxo-6-(4-(trifluoromethoxy)piperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid Lithium hydroxide monohydrate (36 mg, 850.84 μmol, 23.65 μL) was added to a solution of methyl 7-[5-chloranyl-2-[2-[2,6-di(methyl)-4-oxidanylidene-6-[4-[tris(fluoranyl)methoxy]-1-piperidyl]-7,8-dihydro-5H-quinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (120 mg, 170.17 μmol) in a mixture of THF and HO (2 mL and 0.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure at 45 °C. The reaction mass was diluted with water and acidified with saturated aqueous citric acid to pH 4-6. Then, washing with 10% MeOH / dichloromethane (30 mL × 2) was performed. The combined organic layers were concentrated under reduced pressure to give the crude material. The crude material was purified by preparative HPLC (Column name: X-BRIDGE-C18 (150*19mm), 5u, Column number #MCL-PREP-COL-2022-068, Mobile phase A: 10mM ammonium bicarbonate / water, Mobile phase B: acetonitrile, Gradient program (T / %B): 0 / 15, 12 / 50, 12.1 / 98, 14 / 98, 14.1 / 15, 16 / 15, Flow rate (mL / min): 16, Sample loading (mg / injection) to give the desired product as an off-white solid. The isomers were separated by SFC to give the two desired isomers as off-white solids. LCMS: 691.25 [M+1].

[0437] The following ester analogs are prepared using the above protocol and hydrolyzed to the final compounds: [Table 8]

[0438] 7. Experimental Procedures for Compound 239 and Compound 240 [ka] Step-1: Synthesis of methyl 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate (3) This compound was synthesized from 6-(4-methoxy-1-piperidyl)-2-methyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (1.4 g, 5.05 mmol) by general procedure E to give methyl 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate. LCMS: 637.25.

[0439] Step-2: Synthesis of 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (4) This compound was synthesized from methyl 7-[5-chloranyl-2-[2-[6-(4-methoxy-1-piperidyl)-2-methyl-4-oxidanylidene-5,6,7,8-tetrahydroquinazolin-3-yl]ethoxy]phenyl]-5-methyl-thieno[3,2-b]pyridine-3-carboxylate (650 mg, 1.02 mmol) by general procedure B to give 7-(5-chloro-2-(2-(6-(4-methoxypiperidin-1-yl)-2-methyl-4-oxo...

Claims

1. Formula I″: 【Chemistry 1】 Compounds of 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 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 ６－１０ Aryl, 5- to 10-membered heteroaryl, C ３－６ Carbocyclyl, 3- to 6-membered heterocyclyl, —C(═O)NR ｃ S (= O) ２ R ａ , —C(═O)NR ｃ R ｄ , -(CH ２ ) C(=O) OR ｂ or -C(=O)OR ｂ wherein said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R １ is -NR １ａ R １ｂ or -OR １ｃ and R １’ represents hydrogen, deuterium, 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 R １ and R １’ together with the carbon atoms to which they are attached, C ３－１２ forming a carbocyclyl or a 3- to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted; R １ａ and R １ｂ are each independently hydrogen, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, C ３－１２ 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; or R １ａ and R １ｂ together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle, said heterocycle containing one or more R ａｂ optionally replaced by Each R ａｂ 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, 3- to 6-membered heterocyclyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, or —S(═O)R ａ wherein said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or Two adjacent R ａｂ together with the atoms to which they are attached, C ６ forming an aryl or a 5- to 6-membered heteroaryl, said aryl or heteroaryl being optionally substituted; R １ｃ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, C ３－１２ Carbocyclyl, 3- to 12-membered heterocyclyl, —C(═O)R ａ , -C(=O)OR ｂ or —C(═O)NR ｃ R ｄ wherein said alkyl, alkenyl, alkynyl, 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; Two R's Ｘ together with the carbon atom to which they are attached form an oxo, or Two R's Ｘ together with the carbon atoms to which they are attached, C ３－６ forming a carbocyclyl or a 3- to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted; Each R Ａ１ 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 R Ａ１ and adjacent R Ｘ together with the carbon atoms to which they are attached, C ３－４ forming a carbocyclyl or a 3- to 4-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted; 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 hydrogen, —C(═O)NR ｃ S (= O) ２ R ａ , —C(═O)NR ｃ R ｄ , -(CH ２ ) C(=O) OR ｂ or -C(=O)OR ｂ The compound according to any one of claims 1 to 4,

6. R ２ But -C(=O)NHS(=O) ２ CH ３ or —COOH.

7. 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.

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

9. R Ｃ１ The compound of claim 8, wherein is -Cl.

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

11. At least one R Ｄ is C １－６ alkyl or R Ｄ Each of the １－６ The compound of any one of claims 1 to 10, which is alkyl.

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

13. [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 12, wherein - or -C≡C-.

14. Each R Ｌ１ and each R Ｌ２ The compound of claim 13, wherein is hydrogen.

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

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

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

18. At least one R Ａ But C １－６ The compound of any one of claims 1 to 17, which is alkyl.

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

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

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

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

23. Two R's Ｘ together with the carbon atoms to which they are attached, C ３－４ The compound of claim 21, which forms a carbocyclyl or a 3- to 4-membered heterocyclyl.

24. R Ｘ and adjacent R Ａ１ together with the carbon atoms to which they are attached, C ３－４ A compound according to any one of claims 1 to 21, which forms a carbocyclyl or a 3- to 4-membered heterocyclyl.

25. Each R Ａ１ The compound of any one of claims 1 to 21, wherein is hydrogen.

26. R １ But, -NR １ａ R １ｂ The compound according to any one of claims 1 to 25,

27. R １ａ and R １ｂ are each independently hydrogen, —CN, C １－６ Alkyl, 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), or -(C １－６ 27. The compound of claim 26, wherein said alkyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

28. R １ａ and R １ｂ 27. The compound of claim 26, wherein at least one of is not hydrogen.

29. R １ａ and R １ｂ together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle, said heterocycle containing one or more R ａｂ 27. The compound of claim 26, optionally substituted with

30. Each R ａｂ are independently oxo, halogen, —OH, C １－６ Alkyl, C １－６ Alkoxy, C ３－６ Carbocyclyl, 3- to 6-membered heterocyclyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, or —S(═O)R ａ 28. The compound of claim 27, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

31. Two adjacent R ａｂ together with the atoms to which they are attached, C ６ 28. The compound of claim 27, which forms an aryl or a 5-6 membered heteroaryl, said aryl or heteroaryl being optionally substituted.

32. R １ But, -OR １ｃ The compound according to any one of claims 1 to 31,

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

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

35. R １ and R １’ together with the carbon atoms to which they are attached, C ３－６ 26. The compound of any one of claims 1 to 25, which forms a carbocyclyl or a 3- to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted.

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

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

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

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

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

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

42. 37. 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 36.

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

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

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

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