Tricyclic derivatives and related uses

Abstract

The present disclosure relates to compounds of Formula (I'): (I'), and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating Werner Helicase (WRN) activity and may be used in the treatment of disorders in which WRN activity is implicated, such as cancer.

Description

TRICYCLIC DERIVATIVES AND RELATED USES RELATED APPLICATIONS [1] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 537,426, filed on September 8, 2023; U.S. Provisional Application No. 63 / 654,502, filed on May 31, 2024; and U.S. Provisional Application No. 63 / 684,749, filed on August 19, 2024, the entire contents of which are incorporated herein by reference. BACKGROUND [2] The present disclosure relates to small molecule modulators of Werner helicase (WRN), designed for the treatment of a disease or disorder (e.g., cancer). [3] Genome instability is a hallmark of cancer, achieved through loss of DNA mismatch repair in numerous tumor types such as colorectal, gastric, endometrial, neuroendocrine, breast, ovarian, cervical, uterine, liver, prostate, cholangiocarcinoma, thyroid, pancreatic, uveal melanoma, esophageal, glioblastoma, and lung cancers identified as deficient in these pathways. This DNA mismatch repair deficiency (dMMR) leads to a high mutational burden genome-wide, but it is mainly characterized by insertions and deletions at repetitive DNA sequences across the genome known as microsatellites. The resulting phenotype is known as microsatellite instability, and the most severe of which may be graded as microsatellite instability high (MSI-H). Microsatellite instability is sometimes annotated using 3 categories (i.e., microsatellite stable (MSS), microsatellite instability low (MSI-L), and MSI-H) and sometimes as a binary (i.e., MSS or MSI). Thus, MSI-H patients can sometimes be annotated as MSI. Tumor status of dMMR is determined by presence / absence of MMR proteins MLH1, MSH2, MSH6, and / or PMS2 via immunohistochemistry, while MSI is determined by targeted molecular diagnostics of tumor DNA. [4] Standard of care for dMMR / MSI-H solid tumors includes 5-Fluorouracil-containing chemotherapeutic regimens and / or checkpoint inhibitors. These chemotherapeutic regimens have modest long term response rates and can be poorly tolerated by patients. Anti-PD1 therapies have been approved as a first-line therapy in MSI-H cancers, taking advantage of tumor-specific neoantigens created by high mutation levels. Despite treatment with anti-PD-1 checkpoint inhibitors, about half of dMMR / MSI tumors do not respond, thus alternative therapies are needed.[5] In parallel, functional genomics screens identified the essentiality of the WRN helicase in MSI-H cells. Furthermore, the mechanism of WRN helicase essentiality in MSI-H cancer cells has been elucidated, as WRN resolves repetitive large-scale TA dinucleotide expansions that uniquely occur in MSI-H cells at recurrent locations in the genome. These expanded TA dinucleotide repeats form secondary DNA structures that must be resolved by the WRN helicase during DNA replication in order for the cell to duplicate its DNA and divide properly. In the absence of WRN helicase activity, these toxic DNA structures persist, leading to chromosomal breakage at these sites and subsequent cell cycle arrest and cell death. As such, in the absence of WRN helicase activity, a DNA damage-mediated anti-proliferative and pro-apoptotic effect is observed exclusively in MSI-H tumors but not in normal tissues with functioning mismatch repair (MMR). Thus, inhibition of the WRN helicase is an ideal strategy for the treatment of MMR-deficient and / or MSI-H tumors. [6] The disclosure arises from a need to provide further compounds for the modulation of WRN activity with improved therapeutic potential. In particular, compounds with improved physicochemical, pharmacological and / or pharmaceutical properties. SUMMARY [7] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH;R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10- membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), - NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl) is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10- membered heteroaryl optionally substituted with C1-C6alkyl, C1-C6alkyl optionally substituted with C1-C6alkoxy, -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10- membered heteroaryl), or -O(3- to 10-membered heterocyclyl), or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl;R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5 and R6, together with the atoms to which they are attached, form a C4-C10 cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl. [8] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10- membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or - S(C1-C6haloalkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more oxo, -CN, C1-C6alkoxy, -C(O)(C1-C6alkyl), - N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), - O(3- to 10-membered heterocyclyl), C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl, or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl;R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R6is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5 and R6, together with the atoms to which they are attached, form a C4-C10 cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl. [9] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10- membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1- C6alkyl), or -S(C1-C6haloalkyl), wherein the alkyl is optionally substituted with one or more - N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), or - O(3- to 10-membered heterocyclyl), wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl, or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl;R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R6is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0010] In some aspects, the compound of Formula (I’) is a compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0011] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in any one of Schemes 1-18).

[0012] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient, diluent, or carrier, or a combination thereof.

[0013] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples).

[0014] In some aspects, the present disclosure provides a method of modulating Werner helicase (WRN) activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0015] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0016] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0017] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating WRN activity (e.g., in vitro or in vivo).

[0018] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0019] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0020] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating WRN activity (e.g., in vitro or in vivo).

[0021] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0022] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0023] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0024] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0025] 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. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0026] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0027] The present disclosure relates to octahydro-tetraazabenzoazulene derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may modulate Werner helicase (WRN) activity and are accordingly useful in methods of treatment of the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which WRN is implicated, such as cancer. Definitions

[0028] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0029] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non- operable embodiments caused by certain combinations of the options. For example, while variousoptions for variables X, Y, Z, R1, R1a, R1b, R2, R2a, R2a1, R3, R3a, R3a1, R3a2, R4, R4”, R5, R6, R7, R8, and R9are described herein, the disclosure may be interpreted as excluding structures for non- operable compound caused by certain combinations of variables X, Y, Z, R1, R1a, R1b, R2, R2a, R2a1, R3, R3a, R3a1, R3a2, R4, R4”, R5, R6, R7, R8, and R9.

[0030] As used herein, “alkyl”, “C1, C2, C3, C4, C5or C6alkyl” or “C1-C6alkyl” is intended to include C1, C2, C3, C4, C5or C6straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5or C6branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6for straight chain, C3-C6for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0031] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0032] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6for straight chain, C3-C6for branched chain). The term “C2-C6”includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0033] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0034] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6for straight chain, C3-C6for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6alkenylene linker” or “C2-C6alkynylene linker” is intended to include C2, C3, C4, C5or C6chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6alkenylene linker is intended to include C2, C3, C4, C5and C6alkenylene linker groups.

[0035] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino andalkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0036] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocyclyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0037] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0038] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. 1¸, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H- spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2- azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2- azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa- azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocyclyl, only one of the rings in the heterocyclyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0039] It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocyclyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocyclyl.

[0040] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.

[0041] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NoO and S(O)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0042] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.

[0043] The cycloalkyl, heterocyclyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).

[0044] As used herein, the term “about” refers to a recited amount, value, or duration ± 10 % or less of said amount, value, or duration. In some embodiments, “about” refers to a recited amount, value, or duration ± 10 %, ± 8 %, ± 6 %, ± 5 %, ± 4 %, ± 2 %, ± 1 %, or ± 0.5 %. In other embodiments, “about” refers to a recited amount, value, or duration ± 10 %, ± 8 %, ± 6 %, ± 5 %, ± 4 %, or ± 2 %. In other embodiments, “about” refers to a recited amount, value, or duration ± 5 %. In some embodiments, “about” refers to a listed amount, value, or duration ± 2 % or ± 1 %. For example, in some embodiments, when the term “about” is used when reciting a temperature or temperature range, these terms refer to the recited temperature or temperature range ± 5 °C, ± 2 °C, or ± 1 °C. In other embodiments, the term “about” refers to the recited temperature or temperature range ± 2 °C.

[0045] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that issufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0046] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0047] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0048] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-.

[0049] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0050] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0051] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0052] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groupsor alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0053] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0054] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0055] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0056] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. Theprocesses generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0057] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art

[0058] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0059] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[0060] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0061] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0062] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0063] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human thatmay be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0064] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0065] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0066] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0067] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with one or more pharmaceutically acceptable excipient, diluent, adjuvant, carrier, or a combination thereof.

[0068] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in theart will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0069] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0070] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0071] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0072] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0073] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0074] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0075] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0076] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0077] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0078] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrieris applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0079] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0080] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays, powders or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0081] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0082] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unitcontaining a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0083] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0084] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0085] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0086] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0087] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0088] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally.

[0089] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.

[0090] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0091] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0092] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0093] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0094] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Compounds of the Present Disclosure

[0095] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3;R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10- membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), - NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl) is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10- membered heteroaryl optionally substituted with C1-C6alkyl, C1-C6alkyl optionally substituted with C1-C6alkoxy, -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10- membered heteroaryl), or -O(3- to 10-membered heterocyclyl), or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl;R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5 and R6, together with the atoms to which they are attached, form a C4-C10 cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0096] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10- membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or - S(C1-C6haloalkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more oxo, -CN, C1-C6alkoxy, -C(O)(C1-C6alkyl), - N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), - O(3- to 10-membered heterocyclyl), C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl, or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl;R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R6is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5 and R6, together with the atoms to which they are attached, form a C4-C10 cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0097] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10- membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1- C6alkyl), or -S(C1-C6haloalkyl), wherein the alkyl is optionally substituted with one or more - N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), or - O(3- to 10-membered heterocyclyl), wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl, or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl;R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R6is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5 and R6, together with the atoms to which they are attached, form a C4-C10 cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0098] In some embodiments, the compound is of Formula (I’), wherein: X is N or C; Y is NR2 or CR2; Z is NR3or CR3; R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -NO2, -S(C1- C6alkyl), -S(O)2(NH2), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -S(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is halo, cyano, -OH, -O(C1-C6alkyl), -C(O)NH2, or 3- to 10- membered heterocyclyl; R2is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R2a; each R2aindependently is halo, cyano, -OH, -NH2, C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6alkyl), wherein the C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, or -S(C1-C6alkyl) is optionally substituted with one or more R2a1; each R2a1independently is halo or -OH; each R3aindependently is halo, -OH, -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl, wherein the -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10-membered heteroaryl optionally substituted with C1- C6alkyl, or C1-C6alkyl optionally substituted with C1-C6alkoxy, or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the C3-C10cycloalkyl or 3- to 10-membered heterocyclyl is optionally substituted with one or more 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more C1-C6alkyl;R5is H or halo, R6is H, halo, -SO2(C1-C6alkyl), or C1-C6alkyl optionally substituted with one or more - O(C1-C6 alkyl), or -N(C1-C6 alkyl)2, orR5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H or C1-C6alkyl.

[0099] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1a independently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH-C(O)(C1-C6 alkyl), - S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(O)2(C1-C6 alkyl), C1-C6 alkyl, C3-C10 cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo;R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or - S(C1-C6haloalkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more oxo, -CN, C1-C6alkoxy, -C(O)(C1-C6alkyl), - N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), - O(3- to 10-membered heterocyclyl), C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl, ortwo R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl; R5is H, halo, cyano, or C1-C6alkyl; R6is H, halo, cyano, C1-C6alkyl, or C1-C6alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0100] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH-C(O)(C1-C6alkyl), - S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH;R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1- C6alkyl), or -S(C1-C6haloalkyl), wherein the alkyl is optionally substituted with one or more - N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), or - O(3- to 10-membered heterocyclyl), wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl, or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl; R5is H, halo, cyano, or C1-C6alkyl; R6is H, halo, cyano, C1-C6alkyl, or C1-C6alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0101] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2 or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6 alkoxy, C1-C6 haloalkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl,wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10- membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), - NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10- membered heteroaryl optionally substituted with C1-C6alkyl, C1-C6alkyl optionally substituted with C1-C6alkoxy, -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10- membered heteroaryl), or -O(3- to 10-membered heterocyclyl), ortwo R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl; R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0102] In some embodiments, the compound is of Formula (I), wherein: X is C; Y is NR2; Z is CR3; R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1a; each R1aindependently is oxo, cyano, -C(O)NH2, -O(3- to 10-membered heterocyclyl), halo, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl, wherein the -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b;each R1bindependently is -O(C1-C6alkyl) or 3- to 10-membered heterocyclyl; R2is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the C6-C10aryl or 5- to 10- membered heteroaryl is optionally substituted with one or more R2a; each R2aindependently is halo, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or C3-C10cycloalkyl, wherein the C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or C3-C10cycloalkyl is optionally substituted with one or more R2a1; each R2a1independently is halo; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O or N and is optionally substituted with one or more R3a; each R3aindependently is halo, C1-C6alkyl, C1-C6alkoxy, –O(C3-C10cycloalkyl), or - O(3- to 10-membered heterocyclyl), wherein the alkoxy, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with one or more oxo, -CN, -C(O)(C1-C6alkyl), C1-C6alkoxy, C3-C10cycloalkyl, or 5- to 10-membered heteroaryl, or two R3a, together with the atoms to which they are attached, form a 3- to 10-membered heterocyclyl optionally substituted with one or more 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6alkyl; R5is H or halo; R6is H or C1-C6alkyl optionally substituted with -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H or C1-C6alkyl.

[0103] In some embodiments, the compound is of Formula (I), wherein: X is C; Y is NR2; Z is CR3; R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1a; each R1aindependently is oxo, cyano, -C(O)NH2, -O(3- to 10-membered heterocyclyl), halo, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl,wherein the -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is -O(C1-C6alkyl) or 3- to 10-membered heterocyclyl; R2is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the C6-C10aryl or 5- to 10- membered heteroaryl is optionally substituted with one or more R2a; each R2aindependently is halo, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or C3-C10cycloalkyl, wherein the C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or C3-C10cycloalkyl is optionally substituted with one or more R2a1; each R2a1independently is halo; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O or N and is optionally substituted with one or more R3a; each R3aindependently is halo, C1-C6alkyl, C1-C6alkoxy, or –O(C3-C10cycloalkyl); R5is H or halo; R6is H or C1-C6alkyl optionally substituted with -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H or C1-C6alkyl.

[0104] It is understood that, for a compound of the present disclosure, variables X, Y, Z, R1, R1a, R1b, R2, R2a, R2a1, R3, R3a, R3a1, R3a2, R4”, R5, R6, R7, R8, and R9can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables X, Y, Z, R1, R1a, R1b, R2, R2a, R2a1, R3, R3a, R3a1, R3a2, R4”, R5, R6, R7, R8, and R9can be combined, where applicable, with any group described herein for one or more of the remainder of variables X, Y, Z, R1, R1a, R1b, R2, R2a, R2a1, R3, R3a, R3a1, R3a2, R4”, R5, R6, R7, R8, and R9.

[0105] In some embodiments, X is N or C.

[0106] In some embodiments, X is N. In some embodiments, X is C.

[0107] In some embodiments, Y is NR2or CR2.

[0108] In some embodiments, Y is NR2. In some embodiments, Y is CR2.

[0109] In some embodiments, Z is NR3or CR3.

[0110] In some embodiments, Z is NR3.

[0111] In some embodiments, Z is CR3.

[0112] In some embodiments, R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a.

[0113] In some embodiments, R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0114] In some embodiments, R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl is optionally substituted with one or more R1a.

[0115] In some embodiments, R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0116] In some embodiments, R1is C1-C6alkyl.

[0117] In some embodiments, R1is C1-C6alkyl optionally substituted with one or more R1a.

[0118] In some embodiments, R1is C1-C6alkyl substituted with one or more R1a.

[0119] In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is propyl. In some embodiments, R1is butyl. In some embodiments, R1is pentyl. In some embodiments, R1is hexyl. In some embodiments, R1is isopropyl. In some embodiments, R1is isobutyl. In some embodiments, R1is isopentyl. In some embodiments, R1is isohexyl. In some embodiments, R1is secbutyl. In some embodiments, R1is secpentyl. In some embodiments, R1is sechexyl. In some embodiments, R1is tertbutyl.

[0120] In some embodiments, R1is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl).

[0121] In some embodiments, R1is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl) optionally substituted with one or more R1a.

[0122] In some embodiments, R1is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl) substituted with one or more R1a.

[0123] In some embodiments, R1is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl).

[0124] In some embodiments, R1is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl) optionally substituted with one or more R1a.

[0125] In some embodiments, R1is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl) substituted with one or more R1a.

[0126] In some embodiments, R1is C1-C6haloalkyl.

[0127] In some embodiments, R1is C1-C6haloalkyl optionally substituted with one or more R1a.

[0128] In some embodiments, R1is C1-C6haloalkyl substituted with one or more R1a.

[0129] In some embodiments, R1is halomethyl. In some embodiments, R1is haloethyl. In some embodiments, R1is halopropyl. In some embodiments, R1is halobutyl. In some embodiments, R1is halopentyl. In some embodiments, R1is halohexyl.

[0130] In some embodiments, R1is C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a.

[0131] In some embodiments, R1is C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0132] In some embodiments, R1is C3-C10cycloalkyl.

[0133] In some embodiments, R1is C3-C10cycloalkyl optionally substituted with one or more R1a.

[0134] In some embodiments, R1is C3-C10cycloalkyl substituted with one or more R1a.

[0135] In some embodiments, R1is C3-C7cycloalkyl.

[0136] In some embodiments, R1is C3-C7cycloalkyl optionally substituted with one or more R1a.

[0137] In some embodiments, R1is C3-C7cycloalkyl substituted with one or more R1a.

[0138] In some embodiments, R1is C6-C10aryl.

[0139] In some embodiments, R1is C6-C10aryl optionally substituted with one or more R1a.

[0140] In some embodiments, R1is C6-C10aryl substituted with one or more R1a.

[0141] In some embodiments, R1is C6aryl.

[0142] In some embodiments, R1is C6aryl optionally substituted with one or more R1a.

[0143] In some embodiments, R1is C6aryl substituted with one or more R1a.

[0144] In some embodiments, R1is 5- to 10-membered heteroaryl.

[0145] In some embodiments, R1is 5- to 10-membered heteroaryl optionally substituted with one or more R1a.

[0146] In some embodiments, R1is 5- to 10-membered heteroaryl substituted with one or more R1a.

[0147] In some embodiments, R1is 6- to 9-membered heteroaryl.

[0148] In some embodiments, R1is 6- to 9-membered heteroaryl optionally substituted with one or more R1a.

[0149] In some embodiments, R1is 6- to 9-membered heteroaryl substituted with one or more R1a.

[0150] In some embodiments, R1is 9-membered heteroaryl.

[0151] In some embodiments, R1is 9-membered heteroaryl optionally substituted with one or more R1a.

[0152] In some embodiments, R1is 9-membered heteroaryl substituted with one or more R1a.

[0153] In some embodiments, R1is 5- or 6-membered heteroaryl.

[0154] In some embodiments, R1is 5- or 6-membered heteroaryl optionally substituted with one or more R1a.

[0155] In some embodiments, R1is 5- or 6-membered heteroaryl substituted with one or more R1a.

[0156] In some embodiments, R1is 3- to 10-membered heterocyclyl.

[0157] In some embodiments, R1is 3- to 10-membered heterocyclyl optionally substituted with one or more R1a.

[0158] In some embodiments, R1is 3- to 10-membered heterocyclyl substituted with one or more R1a.

[0159] In some embodiments, R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl.

[0160] In some embodiments, R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1a.

[0161] In some embodiments, R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is substituted with one or more R1a.,

[0172] In some embodiments, R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -NO2, -S(C1- C6alkyl), -S(O)2(NH2), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -S(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; and each R1bindependently is halo, cyano, -OH, -O(C1-C6alkyl), -C(O)NH2, or 3- to 10- membered heterocyclyl.

[0173] In some embodiments, R1 is C3-C10 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1a; each R1aindependently is oxo, fluoro, chloro, bromo, cyano, -OH, -OCH3, -OCHF2, - OCF3, -OCH2CF3, -OCH(CH3)2, -OCH2C(O)NH2,-SCH3, -SCF3, -NH2, -NH(CH3),- NH(CH2CF3), -NO2, -CH3, -CH2OH, -(CH2)2OH,-(CH2)2OCH3,-CHF2, -CF2CH3,-CH2CF3,-

[0175] In some embodiments, each R1aindependently is halo, -NH2, -S(C1-C6alkyl), C1-C6alkyl, or C1-C6haloalkyl.

[0176] In some embodiments, each R1aindependently is fluoro, chloro, bromo, -NH2, -SCH3, - CH3, -CF3, or -CF2CH3.

[0177] In some embodiments, each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, - NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1- C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b.

[0178] In some embodiments, each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, - NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1- C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is substituted with one or more R1b.

[0179] In some embodiments, each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, - NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0180] In some embodiments, each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, - NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -C(O)H, -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -O(3- to10-membered heterocyclyl), -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -C(O)H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b.

[0181] In some embodiments, each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, - NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -C(O)H, -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0182] In some embodiments, each R1aindependently is oxo.

[0183] In some embodiments, each R1aindependently is halo.

[0184] In some embodiments, each R1aindependently is F, Cl, Br, or I. In some embodiments, each R1aindependently is F, Cl, or Br. In some embodiments, each R1aindependently is F or Cl.

[0185] In some embodiments, each R1aindependently is F. In some embodiments, each R1aindependently is Cl. In some embodiments, each R1aindependently is Br. In some embodiments, each R1aindependently is I.

[0186] In some embodiments, each R1aindependently is cyano.

[0187] In some embodiments, each R1aindependently is -OH.

[0188] In some embodiments, each R1aindependently is -NH2.

[0189] In some embodiments, each R1aindependently is -NO2.

[0190] In some embodiments, each R1aindependently is -NH-C(O)(C1-C6alkyl).

[0191] In some embodiments, each R1aindependently is -NH-C(O)(C1-C6alkyl), wherein the - NH-C(O)(C1-C6alkyl) is optionally substituted with one or more R1b.

[0192] In some embodiments, each R1aindependently is -NH-C(O)(C1-C6alkyl), wherein the - NH-C(O)(C1-C6alkyl) is substituted with one or more R1b.

[0193] In some embodiments, each R1aindependently is -S(C1-C6alkyl).

[0194] In some embodiments, each R1aindependently is -S(C1-C6alkyl), wherein the -S(C1-C6alkyl) is optionally substituted with one or more R1b.

[0195] In some embodiments, each R1aindependently is -S(C1-C6alkyl), wherein the -S(C1-C6alkyl) is substituted with one or more R1b.

[0196] In some embodiments, each R1aindependently is -S(O)2(C1-C6alkyl).

[0197] In some embodiments, each R1aindependently is -S(O)2(C1-C6alkyl), wherein the - S(O)2(C1-C6alkyl) is optionally substituted with one or more R1b.

[0198] In some embodiments, each R1aindependently is -S(O)2(C1-C6alkyl), wherein the - S(O)2(C1-C6alkyl) is substituted with one or more R1b.

[0199] In some embodiments, each R1aindependently is -S(O)2(NH2).

[0200] In some embodiments, each R1aindependently is -C(O)(H).

[0201] In some embodiments, each R1aindependently is -C(O)NH2.

[0202] In some embodiments, each R1aindependently is -O(3- to 10-membered heterocyclyl).

[0203] In some embodiments, each R1aindependently is -O(3- to 10-membered heterocyclyl), wherein the -O(3- to 10-membered heterocyclyl) is optionally substituted with one or more R1b.

[0204] In some embodiments, each R1aindependently is -O(3- to 10-membered heterocyclyl), wherein the -O(3- to 10-membered heterocyclyl) is substituted with one or more R1b.

[0205] In some embodiments, each R1aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b.

[0206] In some embodiments, each R1aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0207] In some embodiments, each R1aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, or C1-C6haloalkyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, or C1-C6haloalkyl is optionally substituted with one or more R1b.

[0208] In some embodiments, each R1aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, or C1-C6haloalkyl.

[0209] In some embodiments, each R1aindependently is C1-C6alkyl.

[0210] In some embodiments, each R1aindependently is C1-C6alkyl optionally substituted with one or more R1b.

[0211] In some embodiments, each R1aindependently is C1-C6alkyl substituted with one or more R1b.

[0212] In some embodiments, each R1aindependently is methyl. In some embodiments, each R1aindependently is ethyl. In some embodiments, each R1aindependently is propyl. In some embodiments, each R1aindependently is butyl. In some embodiments, each R1aindependently is pentyl. In some embodiments, each R1aindependently is hexyl. In some embodiments, each R1aindependently is isopropyl. In some embodiments, each R1aindependently is isobutyl. In some embodiments, each R1aindependently is isopentyl. In some embodiments, each R1aindependently is isohexyl. In some embodiments, each R1aindependently is secbutyl. In some embodiments, each R1aindependently is secpentyl. In some embodiments, each R1aindependently is sechexyl. In some embodiments, each R1aindependently is tertbutyl.

[0213] In some embodiments, each R1aindependently is C2-C6alkenyl.

[0214] In some embodiments, each R1aindependently is C2-C6alkenyl optionally substituted with one or more R1b.

[0215] In some embodiments, each R1aindependently is C2-C6alkenyl substituted with one or more R1b.

[0216] In some embodiments, each R1aindependently is C2-C6alkynyl.

[0217] In some embodiments, each R1aindependently is C2-C6alkynyl optionally substituted with one or more R1b.

[0218] In some embodiments, each R1aindependently is C2-C6alkynyl substituted with one or more R1b.

[0219] In some embodiments, each R1aindependently is C1-C6alkoxy.

[0220] In some embodiments, each R1aindependently is C1-C6alkoxy optionally substituted with one or more R1b.

[0221] In some embodiments, each R1aindependently is C1-C6alkoxy substituted with one or more R1b.

[0222] In some embodiments, each R1aindependently is C1-C6haloalkyl.

[0223] In some embodiments, each R1aindependently is C1-C6haloalkyl optionally substituted with one or more R1b.

[0224] In some embodiments, each R1aindependently is C1-C6haloalkyl substituted with one or more R1b.

[0225] In some embodiments, each R1aindependently is halomethyl. In some embodiments, each R1aindependently is haloethyl. In some embodiments, each R1aindependently is halopropyl. Insome embodiments, each R1aindependently is halobutyl. In some embodiments, each R1aindependently is halopentyl. In some embodiments, each R1aindependently is halohexyl.

[0226] In some embodiments, each R1aindependently is C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b.

[0227] In some embodiments, each R1aindependently is C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0228] In some embodiments, each R1aindependently is C3-C10cycloalkyl.

[0229] In some embodiments, each R1aindependently is C3-C10cycloalkyl optionally substituted with one or more R1b.

[0230] In some embodiments, each R1aindependently is C3-C10cycloalkyl substituted with one or more R1b.

[0231] In some embodiments, each R1aindependently is C3-C7cycloalkyl.

[0232] In some embodiments, each R1aindependently is C3-C7cycloalkyl optionally substituted with one or more R1b.

[0233] In some embodiments, each R1aindependently is C3-C7cycloalkyl substituted with one or more R1b.

[0234] In some embodiments, each R1aindependently is 3- to 10-membered heterocyclyl.

[0235] In some embodiments, each R1aindependently is 3- to 10-membered heterocyclyl optionally substituted with one or more R1b.

[0236] In some embodiments, each R1aindependently is 3- to 10-membered heterocyclyl substituted with one or more R1b.

[0237] In some embodiments, each R1aindependently is 3- to 7-membered heterocyclyl.

[0238] In some embodiments, each R1aindependently is 3- to 7-membered heterocyclyl optionally substituted with one or more R1b.

[0239] In some embodiments, each R1aindependently is 3- to 7-membered heterocyclyl substituted with one or more R1b.

[0240] In some embodiments, each R1aindependently is C6-C10aryl.

[0241] In some embodiments, each R1aindependently is C6-C10aryl optionally substituted with one or more R1b.

[0242] In some embodiments, each R1aindependently is C6-C10aryl substituted with one or more R1b.

[0243] In some embodiments, each R1aindependently is C6aryl.

[0244] In some embodiments, each R1aindependently is C6aryl optionally substituted with one or more R1b.

[0245] In some embodiments, each R1aindependently is C6aryl substituted with one or more R1b.

[0246] In some embodiments, each R1aindependently is 5- to 10-membered heteroaryl.

[0247] In some embodiments, each R1aindependently is 5- to 10-membered heteroaryl optionally substituted with one or more R1b.

[0248] In some embodiments, each R1aindependently is 5- to 10-membered heteroaryl substituted with one or more R1b.

[0249] In some embodiments, each R1aindependently is 5- or 6-membered heteroaryl.

[0250] In some embodiments, each R1aindependently is 5- or 6-membered heteroaryl optionally substituted with one or more R1b.

[0251] In some embodiments, each R1aindependently is 5- or 6-membered heteroaryl substituted with one or more R1b.

[0252] In some embodiments, each R1aindependently is halo, -OH, -NH2, -NH(C1-C6alkyl), - S(C1-C6alkyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl.

[0253] In some embodiments, each R1aindependently is halo, -OH, -NH2, -NH(C1-C6alkyl), - S(C1-C6alkyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -S(C1-C6alkyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b.

[0254] In some embodiments, each R1aindependently is oxo, cyano, -C(O)NH2, -O(3- to 10- membered heterocyclyl), halo, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl, wherein the -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or 3- to 10-membered heterocyclyl is substituted with one or more R1b.

[0255] In some embodiments, each R1aindependently is oxo, cyano, -O(CH2)C(O)NH2, -O- azetidinyl, -OCF3, -C(O)NH2, -CH2CF3, -C(CH3)2(OH), -OCHF2, -CH3, -OH, Br, -CF3, -CHF2, - (CH2)2-OCH3, -NH2, -NH-CH2-CF3, -(CH2)-oxetanyl, azetidinyl, pyrazolyl, cyclopropyl, - S(O2)(NH2), -SCH3, or -OCH3.

[0256] In some embodiments, each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), -O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo.

[0257] In some embodiments, each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), -O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo.

[0258] In some embodiments, each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), -O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0259] In some embodiments, each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), -O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3- C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo.

[0260] In some embodiments, each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), -O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3- C10cycloalkyl, or 3- to 10-membered heterocyclyl substituted with oxo.

[0261] In some embodiments, each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), -O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3- C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0262] In some embodiments, each R1bindependently is oxo.

[0263] In some embodiments, each R1bindependently is halo.

[0264] In some embodiments, each R1bindependently is F, Cl, Br, or I. In some embodiments, each R1bindependently is F, Cl, or Br. In some embodiments, each R1bindependently is F or Cl.

[0265] In some embodiments, each R1bindependently is F. In some embodiments, each R1bindependently is Cl. In some embodiments, each R1bindependently is Br. In some embodiments, each R1bindependently is I.

[0266] In some embodiments, each R1bindependently is cyano.

[0267] In some embodiments, each R1bindependently is -OH.

[0268] In some embodiments, each R1bindependently is -O(C1-C6alkyl).

[0269] In some embodiments, each R1bindependently is -O(C1-C6haloalkyl).

[0270] In some embodiments, each R1bindependently is -O(C2-C6alkenyl).

[0271] In some embodiments, each R1bindependently is -O(C2-C6alkynyl).

[0272] In some embodiments, each R1bindependently is -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or -NH(C1-C6haloalkyl).

[0273] In some embodiments, each R1bindependently is -NH2.

[0274] In some embodiments, each R1bindependently is -NH(C1-C6alkyl).

[0275] In some embodiments, each R1bindependently is -N(C1-C6alkyl)2.

[0276] In some embodiments, each R1bindependently is -NH(C1-C6haloalkyl).

[0277] In some embodiments, each R1bindependently is -S(C1-C6alkyl).

[0278] In some embodiments, each R1bindependently is -S(O)2(C1-C6alkyl).

[0279] In some embodiments, each R1bindependently is -C(O)NH2.

[0280] In some embodiments, each R1bindependently is C1-C6alkyl.

[0281] In some embodiments, each R1bindependently is C3-C10cycloalkyl.

[0282] In some embodiments, each R1bindependently is C3-C7cycloalkyl.

[0283] In some embodiments, each R1bindependently is 3- to 10-membered heterocyclyl.

[0284] In some embodiments, each R1bindependently is 3- to 10-membered heterocyclyl optionally substituted with oxo.

[0285] In some embodiments, each R1bindependently is 3- to 10-membered heterocyclyl substituted with oxo.

[0286] In some embodiments, each R1bindependently is 3- to 7-membered heterocyclyl.

[0287] In some embodiments, each R1bindependently is 3- to 7-membered heterocyclyl optionally substituted with oxo.

[0288] In some embodiments, each R1bindependently is -O(C1-C6alkyl) or 3- to 10-membered heterocyclyl.

[0289] In some embodiments, each R1bindependently is -OCH3or oxetanyl.

[0290] In some embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10- membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl,C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10- membered heterocyclyl is optionally substituted with one or more R2a.

[0291] In some embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10- membered heterocyclyl.

[0292] In some embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with one or more R2a.

[0293] In some embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0294] In some embodiments, R2is C1-C6alkyl.

[0295] In some embodiments, R2is C1-C6alkyl optionally substituted with one or more R2a.

[0296] In some embodiments, R2is C1-C6alkyl substituted with one or more R2a.

[0297] In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is propyl. In some embodiments, R2is butyl. In some embodiments, R2is pentyl. In some embodiments, R2is hexyl. In some embodiments, R2is isopropyl. In some embodiments, R2is isobutyl. In some embodiments, R2is isopentyl. In some embodiments, R2is isohexyl. In some embodiments, R2is secbutyl. In some embodiments, R2is secpentyl. In some embodiments, R2is sechexyl. In some embodiments, R2is tertbutyl.

[0298] In some embodiments, R2is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl).

[0299] In some embodiments, R2is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl) optionally substituted with one or more R2a.

[0300] In some embodiments, R2is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl) substituted with one or more R2a.

[0301] In some embodiments, R2is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl).

[0302] In some embodiments, R2is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl) optionally substituted with one or more R2a.

[0303] In some embodiments, R2is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl) substituted with one or more R2a.

[0304] In some embodiments, R2is C1-C6haloalkyl.

[0305] In some embodiments, R2is C1-C6haloalkyl optionally substituted with one or more R2a.

[0306] In some embodiments, R2is C1-C6haloalkyl substituted with one or more R2a.

[0307] In some embodiments, R2is halomethyl. In some embodiments, R2is haloethyl. In some embodiments, R2is halopropyl. In some embodiments, R2is halobutyl. In some embodiments, R2is halopentyl. In some embodiments, R2is halohexyl.

[0308] In some embodiments, R2is C1-C6alkoxy.

[0309] In some embodiments, R2is C1-C6alkoxy optionally substituted with one or more R2a.

[0310] In some embodiments, R2is C1-C6alkoxy substituted with one or more R2a.

[0311] In some embodiments, R2is methoxy. In some embodiments, R2is ethoxy. In some embodiments, R2is propoxy. In some embodiments, R2is butoxy. In some embodiments, R2is pentoxy. In some embodiments, R2is hexoxy.

[0312] In some embodiments, R2is C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a.

[0313] In some embodiments, R2is C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0314] In some embodiments, R2is C3-C10cycloalkyl.

[0315] In some embodiments, R2is C3-C10cycloalkyl optionally substituted with one or more R2a.

[0316] In some embodiments, R2is C3-C10cycloalkyl substituted with one or more R2a.

[0317] In some embodiments, R2is C3-C7cycloalkyl.

[0318] In some embodiments, R2is C3-C7cycloalkyl optionally substituted with one or more R2a.

[0319] In some embodiments, R2is C3-C7cycloalkyl substituted with one or more R2a.

[0320] In some embodiments, R2is C6-C10aryl.

[0321] In some embodiments, R2is C6-C10aryl optionally substituted with one or more R2a.

[0322] In some embodiments, R2is C6-C10aryl substituted with one or more R2a.

[0323] In some embodiments, R2is C6aryl.

[0324] In some embodiments, R2is C6aryl optionally substituted with one or more R2a.

[0325] In some embodiments, R2is C6aryl substituted with one or more R2a.

[0326] In some embodiments, R2is 5- to 10-membered heteroaryl.

[0327] In some embodiments, R2is 5- to 10-membered heteroaryl optionally substituted with one or more R2a.

[0328] In some embodiments, R2is 5- to 10-membered heteroaryl substituted with one or more R2a.

[0329] In some embodiments, R2is 5- or 6-membered heteroaryl.

[0330] In some embodiments, R2is 5- or 6-membered heteroaryl optionally substituted with one or more R2a.

[0331] In some embodiments, R2is 5- or 6-membered heteroaryl substituted with one or more R2a.

[0332] In some embodiments, R2is 6-membered heteroaryl.

[0333] In some embodiments, R2is 6-membered heteroaryl optionally substituted with one or more R2a.

[0334] In some embodiments, R2is 6-membered heteroaryl substituted with one or more R2a.

[0335] In some embodiments, R2is 3- to 10-membered heterocyclyl.

[0336] In some embodiments, R2is 3- to 10-membered heterocyclyl optionally substituted with one or more R2a.

[0337] In some embodiments, R2is 3- to 10-membered heterocyclyl substituted with one or more R2a.

[0338] In some embodiments, R2is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the C6- C10aryl or 5- to 10-membered heteroaryl.

[0339] In some embodiments, R2is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the C6- C10aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R2a.

[0340] In some embodiments, R2is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the C6- C10aryl or 5- to 10-membered heteroaryl is substituted with one or more R2a..or.

[0346] In some embodiments, R2is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R2a; each R2aindependently is halo, cyano, -OH, -NH2, C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6alkyl), wherein the C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, or -S(C1-C6alkyl) is optionally substituted with one or more R2a1; and each R2a1independently is halo or -OH.

[0347] In some embodiments, R2is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R2a; and each R2aindependently is fluoro, chloro, cyano, -OH, -NH2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCHF2, -SCF3, -CH3, -CH(CH3)2, -CH2OH, -CF3, -CH(CF3)2,

[0349] In some embodiments, each R2aindependently halo, -OH, or C3-C10cycloalkyl.

[0350] In some embodiments, each R2aindependently is fluoro, -OH, or cyclopropyl.

[0351] In some embodiments, each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, C1-C6alkoxy, -S(C1-C6alkyl), -S(C1-C6haloalkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -S(C1-C6alkyl), -S(C1-C6haloalkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1.

[0352] In some embodiments, each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, C1-C6alkoxy, -S(C1-C6alkyl), -S(C1-C6haloalkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0353] In some embodiments, each R2aindependently is oxo.

[0354] In some embodiments, each R2aindependently is halo.

[0355] In some embodiments, each R2aindependently is F, Cl, Br, or I. In some embodiments, each R2aindependently is F, Cl, or Br. In some embodiments, each R2aindependently is F or Cl.

[0356] In some embodiments, each R2aindependently is F. In some embodiments, each R2aindependently is Cl. In some embodiments, each R2aindependently is Br. In some embodiments, each R2aindependently is I.

[0357] In some embodiments, each R2aindependently is cyano.

[0358] In some embodiments, each R2aindependently is -OH.

[0359] In some embodiments, each R2aindependently is -NH2.

[0360] In some embodiments, each R2aindependently is -NH(C1-C6alkyl).

[0361] In some embodiments, each R2aindependently is -N(C1-C6alkyl)2.

[0362] In some embodiments, each R2aindependently is -SH.

[0363] In some embodiments, each R2aindependently is -S(O)2NH2.

[0364] In some embodiments, each R2aindependently is -SF5.

[0365] In some embodiments, each R2aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -S(C1-C6alkyl), or -S(C1- C6haloalkyl) is optionally substituted with one or more R2a1.

[0366] In some embodiments, each R2aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -S(C1-C6alkyl), or -S(C1-C6haloalkyl).

[0367] In some embodiments, each R2aindependently is C1-C6alkyl.

[0368] In some embodiments, each R2aindependently is C1-C6alkyl optionally substituted with one or more R2a1.

[0369] In some embodiments, each R2aindependently is C1-C6alkyl substituted with one or more R2a1.

[0370] In some embodiments, each R2aindependently is methyl. In some embodiments, each R2aindependently is ethyl. In some embodiments, each R2aindependently is propyl. In some embodiments, each R2aindependently is butyl. In some embodiments, each R2aindependently is pentyl. In some embodiments, each R2aindependently is hexyl. In some embodiments, each R2aindependently is isopropyl. In some embodiments, each R2aindependently is isobutyl. In some embodiments, each R2aindependently is isopentyl. In some embodiments, each R2aindependently is isohexyl. In some embodiments, each R2aindependently is secbutyl. In some embodiments, each R2aindependently is secpentyl. In some embodiments, each R2aindependently is sechexyl. In some embodiments, each R2aindependently is tertbutyl.

[0371] In some embodiments, each R2aindependently is C2-C6alkenyl.

[0372] In some embodiments, each R2aindependently is C2-C6alkenyl optionally substituted with one or more R2a1.

[0373] In some embodiments, each R2aindependently is C2-C6alkenyl substituted with one or more R2a1.

[0374] In some embodiments, each R2aindependently is C2-C6alkynyl.

[0375] In some embodiments, each R2aindependently is C2-C6alkynyl optionally substituted with one or more R2a1.

[0376] In some embodiments, each R2aindependently is C2-C6alkynyl substituted with one or more R2a1.

[0377] In some embodiments, each R2aindependently is C1-C6haloalkyl.

[0378] In some embodiments, each R2aindependently is C1-C6haloalkyl optionally substituted with one or more R2a1.

[0379] In some embodiments, each R2aindependently is C1-C6haloalkyl substituted with one or more R2a1.

[0380] In some embodiments, each R2aindependently is halomethyl. In some embodiments, each R2aindependently is haloethyl. In some embodiments, each R2aindependently is halopropyl. In some embodiments, each R2aindependently is halobutyl. In some embodiments, each R2aindependently is halopentyl. In some embodiments, each R2aindependently is halohexyl.

[0381] In some embodiments, each R2aindependently is C1-C6alkoxy.

[0382] In some embodiments, each R2aindependently is C1-C6alkoxy optionally substituted with one or more R2a1.

[0383] In some embodiments, each R2aindependently is C1-C6alkoxy substituted with one or more R2a1.

[0384] In some embodiments, each R2aindependently is methoxy. In some embodiments, each R2aindependently is ethoxy. In some embodiments, each R2aindependently is propoxy. In some embodiments, each R2aindependently is butoxy. In some embodiments, each R2aindependently is pentoxy. In some embodiments, each R2aindependently is hexoxy.

[0385] In some embodiments, each R2aindependently is -S(C1-C6alkyl).

[0386] In some embodiments, each R2aindependently is -S(C1-C6alkyl), wherein the C1-C6alkyl is optionally substituted with one or more R2a1.

[0387] In some embodiments, each R2aindependently is -S(C1-C6alkyl), wherein the C1-C6alkyl is substituted with one or more R2a1.

[0388] In some embodiments, each R2aindependently is -S(C1-C6haloalkyl).

[0389] In some embodiments, each R2aindependently is -S(C1-C6haloalkyl), wherein the C1-C6haloalkyl is optionally substituted with one or more R2a1.

[0390] In some embodiments, each R2aindependently is -S(C1-C6haloalkyl), wherein the C1-C6haloalkyl is substituted with one or more R2a1.

[0391] In some embodiments, each R2aindependently is C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1.

[0392] In some embodiments, each R2aindependently is C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl.

[0393] In some embodiments, each R2aindependently is C3-C10cycloalkyl.

[0394] In some embodiments, each R2aindependently is C3-C10cycloalkyl optionally substituted with one or more R2a1.

[0395] In some embodiments, each R2aindependently is C3-C10cycloalkyl substituted with one or more R2a1.

[0396] In some embodiments, each R2aindependently is C3-C7cycloalkyl.

[0397] In some embodiments, each R2aindependently is C3-C7cycloalkyl optionally substituted with one or more R2a1.

[0398] In some embodiments, each R2aindependently is C3-C7cycloalkyl substituted with one or more R2a1.

[0399] In some embodiments, each R2aindependently is 3- to 10-membered heterocyclyl.

[0400] In some embodiments, each R2aindependently is 3- to 10-membered heterocyclyl optionally substituted with one or more R2a1.

[0401] In some embodiments, each R2aindependently is 3- to 10-membered heterocyclyl substituted with one or more R2a1.

[0402] In some embodiments, each R2aindependently is 3- to 7-membered heterocyclyl.

[0403] In some embodiments, each R2aindependently is 3- to 7-membered heterocyclyl optionally substituted with one or more R2a1.

[0404] In some embodiments, each R2aindependently is 3- to 7-membered heterocyclyl substituted with one or more R2a1.

[0405] In some embodiments, each R2aindependently is C6-C10aryl.

[0406] In some embodiments, each R2aindependently is C6-C10aryl optionally substituted with one or more R2a1.

[0407] In some embodiments, each R2aindependently is C6-C10aryl substituted with one or more R2a1.

[0408] In some embodiments, each R2aindependently is C6aryl.

[0409] In some embodiments, each R2aindependently is C6aryl optionally substituted with one or more R2a1.

[0410] In some embodiments, each R2aindependently is C6aryl substituted with one or more R2a1.

[0411] In some embodiments, each R2aindependently is 5- to 10-membered heteroaryl.

[0412] In some embodiments, each R2aindependently is 5- to 10-membered heteroaryl optionally substituted with one or more R2a1.

[0413] In some embodiments, each R2aindependently is 5- to 10-membered heteroaryl substituted with one or more R2a1.

[0414] In some embodiments, each R2aindependently is 5- or 6-membered heteroaryl.

[0415] In some embodiments, each R2aindependently is 5- or 6-membered heteroaryl optionally substituted with one or more R2a1.

[0416] In some embodiments, each R2aindependently is 5- or 6-membered heteroaryl substituted with one or more R2a1.

[0417] In some embodiments, each R2aindependently is halo, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or C3-C10cycloalkyl, wherein the C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or C3-C10cycloalkyl is optionally substituted with one or more R2a1.

[0418] In some embodiments, each R2aindependently is methyl, isopropyl, -CH2CF3, -CF3, -NH2, -OCH3, cyclobutyl, cyclopropyl, -OH, -(cyclopropyl)-F2, F, or bicyclo[1.1.1]pentane.

[0419] In some embodiments, each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -NH-C(O)(C1-C6alkyl), - C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -NH-C(O)(C1-C6alkyl), or -OC(O)(C1-C6alkyl) is optionally substituted with one or more -OH.

[0420] In some embodiments, each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -NH-C(O)(C1-C6alkyl), - C(O)NH2, or -OC(O)(C1-C6alkyl).

[0421] In some embodiments, each R2a1independently is oxo, halo, cyano, -OH, -NH2, -NH- C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the -NH-C(O)(C1-C6alkyl) or - OC(O)(C1-C6alkyl) is optionally substituted with one or more -OH.

[0422] In some embodiments, each R2a1independently is oxo, halo, cyano, -OH, -NH2, -NH- C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl).

[0423] In some embodiments, each R2a1independently is oxo.

[0424] In some embodiments, each R2a1independently is halo.

[0425] In some embodiments, each R2a1independently is F, Cl, Br, or I. In some embodiments, each R2a1independently is F, Cl, or Br. In some embodiments, each R2a1independently is F or Cl.

[0426] In some embodiments, each R2a1independently is F. In some embodiments, each R2a1independently is Cl. In some embodiments, each R2a1independently is Br. In some embodiments, each R2a1independently is I.

[0427] In some embodiments, each R2a1independently is cyano.

[0428] In some embodiments, each R2a1independently is -OH.

[0429] In some embodiments, each R2a1independently is -NH2.

[0430] In some embodiments, each R2a1independently is -C(O)NH2.

[0431] In some embodiments, each R2a1independently is -NH-C(O)(C1-C6alkyl).

[0432] In some embodiments, each R2a1independently is -NH-C(O)(C1-C6alkyl), wherein the - OC(O)(C1-C6alkyl) is optionally substituted with one or more -OH.

[0433] In some embodiments, each R2a1independently is -NH-C(O)(C1-C6alkyl), wherein the - OC(O)(C1-C6alkyl) is substituted with one or more -OH.

[0434] In some embodiments, each R2a1independently is -OC(O)(C1-C6alkyl).

[0435] In some embodiments, each R2a1independently is -OC(O)(C1-C6alkyl), wherein the - OC(O)(C1-C6alkyl) is optionally substituted with one or more -OH.

[0436] In some embodiments, each R2a1independently is -OC(O)(C1-C6alkyl), wherein the - OC(O)(C1-C6alkyl) is substituted with one or more -OH.

[0437] In some embodiments, each R2a1independently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with one or more -OH.

[0438] In some embodiments, each R2a1independently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0439] In some embodiments, each R2a1independently is C1-C6alkyl.

[0440] In some embodiments, each R2a1independently is C1-C6alkyl optionally substituted with one or more -OH.

[0441] In some embodiments, each R2a1independently is C1-C6alkyl substituted with one or more -OH.

[0442] In some embodiments, each R2a1independently is methyl. In some embodiments, each R2a1independently is ethyl. In some embodiments, each R2a1independently is propyl. In some embodiments, each R2a1independently is butyl. In some embodiments, each R2a1independently is pentyl. In some embodiments, each R2a1independently is hexyl. In some embodiments, each R2a1independently is isopropyl. In some embodiments, each R2a1independently is isobutyl. In some embodiments, each R2a1independently is isopentyl. In some embodiments, each R2a1independently is isohexyl. In some embodiments, each R2a1independently is secbutyl. In some embodiments, each R2a1independently is secpentyl. In some embodiments, each R2a1independently is sechexyl. In some embodiments, each R2a1independently is tertbutyl.

[0443] In some embodiments, each R2a1independently is C2-C6alkenyl.

[0444] In some embodiments, each R2a1independently is C2-C6alkenyl optionally substituted with one or more -OH.

[0445] In some embodiments, each R2a1independently is C2-C6alkenyl substituted with one or more -OH.

[0446] In some embodiments, each R2a1independently is C2-C6alkynyl.

[0447] In some embodiments, each R2a1independently is C2-C6alkynyl optionally substituted with one or more -OH.

[0448] In some embodiments, each R2a1independently is C2-C6alkynyl substituted with one or more -OH.

[0449] In some embodiments, each R2a1independently is C1-C6haloalkyl.

[0450] In some embodiments, each R2a1independently is C1-C6haloalkyl optionally substituted with one or more -OH.

[0451] In some embodiments, each R2a1independently is C1-C6haloalkyl substituted with one or more -OH.

[0452] In some embodiments, each R2a1independently is halomethyl. In some embodiments, each R2a1independently is haloethyl. In some embodiments, each R2a1independently is halopropyl. In some embodiments, each R2a1independently is halobutyl. In some embodiments, each R2a1independently is halopentyl. In some embodiments, each R2a1independently is halohexyl.

[0453] In some embodiments, each R2a1independently is C1-C6alkoxy.

[0454] In some embodiments, each R2a1independently is C1-C6alkoxy optionally substituted with one or more -OH.

[0455] In some embodiments, each R2a1independently is C1-C6alkoxy substituted with one or more -OH.

[0456] In some embodiments, each R2a1independently is methoxy. In some embodiments, each R2a1independently is ethoxy. In some embodiments, each R2a1independently is propoxy. In some embodiments, each R2a1independently is butoxy. In some embodiments, each R2a1independently is pentoxy. In some embodiments, each R2a1independently is hexoxy.

[0457] In some embodiments, each R2a1independently is F.

[0458] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a.

[0459] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is substituted with one or more R3a.

[0460] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S.

[0461] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O or N and is optionally substituted with one or more R3a.

[0462] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O or N and is substituted with one or more R3a.

[0463] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O or N.

[0464] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is optionally substituted with one or more R3a.

[0465] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is substituted with one or more R3a.

[0466] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O.

[0467] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl optionally substituted with one or more R3a.

[0468] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl substituted with one or more R3a.

[0469] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl.

[0470] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a.

[0471] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is substituted with one or more R3a.

[0472] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S.

[0473] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is optionally substituted with one or more R3a.

[0474] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is substituted with one or more R3a.

[0475] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O.

[0476] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more R3a.

[0477] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl substituted with one or more R3a.

[0478] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl.

[0479] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a.

[0480] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is substituted with one or more R3a.

[0481] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S.

[0482] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is optionally substituted with one or more R3a.

[0483] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is substituted with one or more R3a.

[0484] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O.

[0485] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl optionally substituted with one or more R3a.

[0486] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl substituted with one or more R3a.

[0487] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl.

[0488] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a.

[0489] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is substituted with one or more R3a.

[0490] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S.

[0491] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is optionally substituted with one or more R3a.

[0492] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is substituted with one or more R3a.

[0493] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O.

[0494] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl optionally substituted with one or more R3a.

[0495] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl substituted with one or more R3a.

[0496] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl.

[0497] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a.

[0498] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is substituted with one or more R3a.

[0499] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S.

[0500] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is optionally substituted with one or more R3a.

[0501] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is substituted with one or more R3a.

[0502] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O.

[0503] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl optionally substituted with one or more R3a.

[0504] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl substituted with one or more R3a.

[0505] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 9-membered heterocyclyl.

[0506] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a.

[0507] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is substituted with one or more R3a.

[0508] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S.

[0509] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is optionally substituted with one or more R3a.

[0510] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is substituted with one or more R3a.

[0511] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O.

[0512] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl optionally substituted with one or more R3a.

[0513] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl substituted with one or more R3a.

[0514] In some embodiments, R3and R4, together with the atoms to which they are attached, form a 10-membered heterocyclyl.

[0515] In some embodiments, each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1- C6alkyl), or -S(C1-C6haloalkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more oxo, -CN, C1-C6alkoxy, -C(O)(C1- C6alkyl), -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), -O(3- to 10-membered heterocyclyl), C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl.

[0516] In some embodiments, each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, -S(O)(=NH)(C1-C6alkyl), - SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the alkyl is optionally substituted with one or more -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), or -O(3- to 10-membered heterocyclyl), wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more C1-C6alkyl.

[0517] In some embodiments, each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, -S(O)(=NH)(C1-C6alkyl), - SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the alkyl is optionally substituted with one or more -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), or -O(3- to 10-membered heterocyclyl).

[0518] In some embodiments, each R3aindependently is cyano, halo, -OH, -NH2, -NH-C(O)(C1- C6alkyl), -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), -O(C3-C10cycloalkyl), C1-C6alkyl optionally substituted with -N(R3a1)CO(R3a2), C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, 3- to 10-membered heterocyclyl, - S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl); or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0519] In some embodiments, each R3aindependently is cyano, halo, -OH, -NH2, -NH-C(O)(C1- C6alkyl), -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), -O(C3-C10cycloalkyl), C1-C6alkyl optionally substituted with -N(R3a1)CO(R3a2), C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, 3- to 10-membered heterocyclyl, - S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl).

[0520] In some embodiments, two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl.

[0521] In some embodiments, two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0522] In some embodiments, two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl.

[0523] In some embodiments, two R3a, together with the atoms to which they are attached, form a 3- to 10-membered heterocyclyl.

[0524] In some embodiments, two R3a, together with the atoms to which they are attached, form a 3- to 10-membered heterocyclyl optionally substituted with one or more 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6alkyl.

[0525] In some embodiments, two R3a, together with the atoms to which they are attached, form a 3- to 10-membered heterocyclyl substituted with one or more 5- to 10-membered heteroaryl substituted with one or more C1-C6alkyl.

[0526] In some embodiments, two R3a, together with the atoms to which they are attached, form cyclopropyl or azetidinyl substituted with.

[0527] In some embodiments, each R3aindependently is cyano.

[0528] In some embodiments, each R3aindependently is halo.

[0529] In some embodiments, each R3aindependently is -OH.

[0530] In some embodiments, each R3aindependently is -NH2.

[0531] In some embodiments, each R3aindependently is F, Cl, Br, or I. In some embodiments, each R3aindependently is F, Cl, or Br. In some embodiments, each R3aindependently is F or Cl.

[0532] In some embodiments, each R3aindependently is F. In some embodiments, each R3aindependently is Cl. In some embodiments, each R3aindependently is Br. In some embodiments, each R3aindependently is I.

[0533] In some embodiments, each R3aindependently is -NH-C(O)(C1-C6alkyl).

[0534] In some embodiments, each R3aindependently is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or -N(C1-C6alkyl)(C1-C6haloalkyl).

[0535] In some embodiments, each R3aindependently is -NH(C1-C6alkyl).

[0536] In some embodiments, each R3aindependently is -N(C1-C6alkyl)2.

[0537] In some embodiments, each R3aindependently is -N(C1-C6alkyl)(C1-C6haloalkyl).

[0538] In some embodiments, each R3aindependently is -S(C1-C6alkyl).

[0539] In some embodiments, each R3aindependently is -S(C1-C6haloalkyl).

[0540] In some embodiments, each R3aindependently is -S(O)(=NH)(C1-C6alkyl).

[0541] In some embodiments, each R3aindependently is -SO2(C1-C6alkyl).

[0542] In some embodiments, each R3aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0543] In some embodiments, each R3aindependently is C1-C6alkyl.

[0544] In some embodiments, each R3aindependently is C1-C6alkyl optionally substituted with one or more -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10-membered heteroaryl), or -O(3- to 10-membered heterocyclyl).

[0545] In some embodiments, each R3aindependently is C1-C6alkyl optionally substituted with one or more -N(R3a1)CO(R3a2).

[0546] In some embodiments, each R3aindependently is C1-C6alkyl optionally substituted with one or more -O(C3-C10cycloalkyl).

[0547] In some embodiments, each R3aindependently is C1-C6alkyl optionally substituted with one or more -O(C6-C10aryl).

[0548] In some embodiments, each R3aindependently is C1-C6alkyl optionally substituted with one or more -O(5- to 10-membered heteroaryl).

[0549] In some embodiments, each R3aindependently is C1-C6alkyl optionally substituted with one or more -O(3- to 10-membered heterocyclyl).

[0550] In some embodiments, each R3aindependently is methyl. In some embodiments, each R3aindependently is ethyl. In some embodiments, each R3aindependently is propyl. In some embodiments, each R3aindependently is butyl. In some embodiments, each R3aindependently is pentyl. In some embodiments, each R3aindependently is hexyl. In some embodiments, each R3aindependently is isopropyl. In some embodiments, each R3aindependently is isobutyl. In some embodiments, each R3aindependently is isopentyl. In some embodiments, each R3aindependently is isohexyl. In some embodiments, each R3aindependently is secbutyl. In some embodiments, each R3aindependently is secpentyl. In some embodiments, each R3aindependently is sechexyl. In some embodiments, each R3aindependently is tertbutyl.

[0551] In some embodiments, each R3aindependently is C2-C6alkenyl.

[0552] In some embodiments, each R3aindependently is C2-C6alkynyl.

[0553] In some embodiments, each R3aindependently is C1-C6haloalkyl.

[0554] In some embodiments, each R3aindependently is halomethyl. In some embodiments, each R3aindependently is haloethyl. In some embodiments, each R3aindependently is halopropyl. In some embodiments, each R3aindependently is halobutyl. In some embodiments, each R3aindependently is halopentyl. In some embodiments, each R3aindependently is halohexyl.

[0555] In some embodiments, each R3aindependently is C1-C6alkoxy.

[0556] In some embodiments, each R3aindependently is methoxy. In some embodiments, each R3aindependently is ethoxy. In some embodiments, each R3aindependently is propoxy. In some embodiments, each R3aindependently is butoxy. In some embodiments, each R3aindependently is pentoxy. In some embodiments, each R3aindependently is hexoxy.

[0557] In some embodiments, each R3aindependently is C1-C6haloalkoxy.

[0558] In some embodiments, each R3aindependently is halomethoxy. In some embodiments, each R3aindependently is haloethoxy. In some embodiments, each R3aindependently is halopropoxy. In some embodiments, each R3aindependently is halobutoxy. In some embodiments, each R3aindependently is halopentoxy. In some embodiments, each R3aindependently is halohexoxy.

[0559] In some embodiments, each R3aindependently is C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0560] In some embodiments, each R3aindependently is –O(C3-C10cycloalkyl) or –(O)(3- to 10- membered heterocyclyl).

[0561] In some embodiments, each R3aindependently is –O(C3-C10cycloalkyl) or –(O)(3- to 10- membered heterocyclyl), wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more -C(O)(C1-C6alkyl) or -CN.

[0562] In some embodiments, each R3aindependently is –O(C3-C10cycloalkyl).

[0563] In some embodiments, each R3aindependently is –O(C3-C10cycloalkyl) optionally substituted with -CN.

[0564] In some embodiments, each R3aindependently is –O(C3-C10cycloalkyl) substituted with -CN.

[0565] In some embodiments, each R3aindependently is –(O)(3- to 10-membered heterocyclyl).

[0566] In some embodiments, each R3aindependently is –(O)(3- to 10-membered heterocyclyl) optionally substituted with -C(O)(C1-C6alkyl).

[0567] In some embodiments, each R3aindependently is –(O)(3- to 10-membered heterocyclyl) substituted with -C(O)(C1-C6alkyl).

[0568] In some embodiments, each R3aindependently is 5- to 10-membered heteroaryl optionally substituted with oxo.

[0569] In some embodiments, each R3aindependently is 5- to 10-membered heteroaryl substituted with oxo.

[0570] In some embodiments, each R3aindependently is C1-C6alkoxy optionally substituted with one or more C1-C6alkoxy, C3-C10cycloalkyl, or 5- to 10-membered heteroaryl.

[0571] In some embodiments, each R3aindependently is C1-C6alkoxy optionally substituted with one or more C1-C6alkoxy or C3-C10cycloalkyl.

[0572] In some embodiments, each R3aindependently is C1-C6alkoxy substituted with C1-C6alkoxy and C3-C10cycloalkyl.

[0573] In some embodiments, each R3aindependently is C1-C6alkoxy substituted with 5- to 10- membered heteroaryl.

[0574] In some embodiments, each R3aindependently is halo, C1-C6alkyl, C1-C6alkoxy, or – O(C3-C10cycloalkyl).

[0575] In some embodiments, each R3aindependently is halo, -OH, -O(C3-C10cycloalkyl), - O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl, wherein the -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10-membered heteroaryl optionally substituted with C1-C6alkyl, or C1-C6alkyl optionally substituted with C1-C6alkoxy.

[0576] In some embodiments, each R3aindependently is F, CH3, -OH, -OCH3, -O(cyclopropyl),

[0577] In some embodiments, each R3aindependently is F, CH3, -OCH3, or -O(cyclopropyl).

[0578] In some embodiments, each R3a independently is halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0579] In some embodiments, each R3aindependently is F, CH3, or -OCH3.

[0580] In some embodiments, R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10-membered heterocyclyl.

[0584] somesome embodiments, R4”is

[0586] some

[0587] In some embodiments,some embodiments,

[0588] In some embodiments,some embodiments,

[0589] In some

[0590] In some embodiments, R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0591] In some embodiments, R5is H.

[0592] In some embodiments, R5is halo or cyano.

[0593] In some embodiments, R5 is halo.

[0594] In some embodiments, R5is F, Cl, Br, or I. In some embodiments, R5is F, Cl, or Br. In some embodiments, R5is F or Cl.

[0595] In some embodiments, R5is F. In some embodiments, R5is Cl. In some embodiments, R5is Br. In some embodiments, R5is I.

[0596] In some embodiments, R5is cyano.

[0597] In some embodiments, R5is H or halo.

[0598] In some embodiments, R5is H or F.

[0599] In some embodiments, R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0600] In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is C2-C6 alkenyl. In some embodiments, R5is C2-C6alkynyl. In some embodiments, R5is C1-C6haloalkyl. In some embodiments, R5is C1-C6alkoxy.

[0601] In some embodiments, R6is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0602] In some embodiments, R6is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy.

[0603] In some embodiments, R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0604] In some embodiments, R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is substituted with one or more -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0605] In some embodiments, R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy.

[0606] In some embodiments, R6is H, chloro, -SO2(C1-C6alkyl), or C1-C6alkyl optionally substituted with -N(C1-C6alkyl)2or -O(C1-C6alkyl).

[0607] In some embodiments, R6is H, chloro, -SO2(C1-C6alkyl), or C1-C6alkyl substituted with -N(C1-C6alkyl)2or -O(C1-C6alkyl).

[0608] In some embodiments, R6is H, chloro, -SO2(C1-C6alkyl), or C1-C6alkyl.

[0609] In some embodiments, R6is H.

[0610] In some embodiments, R6is halo, or cyano.

[0611] In some embodiments, R6is halo.

[0612] In some embodiments, R6is F, Cl, Br, or I. In some embodiments, R6is F, Cl, or Br. In some embodiments, R6is F or Cl.

[0613] In some embodiments, R6is F. In some embodiments, R6is Cl. In some embodiments, R6is Br. In some embodiments, R6is I.

[0614] In some embodiments, R6is cyano.

[0615] In some embodiments, R6is -SO2(C1-C6alkyl).

[0616] In some embodiments, R6is C1-C6alkyl.

[0617] In some embodiments, R6is C1-C6alkyl optionally substituted with -OH.

[0618] In some embodiments, R6is C1-C6alkyl substituted with -OH.

[0619] In some embodiments, R6is C1-C6alkyl optionally substituted with -O(C1-C6alkyl).

[0620] In some embodiments, R6is C1-C6alkyl substituted with -O(C1-C6alkyl).

[0621] In some embodiments, R6is C1-C6alkyl optionally substituted with -NH2.

[0622] In some embodiments, R6is C1-C6alkyl substituted with -NH2.

[0623] In some embodiments, R6is C1-C6alkyl.

[0624] In some embodiments, R6is C1-C6alkyl optionally substituted with -NH(C1-C6alkyl).

[0625] In some embodiments, R6is C1-C6alkyl substituted with -NH(C1-C6alkyl).

[0626] In some embodiments, R6is C1-C6alkyl.

[0627] In some embodiments, R6is C1-C6alkyl optionally substituted with -N(C1-C6alkyl)2.

[0628] In some embodiments, R6is C1-C6alkyl substituted with -N(C1-C6alkyl)2.

[0629] In some embodiments, R6is C1-C6alkoxy.

[0630] In some embodiments, R6is C2-C6alkenyl optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0631] In some embodiments, R6is C2-C6alkenyl optionally substituted with one or more OH, - O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0632] In some embodiments, R6is C2-C6alkenyl.

[0633] In some embodiments, R6is C2-C6alkynyl optionally substituted with one or more -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0634] In some embodiments, R6is C2-C6alkynyl optionally substituted with one or more OH, - O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0635] In some embodiments, R6is C2-C6alkynyl.

[0636] In some embodiments, R6is C1-C6alkoxy optionally substituted with one or more -NH2, - NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0637] In some embodiments, R6is C1-C6alkoxy optionally substituted with one or more OH, - O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0638] In some embodiments, R6is C1-C6alkoxy.

[0639] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl.

[0640] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C4cycloalkenyl.

[0641] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C5cycloalkenyl.

[0642] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C6cycloalkenyl.

[0643] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C7cycloalkenyl.

[0644] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C8cycloalkenyl.

[0645] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C9cycloalkenyl.

[0646] In some embodiments, R5and R6, together with the atoms to which they are attached, form a C10cycloalkenyl.

[0647] In some embodiments, each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1- C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0648] In some embodiments, each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1- C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl).

[0649] In some embodiments, each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0650] In some embodiments, each R7, R8, and R9independently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0651] In some embodiments, each R7, R8, and R9independently is H.

[0652] In some embodiments, each R7, R8, and R9independently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0653] In some embodiments, R7is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0654] In some embodiments, R7is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl).

[0655] In some embodiments, R7is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0656] In some embodiments, R7is H.

[0657] In some embodiments, R7is H or C1-C6alkyl.

[0658] In some embodiments, R7is cyano.

[0659] In some embodiments, R7is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0660] In some embodiments, R7is C1-C6alkyl.

[0661] In some embodiments, R7is methyl. In some embodiments, R7is ethyl. In some embodiments, R7is propyl. In some embodiments, R7is butyl. In some embodiments, R7is pentyl. In some embodiments, R7is hexyl. In some embodiments, R7is isopropyl. In some embodiments, R7is isobutyl. In some embodiments, R7is isopentyl. In some embodiments, R7is isohexyl. In some embodiments, R7is secbutyl. In some embodiments, R7is secpentyl. In some embodiments, R7is sechexyl. In some embodiments, R7is tertbutyl.

[0662] In some embodiments, R7is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl).

[0663] In some embodiments, R7is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl).

[0664] In some embodiments, R7is C1-C6haloalkyl.

[0665] In some embodiments, R7is halomethyl. In some embodiments, R7is haloethyl. In some embodiments, R7is halopropyl. In some embodiments, R7is halobutyl. In some embodiments, R7is halopentyl. In some embodiments, R7is halohexyl.

[0666] In some embodiments, R7is C1-C6alkoxy.

[0667] In some embodiments, R7is methoxy. In some embodiments, R7is ethoxy. In some embodiments, R7is propoxy. In some embodiments, R7is butoxy. In some embodiments, R7is pentoxy. In some embodiments, R7is hexoxy.

[0668] In some embodiments, R8is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl).

[0669] In some embodiments, R8is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0670] In some embodiments, R8is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0671] In some embodiments, R8is H.

[0672] In some embodiments, R8is H or C1-C6alkyl.

[0673] In some embodiments, R8is cyano.

[0674] In some embodiments, R8is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0675] In some embodiments, R8is C1-C6alkyl.

[0676] In some embodiments, R8is methyl. In some embodiments, R8is ethyl. In some embodiments, R8is propyl. In some embodiments, R8is butyl. In some embodiments, R8is pentyl. In some embodiments, R8is hexyl. In some embodiments, R8is isopropyl. In some embodiments, R8is isobutyl. In some embodiments, R8is isopentyl. In some embodiments, R8is isohexyl. In some embodiments, R8is secbutyl. In some embodiments, R8is secpentyl. In some embodiments, R8is sechexyl. In some embodiments, R8is tertbutyl.

[0677] In some embodiments, R8is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl).

[0678] In some embodiments, R8is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl).

[0679] In some embodiments, R8is C1-C6haloalkyl.

[0680] In some embodiments, R8is halomethyl. In some embodiments, R8is haloethyl. In some embodiments, R8is halopropyl. In some embodiments, R8is halobutyl. In some embodiments, R8is halopentyl. In some embodiments, R8is halohexyl.

[0681] In some embodiments, R8is C1-C6alkoxy.

[0682] In some embodiments, R8is methoxy. In some embodiments, R8is ethoxy. In some embodiments, R8is propoxy. In some embodiments, R8is butoxy. In some embodiments, R8is pentoxy. In some embodiments, R8is hexoxy.

[0683] In some embodiments, R9is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl).

[0684] In some embodiments, R9is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0685] In some embodiments, R9is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0686] In some embodiments, R9is H.

[0687] In some embodiments, R9is H or C1-C6alkyl.

[0688] In some embodiments, R9is cyano.

[0689] In some embodiments, R9is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0690] In some embodiments, R9is C1-C6alkyl.

[0691] In some embodiments, R9is methyl. In some embodiments, R9is ethyl. In some embodiments, R9is propyl. In some embodiments, R9is butyl. In some embodiments, R9is pentyl. In some embodiments, R9is hexyl. In some embodiments, R9is isopropyl. In some embodiments, R9is isobutyl. In some embodiments, R9is isopentyl. In some embodiments, R9is isohexyl. In some embodiments, R9is secbutyl. In some embodiments, R9is secpentyl. In some embodiments, R9is sechexyl. In some embodiments, R9is tertbutyl.

[0692] In some embodiments, R9is C2-C6alkenyl (e.g., ethenyl, propenyl, butenyl).

[0693] In some embodiments, R9is C2-C6alkynyl (e.g., ethynyl, propynyl, butynyl).

[0694] In some embodiments, R9is C1-C6haloalkyl.

[0695] In some embodiments, R9is halomethyl. In some embodiments, R9is haloethyl. In some embodiments, R9is halopropyl. In some embodiments, R9is halobutyl. In some embodiments, R9is halopentyl. In some embodiments, R9is halohexyl.

[0696] In some embodiments, R9is C1-C6alkoxy.

[0697] In some embodiments, R9is methoxy. In some embodiments, R9is ethoxy. In some embodiments, R9is propoxy. In some embodiments, R9is butoxy. In some embodiments, R9is pentoxy. In some embodiments, R9is hexoxy.

[0698] In some embodiments, R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0699] In some embodiments, R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl.

[0700] In some embodiments, R7and R8, together with the atoms to which they are attached, form a 3- to 10-membered heterocyclyl.

[0701] In some embodiments, the compound of Formula (I) is of Formula (II-a), (II-b), (II-c), (II- d), or (II-e):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

[0702] In some embodiments, the compound of Formula (I) is of Formula (II-a) or (II-b) wherein R1is 5- to 10-membered heteroaryl.

[0703] In some embodiments, the compound of Formula (I) is of Formula (II-a1), (II-b1), (II- c1), (II-d1),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

[0704] In some embodiments, the compound of Formula (I) is of Formula (II-a1) or (II-b1) wherein R1is 5- to 10-membered heteroaryl.

[0705] In some embodiments, the compound of Formula (I) is of Formula (III-a’), (III-b’), or (III-c’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.

[0706] In some embodiments, the compound of Formula (I) is of Formula (III-a), (III-b), or (III- c):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4 and p is 0, 1, 2, 3, 4, 5, or 6.

[0707] In some embodiments, the compound of Formula (I) is of Formula (III-a”’), (III-b”’),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4 and p is 0, 1, 2, 3, 4, 5, or 6.

[0708] In some embodiments, the compound of Formula (I) is of Formula (III-a’), (III-b’), (III- c’), (III-a), (III-b), or (III-c) wherein R1is 5- to 10-membered heteroaryl.

[0709] In some embodiments, the compound of Formula (I) is of Formula (III-a”’), (III-b”’), (III-c”’), (III-a”), (III-b”), or (III-c”) wherein R1is 5- to 10-membered heteroaryl.

[0710] In some embodiments, the compound of Formula (I) is of Formula (IV-a), (IV-b), oror a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, or 5.

[0711] In some embodiments, the compound of Formula (I) is of Formula (IV-d), (IV-e), oror a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

[0712] In some embodiments, the compound of Formula (I) is of Formula (IV-g), (IV-h), oror a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

[0713] In some embodiments, the compound of Formula (I) is of Formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-f), (IV-g), (IV-h), or (IV-i), wherein each R2aindependently is halo, -OH, or C3-C10cycloalkyl.

[0714] In some embodiments, the compound of Formula (I) is of Formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-f), (IV-g), (IV-h), or (IV-i), wherein each R2aindependently is fluoro, -OH, or cyclopropyl.

[0715] In some embodiments, the compound of Formula (I) is of Formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-f), (IV-g), (IV-h), or (IV-i), wherein each R1aindependently is halo, -NH2, - S(C1-C6alkyl), C1-C6alkyl, or C1-C6haloalkyl.

[0716] In some embodiments, the compound of Formula (I) is of Formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-f), (IV-g), (IV-h), or (IV-i), wherein each R1aindependently is fluoro, chloro, bromo, -NH2, -SCH3, -CH3, -CF3, or -CF2CH3.

[0717] In some embodiments, the compound of Formula (I) is of Formula (IV-a’), (IV-b’), (IV-i’), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

[0718] In some embodiments, the compound of Formula (I) is of Formula (IV-a’), (IV-b’), (IV- c’), (IV-d’), (IV-e’), (IV-f’), (IV-g’), (IV-h’), or (IV-i’), wherein each R2aindependently is halo, -OH, or C3-C10cycloalkyl.

[0719] In some embodiments, the compound of Formula (I) is of Formula (IV-a’), (IV-b’), (IV- c’), (IV-d’), (IV-e’), (IV-f’), (IV-g’), (IV-h’), or (IV-i’), wherein each R2aindependently is fluoro, -OH, or cyclopropyl.

[0720] In some embodiments, the compound of Formula (I) is of Formula (IV-a’), (IV-b’), (IV- c’), (IV-d’), (IV-e’), (IV-f’), (IV-g’), (IV-h’), or (IV-i’), wherein each R1aindependently is halo, -NH2, -S(C1-C6alkyl), C1-C6alkyl, or C1-C6haloalkyl.

[0721] In some embodiments, the compound of Formula (I) is of Formula (IV-a’), (IV-b’), (IV- c’), (IV-d’), (IV-e’), (IV-f’), or (IV-g’), (IV-h’), or (IV-i’), wherein each R1aindependently is fluoro, chloro, bromo, -NH2, -SCH3, -CH3, -CF3, or -CF2CH3.

[0722] In some embodiments, the compound of Formula (I) is of Formula (V-a) or (V-b):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, or 5.

[0723] In some embodiments, the compound of Formula (I) is of Formula (V-c) or (V-d):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

[0724] In some embodiments, the compound of Formula (I) is of Formula (V-a’), (V-b’), (V-c’), or (V-d’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

[0725] In some embodiments, the compound of Formula (I) is of Formula (VI-a) or (VI-b):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, or 5.

[0726] In some embodiments, the compound of Formula (I) is of Formula (VI-c) or (VI-d):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

[0727] In some embodiments, the compound of Formula (I) is of Formula (VI-a’), (VI-b’), (VI-or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

[0728] In some embodiments, the compound of Formula (I) is of Formula (VII-a) or (VII-b):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, or 5.

[0729] In some embodiments, the compound of Formula (I) is of Formula (VII-c) or (VII-d):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

[0730] In some embodiments, the compound of Formula (I) is of Formula (VII-a’), (VII-b’), (VII-c’), or (VII-d’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

[0731] In some embodiments, the compound of Formula (I) is of Formula (VIII-a) or (VIII-b):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, or 5.

[0732] In some embodiments, the compound of Formula (I) is of Formula (VIII-c) or (VIII-d):(VIII-d),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

[0733] In some embodiments, the compound of Formula (I) is of Formula (VIII-a’), (VIII-b’),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

[0734] In some embodiments, n is 0, 1, 2, 3, 4, or 5.

[0735] In some embodiments, n is 1, 2, 3, 4, or 5.

[0736] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0737] In some embodiments, n is 1 or 2.

[0738] In some embodiments, m is 0, 1, 2, 3, or 4.

[0739] In some embodiments, m is 1, 2, 3, or 4.

[0740] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0741] In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6.

[0742] In some embodiments, p is 1, 2, 3, 4, 5, or 6.

[0743] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0744] In some embodiments, p is 1 or 2.

[0745] In some embodiments, q is 0, 1, 2, 3, 4, or 5.

[0746] In some embodiments, q is 1, 2, 3, 4, or 5.

[0747] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.

[0748] In some embodiments, q is 1 or 2.

[0749] In some embodiments, r is 1, 2, 3, or 4.

[0750] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0751] In some embodiments, r is 1 or 2.

[0752] In some embodiments, r is 3; m is 1; and p is 0.

[0753] In some embodiments, the compound is selected from the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0754] In some embodiments, the compound is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0755] In some embodiments, the compound is selected from the prodrugs of compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0756] In some embodiments, the compound is selected from the compounds described in Table 1.

[0757] In some embodiments, the compound of Table 1 comprises one (S) stereocenter.

[0758] In some embodiments, the compound of Table 1 comprises one (R) stereocenter.

[0759] In some embodiments, the compound of Table 1 comprises one (S) stereocenter and one (R) stereocenter.

[0760] In some embodiments, the compound of Table 1 comprises two (S) stereocenters.

[0761] In some embodiments, the compound of Table 1 comprises two (R) stereocenters.

[0762] In some embodiments, the compound is selected from the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0763] In some embodiments, the compound is selected from the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0764] In some embodiments, the compound is selected from the prodrugs of compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0765] In some embodiments, the compound is selected from the compounds described in Table 2.

[0766] In some embodiments, the compound of Table 2 comprises one (S) stereocenter.

[0767] In some embodiments, the compound of Table 2 comprises one (R) stereocenter.

[0768] In some embodiments, the compound of Table 2 comprises one (S) stereocenter and one (R) stereocenter.

[0769] In some embodiments, the compound of Table 2 comprises two (S) stereocenters.

[0770] In some embodiments, the compound of Table 2 comprises two (R) stereocenters.

[0771] In some embodiments, the compound is selected from the compounds described in Table 1A, or a prodrug or pharmaceutically acceptable salt thereof.

[0772] In some embodiments, the compound is selected from the compounds described in Table 1A, or a pharmaceutically acceptable salt thereof.

[0773] In some embodiments, the compound is selected from the prodrugs of compounds described in Table 1A, or a pharmaceutically acceptable salt thereof.

[0774] In some embodiments, the compound is selected from the compounds described in Table 1A.

[0775] In some embodiments, the compound is selected from the compounds described in Table 2A, or a prodrug or pharmaceutically acceptable salt thereof.

[0776] In some embodiments, the compound is selected from the compounds described in Table 2A, or a pharmaceutically acceptable salt thereof.

[0777] In some embodiments, the compound is selected from the prodrugs of compounds described in Table 2A, or a pharmaceutically acceptable salt thereof.

[0778] In some embodiments, the compound is selected from the compounds described in Table 2A.Table 1Table 2Table 1ATable 2A

[0779] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0780] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0781] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0782] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0783] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0784] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0785] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 2.

[0786] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0787] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0788] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0789] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.

[0790] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1A.

[0791] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1A, or a prodrug or pharmaceutically acceptable salt thereof.

[0792] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1A, or a pharmaceutically acceptable salt thereof.

[0793] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1A, or a pharmaceutically acceptable salt thereof.

[0794] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1A.

[0795] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 2A.

[0796] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2A, or a prodrug or pharmaceutically acceptable salt thereof.

[0797] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2A, or a pharmaceutically acceptable salt thereof.

[0798] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 2A, or a pharmaceutically acceptable salt thereof.

[0799] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2A.

[0800] In some embodiments, the compound is selected from Compound Nos.5, 14, 21, 23, 25, 26, 27, 32, 67, 87, or 92, or a prodrug or pharmaceutically acceptable salt thereof.

[0801] In some embodiments, the compound is selected from Compound Nos 5, 14, 21, 23, 25, 26, 27, 32, 67, 87, or 92, or a pharmaceutically acceptable salt thereof.

[0802] In some embodiments, the compound is selected from Compound Nos 5, 14, 21, 23, 25, 26, 27, 32, 67, 87, or 92.

[0803] In some embodiments, the compound is selected from Compound Nos.128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a prodrug or pharmaceutically acceptable salt thereof.

[0804] In some embodiments, the compound is selected from Compound Nos.128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a pharmaceutically acceptable salt thereof.

[0805] In some embodiments, the compound is selected from Compound Nos.128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228.

[0806] In some embodiments, the compound is selected from Compound Nos.128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, or 228A, or a prodrug or pharmaceutically acceptable salt thereof.

[0807] In some embodiments, the compound is selected from Compound Nos.128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, or 228A, or a pharmaceutically acceptable salt thereof.

[0808] In some embodiments, the compound is selected from Compound Nos.128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, or 228A.

[0809] In some embodiments, the compound is selected from Compound Nos.5, 14, 21, 23, 25, 26, 27, 32, 67, 87, 92, 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a prodrug or pharmaceutically acceptable salt thereof.

[0810] In some embodiments, the compound is selected from Compound Nos.5, 14, 21, 23, 25, 26, 27, 32, 67, 87, 92, 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a pharmaceutically acceptable salt thereof.

[0811] In some embodiments, the compound is selected from 5, 14, 21, 23, 25, 26, 27, 32, 67, 87, 92, 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228.

[0812] In some embodiments, the compound is selected from Compound Nos. 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a prodrug or pharmaceutically acceptable salt thereof.

[0813] In some embodiments, the compound is selected from Compound Nos. 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a pharmaceutically acceptable salt thereof.

[0814] In some embodiments, the compound is selected from Compound Nos. 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228.

[0815] In some embodiments, the compound is selected from Compound Nos. 128, 163, 178, 191, 194, 202, 203, 206, 208, 210, 218, or 228, or a prodrug or pharmaceutically acceptable salt thereof.

[0816] In some embodiments, the compound is selected from Compound Nos. 128, 163, 178, 191, 194, 202, 203, 206, 208, 210, 218, or 228, or a pharmaceutically acceptable salt thereof.

[0817] In some embodiments, the compound is selected from Compound Nos. 128, 163, 178, 191, 194, 202, 203, 206, 208, 210, 218, or 228.

[0818] In some embodiments, the compound is Compound No. 128 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 163 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 178 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.191 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 194 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 202 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 203 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.206 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 208 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 210 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 218 or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.228 or a prodrug or pharmaceutically acceptable salt thereof.

[0819] In some embodiments, the compound is Compound No. 128 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 163 or apharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 178 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 191 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 194 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.202 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.203 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 206 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 208 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 210 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 218 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.228 or a pharmaceutically acceptable salt thereof.

[0820] In some embodiments, the compound is Compound No.128. In some embodiments, the compound is Compound No.163. In some embodiments, the compound is Compound No.178. In some embodiments, the compound is Compound No.191. In some embodiments, the compound is Compound No. 194. In some embodiments, the compound is Compound No. 202. In some embodiments, the compound is Compound No. 203. In some embodiments, the compound is Compound No. 206. In some embodiments, the compound is Compound No. 208. In some embodiments, the compound is Compound No. 210. In some embodiments, the compound is Compound No.218. In some embodiments, the compound is Compound No.228.

[0821] In some embodiments, the compound is selected from Compound Nos. 128A, 163A, 178A, 191A, 194A, 202A, 203A, 206A, 208A, 210A, 218A, or 228A, or a prodrug or pharmaceutically acceptable salt thereof.

[0822] In some embodiments, the compound is selected from Compound Nos. 128A, 163A, 178A, 191A, 194A, 202A, 203A, 206A, 208A, 210A, 218A, or 228A, or a pharmaceutically acceptable salt thereof.

[0823] In some embodiments, the compound is selected from Compound Nos. 128A, 163A, 178A, 191A, 194A, 202A, 203A, 206A, 208A, 210A, 218A, or 228A.

[0824] In some embodiments, the compound is Compound No. 128A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 163A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, thecompound is Compound No. 178A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 191A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.194A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 202A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 203A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 206A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.208A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 210A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 218A or a prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 228A or a prodrug or pharmaceutically acceptable salt thereof.

[0825] In some embodiments, the compound is Compound No. 128A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 163A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 178A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 191A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 194A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.202A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 203A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.206A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 208A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 210A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No. 218A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound No.228A or a pharmaceutically acceptable salt thereof.

[0826] In some embodiments, the compound is Compound No.128A. In some embodiments, the compound is Compound No.163A. In some embodiments, the compound is Compound No.178A. In some embodiments, the compound is Compound No. 191A. In some embodiments, the compound is Compound No.194A. In some embodiments, the compound is Compound No.202A.In some embodiments, the compound is Compound No. 203A. In some embodiments, the compound is Compound No.206A. In some embodiments, the compound is Compound No.208A. In some embodiments, the compound is Compound No. 210A. In some embodiments, the compound is Compound No.218A. In some embodiments, the compound is Compound No.228A.

[0827] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0828] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0829] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0830] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof). In some embodiments, the compound is a18F labeled compound. In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof. In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0831] It is understood that the18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0832] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and36S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,,18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0833] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0834] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 daltons or less.

[0835] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0836] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0837] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound.

[0838] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0839] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0840] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0841] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

[0842] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0843] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compoundshave chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0844] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0845] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0846] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0847] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0848] Compounds that have the same molecular formula but 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”. Stereoisomersthat are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0849] The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centers (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess WRN inhibitory activity.

[0850] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0851] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0852] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between acation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0853] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0854] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0855] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound.

[0856] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0857] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0858] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, amono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess WRN activity.

[0859] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess WRN activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0860] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0861] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N- oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0862] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0863] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically- produced compound.

[0864] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0865] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosedherein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1- C10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include D-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0866] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4alkoxy-C2-C4alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0867] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1- ylmethyl.

[0868] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0869] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Methods of Synthesis

[0870] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0871] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0872] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.

[0873] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0874] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0875] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0876] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0877] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0878] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0879] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0880] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or forexample a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0881] Once a compound of Formula (I) has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0882] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.

[0883] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0884] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0885] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0886] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0887] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0888] General routes for the preparation of a compound of the application are described in Schemes 1-18 herein.Scheme 1

[0889] Compounds of the formula Gen-A can be prepared by the synthetic route depicted in Scheme 1, wherein A is C or N; X is halo; and PG is a protecting group. Amine-protected bis- carbonyl ester Gen-1 can be combined with a halo-functionalized hydrazine to form pyrazole ester Gen-2. Ester Gen-2 can then be reduced to the corresponding primary alcohol (e.g., with the use of DIBAL-H) and the resulting primary alcohol transformed to the O-mesylate (e.g., with the use of methanesulfonic anhydride and a base, e.g., triethylamine). The resulting mesylate can then be displaced with a cyanide nucleophile (e.g., with trimethylsilyl cyanide) to afford Gen-3. Gen-3 can then be subjected to hydrolysis conditions (e.g., through the use of a hydroxide base like sodium hydroxide) to afford the corresponding carboxylic acid, which can then be transformed to the corresponding methyl ester through the use of a base and iodomethane to afford Gen-4. Gen-4 can then to oxidized to the corresponding imine (e.g., through the use of TEMPO+BF4-) and a cyanide nucleophile (e.g., TMSCN) can be added to afford Gen-5. Nitrile Gen-5 can then be reduced to the corresponding primary amine with a suitable catalyst (e.g., with Raney Nickel) and this resulting primary amine can cyclize in situ or through the use of additional base (e.g., potassium carbonate) to afford lactam Gen-6. Gen-6 can then be cross-coupled using palladium catalysis with a boronic acid or ester (e.g., through Suzuki coupling conditions with a standard catalyst system and base) to afford Gen-7. It is noted that intermediates Gen-2, Gen-3, or Gen-4 can also alternatively beused in a cross-coupling reaction to functionalize the halogen (e.g., in a cross-coupling reaction with a suitable catalyst) and the resulting intermediates can be advanced through the analogous synthetic sequence depicted in Scheme 1. Gen-7 can then be reduced (e.g., through the use of borane tetrahydrofuran complex) to afford amine Gen-8. Amine Gen-8 can then be functionalized with a suitable carboxylic acid ( (e.g., using standard amide coupling conditions, or acid chloride or sulfonyl chloride using a suitable base) to provide Gen-9. Gen-9 can then be deprotected using standard protecting group deprotection conditions (e.g., a Boc group can be removed via treatment with acid, e.g., trifluoroacetic acid) to afford Gen-10. Amine Gen-10 can then be coupled with a carboxylic acid using amide coupling conditions (e.g., HOBT and EDC and a suitable base) to afford Gen-A. In some cases, Gen-10 can be combined with an acid chloride and a suitable base to afford Gen-A. At any point in the synthetic route, the intermediate or final compound may undergo chiral and / or diastereomer separation and a single enantiomer or diastereomer can be carried through the remaining steps of the route. Scheme 2

[0890] Compounds of the formula Gen-A-1 can be prepared by the synthetic route depicted in Scheme 2, wherein A is C or N and PG is a protecting group. In some instances, a compound of the structure Gen-8-1 can be protected with a suitable protecting group to form Gen-8-2, which can then be functionalized at an aryl carbon at the ortho position to provide phenol Gen-8-3 (e.g., Gen-8-2 can be treated with a palladium catalyst and acetic acid to form the ortho-acetate, which can then be hydrolyzed using a suitable base to provide phenol Gen-8-3). Gen-8-3 can then be deprotected to form Gen-8-4, which can proceed to Gen-9 as described in Scheme 1. In some stepsof Scheme 1, the phenol may become esterified, and the resulting ester can be cleaved through the use of a suitable base (e.g., lithium hydroxide) to provide compounds of Gen-A-1. Scheme 3

[0891] Compounds of the formula Gen-A-2 can be prepared by the synthetic route depicted in Scheme 3, wherein A is C or N and PG is a protecting group. In some instances, intermediate Gen- 7 can be functionalized at the benzylic position to form azide Gen-7-1 (e.g., through the use of 4- methylbenzenesulfonyl azide solution). Azide Gen-7-1 could then be functionalized with a nucleophile (e.g., MeOH could be added to provide Gen-7-2 where R3ais -OCH3). Gen-7-2 could then be advanced to Gen-A-2 via the synthetic sequence depicted in Scheme 1. Scheme 4

[0892] Compounds of the formula Gen-2’ can be prepared by the synthetic route depicted in Scheme 4, wherein A is C or N; X is halo; and PG is a protecting group. In some cases, the hydrazine employed in step 1 of scheme 1 already contains the R2agroup in place of a halogen,and the resulting Gen-2’ is carried through the rest of the route depicted in scheme 1, forgoing the coupling step to introduce R2aat the halogen position. Scheme 5

[0893] Compounds of the formula Gen-B can be prepared by the synthetic route depicted in Scheme 5, wherein A is C or N; X is halo; and PG is a protecting group. Keto-ester Gen-11 can be combined with hydrazine to form pyrazole Gen-12. Gen-12 can then be combined with a suitable substituted bis-halogenated aryl or heteroaryl ring in a cross-coupling reaction (e.g., through the use of a copper catalyst and cesium carbonate) to provide Gen-13. Gen-13 can then be oxidized to the corresponding imine (e.g., through the use of TEMPO+BF4- and a cyanide nucleophile, e.g., TMSCN) can be added to afford the corresponding nitrile, which can then be reduced (e.g., through the use of sodium borohydride) to afford the primary amine Gen-14. Amino alcohol Gen-14 can then be cyclized through the use of chloroacetyl chloride and a base to afford cyclic lactam Gen- 15. Gen-15 can then be reduced to the secondary amine (e.g., through the use of sodium borohydride) and the resulting amine protected with a suitable orthogonal protecting group to provide Gen-16. Gen-16 can then undergo a cross-coupling reaction to functionalize the remaining halogen (e.g., Gen-16 can engage in a Suzuki reaction with a palladium catalyst and corresponding boronic acid or ester to provide Gen-17). Intermediate Gen-17 can then engage in analogous stepsto Schemes 2 and 1 in the above examples to provide compounds of the structure of Gen-B. It is noted that Gen-15 can also alternatively be used in a cross-coupling reaction to functionalize the halogen (e.g., in a cross-coupling reaction with a suitable catalyst) and the resulting intermediates can be advanced in an analogous fashion. Scheme 6

[0894] Compounds of the formula Gen-13’ can be prepared by the synthetic route depicted in Scheme 6, wherein A is C or N; X is halo; and PG is a protecting group. In some cases, Gen-12 can be combined with a suitable substituted halogenated aryl or heteroaryl ring already functionalized with one or more R2agroup in the cross-coupling reaction (e.g., through the use of a copper catalyst and cesium carbonate) to provide Gen-13’, which can be advanced through an analogous synthetic sequence of Scheme 5. Scheme 7

[0895] Compounds of the formula Gen-13’ can be prepared by the synthetic route depicted in Scheme 7, wherein A is C or N; X is halo; and PG is a protecting group. In some cases, Gen-13’ can be accessed via amino-pyrazole Gen-18, which can be cross-coupled with a halogenated aryl or heteroaryl ring (e.g., through the use of copper catalysis) to afford Gen-19. Gen-19 can then be transformed to the halogenated pyrazole (e.g., through the use of iodine and isoamyl nitrite to afford the iodinated pyrazole) and the subsequent halogen can engage in a cross-coupling reaction with a suitable alcohol (e.g., methanol under copper catalysis) to afford Gen-20. Gen-20 can then be transformed to Gen-13’ through the use of a demethylating reagent (e.g., lithium tri-sec- butylhydroborate). Gen-13’ can then engage in a synthetic route analogous to those described in Scheme 5 to afford compounds of the structure of Gen-B.Scheme 8

[0896] Compounds of the formula Gen-B-1 can be prepared by the synthetic route depicted in Scheme 8, wherein A is C or N; X is halo; and PG is a protecting group. In some instances, heterocyclic phenol Gen-13 can be alkylated with an alpha-halo carboxylic ester (e.g., with ethyl 2-bromopropanoate). The resulting ester Gen-21 can then be cross-coupled with a suitable cross- coupling partner (e.g., Gen-21 could react with a boronic acid under palladium-catalyzed Suzuki conditions) to afford Gen-22. Ester Gen-22 can then be oxidized to the corresponding imine (e.g., through the use of TEMPO+BF4- , and a cyanide nucleophile, e.g., TMSCN) can be added to afford the corresponding nitrile, which can then be reduced (e.g., through the use of sodium borohydride) to afford the primary amine Gen-23. Amine Gen-23 can then be saponified to the corresponding carboxylic acid (e.g., via reaction with lithium hydroxide) and the resulting amino acid can be cyclized via use of a base and a standard peptide coupling reagent to afford lactam Gen-15’. Lactam Gen-15’ could then engage in synthetic routes analogous to those described in Scheme 5 starting from Gen-15.Scheme 9

[0897] Compounds of the formula Gen-C can be prepared by the synthetic route depicted in Scheme 9, wherein A is C or N and PG is a protecting group. In some cases, Gen-19 can be reacted with an oxoacetate (e.g., methyl 2-oxoacetate) under reductive amination conditions (e.g., through the use of sodium borohydride) to provide secondary amine Gen-24. The amine Gen-24 can then be functionalized by an additional reductive amination (e.g., by using formaldehyde and palladium on carbon) to afford Gen-25. Gen-25 can then be used in place of Gen-22 in synthetic routes analogous to those described in Schemes 8 and 5 to advance to compounds of the formula Gen-C.Scheme 10

[0898] Compounds of the formula Gen-B-2 can be prepared by the synthetic route depicted in Scheme 10, wherein A is C or N and PG is a protecting group. In some instances, a compound of the structure of Gen-17’ can be functionalized at an aryl carbon at the ortho position to provide phenol Gen-26 (e.g.,, Gen-17’ can be treated with a palladium catalyst and acetic acid to form the ortho-acetate, which can then be hydrolyzed using a suitable base to provide phenol Gen-26). Gen- 26 can then be deprotected to form Gen-27, which can proceed to Gen-B-2 as described in Scheme 1. In some steps of Scheme 1, the phenol may become esterified, and the resulting ester can be cleaved through the use of a suitable base, for example lithium hydroxide, to provide compounds of Gen-B-2. Scheme 11

[0899] Compounds of the formula Gen-C can be prepared by the synthetic route depicted in Scheme 11, wherein A is C or N and PG is a protecting group. In some cases, Gen-2’ can be directly oxidized to the corresponding imine (e.g., through the use of TEMPO+BF4- , and a cyanide nucleophile, e.g., TMSCN) can be added to afford Gen-28. Nitrile Gen-28 can then be reduced to the corresponding primary amine with a suitable catalyst (e.g., with Raney Nickel). The ester can then be saponified, (e.g., through the use of a base like lithium hydroxide) and the resulting amino- acid can be cyclized to the lactam (e.g., through the use of standard amide coupling reagents) to lactam Gen-29. Lactam Gen-29 can then engage in analogous sequences to Schemes 1-4 to afford compounds of the structure Gen-C. Scheme 12

[0900] Compounds of the formula Gen-D can be prepared by the synthetic route depicted in Scheme 12, wherein A is C or N; X is halo; and PG is a protecting group. In some cases, Gen-2’ can be reduced to the primary alcohol (e.g., through the use of DIBAL-H) and the resulting alcohol can be transformed to the alkyl halide (e.g., through the use of triphenylphosphine and 1,2- dibromo-1,1,2,2-tetrachloroethane) to afford the alkyl bromide. The halide can then be displaced with a nucleophile (e.g., ethyl 2-hydroxyacetate) to afford esters of the formula Gen-30. Gen-30 can then be oxidized to the corresponding imine (e.g., through the use of TEMPO+BF4- , and a cyanide nucleophile, e.g., TMSCN) can be added to afford Gen-31. Nitrile Gen-31 can then be advanced to compounds of the structure Gen-D by employing synthetic steps analogous to those described in Scheme 11.Scheme 13

[0901] Compounds of the formula Gen-E can be prepared by the synthetic route depicted in Scheme 13, wherein A is C or N and PG is a protecting group. In some cases, 7-chloro-1H- pyrazolo[3,4-c]pyridine may be N-functionalized with an alkyl halide to afford a compound of Gen-32. Aryl iodide Gen-32 can then be reacted with a boronic acid or ester under cross-coupling conditions, (e.g., with the use of a palladium catalyst under Suzuki conditions) to afford aryl pyrazole Gen-33. Gen-33 can then be elaborated to a nitrile through the use of zinc cyanide to afford Gen-34. Gen-34 can then be reduced to the corresponding primary amine (e.g., through the use of DIBAL-H) and subsequently protected with a suitable amine protecting group. The alcohol can then be deprotected (e.g., a silyl protecting group can be removed through the use of TBAF) and the subsequent primary alcohol can be activated (e.g., with the use of triphenylphosphine) and displaced intramolecularly with the protected amine to afford the cyclized compound Gen-36. Gen-36 can then be partially hydrogenated (e.g., with the use of platinum oxide under an atmosphere of hydrogen gas) to afford pyrazole Gen-37. Gen-37 can then engage in an amide couple at the secondary amine to afford amide Gen-38. Gen-38 can then be deprotected to afford a secondary amine, which can then be functionalized with a suitable carboxylic acid (e.g., using standard amide coupling conditions, or acid chloride or sulfonyl chloride using a suitable base), to provide compounds of the formula Gen-E.Scheme 14

[0902] In some cases, a compound of the formula Gen-F can be obtained by following the sequence described in Scheme 14. 2-bromo-1H-imidazole can be reacted with a protected (2- bromoethyl) carbamate to afford a protected 2-(2-bromo-1H-imidazol-1-yl)ethan-1-amine. This heteroaryl bromide can then engage in a cross coupling reaction with a suitable coupling partner (e.g., the bromo-imidazole can be coupled with an aryl or heteroaryl boronic acid or ester under Suzuki conditions to afford aryl imidazoles of the structure of Gen-39). Amine Gen-39 can then be deprotected (e.g., a Boc group can be removed through the use of acid) and the resulting primary amine can engage in a cyclization reaction with a protected amine-bearing aldehyde to afford diamine Gen-40. The resulting secondary amine can then be protected, and the imidazole can undergo a bromination reaction (e.g., through the use of NBS). The resulting aryl bromide can then engage in a cross-coupling reaction with an enol-ether boronic ester or acid (e.g., under palladium- catalyzed conditions) to afford Gen-42. Gen-42 can be deprotected both at the primary amine and at the enol ether (e.g., the primary amine may be protected by a phthalamide derivative, which can be removed through the use of ammonia, and aldehyde can be revealed from the enol ether under acidic conditions). The resulting amino-aldehyde can undergo intramolecular imine formation to provide Gen-43. Imine Gen-43 can then be reduced to the amine (e.g., through the use of sodiumborohydride) and the resulting amine protected with a suitable protecting group to afford Gen-44. Gen-44 can then undergo amine deprotection at the alternate secondary amine through the use of an orthogonal, compatible protecting group and standard deprotection conditions (e.g., an N-alkyl nitrobenzenesulfonamide could be removed by treating with 4-methoxy-benzenethiol). The resulting free secondary amine can then engage with a carboxylic acid or acid chloride (e.g., a carboxylic acid can undergo amide coupling under standard conditions) to afford amide Gen-45. Gen-45 can then be deprotected to afford a secondary amine (e.g., a Boc group can be removed by treatment with acid) and the resulting amine can then be functionalized with a suitable carboxylic acid (e.g., using standard amide coupling conditions, or acid chloride or sulfonyl chloride using a suitable base), to provide compounds of the formula Gen-F. Scheme 15

[0903] Compounds of the formula Gen-A can also be prepared by the synthetic route depicted in Scheme 15, wherein Gen-8-2 can be functionalized at the ortho position to provide either Gen-8- 6 directly, or to provide halide Gen-8-5 (e.g., Gen-8-2 can be treated with a rhodium complex and iodobenzenediacetate to provide Gen-8-5 wherein x = I). Gen-8-5 can then be further functionalized under standard cross-coupling conditions with a suitable coupling partner, forexample to provide an alkylated analog. In some cases, this added group can be further functionalized to a final R2a. Gen-8-6 can then be elaborated to provide compounds of the formula Gen-A in an analogous manner to general Scheme 1. Scheme 16 '

[0904] In some cases, compounds of the formula Gen-8-7 (prepared as described in Scheme 2) can be further functionalized on the phenol oxygen to provide intermediates of the formula Gen- 8-8 (for example, the phenol can be treated with sodium chloro(difluoro)acetate to provide the corresponding difluoromethoxyphenol, which can then be elaborated to provide compounds of the formula Gen-A-3 through the general route described in Scheme 1. Scheme 17

[0905] In some cases, intermediates of the formula Gen-4 can be prepared via cross-coupling of a protected methyl 2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)acetate with a suitable coupling partner and the use of a metal catalyst, for example a copper catalyst. Esters Gen-4 can then be elaborated as in Schemes 1 and 2 to final compounds.Scheme 18

[0906] In some cases, a protected methyl 2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3- yl)acetate can be further protected with an orthogonal protecting group, for example a THP group on the azole nitrogen. This protected pyrazole can then undergo analogous steps to those described in general Scheme 1 to provide compounds of Gen-8-1. Amine Gen-8-1 can then be functionalized with a suitable carboxylic acid (e.g., using standard amide coupling conditions, or acid chloride or sulfonyl chloride using a suitable base) to provide Gen-12. Gen-12 can then be deprotected at the pyrazole to afford the free pyrazole, which can engage in a cross-coupling reaction with a suitable alkyl or aryl coupling partner or alkylated with a suitable alkyl halide. Gen-9-1 can then be elaborated to compounds of the formula Gen-A-4 via steps analogous to those depicted in general Scheme 1. Biological Assays

[0907] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0908] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0909] Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0910] In some embodiments, the biological assay is described in the Examples herein.

[0911] In some embodiments, the Werner helicase construct is produced and purified for use in the biological assay.

[0912] In some embodiments, WRN activity may be measured using an ATPase assay.

[0913] In some embodiments, Full length WRN protein (aa 2-1432) may be used in the ATPase assay.

[0914] In some embodiments, the compound may be incubated with the protein under optimized conditions.

[0915] In some embodiments, control wells may be utilized to included compounds which show no inhibition of WRN and compounds which show maximum inhibition of WRN.

[0916] In some embodiments, the inhibition may be observed with luminescence was (e.g., on a PHERAstar) followed by a data fit to obtain IC50values.

[0917] In some embodiments, the compounds may be incubated with a cancer cell line (e.g., a colon carcinoma line). In some embodiments, the incubation may take place for a period of time at a specified temperature. In some embodiments, luminescence quantification of activity may be performed followed by a fit (e.g., linear least squares fit) to provide IC50values.

[0918] In some embodiments, the biological assay is completed more than one time (e.g., in duplicate) and the reported IC50is an average. Pharmaceutical Compositions

[0919] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described in Table 1 or Table 2. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1 or Table 2. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described in Table 1A or Table 2A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1A or Table 2A.

[0920] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Compound Nos.128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, and 228.

[0921] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, or 228A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Compound Nos.128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, and 228A.

[0922] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.128, 163, 178, 191, 194, 202, 203, 206, 208, 210, 218, or 228. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Compound Nos.128, 163, 178, 191, 194, 202, 203, 206, 208, 210, 218, and 228.

[0923] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 128. In some embodiments, the present disclosure provides apharmaceutical composition comprising Compound No. 163. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 178. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 191. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 194. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 202. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.203. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 206. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 208. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 210. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.218. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.228.

[0924] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 128A, 163A, 178A, 191A, 194A, 202A, 203A, 206A, 208A, 210A, 218A, or 228A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Compound Nos.128A, 163A, 178A, 191A, 194A, 202A, 203A, 206A, 208A, 210A, 218A, and 228A.

[0925] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 128A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.163A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 178A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 191A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 194A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.202A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.203A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 206A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No. 208A. In some embodiments, the present disclosureprovides a pharmaceutical composition comprising Compound No.210A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.218A. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound No.228A.

[0926] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0927] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0928] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0929] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-ȕ- cyclodextrin, methyl-ȕ-cyclodextrin, randomly methylated-ȕ-cyclodextrin, ethylated-ȕ- cyclodextrin, triacetyl-ȕ-cyclodextrin, peracetylated-ȕ-cyclodextrin, carboxymethyl-ȕ- cyclodextrin, hydroxyethyl-ȕ-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-ȕ- cyclodextrin, glucosyl-ȕ-cyclodextrin, sulfDWHG^ȕ-cyclodextrin (S-ȕ-CD), maltosyl-ȕ-cyclodextrin, ȕ-cyclodextrin sulfobutyl ether, branched-ȕ-cyclodextrin, hydroxypropyl-Ȗ-cyclodextrin, randomly methylated-Ȗ-cyclodextrin, and trimethyl-Ȗ-cyclodextrin, and mixtures thereof.

[0930] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0931] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferablybenzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl- p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0932] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0933] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0934] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0935] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereofincluding disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including VRGLXP^FLWUDWH^^^DQG^İ-aminocaproic acid, and mixtures thereof.

[0936] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0937] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0938] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0939] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solutionfor intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0940] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0941] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a WRN related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0942] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a WRN related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0943] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use

[0944] In some aspects, the present disclosure provides a method of modulating WRN activity, comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0945] In some aspects, the present disclosure provides a method of modulating WRN activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0946] In some aspects, the present disclosure provides a method of modulating WRN activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0947] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0948] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0949] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0950] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0951] In some aspects, the present disclosure provides a method for inhibiting DNA repair by WRN in a cancer cell comprising contacting the cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0952] In some embodiments, the cancer is a microsatellite instable (MSI) and / or mismatch repair deficient (dMMR) cancer.

[0953] In some embodiments, the cancer is a microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR) cancer.

[0954] In some embodiments, the cancer is a microsatellite instable (MSI) cancer. In some embodiments, the cancer is a microsatellite instability-high (MSI-H) cancer. In some embodiments, the cancer is a mismatch repair deficient (dMMR) cancer.

[0955] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MMR gene expression, in which MMR genes include: MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, PMS1, and EPCAM, the absence of MMR genes, or reduced function of MMR proteins, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0956] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MMR gene expression, in which MMR genes include: MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, PMS1,and EPCAM, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0957] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by the absence of MMR genes, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0958] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by a reduced function of MMR proteins, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0959] In some embodiments, the disease or disorder is associated with an implicated WRN activity. In some embodiments, the disease or disorder is a disease or disorder in which WRN activity is implicated.

[0960] In some embodiments, the disease or disorder is associated with an implicated WRN activity. In some embodiments, the disease or disorder is a disease or disorder in which WRN activity is implicated.

[0961] In some embodiments, the disease or disorder is cancer.

[0962] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0963] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0964] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0965] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0966] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in modulating WRN activity.

[0967] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating WRN activity (e.g., in vitro or in vivo).

[0968] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating WRN activity (e.g., in vitro or in vivo).

[0969] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for inhibiting DNA repair by WRN in a cell. In some embodiments, the cell is an MSI and / or MMR-deficient cell. In some embodiments, the cell is an MSI-H and / or MMR-deficient cell.

[0970] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease in a patient, wherein the disease is characterized by overexpression of WRN.

[0971] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a cancer in a ...

Claims

CLAIMS:

1. A compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2-NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6alkenyl), -O(C2-C6alkynyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10- membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), - NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl) is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10-membered heteroaryl optionally substituted with C1-C6alkyl, C1-C6alkyl optionally substituted with C1-C6alkoxy, -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10- membered heteroaryl), or -O(3- to 10-membered heterocyclyl), or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl;R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5 and R6, together with the atoms to which they are attached, form a C4-C10 cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), orR7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

2. A compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1a; each R1a independently is oxo, halo, cyano, -OH, -NH2, -NO2, -NH(C1-C6 alkyl), -N(C1- C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -S(O)2(NH2), -C(O)(H), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH-C(O)(C1-C6alkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is oxo, halo, cyano, -OH, -O(C1-C6alkyl), -O(C1-C6haloalkyl), - O(C2-C6 alkenyl), -O(C2-C6 alkynyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6haloalkyl), -S(C1-C6alkyl), -S(O)2(C1-C6alkyl), -C(O)NH2, C1-C6alkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl optionally substituted with oxo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a; each R2aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3-C10cycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6haloalkyl), -S(C1-C6alkyl), C3- C10cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R2a1; each R2a1independently is oxo, halo, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, -NH-C(O)(C1-C6alkyl), -C(O)NH2, or -OC(O)(C1-C6alkyl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl or C1-C6alkyl is optionally substituted with one or more -OH; R3and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional N, O, or S and is optionally substituted with one or more R3a; each R3aindependently is cyano, halo, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - N(C1-C6alkyl)(C1-C6haloalkyl), -NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10- membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10- membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), wherein the -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -N(C1-C6alkyl)(C1-C6haloalkyl), - NH-C(O)(C1-C6alkyl), -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6alkyl), -SO2(C1-C6alkyl), -S(C1-C6alkyl), or -S(C1-C6haloalkyl), is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10-membered heteroaryl optionally substituted with C1-C6alkyl, C1-C6alkyl optionally substituted with C1-C6alkoxy, -N(R3a1)CO(R3a2), -O(C3-C10cycloalkyl), -O(C6-C10aryl), -O(5- to 10- membered heteroaryl), or -O(3- to 10-membered heterocyclyl), or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C1-C6alkyl; R3a1and R3a2, together with the atoms to which they are attached, form a 3- to 10- membered heterocyclyl; R5is H, halo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R6is H, halo, cyano, -SO2(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more oxo, halo, cyano, -OH, -NH2, C1-C6alkoxy, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NH(C1-C6haloalkyl), or -S(C1-C6alkyl), or R7and R8, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

3. The compound of claim 1 or claim 2, wherein: X is N or C; Y is NR2or CR2; Z is NR3or CR3; R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1a;each R1aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -NO2, -S(C1- C6alkyl), -S(O)2(NH2), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6alkyl), -S(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b; each R1bindependently is halo, cyano, -OH, -O(C1-C6alkyl), -C(O)NH2, or 3- to 10- membered heterocyclyl; R2is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R2a; each R2aindependently is halo, cyano, -OH, -NH2, C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, -S(C1-C6alkyl), wherein the C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, or -S(C1-C6alkyl) is optionally substituted with one or more R2a1; each R2a1independently is halo or -OH; each R3aindependently is halo, -OH, -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl, wherein the -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10-membered heteroaryl optionally substituted with C1- C6alkyl, or C1-C6alkyl optionally substituted with C1-C6alkoxy, or two R3a, together with the atoms to which they are attached, form a C3-C10cycloalkyl or 3- to 10-membered heterocyclyl, wherein the C3-C10cycloalkyl or 3- to 10-membered heterocyclyl is optionally substituted with one or more 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more C1-C6alkyl;R5 is H or halo,R6is H, halo, -SO2(C1-C6alkyl), or C1-C6alkyl optionally substituted with one or more - O(C1-C6alkyl), or -N(C1-C6alkyl)2, or R5and R6, together with the atoms to which they are attached, form a C4-C10cycloalkenyl; and each R7, R8, and R9independently is H or C1-C6alkyl.

4. The compound of any one of the preceding claims, wherein X is C.

5. The compound of any one of the preceding claims, wherein Y is NR2.

6. The compound of any one of the preceding claims, wherein Z is CR3.

7. The compound of any one of the preceding claims, wherein R1is C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C10cycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl is substituted with one or more R1a.

8. The compound of any one of the preceding claims, wherein R1is, ,NH2F H2N N F NH2FF NFNN Br N NH , N ON NH NH F F F N Br N F O F , NH , N Br , NH F , N F F Br H2N Br F F NNHF ,NNH,NNHF ,NNH,9. The compound of any one of the preceding claims, wherein R1aindependently is oxo, halo, cyano, -OH, -NH2, -NH(C1-C6alkyl), -NO2, -S(C1-C6alkyl), -S(O)2(NH2), -C(O)NH2, -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the -NH(C1-C6 alkyl), - S(C1-C6alkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C10cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally substituted with one or more R1b.

10. The compound of any one of the preceding claims, wherein R1aindependently is oxo, fluoro, chloro, bromo, cyano, -OH, -OCH3, -OCHF2, -OCF3, -OCH2CF3, -OCH(CH3)2, -OCH2C(O)NH2,11. The compound of any one of the preceding claims, wherein R2is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R2a13. The compound of any one of the preceding claims, wherein each R2aindependently halo, cyano, -OH, -NH2, C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, - S(C1-C6alkyl), wherein the C1-C6alkyl, C6-C10aryl, C3-C10cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, or -S(C1-C6alkyl) is optionally substituted with one or more R2a1.

14. The compound of any one of the preceding claims, wherein each R2aindependently is fluoro, chloro, cyano, -OH, -NH2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCHF2, -15. The compound of any one of the preceding claims, wherein R3and R4, together with the atoms to which they are attached, form a 6-membered heterocyclyl optionally substituted with one or more R3a.

16. The compound of any one of the preceding claims, wherein R3and R4, together with the atoms to which they are attached, form a 7-membered heterocyclyl optionally substituted with one or more R3a.

17. The compound of any one of the preceding claims, wherein R3and R4, together with the atoms to which they are attached, form a 8-membered heterocyclyl, wherein the heterocyclyl optionally comprises one or more additional O and is optionally substituted with one or more R3a.

18. The compound of any one of the preceding claims, wherein each R3aindependently is halo, - OH, -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl, wherein the -O(C3-C10cycloalkyl), -O(3- to 10-membered heterocyclyl), C1-C6alkyl, C1-C6alkoxy, 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclyl, -C(O)(C1-C6alkyl), 5- to 10- membered heteroaryl optionally substituted with C1-C6alkyl, or C1-C6alkyl optionally substituted with C1-C6alkoxy.

19. The compound of any one of the preceding claims, wherein each R3aindependently is F, CH3, -OH, -OCH3, -O(cyclopropyl),20. The compound of any one of the preceding claims, wherein R5is H or halo.

21. The compound of any one of the preceding claims, wherein R6is H, chloro, -SO2(C1-C6alkyl), or C1-C6alkyl optionally substituted with -N(C1-C6alkyl)2or -O(C1-C6alkyl).

22. The compound of any one of the preceding claims, wherein R5and R6, together with the atoms to which they are attached, form a C4cycloalkenyl.

23. The compound of any one of the preceding claims, wherein each R7, R8, and R9independently is H.

24. The compound of any one of the preceding claims, wherein the compound is of Formula (II-or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

25. The compound of claim 1 or claim 2, wherein the compound is of Formula (II-a1), (II-b1), (II-c1), (II-d1), or (II-e1):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

26. The compound of claim 1 or claim 2, wherein the compound is of Formula (III-a’), (III-b’),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4 and p is 0, 1, 2, 3, 4, 5, or 6.

27. The compound of claim 1 or claim 2, wherein the compound is of Formula (III-a”’), (III-b”’),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4 and p is 0, 1, 2, 3, 4, 5, or 6.

28. The compound of claim 1 or claim 2, wherein the compound is of Formula (IV-a), (IV-b),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

29. The compound of claim 1 or claim 2, wherein the compound is of Formula (IV-a’), (IV-b’), (IV-c’), (IV-d’), (IV-e’), (IV-f’), (IV-g’), (IV-h’), or (IV-i’):i’), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, or 4.

30. The compound of claim 1 or claim 2, wherein the compound is of Formula (V-a’), (V-b’),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

31. The compound of claim 1 or claim 2, wherein the compound is of Formula (VI-a’), (VI-b’),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

32. The compound of claim 1 or claim 2, wherein the compound is of Formula (VII-a’), (VII-b’),or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

33. The compound of claim 1 or claim 2, wherein the compound is of Formula (VIII-a’), (VIII-or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, or 5; and r is 0, 1, 2, 3, or 4.

34. The compound of any one of the preceding claims, wherein the compound is selected from a compound described in Table 1, Table 2, Table 1A, or Table 2A, or a pharmaceutically acceptable salt thereof.

35. The compound of any one of the preceding claims, wherein the compound is Compound No. 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a pharmaceutically acceptable salt thereof.

36. The compound of any one of the preceding claims, wherein the compound is Compound No. 128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, or 228A, or a pharmaceutically acceptable salt thereof.

37. A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in any one of Schemes 1-18.

38. A pharmaceutical composition comprising the compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

39. The pharmaceutical composition of claim 38, wherein the compound is selected from acompound described in Table 1, Table 2, Table 1A, or Table 2A.

40. The pharmaceutical composition of claim 38 or claim 39, wherein the compound is Compound No.128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a pharmaceutically acceptable salt thereof.

41. The pharmaceutical composition of claim 38 or claim 39, wherein the compound is Compound No.128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, or 228A, or a pharmaceutically acceptable salt thereof.

42. A method of modulating WRN activity, comprising contacting a cell with a compound of any one of claims 1-37 or a pharmaceutical composition of any one of claims 38-41.

43. The compound of any one of claims 1-37 or pharmaceutical composition of any one of claims 38-41for use in modulating WRN activity.

44. Use of the compound of any one of claims 1-37 in the manufacture of a medicament for modulating WRN activity.

45. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-37 or pharmaceutical composition of any one of claims 38-41.

46. The compound of any one of claims 1-37 or pharmaceutical composition of any one of claims 38-41 for use in treating or preventing a disease or disorder.

47. Use of the compound of any one of claims 1-37 in the manufacture of a medicament for treating or preventing a disease or disorder.

48. The method, compound, pharmaceutical composition, or use of any one of claims 45-47, wherein the disease or disorder is associated with an implicated WRN activity.

49. The method, compound, pharmaceutical composition, or use of any one of claims 45-48, wherein the disease or disorder is cancer.

50. The method, compound, pharmaceutical composition, or use of claim 49, wherein the cancer is MSI, MSI-H, and / or MMR-deficient cancer.

51. The method, compound, pharmaceutical composition, or use of claim 49, wherein the cancer is a TA-repeat expanded tumor.

52. The method, compound, pharmaceutical composition, or use of any one of claims 42-51, wherein the subject is human.