Therapeutic compounds and methods of use

This application claims priority to and benefit of U.S. Provisional Patent Application No. 63/283,119, filed Nov. 24, 2021, and U.S. Provisional Patent Application No. 63/344,027, filed May 19, 2022, the disclosures of which are hereby incorporated herein by reference in their entireties.

The content of the electronic Sequence Listing (file name: 146392054800SeqList.xml, date created: Nov. 21, 2022, size: 20,029 bytes) is herein incorporated by reference in its entirety.

The present disclosure relates to compounds useful for therapy and/or prophylaxis in a mammal, and in particular as inhibitors of TEAD useful for treating cancer.

The Hippo pathway is a signaling pathway that regulates cell proliferation and cell death and determines organ size. The pathway is believed to play a role as a tumor suppressor in mammals, and disorders of the pathway are often detected in human cancers. The pathway is involved in and/or may regulate the self-renewal and differentiation of stem cells and progenitor cells. In addition, the Hippo pathway may be involved in wound healing and tissue regeneration. Furthermore, it is believed that as the Hippo pathway cross-talks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK/ERK, it may influence a wide variety of biological events, and that its dysfunction could be involved in many human diseases in addition to cancer. For reviews, see, for example, Halder et al., 2011, Development 138:9-22; Zhao et al., 2011, Nature Cell Biology 13:877-883; Bao et al., 2011, J. Biochem. 149:361-379; Zhao at al., 2010, J. Cell Sci. 123:4001-4006.

The Hippo signaling pathway is conserved from drosophila to mammals (Vassilev et al., Genes and Development, 2001, 15, 1229-1241; Zeng and Hong, Cancer Cell, 2008, 13, 188-192). The core of the pathway consists of a cascade of kinases (Hippo-MSTI-2 being upstream of Lats 1-2 and NDRI-2) leading to the phosphorylation of two transcriptional co-activators, YAP (Yes-Associated Protein) and TAZ (Transcription co-activator with PDZ binding motif or tafazzin; Zhao et al., Cancer Res., 2009, 69, 1089-1098; Lei et al., Mol. Cell. Biol., 2008, 28, 2426-2436).

Because the Hippo signaling pathway is a regulator of animal development, organ size control and stem cell regulation, it has been implicated in cancer development (Review in Harvey et al., Nat. Rev. Cancer, 2013, 13, 246-257; Zhao et al., Genes Dev. 2010, 24, 862-874). In vitro, the overexpression of YAP or TAZ in mammary epithelial cells induces cell transformation, through interaction of both proteins with the TEAD family of transcription factors. Increased YAP/TAZ transcriptional activity induces oncogenic properties such as epithelial-mesenchymal transition and was also shown to confer stem cells properties to breast cancer cells. In vivo, in mouse liver, the overexpression of YAP or the genetic knockout of its upstream regulators MST1-2 triggers the development of hepatocellular carcinomas. Furthermore, when the tumor suppressor NF2 is inactivated in the mouse liver, the development of hepatocellular carcinomas can be blocked completely by the co-inactivation of YAP.

It is believed that deregulation of the Hippo tumor suppressor pathway is a major event in the development of a wide range of malignancies, including with no limitations, lung cancer (NSCLC; Zhou et al., Oncogene, 2011, 30, 2181-2186; Wang et al., Cancer Sci., 2010, 101, 1279-1285), breast cancer (Chan et al., Cancer Res., 2008, 68, 2592-2598; Lamar et al., Proc. Natl. Acad. Sci, USA, 2012; 109, E2441-E2250; Wang et al., Eur. J. Cancer, 2012, 48, 1227-1234), head and neck cancer (Gasparotto et al., Oncotarget., 2011, 2, 1165-1175; Steinmann et al., Oncol. Rep., 2009, 22, 1519-1526), colon cancer (Angela et al., Hum. Pathol., 2008, 39, 1582-1589; Yuen et al., PLoS One, 2013, 8, e54211; Avruch et al., Cell Cycle, 2012, 11, 1090-1096), ovarian cancer (Angela et al., Hum. Pathol., 2008, 39, 1582-1589; Chad et al., Cancer Res., 2010, 70, 8517-8525; Hall et al., Cancer Res., 2010, 70, 8517-8525), liver cancer (Jie et al., Gastroenterol. Res. Pract., 2013, 2013, 187070; Ahn et al., Mol. Cancer. Res., 2013, 11, 748-758; Liu et al., Expert. Opin. Ther. Targets, 2012, 16, 243-247), brain cancer (Orr et al., J Neuropathol. Exp. Neurol. 2011, 70, 568-577; Baia et al., Mol. Cancer Res., 2012, 10, 904-913; Striedinger et al., Neoplasia, 2008, 10, 1204-1212) and prostate cancer (Zhao et al., Genes Dev., 2012, 26, 54-68; Zhao et al., Genes Dev., 2007, 21, 2747-2761), mesotheliomas (Fujii et al., J. Exp. Med., 2012, 209, 479-494; Mizuno et al., Oncogene, 2012, 31, 5117-5122; Sekido Y., Pathol. Int., 2011, 61, 331-344), sarcomas (Seidel et al., Mol. Carcinog., 2007, 46, 865-871) and leukemia (Jimenez-Velasco et al., Leukemia, 2005, 19, 2347-2350).

Two of the core components of the mammalian Hippo pathway are Lats1 and Lats2, which are nuclear Dbf2-related (NDR) family protein kinases homologous to Drosophila Warts (Wts). The Lats1/2 proteins are activated by association with the scaffold proteins Mob1A/B (Mps one binder kinase activator-like 1A and 1B), which are homologous to Drosophila Mats. Lats1/2 proteins are also activated by phosphorylation by the STE20 family protein kinases Mst1 and Mst2, which are homologous to Drosophila Hippo. Lats1/2 kinases phosphorylate the downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif; WWTR1), which are homologous to Drosophila Yorkie. The phosphorylation of YAP and TAZ by Lats1/2 are crucial events within the Hippo signaling pathway. Lats1/2 phosphorylates YAP at multiple sites, but phosphorylation of Ser127 is critical for YAP inhibition. Phosphorylation of YAP generates a protein-binding motif for the 14-3-3 family of proteins, which upon binding of a 14-3-3 protein, leads to retention and/or sequestration of YAP in the cell cytoplasm. Likewise, Lats1/2 phosphorylates TAZ at multiple sites, but phosphorylation of Ser89 is critical for TAZ inhibition. Phosphorylation of TAZ leads to retention and/or sequestration of TAZ in the cell cytoplasm. In addition, phosphorylation of YAP and TAZ is believed to destabilize these proteins by activating phosphorylation-dependent degradation catalyzed by YAP or TAZ ubiquitination. Thus, when the Hippo pathway is “on”, YAP and/or TAZ is phosphorylated, inactive, and generally sequestered in the cytoplasm; in contrast, when the Hippo pathway is “off”, YAP and/or TAZ is non-phosphorylated, active, and generally found in the nucleus.

Non-phosphorylated, activated YAP is translocated into the cell nucleus where its major target transcription factors are the four proteins of the TEAD-domain-containing family (TEAD1-TEAD4, collectively “TEAD”). YAP together with TEAD (or other transcription factors such as Smad1, RUNX, ErbB4 and p73) has been shown to induce the expression of a variety of genes, including connective tissue growth factor (CTGF), Gli2, Birc5, Birc2, fibroblast growth factor 1 (FGF1), and amphiregulin (AREG). Like YAP, non-phosphorylated TAZ is translocated into the cell nucleus where it interacts with multiple DNA-binding transcription factors, such as peroxisome proliferator-activated receptor γ (PPARγ), thyroid transcription factor-1 (TTF-1), Pax3, TBX5, RUNX, TEAD1 and Smad2/3/4. Many of the genes activated by YAP/TAZ-transcription factor complexes mediate cell survival and proliferation. Therefore, under some conditions YAP and/or TAZ acts as an oncogene and the Hippo pathway acts as a tumor suppressor. Hence, pharmacological targeting of the Hippo cascade through inhibition of TEAD would be valuable approach for the treatment of cancers that harbor functional alterations of this pathway.

Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch for central growth signaling pathways. In response to extracellular signals, Ras is converted from a GDP-bound (Ras GDP ) to a GTP-bound (Ras GTP ) state, as catalyzed by guanine nucleotide exchange factors (GEFs), notably the SOS1 protein. Active Ras GTP mediates its diverse growth-stimulating functions through its direct interactions with effectors including Raf, P13K, and RaI guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP to terminate Ras signaling. The Ras GTPase activity can be further accelerated by its interactions with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

Mutant Ras has a reduced GTPase activity, which prolongs its activated conformation, thereby promoting Ras-dependent signaling and cancer cell survival or growth. Mutation in Ras which affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive RAS signaling may ultimately lead to cancer. Mutations in any one of the three main isoforms of RAS (H-Ras, N-Ras, or K-Ras) genes are common events in human tumorigenesis. Among the three Ras isoforms (K, N, and H), K-Ras is most frequently mutated.

The most common K-Ras (or KRAS) mutations are found at residue G12 and G13 in the P-loop and at residue Q61. G12C is a frequent mutation of K-Ras gene (glycine-12 to cysteine). G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis (see, e.g., Hallin et al. (Cancer Discov, 2020, 10(1): 54-71), Skoulidis et al. (N. Engl. J. Med., 2021, 384(25): 2371-2381), and Hong et al. (N. Engl. J. Med., 2020, 383(13): 1207-1217)). G12D, G12V, and G13D are other frequent mutations. Mutations of Ras in cancer are associated with poor prognosis.

Inactivation of oncogenic Ras in mice results in tumor shrinkage. Thus, Ras is widely considered an oncology target of exceptional importance. However, treatment with inhibitors of Ras (for example, KRAS) can lead to resistance through bypass of KRAS/MAPK pathway dependence, and activation of the Hippo pathway.

There is, therefore, a need for therapies that improve the ability of inhibitors of Ras (for example, KRAS) and inhibitors of YAP, TAZ, TEAD, and/or the YAP:TEAD protein-protein interaction to treat a range of diseases, disorders, and conditions, including cancer.

In some aspect, provided is a compound for formula (II-AB′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

L′ is *—N(R 3 )-L-** or

or Z-L′ is

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 -alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is

i) phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; ii) C 1-6 alkyl, optionally substituted with one or more halo; or iii) cyclobutenyl or bicyclobutanyl;

L is methylene or ethylene, wherein the methylene of L is optionally substituted with one C 1-6 alkyl;

Y is CH or C(CN), and

n and m are each independently 1 or 2;

provided that:

i) when i-1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and i-2) X 2 or X 3 is N, B of formula (II-AB′) is phenyl and R 2 is haloC 1-6 alkoxyl; and

ii) when n=1 and m=2, or n=2 and m=1, B is phenyl substituted by halomethyoxyl; and

iii) the compound of formula (II-AB′) is not any one of following:

N-((8-(4-fluorophenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

N-((8-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

N-((7-fluoro-4-(4-(trifluoromethoxy)phenyl)quinazolin-2-yl)methyl)acrylamide;

N-((8-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

1-(4-(4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)piperidin-1-yl)ethan-1-one;

4-(4-methoxyphenyl)-1-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine;

6-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridine;

6-(1-(ethylsulfonyl)piperidin-4-yl)-1-isopropyl-4-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridine;

4-(4-methoxyphenyl)-1-methyl-6-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine; and

N-((4-(4-fluorophenyl)-1,8-naphthyridin-2-yl)methyl)acetamide.

In some aspects, provided is a compound of formula (II-AB):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

L′ is selected from the group consisting of *—N(R 3 )-L-** and

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 -alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more W, wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and wherein R d and RC are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein

R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , or —S(O) 2 R b ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and m are 1; or n and m are 2;

provided that when 1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, 2) X 2 or X 3 is N, and 3) L′ is

B of formula (II-AB) is phenyl and R 2 is haloC 1-6 alkoxyl.

In some aspects, provided herein is a compound of formula (II-A) or (II-B):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and

wherein R d and R e are each independently H or C 1-6 alkyl and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from the group consisting of H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl; and

wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R 2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and

R d and R e are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein

R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , or —S(O) 2 R b ,

wherein R d and RC are each independently H or C 1-6 alkyl and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and m are each independently 1 or 2.

In some aspects, a pharmaceutical composition comprising a compound of formula (II-A) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, is provided.

In some aspects, a pharmaceutical composition comprising a compound of formula (II-B) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, is provided.

In some aspects, a pharmaceutical composition comprising a compound of formula (II-AB) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, is provided.

In some aspects, a pharmaceutical composition comprising a compound of formula (II-AB′) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, is provided.

In some aspects, a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for use in medical therapy.

In some aspects, a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for use in medical therapy.

In some aspects, a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for use in medical therapy.

In some aspects, a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the treatment or prophylaxis of cancer.

In some aspects, a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the treatment or prophylaxis of cancer.

In some aspects, a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the treatment or prophylaxis of cancer.

In some aspects, a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment or prophylaxis of cancer.

In some aspects, a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment or prophylaxis of cancer.

In some aspects, a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment or prophylaxis of cancer.

In some aspects, a method for treating cancer in a mammal is provided, the method comprising, administering a therapeutically effective amount of a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

In some aspects, a method for treating cancer in a mammal is provided, the method comprising, administering a therapeutically effective amount of a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

In some aspects, a method for treating cancer in a mammal is provided, the method comprising, administering a therapeutically effective amount of a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

In some aspects, a method for treating cancer in a mammal is provided, the method comprising administering a therapeutically effective amount of a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal in combination with a second therapeutic agent.

In some aspects, a method for treating cancer in a mammal is provided, the method comprising administering a therapeutically effective amount of a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal in combination with a second therapeutic agent.

In some aspects, a method for treating cancer in a mammal is provided, the method comprising administering a therapeutically effective amount of a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal in combination with a second therapeutic agent.

In some aspects, a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for modulating TEAD activity.

In some aspects, a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for modulating TEAD activity.

In some aspects, a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for modulating TEAD activity.

In some aspects, a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the treatment or prophylaxis of a disease or condition mediated by TEAD activity.

In some aspects, a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the treatment or prophylaxis of a disease or condition mediated by TEAD activity.

In some aspects, a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the treatment or prophylaxis of a disease or condition mediated by TEAD activity.

In some aspects, a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for use for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TEAD activity.

In some aspects, a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for use for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TEAD activity.

In some aspects, a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for use for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TEAD activity.

In some aspects, a method for modulating TEAD activity is provided, the method comprising contacting TEAD with a therapeutically effective amount of a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In some aspects, a method for modulating TEAD activity is provided, the method comprising contacting TEAD with a therapeutically effective amount of a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In some aspects, a method for modulating TEAD activity is provided, the method comprising contacting TEAD with a therapeutically effective amount of a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In some aspects, a method for treating a disease or condition mediated by TEAD activity in a mammal is provided, the method comprising administering a therapeutically effective amount of a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

In some aspects, a method for treating a disease or condition mediated by TEAD activity in a mammal is provided, the method comprising administering a therapeutically effective amount of a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

In some aspects, a method for treating a disease or condition mediated by TEAD activity in a mammal is provided, the method comprising administering a therapeutically effective amount of a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

In one aspect, the present disclosure is directed to a combination comprising: (i) one or more YAP/TAZ-TEAD inhibitors, or a pharmaceutically acceptable salt thereof; and (ii) one or more KRAS inhibitors, or a pharmaceutically acceptable salt thereof. In some aspects, one or more YAP/TAZ-TEAD inhibitors and one or more KRAS inhibitors are co-administered to an individual. In some aspects, the combination is administered to an individual in the same composition. In some aspects, the combination is administered to an individual in different compositions. Thus, it is understood that the one or more YAP/TAZ-TEAD inhibitors and the one or more KRAS inhibitors may be administered simultaneously or sequentially to the individual. In some aspects, provided herein are compositions comprising one or more YAP/TAZ-TEAD inhibitors and one or more KRAS inhibitors. In another aspect, the present disclosure is directed to methods of modulating or inhibiting KRAS activity in a cell, comprising administering to the cell an effective amount of such combinations. In another aspect, the present disclosure is directed to methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of such combinations. In another aspect, the present disclosure is directed to methods of reducing resistance of a subject to treatment comprising a KRAS inhibitor, wherein the method comprises administering to the subject a therapeutically effective amount of a TEAD inhibitor.

In one aspect, the present disclosure is directed to processes of preparing one or more TEAD inhibitors described herein.

The following embodiments are representative of some aspects of the disclosure.

FIG. 1 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 2 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 3 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 4 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 5 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 6 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 7 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 8 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 9 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 10 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 11 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 12 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 13 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 14 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 15 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 16 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 17 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 18 depicts % inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 19 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 20 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 21 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 22 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 23 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 24 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 25 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 26 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 27 depicts % inhibition of H358 resistant cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 28 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 29 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 30 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 31 depicts % inhibition of H358 Parental cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 32 depicts % inhibition of H358 Parental cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 33 depicts % inhibition of H358 Parental cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 34 depicts % inhibition of H358 Resistant cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor).

FIG. 35 depicts % inhibition of H358 Resistant cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor).

FIG. 36 depicts % inhibition of H358 Resistant cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor).

FIG. 37 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 38 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 39 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 40 depicts % inhibition of H2030 cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 41 depicts % inhibition of H358 Parental cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 42 depicts % inhibition of H358 Parental cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 43 depicts % inhibition of H358 Parental cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 44 depicts % inhibition of H358 Parental cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 45 depicts % inhibition of H358 Resistant cells (KRAS G12C) following administration of a combination comprising Compound T1 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 46 depicts % inhibition of H358 Resistant cells (KRAS G12C) following administration of a combination comprising Compound T2 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 47 depicts % inhibition of H358 Resistant cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

FIG. 48 depicts % inhibition of H358 Resistant cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP/TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor).

Unless otherwise indicated, the following specific terms and phrases used in the description and claims are defined as follows.

The term “moiety” refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule.

The term “substituted” refers to the fact that at least one of the hydrogen atoms of that moiety is replaced by another substituent or moiety.

The term “alkyl” refers to an aliphatic straight-chain or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, or 1 to 6 carbon atoms. Alkyl groups may be optionally substituted.

In some embodiments, alkyl is unsubstituted.

In some embodiments, “hydroxylalkyl” is alkyl substituted with one or more —OH.

In some embodiments, “alkoxy” is —O-alkyl.

The term “cycloalkyl” means a saturated or partially unsaturated carbocyclic moiety having mono- or bicyclic (including bridged bicyclic) rings and 3 to 10 carbon atoms in the ring. In particular aspects, cycloalkyl may contain from 3 to 8 carbon atoms (i.e., (C 3 -C 8 )cycloalkyl). In other particular aspects cycloalkyl may contain from 3 to 6 carbon atoms (i.e., (C 3 -C 6 )cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl). The cycloalkyl moiety can be attached in a spirocycle fashion such as spirocyclopropyl:

The term “haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms, such as fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoromethyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. Haloalkyl groups may be optionally substituted.

In some embodiments, haloalkyl is unsubstituted.

The term “alkenyl” refers to a straight or branched chain alkyl or substituted alkyl group as defined elsewhere herein having at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted.

In some embodiments, alkenyl is unsubstituted.

The term “alkynyl” refers to a straight or branched chain alkyl or substituted alkyl group as defined elsewhere herein having at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted.

In some embodiments, alkynyl is unsubstituted. In some embodiments, hydroxylalkynyl is alkynyl substituted with one or more —OH.

The terms “heterocyclyl” and “heterocycle” refer to a 4, 5, 6 and 7-membered monocyclic or 7, 8, 9 and 10-membered bicyclic (including bridged bicyclic) heterocyclic moiety that is saturated or partially unsaturated, and has one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon. When used in reference to a ring atom of a heterocycle, a nitrogen or sulfur may also be in an oxidized form, and a nitrogen may be substituted. The heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocycles include, without limitation, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazolyl, thiazepinyl, morpholinyl, and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as benzothiazolyl, benzofuranyl, furopyridinyl, indolinyl, 3H-indolyl, chromanyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl. Heterocyclyl groups may be optionally substituted.

In some embodiments, heterocyclyl is unsubstituted.

The term “aryl” refers to a cyclic aromatic hydrocarbon moiety having a mono-, bi- or tricyclic aromatic ring of 5 to 20 carbon ring atoms. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, benzyl, and the like. The term “aryl” also includes partially hydrogenated derivatives of the cyclic aromatic hydrocarbon moiety provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each being optionally substituted. In some aspects, monocyclic aryl rings may have 5 or 6 carbon ring atoms. Aryl groups may be optionally substituted.

In some embodiments, aryl is unsubstituted.

The term “heteroaryl” refers an aromatic heterocyclic mono- or bicyclic ring system of 1 to 20 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. Heteroaryl groups may be optionally substituted.

In some embodiments, heteroaryl is unsubstituted.

The terms “halo” and “halogen” refer fluoro, chloro, bromo and iodo. In some aspects, halo is fluoro or chloro.

The term “oxo” refers to the ═O moiety.

The term “cyano” refers to the —C≡N moiety.

The terms “spirocycle” and “spirocyclyl” refer to carbogenic bicyclic ring systems comprising between 5 and 13 carbon atoms with both rings connected through a single atom. The rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., 0, N, S, or P). Spirocycle groups may be optionally substituted.

In some embodiments, the spirocycle is unsubstituted.

The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, N-acetylcystein and the like. In addition, salts may be prepared by the addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like.

The term “prodrug” refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

In some prodrug aspects, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present disclosure. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

In some other prodrug aspects, a free carboxyl group of a compound of the disclosure can be derivatized as an amide or alkyl ester. In yet other prodrug aspects, prodrugs comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C 1-6 )alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N—(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkanoyl, alpha-amino(C 1-4 )alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , —P(O)(O(C 1-6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

Additionally, the present disclosure provides for metabolites of compounds of the disclosure. As used herein, a “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

Metabolite products typically are identified by preparing a radiolabeled (e.g., 14 C or 3 H) isotope of a compound of the disclosure, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the disclosure.

Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

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.” Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold 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”. In certain aspects the compound is enriched by at least about 90% by weight with a single diastereomer or enantiomer. In other aspects the compound is enriched by at least about 95%, 98%, or 99% by weight with a single diastereomer or enantiomer.

Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

Unless otherwise indicated, the term “a compound of the formula” or “a compound of formula” or “compounds of the formula” or “compounds of formula” refers to any compound selected from the genus of compounds as defined by the formula. In some embodiments or aspects, the term also includes a pharmaceutically acceptable salt or ester of any such compound, a stereoisomer, or a tautomer of such compound. The term “a therapeutically effective amount” of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this disclosure can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 kg, a daily dosage of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.

In some embodiments, the term “a therapeutically effective amount” of a compound means an amount of compound that is effective to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this disclosure can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 kg, a daily dosage of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.

In embodiments herein, a therapeutically effective amount of a compound may be an amount of compound that is effective to alleviate or ameliorate a condition or disease, or symptoms thereof, or prolong the survival of the subject being treated.

The term “pharmaceutically acceptable carrier” is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with a compound of the disclosure, use thereof in the compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

In some aspects, provided is a compound for formula (II-AB′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

L′ is *—N(R 3 )-L-** or

or Z-L′ is

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5 -6cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-6 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e ;

wherein the C 1-5 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t , wherein R t is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is

i) phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; ii) C 1-6 alkyl, optionally substituted with one or more halo; or iii) cyclobutenyl or bicyclobutanyl;

L is methylene or ethylene, wherein the methylene of L is optionally substituted with one C 1-6 alkyl;

Y is CH or C(CN), and

n and m are each independently 1 or 2;

provided that:

i) when i-1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and i-2) X 2 or X 3 is N, B of formula (II-AB′) is phenyl and R 2 is haloC 1-6 alkoxyl; and

ii) when n=1 and m=2, or n=2 and m=1, B is phenyl substituted by halomethyoxyl; and

iii) the compound of formula (II-AB′) is not any one of following:

N-((8-(4-fluorophenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

N-((8-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

N-((7-fluoro-4-(4-(trifluoromethoxy)phenyl)quinazolin-2-yl)methyl)acrylamide;

N-((8-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide; 1-(4-(4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)piperidin-1-yl)ethan-1-one;

4-(4-methoxyphenyl)-1-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine;

6-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridine;

6-(1-(ethylsulfonyl)piperidin-4-yl)-1-isopropyl-4-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridine;

4-(4-methoxyphenyl)-1-methyl-6-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine; and

N-((4-(4-fluorophenyl)-1,8-naphthyridin-2-yl)methyl)acetamide.

Any embodiments, aspects, variations, described herein with respect to one formula, may, where applicable, be applied to any other formula listed herein. For example, any embodiments, aspects, variations, described herein with respect to any one or more of formula (II-AB), (II-A), and (II-B) apply to formula (II-AB′), the same as if each and every embodiments, aspects, and variations is specifically and individually listed with respect to formula (II-AB′). It is understood that such embodiments apply to structural features of compounds, as well as methods of making and using such compounds. For example, it is understood that methods of using any one or more of formula (II-AB), (II-A), and (II-B), where applicable, apply to methods of using compounds of formula (II-AB′), the same as if each and every embodiments, aspects, and variations is specifically and individually listed with respect to formula (II-AB′).

In some embodiments, in conjunction with embodiments above or below, L′ of formula (II-AB′) is *—N(R 3 )-L-**. In some embodiments, in conjunction with embodiments above or below, L′ of formula (II-AB′) is

In some embodiments, provided is a compound of formula (II-AB):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

L′ is selected from the group consisting of *—N(R 3 )-L-** and

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-5 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 -alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein

R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R b ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and m are 1; or n and m are 2;

provided that when 1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and 2) X 2 or X 3 is N,

B of formula (II-AB) is phenyl and R 2 is haloC 1-6 alkoxyl.

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A) or formula (II-B) is provided:

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from C 1-3 alkyl, —OH, oxo, C 1-3 alkoxy, and —NR d R e ; and

wherein R d and R e are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from the group consisting of H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-25 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl; and

wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and

wherein R d and R e are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one to five R 2 ;

R 2 is independently, at each occurrence, i) halo; ii) S(R y ) 5 , wherein each R y is halo; or iii) C 1-6 alkoxy, optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R a ,

wherein R d and R e are each independently H or C 1-6 alkyl and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

R a is i) C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and m are each independently 1 or 2.

In some embodiments, provided is a compound of formula (II-A) or (II-B):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-6 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R 2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein

R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , or —S(O) 2 R b ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and m are 1; or n and m are 2;

provided that when 1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and 2) X 2 or X 3 is N,

B of formula (II-B) is phenyl and R 2 is haloC 1-6 alkoxyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L′ is *—N(R 3 )-L-**, wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L′ is

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, R d and R e are each independently H or C 1-6 alkyl. In some embodiments, R d is H or C 1-6 alkyl. In some embodiments, R d is H. In some embodiments, R d is C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, R e is H. In some embodiments, R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is independently, at each occurrence, selected from the group consisting of halo, C 1-15 -alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is 5 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X, is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R, and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R t and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d RC. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and RC are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R 1 , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is N or CR s , wherein R s is H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , or —NR d R e . In some embodiments, X 2 is N. In some embodiments, X 2 is CR s . In some embodiments, X 2 is CR s , wherein R s is H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , or —NR d R e . In some embodiments, X 2 is CR s , wherein R s is H. In some embodiments, X 2 is CR s , wherein R s is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl. In some embodiments, X 2 is CR s , wherein R s is C 3-20 cycloalkyl. In some embodiments, X 2 is CR s , wherein R s is 3 to 15 membered heterocyclyl. In some embodiments, X 2 is CR s , wherein R s is —OH. In some embodiments, X 2 is CR s , wherein R s is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy. In other embodiments, X 2 is CR s , wherein R s is —NR d COR e . In other embodiments, X 2 is CR s , wherein R s is —CONR d R e . In other embodiments, X 2 is CR s , wherein R s is —SO 2 R d . In other embodiments, X 2 is CR s , wherein R s is —SO 2 NR d R e . In other embodiments, X 2 is CR s , wherein R s is —NR d SO 2 R e . In some embodiments, X 2 is CR s , wherein R s is —NR d R e . In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is H. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkyl or C 1-15 alkoxy, wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t is independently at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t , wherein R t is independently at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t is oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t is —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t , wherein R t is —NR d R e .

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R 1 , wherein R t is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e .

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d and R t1 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl of R d or R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 , is —NR d R e , wherein R d is H. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is H. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d or R e are independently C 1-6 alkyl, the C 1-6 alkyl of R d or R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-6 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more W, wherein R t is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more halo. In some embodiments, X 2 is CR s , wherein R 1 is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more —CN.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, or 3 to 15 membered heterocyclyl, wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R 1 is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R 1 is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R 2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R 2 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R 2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R 1 is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R 1 is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-6 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R 2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R 2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R e , wherein R 2 is —CN. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R 2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with one or more R 2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R 2 is oxo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t z, wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R 2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 3 is N or CH. In some embodiments, X 3 is N. In some embodiments, X 3 is CH.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one to five R 2 . In some embodiments, B is phenyl independently substituted with one to five R 2 . In some embodiments, B is 5 to 6 membered heteroaryl independently substituted with one to five R 2 .

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is independently, at each occurrence, i) halo; ii) S(R y ) 5 , wherein each R y is halo; or iii) C 1-6 alkoxy, optionally substituted with one or more halo. In some embodiments, R 2 is halo. In some embodiments, R 2 is S(R y ) 5 , wherein each R y is halo. In some embodiments, R 2 is C 1-6 alkoxy, optionally substituted with one or more halo. In some embodiments, R 2 is unsubstituted C 1-6 alkoxy.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 is H or C 1-6 alkyl. In some embodiments, R 3 is H. In some embodiments, R 3 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R a . In some embodiments, Z is —OH. In some embodiments, Z is NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, Z is NR d R e , wherein R d is H. In some embodiments, Z is NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, Z is NR d R e , wherein R e is H. In some embodiments, Z is NR d R e , wherein R e is C 1-6 alkyl. In some embodiments, Z is —C(O)R a . In some embodiments, Z is —C(O)R a , wherein R a is i) C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl. In some embodiments, Z is —C(O)R a , wherein R a is C 1-6 alkyl, optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium. In some embodiments, Z is —C(O)R a , wherein R a is C 1-6 alkyl. In some embodiments, Z is —C(O)R a , wherein R a is haloC 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more halo; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 -alkenyl optionally substituted with one or more C 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo.

In some embodiments, provided herein is a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is C or N, and X 1 is taken together with R 1 , and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5 cycloalkyl fused to ring A; X 2 is N or CR s , wherein R s is selected from C 1-15 alkyl optionally substituted with —OH, 5-membered heteroaryl and —CN; X 3 is N or CH; B is phenyl or 5-membered heteroaryl, wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, S(R y ) 5 , wherein each R y is independently halo, or C 1-6 alkoxy optionally substituted with one or more halo; L is methylene, optionally substituted with C 1-6 alkyl; R 3 is H or C 1-6 alkyl; and Z is —C(O)R a , —S(O) 2 R b , wherein R a is C 2-6 alkenyl optionally substituted with deuterium, or C 1-6 alkyl substituted with halo, and R b is C 1-6 alkyl substituted with halo. In some embodiments, R s is methyl or ethyl. In some embodiments, each R y is fluoro. In some embodiments, R 2 is trifluoromethoxy. In some embodiments, R a is ethenyl. In some embodiments, R a is chloromethyl. In some embodiments, R b is chloromethyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is C or N. In some embodiments, X 1 is C. In some embodiments, X 1 is N. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R t and the atoms to which they are attached to form a 5 to 6 membered heteroaryl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached to form a 5 to 6 membered heterocyclyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached to form a phenyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached to form a C 5-6 cycloalkyl that is fused to ring A. In some embodiments, X 1 is N and is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl or a 5 to 6 membered heterocyclyl that is fused to ring A. In some embodiments, X 1 is N and is taken together with R 1 and the atoms to which they are attached to form a 5 to 6 membered heteroaryl that is fused to ring A. In some embodiments, X 1 is N and is taken together with R 1 and the atoms to which they are attached to form a 5 to 6 membered heterocyclyl that is fused to ring A.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is selected from the group consisting of

In some embodiments, in conjunction with embodiments above or below, the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is not substituted with one or more R t .

It is understood that embodiments described herein with respect to any one of formula (II-AB), (II-A), or (II-B) apply to formula (II-AB′), the same as if each and every embodiment is specifically and individually listed with respect to formula (II-AB′).

In some embodiments, provided herein is a compound of formula (II-AB), (II-A), or (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is selected from the group consisting of

each of which is optionally substituted with one or more R t . In some embodiments, each R 1 is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN. In some embodiments, R 1 is selected from the group consisting of methyl and —CHF 2 .

In some embodiments, in conjunction with embodiments above or below, the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-AB), (II-A), or (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is selected from the group consisting of

In some embodiments, each R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN. In some embodiments, R t is selected from the group consisting of methyl and —CHF 2 .

In some embodiments, in conjunction with embodiments above or below, the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-AB), (II-A), or (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is selected from the group consisting of

each of which is optionally substituted with one or more R t . In some embodiments, each R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN. In some embodiments, R t is selected from the group consisting of methyl and —CHF 2 .

In some embodiments, in conjunction with embodiments above or below, the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-AB), (II-A), or (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is selected from the group consisting of

In some embodiments, each R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN. In some embodiments, R 1 is selected from the group consisting of methyl and —CHF 2 .

In some embodiments, in conjunction with embodiments above or below, the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, R d and R e are each independently H or C 1-6 alkyl. In some embodiments, R d is H or C 1-6 alkyl. In some embodiments, R d is H. In some embodiments, R d is C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, R e is H. In some embodiments, R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R d and R 1 are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H1. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In embodiments, in conjunction with embodiments above or below, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X, is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is 5 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R 1 , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In embodiments, in conjunction with embodiments above or below, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In embodiments, in conjunction with embodiments above or below, X 1 is taken together with R 1 and the atoms to which they are attached, to form phenyl, wherein the phenyl is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R 1 is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d SO 2 R t . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein RC is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In embodiments, in conjunction with embodiments above or below, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is not substituted with one or more R t .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is N or CR s , wherein R s is H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , or —NR d R e . In some embodiments, X 2 is N. In some embodiments, X 2 is CR s . In some embodiments, X 2 is CR s , wherein R s is H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , or —NR d R e . In some embodiments, X 2 is CR s , wherein R s is H. In some embodiments, X 2 is CR s , wherein R s is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl. In some embodiments, X 2 is CR s , wherein R s is C 3-20 cycloalkyl. In some embodiments, X 2 is CR s , wherein R s is 3 to 15 membered heterocyclyl. In some embodiments, X 2 is CR s , wherein R s is —OH. In some embodiments, X 2 is CR s , wherein R s is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy. In other embodiments, X 2 is CR s , wherein R s is —NR d COR e . In other embodiments, X 2 is CR s , wherein R s is —CONR d R e . In other embodiments, X 2 is CR s , wherein R s is —SO 2 R d . In other embodiments, X 2 is CR s , wherein R s is —SO 2 NR d R e . In other embodiments, X 2 is CR s , wherein R s is —NR d SO 2 R e . In some embodiments, X 2 is CR s , wherein R s is —NR d R e . In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is H. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkyl or C 1-15 alkoxy, wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t1 is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t1 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-5 alkyl, optionally substituted with one or more R t1 , wherein R t1 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t is —NR d R e .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t l is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R 1 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and the C 1-6 alkyl of R d or R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d or R e are independently C 1-6 alkyl, the C 1-6 alkyl of R d or R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein RC is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of RC is optionally substituted with one or more —CN.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, or 3 to 15 membered heterocyclyl, wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R a , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-25 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R 2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R t a is oxo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R 1 is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R 2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with one or more R 2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R 2 is halo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R 2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R a , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 3 is N or CH. In some embodiments, X 3 is N. In some embodiments, X 3 is CH.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one to five R 2 . In some embodiments, B is phenyl independently substituted with one to five R 2 . In some embodiments, B is 5 to 6 membered heteroaryl independently substituted with one to five R 2 .

In some embodiments, in conjunction with embodiments above or below, B is 5 to 6 membered heteroaryl independently substituted with one R 2 .

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is independently, at each occurrence, i) halo; ii) S(R y ) 5 , wherein each R y is halo; or iii) C 1-6 alkoxy, optionally substituted with one or more halo. In some embodiments, R 2 is halo. In some embodiments, R 2 is S(R y ) 5 , wherein each R y is halo. In some embodiments, R 2 is C 1-6 alkoxy, optionally substituted with one or more halo. In some embodiments, R 2 is unsubstituted C 1-6 alkoxy.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 is H or C 1-6 alkyl. In some embodiments, R 3 is H. In some embodiments, R 3 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R a . In some embodiments, Z is —OH. In some embodiments, Z is NR d R e , wherein R d and RC are each independently H or C 1-6 alkyl. In some embodiments, Z is NR d R e , wherein R d is H. In some embodiments, Z is NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, Z is NR d R e , wherein R e is H. In some embodiments, Z is NR d R e , wherein R e is C 1-6 alkyl. In some embodiments, Z is —C(O)R a . In some embodiments, Z is —C(O)R a , wherein R a is i) C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl. In some embodiments, Z is —C(O)R a , wherein R a is C 1-6 alkyl, optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium. In some embodiments, Z is —C(O)R a , wherein R a is C 1-6 alkyl. In some embodiments, Z is —C(O)R a , wherein R a is haloC 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more halo; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 -alkenyl optionally substituted with one or more C 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo.

In some embodiments, provided herein is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is C or N, and X 1 is taken together with R 1 , and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5 cycloalkyl fused to ring A; X 2 is N or CR s , wherein R s is selected from C 1-15 alkyl optionally substituted with —OH, 5-membered heteroaryl and —CN; X 3 is N or CH; B is phenyl or 5-membered heteroaryl, wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, S(R y ) 5 , wherein each R y is independently halo, or C 1-6 alkoxy optionally substituted with one or more halo; L is methylene, optionally substituted with C 1-6 alkyl; R s is H or C 1-6 alkyl; and Z is —C(O)R a , —S(O) 2 R b , wherein R a is C 2-6 alkenyl optionally substituted with deuterium, or C 1-6 alkyl substituted with halo, and R b is C 1-6 alkyl substituted with halo. In some embodiments, R s is methyl or ethyl. In some embodiments, each R y is fluoro. In some embodiments, R 2 is trifluoromethoxy. In some embodiments, R a is ethenyl. In some embodiments, R a is chloromethyl. In some embodiments, R b is chloromethyl.

In some embodiments, provided herein is a compound of formula (II-AB), (II-A), or (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s . In some embodiments, X 2 is CR s and R s is hydroxylC 1-6 alkynyl.

In some embodiments, provided herein is a compound of formula (II-AB), (II-A), or (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s . In some embodiments, X 2 is CR s and R s is —S(O)NHR d , wherein R d is selected from the group consisting of H and C 1-6 alkyl optionally substituted by one or more substituents selected from the group consisting of halo, oxo, —OH and —CN. In some embodiments, X 2 is CR s , R s is —S(O)NHR d , and R d is H. In some embodiments, X 2 is CR s , R s is —S(O)NHR d , and R d is unsubstituted C 1-6 alkyl. In some embodiments, X 2 is CR s , R s is —S(O)NHR d , and R d is C 1-6 alkyl substituted with one or more halo. In some embodiments, X 2 is CR s , R s is —S(O)NHR d , and R d is C 1-6 alkyl substituted with one or more oxo. In some embodiments, X 2 is CR s , R s is —S(O)NHR d , and R d is C 1-6 alkyl substituted with one or more —OH. In some embodiments, X 2 is CR s , R s is —S(O)NHR d , and R d is C 1-6 alkyl substituted with one or more —CN.

In some embodiments, provided herein is a compound of formula (II-AB), (II-A), or (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s . In some embodiments, X 2 is CR s and R s is selected from the group consisting of —CN, —CH 3 ,

In some embodiments, X 2 is CR s and R s is —CN. In some embodiments, X 2 is CR s and R s is —CH 3 . In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is.

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, X 2 is CR s and R s is

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is C or N. In some embodiments, X 1 is C. In some embodiments, X is N. In some embodiments, X is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached to form a 5 to 6 membered heteroaryl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached to form a 5 to 6 membered heterocyclyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached to form a phenyl that is fused to ring A. In some embodiments, X 1 is C and is taken together with R 1 and the atoms to which they are attached to form a C 5-6 cycloalkyl that is fused to ring A. In some embodiments, X 1 is N and is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl or a 5 to 6 membered heterocyclyl that is fused to ring A. In some embodiments, X 1 is N and is taken together with R 1 and the atoms to which they are attached to form a 5 to 6 membered heteroaryl that is fused to ring A. In some embodiments, X 1 is N and is taken together with R 1 and the atoms to which they are attached to form a 5 to 6 membered heterocyclyl that is fused to ring A.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A is selected from the group consisting of

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A, wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, R d and R e are each independently H or C 1-6 alkyl. In some embodiments, R d is H or C 1-6 alkyl. In some embodiments, R d is H. In some embodiments, R d is C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, R e is H. In some embodiments, R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R 1 , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R 1 is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d COR t . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is 5 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R 1 is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl, wherein the 5 to 6 membered heterocyclyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R t and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R t1 are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R 1 , wherein R 1 is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R 1 is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl, wherein the phenyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 -alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is halo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R 1 is C 1-15 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 6-20 aryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is 5 to 15 membered heteroaryl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 3-20 cycloalkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is 3 to 15 membered heterocyclyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R 1 is —OH. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —CN. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R 1 is oxo. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is C 1-15 alkoxy. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d COR e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —CONR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —SO 2 R d . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —SO 2 NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d SO 2 R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e . In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R t1 is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is H. In some embodiments, X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl, wherein the C 5-6 cycloalkyl is substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is N or CR s , wherein R s is H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , or —NR d R e . In some embodiments, X 2 is N. In some embodiments, X 2 is CR s . In some embodiments, X 2 is CR s , wherein R s is H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, or —NR d R e . In some embodiments, X 2 is CR s , wherein R s is H. In some embodiments, X 2 is CR s , wherein R s is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl. In some embodiments, X 2 is CR s , wherein R s is C 3-20 cycloalkyl. In some embodiments, X 2 is CR s , wherein R s is 3 to 15 membered heterocyclyl. In some embodiments, X 2 is CR s , wherein R s is —OH. In some embodiments, X 2 is CR s , wherein R s is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy. In other embodiments, X 2 is CR s , wherein R s is —NR d COR e . In other embodiments, X 2 is CR s , wherein R s is —CONR d R e . In other embodiments, X 2 is CR s , wherein R s is —SO 2 R d . In other embodiments, X 2 is CR s , wherein R s is —SO 2 NR d R e . In other embodiments, X 2 is CR s , wherein R s is —NR d SO 2 R e . In some embodiments, X 2 is CR s , wherein R s is —NR d R e . In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is H. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H or C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is H. In some embodiments, X 2 is CR s , wherein R s is —NR d R e , wherein R e is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkyl or C 1-15 alkoxy, wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t I, wherein R t l is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t1 is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t I, wherein R t l is oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t I, wherein R t l is —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t l is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkyl, optionally substituted with one or more R t1 , wherein R t l is —NR d R e .

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R 1 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t t is —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e .

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t , wherein R t t is —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and the C 1-6 alkyl of R d or R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is H. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t I is —NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is H. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R d or R e are independently C 1-6 alkyl, the C 1-6 alkyl of R d or R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 -alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t I, wherein R t is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R d is C 1-6 alkyl, the C 1-6 alkyl of R d is optionally substituted with one or more —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more halo, oxo, —OH, or —CN. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more halo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more oxo. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more —OH. In some embodiments, X 2 is CR s , wherein R s is C 1-15 alkoxy, optionally substituted with one or more R t1 , wherein R t1 is —NR d R e , wherein R e is C 1-6 alkyl, the C 1-6 alkyl of R e is optionally substituted with one or more —CN.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, or 3 to 15 membered heterocyclyl, wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R 2 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R 2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is C 6-20 aryl, the C 6-20 aryl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with one or more R 2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R 2 is —OH. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R 2 , wherein R 2 is —CN. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heteroaryl, the 5 to 15 membered heteroaryl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 -alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is C 6-20 cycloalkyl, the C 6-20 cycloalkyl of R s is optionally substituted with R t2 , wherein R t2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e . In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is halo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is oxo. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is —OH. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R t2 is —CN. In some embodiments, X 2 is CR s , wherein R s is 5 to 15 membered heterocyclyl, the 5 to 15 membered heterocyclyl of R s is optionally substituted with R t2 , wherein R 2 is C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X 3 is N or CH. In some embodiments, X 3 is N. In some embodiments, X 3 is CH.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one to five R 2 . In some embodiments, B is phenyl independently substituted with one to five R 2 . In some embodiments, B is 5 to 6 membered heteroaryl independently substituted with one to five R 2 .

In some embodiments, in conjunction with embodiments above or below, B is 5 to 6 membered heteroaryl independently substituted with one R 2 .

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is independently, at each occurrence, i) halo; ii) S(R y ) 5 , wherein each R y is halo; or iii) C 1-6 alkoxy, optionally substituted with one or more halo. In some embodiments, R 2 is halo. In some embodiments, R 2 is S(R y ) 5 , wherein each R y is halo. In some embodiments, R 2 is C 1-6 alkoxy, optionally substituted with one or more halo. In some embodiments, R 2 is unsubstituted C 1-6 alkoxy.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R a . In some embodiments, Z is —OH. In some embodiments, Z is NR d R e , wherein R d and RC are each independently H or C 1-6 alkyl. In some embodiments, Z is NR d R e , wherein R d is H. In some embodiments, Z is NR d R e , wherein R d is C 1-6 alkyl. In some embodiments, Z is NR d R e , wherein R e is H. In some embodiments, Z is NR d R e , wherein R e is C 1-6 alkyl. In some embodiments, Z is —C(O)R a . In some embodiments, Z is —C(O)R a , wherein R a is i) C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl. In some embodiments, Z is —C(O)R a , wherein R a is C 1-6 alkyl, optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium. In some embodiments, Z is —C(O)R a , wherein R a is C 1-6 alkyl. In some embodiments, Z is —C(O)R a , wherein R a is haloC 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more deuterium; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more halo; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 -alkenyl optionally substituted with one or more C 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo.

In some embodiments, provided herein is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein n and m are each independently 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1 and m is 1. In some embodiments, n is 1 and m is 2. In some embodiments, n is 2 and m is 1. In some embodiments, n is 2 and m is 2.

In some embodiments, in conjunction with embodiments above or below, provided herein is a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein B is i) phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; C 1-6 alkoxy optionally substituted with one or more halo; or ii)—O-phenyl substituted with haloC 1-3 alkyl, provided that when B is —O-phenyl substituted with haloC 1 -3alkyl, L′ is *—N(R 3 )-L-**, Z is —C(O)CHCH 2 , X 1 is C, X 2 is CR s , and X 3 is CH; or iii) bicyclopentane substituted by C 1-3 alkyl, provided that when B is bicyclopentane substituted by C 1-3 alkyl, L′ is *—N(R 3 )-L-** and Z is —C(O)CHCH 2 ; or iv) phenyl substituted with ethynyl or haloC 1-3 alkyl, provided that when B is phenyl substituted with ethynyl or haloC 1-3 alkyl, L′ is *—N(R 3 )-L-**, Z is —C(O)CHCH 2 , and R s is C 1-3 alkyl substituted with one or more —OH; or v) piperidine substituted with haloC 1-3 alkyl or haloC 1-3 alkoxy, provided that when B is piperidine substituted with haloC 1-3 alkyl or haloC 1-3 alkoxy, L′ is *—N(R 3 )-L-** and Z is —C(O)CHCH 2 . In some embodiments, B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; C 1-6 alkoxy optionally substituted with one or more halo. In some embodiments, B is —O-phenyl substituted with haloC 1-3 alkyl, provided that when B is —O-phenyl substituted with haloC 1-3 alkyl, L′ is *—N(R 3 )-L-**, Z is —C(O)CHCH 2 , X 1 is C, X 2 is CR s , and X 3 is CH. In some embodiments, B is bicyclopentane substituted by C 1-3 alkyl, provided that when B is bicyclopentane substituted by C 1-3 alkyl, L′ is *—N(R 3 )-L-** and Z is —C(O)CHCH 2 . In some embodiments, B is phenyl substituted with ethynyl or haloC 1-3 alkyl, provided that when B is phenyl substituted with ethynyl or haloC 1-3 alkyl, L′ is *—N(R 3 )-L-**, Z is —C(O)CHCH 2 , and R s is C 1-3 alkyl substituted with one or more —OH. In some embodiments, B is piperidine substituted with haloC 1-3 alkyl or haloC 1-3 alkoxy, provided that when B is piperidine substituted with haloC 1-3 alkyl or haloC 1 -3alkoxy, L′ is *—N(R 3 )-L-** and Z is —C(O)CHCH 2 .

In some embodiments, in conjunction with embodiments above or below, provided herein is a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , or —S(O) 2 R b , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; ii) C 1-6 alkyl, optionally substituted with one or more halo; or iii) cyclobutenyl or bicyclobutanyl. In some embodiments, Z is —C(O)R a or —S(O) 2 R b , wherein R a and R b are each independently C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl. In some embodiments, Z is —C(O)R a or —S(O) 2 R b , wherein R a and R b are each independently C 1-6 alkyl, optionally substituted with one or more halo. In some embodiments, Z is —C(O)R a or —S(O) 2 R b , wherein R a and R b are each independently cyclobutenyl or bicyclobutanyl.

In some embodiments, in conjunction with embodiments above or below, provided herein is a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is methylene or ethylene, wherein the methylene of L is optionally substituted with one C 1-6 alkyl. In some embodiments, L is methylene optionally substituted with one C 1-6 alkyl. In some embodiments, L is ethylene.

In some embodiments, in conjunction with embodiments above or below, provided herein is a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L′ is

and Y is CH or C(CN). In some embodiments, in conjunction with embodiments above or below, provided herein is a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z-L′ is

In some embodiments, in conjunction with embodiments above or below, provided herein is a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein n and m are each independently 1 or 2.

In some embodiments, in conjunction with embodiments above or below, provided herein is a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein when X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and X 2 or X 3 is N, B is phenyl and R 2 is haloC 1-6 alkoxyl; wherein when n=1 and m=2, or n=2 and m=1, B is phenyl substituted by halomethyoxyl; and wherein the compound of formula (II-AB′) is not any one of following: N-((8-(4-fluorophenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide; N-((8-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide; N-((7-fluoro-4-(4-(trifluoromethoxy)phenyl)quinazolin-2-yl)methyl)acrylamide; N-((8-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide; 1-(4-(4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)piperidin-1-yl)ethan-1-one; 4-(4-methoxyphenyl)-1-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine; 6-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridine; 6-(1-(ethylsulfonyl)piperidin-4-yl)-1-isopropyl-4-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridine; 4-(4-methoxyphenyl)-1-methyl-6-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine; and N-((4-(4-fluorophenyl)-1,8-naphthyridin-2-yl)methyl)acetamide.

In some embodiments, in conjunction with embodiments above or below, reference to “one or more” may be 1 to 5, 1 to 4, 1 to 3, 1 to 2, 5, 4, 3, 2, or 1.

In some embodiments, in conjunction with embodiments above or below, reference to “one or more substituents”, for example, “one or more substituents of C 1-6 alkyl”, may be 1 to 3 substituents, 1 to 2 substituents, 2 substituents, or 1 substituent.

In some embodiments, in conjunction with embodiments above or below, wherein when B is optionally substituted with one or more R t , R t is C 1-15 alkoxy optionally substituted with 1-3 halo. In some embodiments, in conjunction with embodiments above or below, R t is C 1-15 alkoxy substituted with 1-3 halo. In some embodiments, in conjunction with embodiments above or below, R t is OCF 3 .

In some embodiments, in conjunction with embodiments above or below, wherein when X 1 is CR s , R s is

or a stereoisomer thereof. In some embodiments, R s is

In some embodiments, in conjunction with embodiments above or below, n and m are each 1.

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-1) is provided:

In one aspect, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z of formula (II-A-1) are as defined in formula (II-AB′). In one aspect, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z of formula (II-A-1) are as defined in formula (II-AB). In one aspect, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z of formula (II-A-1) are as defined in formula (II-A). It is understood that embodiments of X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z described for formula (II-AB′), (II-AB) or (II-A) may, where applicable, apply in some embodiments to formula (II-A-1).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-2) is provided:

In one aspect, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z of formula (II-A-2) are as defined in formula (II-AB′). In one aspect, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z of formula (II-A-2) are as defined in formula (II-AB). In one aspect, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z of formula (II-A-2) are as defined in formula (II-A). It is understood that embodiments of X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , L, A, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-2).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-3) is provided:

In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-3) are as defined in formula (II-AB′). In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-3) are as defined in formula (II-AB). In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-3) are as defined in formula (II-A). It is understood that embodiments of X 1 , R 1 , R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-3).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-4) is provided:

In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-4) are as defined in formula (II-AB′). In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-4) are as defined in formula (II-AB). In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-4) are as defined in formula (II-A). It is understood that embodiments of X 1 , R 1 , R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-4).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-5) is provided:

In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-5) are as defined in formula (II-AB′). In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-5) are as defined in formula (II-AB). In one aspect, X 1 , R 1 , R 3 , L, A, B, and Z of formula (II-A-5) are as defined in formula (II-A). It is understood that embodiments of X 1 , R 1 , R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-5).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-6) is provided:

In one aspect, X 2 , X 3 , R 3 , L, A, B, and Z of formula (II-A-6) are as defined in formula (II-AB′). In one aspect, X 2 , X 3 , R 3 , L, A, B, and Z of formula (II-A-6) are as defined in formula (II-AB). In one aspect, X 2 , X 3 , R 3 , L, A, B, and Z of formula (II-A-6) are as defined in formula (II-A). It is understood that embodiments of X 2 , X 3 , R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-6).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-7) is provided:

In one aspect, X 3 , R 3 , L, A, B, and Z of formula (II-A-7) are as defined in formula (II-AB′). In one aspect, X 3 , R 3 , L, A, B, and Z of formula (II-A-7) are as defined in formula (II-AB). In one aspect, X 3 , R 3 , L, A, B, and Z of formula (II-A-7) are as defined in formula (II-A). It is understood that embodiments of X 3 , R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-7).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-8) is provided:

In one aspect, R 3 , L, A, B, and Z of formula (II-A-8) are as defined in formula (II-AB′). In one aspect, R 3 , L, A, B, and Z of formula (II-A-8) are as defined in formula (II-AB). In one aspect, R 3 , L, A, B, and Z of formula (II-A-8) are as defined in formula (II-A). It is understood that embodiments of R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-8).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-9) is provided:

In one aspect, R 3 , L, A, B, and Z of formula (II-A-9) are as defined in formula (II-AB′). In one aspect, R 3 , L, A, B, and Z of formula (II-A-9) are as defined in formula (II-AB). In one aspect, R 3 , L, A, B, and Z of formula (II-A-9) are as defined in formula (II-A). It is understood that embodiments of R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-9).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-10) is provided:

In one aspect, R 3 , L, A, B, and Z of formula (II-A-10) are as defined in formula (II-AB′). In one aspect, R 3 , L, A, B, and Z of formula (II-A-10) are as defined in formula (II-AB). In one aspect, R 3 , L, A, B, and Z of formula (II-A-10) are as defined in formula (II-A). It is understood that embodiments of R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-10).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-11) is provided:

In one aspect, R 3 , L, A, B, and Z of formula (II-A-11) are as defined in formula (II-AB′). In one aspect, R 3 , L, A, B, and Z of formula (II-A-11) are as defined in formula (II-AB). In one aspect, R 3 , L, A, B, and Z of formula (II-A-11) are as defined in formula (II-A). It is understood that embodiments of R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-11).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-12) is provided:

In one aspect, X 2 , X 3 , R 3 , L, A, B, and Z of formula (II-A-12) are as defined in formula (II-AB′). In one aspect, X 2 , X 3 , R 3 , L, A, B, and Z of formula (II-A-12) are as defined in formula (II-AB). In one aspect, X 2 , X 3 , R 3 , L, A, B, and Z of formula (II-A-12) are as defined in formula (II-A). It is understood that embodiments of X 2 , X 3 , R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-12).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-13) is provided:

In one aspect, X 2 , R 3 , L, A, B, and Z of formula (II-A-13) are as defined in formula (II-AB′). In one aspect, X 2 , R 3 , L, A, B, and Z of formula (II-A-13) are as defined in formula (II-AB). In one aspect, X 2 , R 3 , L, A, B, and Z of formula (II-A-13) are as defined in formula (II-A). It is understood that embodiments of X 2 , R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-13).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-14) is provided:

In one aspect, R 3 , L, A, B, and Z of formula (II-A-14) are as defined in formula (II-AB′). In one aspect, R 3 , L, A, B, and Z of formula (II-A-14) are as defined in formula (II-AB). In one aspect, R 3 , L, A, B, and Z of formula (II-A-14) are as defined in formula (II-A). It is understood that embodiments of R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-14).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-15) is provided:

In one aspect, R 3 , L, A, B, and Z of formula (II-A-15) are as defined in formula (II-AB′). In one aspect, R 3 , L, A, B, and Z of formula (II-A-15) are as defined in formula (II-AB). In one aspect, R 3 , L, A, B, and Z of formula (II-A-15) are as defined in formula (II-A). It is understood that embodiments of R 3 , L, A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-15).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-16) is provided:

In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , and A of formula (II-A-16) are as defined in formula (IL-AB′). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , and A of formula (II-A-16) are as defined in formula (II-AB). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , and A of formula (II-A-16) are as defined in formula (II-A). It is understood that embodiments of R 1 , R 2 , X 1 , X 2 , X 3 , and A described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-16).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-17) is provided:

In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , and A of formula (II-A-17) are as defined in formula (II-AB′). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , and A of formula (II-A-17) are as defined in formula (II-AB). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , and A of formula (II-A-17) are as defined in formula (II-A). It is understood that embodiments of R 1 , R 2 , X 1 , X 2 , X 3 , and A described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-17).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-18) is provided:

In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , L, A, and Z of formula (II-A-18) are as defined in formula (II-AB′). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , L, A, and Z of formula (II-A-18) are as defined in formula (II-AB). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , L, A, and Z of formula (II-A-18) are as defined in formula (II-A). It is understood that embodiments of R 1 , R 3 , X 1 , X 2 , X 3 , L, A, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-18).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-19) is provided:

In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and L of formula (II-A-19) are as defined in formula (II-AB′). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and L of formula (II-A-19) are as defined in formula (II-AB). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and L of formula (II-A-19) are as defined in formula (II-A). It is understood that embodiments of R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and L described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-19).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-20) is provided:

In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, and L of formula (II-A-20) are as defined in formula (II-AB′). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, and L of formula (II-A-20) are as defined in formula (II-AB). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, and L of formula (II-A-20) are as defined in formula (II-A). It is understood that embodiments of R 1 , R 3 , X 1 , X 2 , X 3 , A, and L described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-20).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-21) is provided:

In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and Z of formula (II-A-21) are as defined in formula (II-AB′). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and Z of formula (II-A-21) are as defined in formula (II-AB). In one aspect, R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and Z of formula (II-A-21) are as defined in formula (II-A). It is understood that embodiments of R 1 , R 3 , X 1 , X 2 , X 3 , A, B, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-21).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-22) is provided:

In one aspect, R t , R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-22) are as defined in formula (II-AB′). In one aspect, R, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-22) are as defined in formula (II-AB). In one aspect, R t , R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-22) are as defined in formula (II-A). It is understood that embodiments of R t , R 3 , X 2 , X 3 , A, B, L, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-22).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-23) is provided:

In one aspect, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-23) are as defined in formula (II-AB′). In one aspect, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-23) are as defined in formula (II-AB). In one aspect, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-23) are as defined in formula (II-A). It is understood that embodiments of R 3 , X 2 , X 3 , A, B, L, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-23).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-24) is provided:

In one aspect, R, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-24) are as defined in formula (II-AB′). In one aspect, R t , R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-24) are as defined in formula (II-AB). In one aspect, R, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-24) are as defined in formula (II-A). It is understood that embodiments of R, R 3 , X 2 , X 3 , A, B, L, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-24).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-25) is provided:

In one aspect, R t , R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-25) are as defined in formula (II-AB′). In one aspect, R t , R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-25) are as defined in formula (II-AB). In one aspect, R t , R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-25) are as defined in formula (II-A). It is understood that embodiments of R t , R 3 , X 2 , X 3 , A, B, L, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-25).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-A-26) is provided:

In one aspect, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-26) are as defined in formula (II-AB′). In one aspect, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-26) are as defined in formula (II-AB). In one aspect, R 3 , X 2 , X 3 , A, B, L, and Z of formula (II-A-26) are as defined in formula (II-A). It is understood that embodiments of R 3 , X 2 , X 3 , A, B, L, and Z described for formula (II-AB′), (II-AB), or (II-A) may, where applicable, apply in some embodiments to formula (II-A-26).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-1) is provided:

In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-1) are as defined in formula (II-AB′). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-1) are as defined in formula (II-AB). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-1) are as defined in formula (IL-B). It is understood that embodiments of R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-1).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-2) is provided:

In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-2) are as defined in formula (II-AB′). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-2) are as defined in formula (II-AB). In one aspect, R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-2) are as defined in formula (II-B). It is understood that embodiments of R 1 , R 2 , X 1 , X 2 , X 3 , n, m, A, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-2).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-3) is provided:

In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-3) are as defined in formula (II-AB′). In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-3) are as defined in formula (II-AB). In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-3) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 1 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-3).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-4) is provided:

In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-4) are as defined in formula (II-AB′). In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-4) are as defined in formula (II-AB). In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-4) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 1 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-4).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-5) is provided:

In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-5) are as defined in formula (II-AB′). In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-5) are as defined in formula (II-AB). In one aspect, R 1 , X 1 , n, m, A, B, and Z of formula (II-B-5) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 1 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (IL-B) may, where applicable, apply in some embodiments to formula (II-B-5).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-6) is provided:

In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-6) are as defined in formula (II-AB′). In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-6) are as defined in formula (II-AB). In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-6) are as defined in formula (II-B). It is understood that embodiments of X 2 , X 3 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-6).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-7) is provided:

In one aspect, X 3 , n, m, A, B, and Z of formula (II-B-7) are as defined in formula (II-AB′). In one aspect, X 3 , n, m, A, B, and Z of formula (II-B-7) are as defined in formula (II-AB). In one aspect, X 3 , n, m, A, B, and Z of formula (II-B-7) are as defined in formula (II-B). It is understood that embodiments of X 3 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-7).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-8) is provided:

In one aspect, n, m, A, B, and Z of formula (II-B-8) are as defined in formula (II-AB′). In one aspect, n, m, A, B, and Z of formula (II-B-8) are as defined in formula (II-AB). In one aspect, n, m, A, B, and Z of formula (II-B-8) are as defined in formula (II-B). It is understood that embodiments of n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-8).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-9) is provided:

In one aspect, n, m, A, B, and Z of formula (II-B-9) are as defined in formula (II-AB′). In one aspect, n, m, A, B, and Z of formula (II-B-9) are as defined in formula (II-AB). In one aspect, n, m, A, B, and Z of formula (II-B-9) are as defined in formula (II-B). It is understood that embodiments of n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-9).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-10) is provided:

In one aspect, n, m, A, B, and Z of formula (II-B-10) are as defined in formula (II-AB′). In one aspect, n, m, A, B, and Z of formula (II-B-10) are as defined in formula (II-AB). In one aspect, n, m, A, B, and Z of formula (II-B-10) are as defined in formula (II-B). It is understood that embodiments of n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-10).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-11) is provided:

In one aspect, n, m, A, B, and Z of formula (II-B-11) are as defined in formula (II-AB′). In one aspect, n, m, A, B, and Z of formula (II-B-11) are as defined in formula (II-AB). In one aspect, n, m, A, B, and Z of formula (II-B-11) are as defined in formula (II-B). It is understood that embodiments of n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-11).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-12) is provided:

In one aspect, X 1 , X 2 , n, m, A, B, and Z of formula (II-B-12) are as defined in formula (II-AB′). In one aspect, X 1 , X 2 , n, m, A, B, and Z of formula (II-B-12) are as defined in formula (II-AB). In one aspect, X 1 , X 2 , n, m, A, B, and Z of formula (II-B-12) are as defined in formula (II-B). It is understood that embodiments of X 1 , X 2 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-12).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-13) is provided:

In one aspect, X 2 , n, m, A, B, and Z of formula (II-B-13) are as defined in formula (II-AB′). In one aspect, X 2 , n, m, A, B, and Z of formula (II-B-13) are as defined in formula (II-AB). In one aspect, X 2 , n, m, A, B, and Z of formula (II-B-13) are as defined in formula (II-B). It is understood that embodiments of X 2 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-13).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-14) is provided:

In one aspect, n, m, A, B, and Z of formula (II-B-14) are as defined in formula (II-AB′). In one aspect, n, m, A, B, and Z of formula (II-B-14) are as defined in formula (II-AB). In one aspect, n, m, A, B, and Z of formula (II-B-14) are as defined in formula (II-B). It is understood that embodiments of n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-14).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-15) is provided:

In one aspect, X 2 , n, m, A, B, and Z of formula (II-B-15) are as defined in formula (II-AB′). In one aspect, X 2 , n, m, A, B, and Z of formula (II-B-15) are as defined in formula (II-AB). In one aspect, X 2 , n, m, A, B, and Z of formula (II-B-15) are as defined in formula (II-B). It is understood that embodiments of X 2 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-15).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-16) is provided

In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-16) are as defined in formula (II-AB′). In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-16) are as defined in formula (II-AB). In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, A, and Z of formula (II-B-16) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 1 , X 2 , X 3 , n, m, A, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-16).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-17) is provided

In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, A, and B of formula (II-B-17) are as defined in formula (II-AB′). In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, A, and B of formula (II-B-17) are as defined in formula (II-AB). In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, A, and B of formula (II-B-17) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 1 , X 2 , X 3 , n, m, A, and B described for formula (II-AB′), (II-AB), or (IL-B) may, where applicable, apply in some embodiments to formula (II-B-17).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-18) is provided

In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, and A of formula (II-B-18) are as defined in formula (II-AB′). In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, and A of formula (II-B-18) are as defined in formula (II-AB). In one aspect, R 1 , X 1 , X 2 , X 3 , n, m, and A of formula (II-B-18) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 1 , X 2 , X 3 , n, m, and A described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-18).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-19) is provided

In one aspect, R 1 , X 1 , X 2 , X 3 , A, B, and Z of formula (II-B-19) are as defined in formula (II-AB′). In one aspect, R 1 , X 1 , X 2 , X 3 , A, B, and Z of formula (II-B-19) are as defined in formula (II-AB). In one aspect, R 1 , X 1 , X 2 , X 3 , A, B, and Z of formula (II-B-19) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 1 , X 2 , X 3 , A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-19).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-20) is provided

In one aspect, R 1 , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-20) are as defined in formula (II-AB′). In one aspect, R t , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-20) are as defined in formula (II-AB). In one aspect, R 1 , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-20) are as defined in formula (II-B). It is understood that embodiments of R 1 , X 2 , X 3 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-20).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-21) is provided

In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-21) are as defined in formula (II-AB′). In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-21) are as defined in formula (II-AB). In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-21) are as defined in formula (II-B). It is understood that embodiments of X 2 , X 3 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-21).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-22) is provided

In one aspect, R t , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-22) are as defined in formula (II-AB′). In one aspect, R t , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-22) are as defined in formula (II-AB). In one aspect, R t , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-22) are as defined in formula (II-B). It is understood that embodiments of R t , X 2 , X 3 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-22).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-23) is provided

In one aspect, R t , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-23) are as defined in formula (II-AB′). In one aspect, R %, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-23) are as defined in formula (II-AB). In one aspect, R t , X 2 , X 3 , n, m, A, B, and Z of formula (II-B-23) are as defined in formula (II-B). It is understood that embodiments of R, X 2 , X 3 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-23).

In some aspects, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the following formula (II-B-24) is provided

In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-24) are as defined in formula (II-AB′). In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-24) are as defined in formula (II-AB). In one aspect, X 2 , X 3 , n, m, A, B, and Z of formula (II-B-24) are as defined in formula (II-B). It is understood that embodiments of X 2 , X 3 , n, m, A, B, and Z described for formula (II-AB′), (II-AB), or (II-B) may, where applicable, apply in some embodiments to formula (II-B-24).

In some embodiments, in conjunction with embodiments above or below, wherein when B is phenyl substituted with one or more R 2 , R 2 cannot be halo. In some embodiments, in conjunction with embodiments above or below, L′ of formula (II-AB′) or (II-AB) is *—N(R 3 )-L**.

In some embodiments, in conjunction with embodiments above or below, wherein when L′ of formula (II-AB′) or (II-AB) is

and B is phenyl substituted with one or more alkoxy, the one or more alkoxy is substituted with one or more halo (e.g., F, Cl, or Br).

In some embodiments, in conjunction with embodiments above or below, wherein when X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A, and wherein when the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently substituted with one or more R t , R t cannot be oxo.

In some embodiments, in conjunction with embodiments above or below, wherein when L′ of formula (II-AB′) or (II-AB) is *—N(R 3 )-L-**, Z is —C(O)R a or —S(O) 2 R b , wherein R a and R b are C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl.

In some embodiments, in conjunction with embodiments above or below, wherein when L′ of formula (II-AB′) or (II-AB) is

Z is —C(O)R a , wherein R a is C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl.

In some aspects, compounds of formula (II-AB′), (II-AB), (II-A), or (II-B), or any variation or embodiment thereof, as appropriate, are selected from the compounds listed in Table 1 below, including racemic mixtures and resolved isomers:

Provided herein is a compound selected from the group consisting of:

2-chloro-N-methyl-N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]acetamide N-[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[7-(hydroxymethyl)-4-[6-(trifluoromethoxy)-3-pyridyl]-1,3-benzoxazol-6-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl]methyl]prop-2-enamide N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]quinazolin-2-yl]methyl]prop-2-enamide N-[[7-[2-fluoro-4-(trifluoromethoxy)phenyl]-4-(hydroxymethyl)-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[7-[4-(trifluoromethoxy)phenyl]oxazolo[5,4-b]pyridin-5-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]furo[3,2-d]pyrimidin-2-yl]methyl]prop-2-enamide N-methyl-N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl]methyl]prop-2-enamide 1-chloro-N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]methanesulfonamide 2-chloro-N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]acetamide N-[[5-cyano-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]prop-2-enamide N-[(1R)-1-[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]ethyl]prop-2-enamide N-[(1S)-1-[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]ethyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]ethenesulfonamide 2,3,3-trideuterio-N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-(5-isopropoxythiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[4-imidazol-1-yl-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-[4-(pentafluoro-lambda6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide 2-chloro-N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]acetamide N-[[5-ethyl-8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide; N-[[4-cyano-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[5-[(1R)-1,2-dihydroxyethyl]-8-[4-(trifluoromethoxy)phenyl]quinoxalin-6-yl]methyl]prop-2-enamide; N-[[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1S)-1,2-dihydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1R)-1,2-dihydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1R)-1-hydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1S)-1-hydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-(1H-pyrazol-4-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[2-methyl-7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]prop-2-enamide; N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]-N-methyl-prop-2-enamide; N-[[8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide); N-methyl-N-[[8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide; N-[[3-(difluoromethyl)-4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; (R)—N-((1-(difluoromethyl)-7-(1,2-dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; (S)—N-((1-(difluoromethyl)-7-(1,2-dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; N-[2-[4-cyano-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]ethyl]prop-2-enamide; N-[[8-methyl-5-[4-(trifluoromethoxy)phenyl]-7-quinolyl]methyl]prop-2-enamide; N-[[8-(hydroxymethyl)-5-[4-(trifluoromethoxy)phenyl]-7-quinolyl]methyl]prop-2-enamide; (S)—N-((8-(1,2-dihydroxyethyl)-5-(4-(trifluoromethoxy)phenyl)quinolin-7-yl)methyl)acrylamide; (R)—N-((8-(1,2-dihydroxyethyl)-5-(4-(trifluoromethoxy)phenyl)quinolin-7-yl)methyl)acrylamide; (S)—N-((5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)methyl) acrylamide; (R)—N-((5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)methyl) acrylamide; N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]-N-methyl-prop-2-enamide; N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]prop-2-enamide; N-[[5-[(1S)-1,2-dihydroxyethyl]-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]-N-methyl-prop-2-enamide; N-[[5-[(1R)-1,2-dihydroxyethyl]-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]-N-methyl-prop-2-enamide; (S)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; (R)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; (S)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)-N-methylacrylamide; (R)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)-N-methylacrylamide; N-[[3-methyl-4-methylsulfonyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[4-(3-hydroxyprop-1-ynyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; 2-fluoro-1-[3-[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]azetidin-1-yl]prop-2-en-1-one; (S)—N-((1-methyl-7-(S-methylsulfonimidoyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; (R)—N-((1-methyl-7-(S-methylsulfonimidoyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; 1-[3-[9-methyl-6-[4-(trifluoromethoxy)phenyl]purin-2-yl]azetidin-1-yl]prop-2-en-1-one; 2-fluoro-N-[[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; (E)-4-hydroxy-N-[[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]-N-methyl-but-2-enamide; (R)—N-((7-(1,2-dihydroxyethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)-2-fluoro-N-methylacrylamide; (S)—N-((7-(1,2-dihydroxyethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)-2-fluoro-N-methylacrylamide; N-[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]-2-fluoro-prop-2-enamide; N-[[1-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[9-methyl-6-[4-(trifluoromethoxy)phenyl]purin-2-yl]methyl]prop-2-enamide; N-[[7-[(1S)-1,2-dihydroxyethyl]-1-methyl-4-[4-(trifluoromethoxy)phenyl]imidazo[4,5-c]pyridin-6-yl]methyl]prop-2-enamide; N-[[7-[(1R)-1,2-dihydroxyethyl]-1-methyl-4-[4-(trifluoromethoxy)phenyl]imidazo[4,5-c]pyridin-6-yl]methyl]prop-2-enamide; N-[[3-methyl-4-(1H-pyrazol-4-yl)-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-((7-(hydroxymethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-6-yl)methyl)acrylamide; (S)—N-((7-(3,4-dihydroxybut-1-yn-1-yl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; (R)—N-((7-(3,4-dihydroxybut-1-yn-1-yl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; 3-methyl-5-[(prop-2-enoylamino)methyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazole-4-carboxamide; N-[[4-(difluoromethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-((7-(1H-imidazol-1-yl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; (S)—N-((5-(1,2-Dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)acrylamide; (R)—N-((5-(1,2-Dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)-2-fluoroacrylamide; (R)—N-((5-(1,2-Dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)cyclobut-1-ene-1-carboxamide; (R)—N-((5-(1-Hydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)acrylamide; (S)—N-((5-(1-hydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)acrylamide; N-((5-(Hydroxymethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)acrylamide; N-((5-Cyano-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)acrylamide; (R)-Cyclobut-1-en-1-yl(3-(5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)azetidin-1-yl)methanone; (S)-Cyclobut-1-en-1-yl(3-(5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethoxy) phenyl)quinoxalin-6-yl)azetidin-1-yl)methanone; N-((4-(Hydroxymethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)-N-methylacrylamide; N-((4-((1S,2S)-1,2-Dihydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; N-((4-((1R,2R)-1,2-dihydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; (R)—N-((4-(2-Cyano-1-hydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; (S)—N-((4-(2-cyano-1-hydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; N-((7-(4-Ethynylphenyl)-4-(hydroxymethyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; N-((7-(4-Ethynylphenyl)-4-(hydroxymethyl)-2,3-dihydrobenzofuran-5-yl)methyl)-N-methylacrylamide; N-((4-cyano-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)-N-methylacrylamide; N-[[7-[4-(Pentafluoro-6-sulfanyl)phenyl]-4-[rac-(1R)-1,2-dihydroxyethyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide; N-[[7-[4-(pentafluoro-6-sulfanyl)phenyl]-4-[rac-(1S)-1,2-dihydroxyethyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide; N-ethyl-N-((7-(4-(trifluoromethoxy)phenyl)thiazolo[5,4-d]pyrimidin-5-yl)methyl)acrylamide; 1-(3-(7-(4-(Trifluoromethoxy)phenyl)thiazolo[5,4-d]pyrimidin-5-yl)azetidin-1-yl)prop-2-en-1-one; (E)-4-Hydroxy-1-(3-(7-(4-(trifluoromethoxy)phenyl)thiazolo[5,4-d]pyrimidin-5-yl)azetidin-1-yl)but-2-en-1-one; N-((7-(4-(trifluoromethoxy)phenyl)thiazolo[5,4-d]pyrimidin-5-yl)methyl)acrylamide-2,3,3-d3; N-((7-(3-Isopropylbicyclo[1.1.1]pentan-1-yl)thiazolo[5,4-d]pyrimidin-5-yl)methyl)acrylamide; N-methyl-N-[[7-[4-(pentafluoro-6-sulfanyl)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]prop-2-enamide; N-((7-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]thiazol-6-yl)methyl)acrylamide; (S)—N-((7-(1,2-Dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-6-yl)methyl)acrylamide; (R)—N-((7-(1,2-dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-6-yl)methyl)acrylamide; (S)—N-((7-(1,2-Dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-6-yl)methyl)-N-methylacrylamide; (R)—N-((7-(1,2-dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-6-yl)methyl)-N-methylacrylamide; (S)—N-((7-(1,2-Dihydroxyethyl)-4-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-6-yl)methyl)acrylamide; (R)—N-((7-(1,2-dihydroxyethyl)-4-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-6-yl)methyl)acrylamide; (S)—N-((7-(2-Oxooxazolidin-5-yl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-6-yl)methyl)acrylamide; (R)—N-((7-(2-oxooxazolidin-5-yl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-6-yl)methyl)acrylamide; N-((7-(Hydroxymethyl)-4-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-6-yl)methyl)acrylamide; N-((7-(Hydroxymethyl)-4-(6-(trifluoromethoxy)pyridin-3-yl)benzo[d]oxazol-6-yl)methyl)acrylamide; Cyclobut-1-en-1-yl(3-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-1-yl)methanone; (E)-9-Methyl-2-(1-(prop-1-en-1-ylsulfonyl)azetidin-3-yl)-6-(4-(trifluoromethoxy)phenyl)-9H-purine; (E)-4-Hydroxy-1-(3-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-1-yl)but-2-en-1-one; 2-Fluoro-1-(3-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-1-yl)prop-2-en-1-one; Bicyclo[1.1.0]butan-1-yl(3-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-1-yl)methanone; (E)-2-Methyl-1-(3-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-1-yl)but-2-en-1-one; (E)-1-(3-(9-Methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-1-yl)but-2-en-1-one; (R)-1-(3-(9-Methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)pyrrolidin-1-yl)prop-2-en-1-one; (S)-1-(3-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)pyrrolidin-1-yl)prop-2-en-1-one; 1-(4-(9-Methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)piperazin-1-yl)prop-2-en-1-one; (E)-4-Hydroxy-1-(4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)piperazin-1-yl)but-2-en-1-one; 2-Fluoro-1-(4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)piperazin-1-yl)prop-2-en-1-one; N-(1-(9-Methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-3-yl)acrylamide; (E)-1-(4-Hydroxybut-2-enoyl)-3-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidine-3-carbonitrile; 1-((9-Methyl-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)methyl)-3-methylenepyrrolidin-2-one; N-((9-Methyl-6-(4-(trifluoromethyl)piperidin-1-yl)-9H-purin-2-yl)methyl)acrylamide; N-((9-Methyl-6-(4-(trifluoromethoxy)piperidin-1-yl)-9H-purin-2-yl)methyl)acrylamide; 1-(3-(9-(Difluoromethyl)-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one; N-((9-Methyl-2-(4-(trifluoromethoxy)phenyl)-9H-purin-6-yl)methyl)acrylamide; 6-(1-(2-Fluoroacryloyl)azetidin-3-yl)-8-(4-(trifluoromethoxy)phenyl)pyrido[3,4-b]pyrazin-5(6H)-one; 6-(1-(Cyclobut-1-ene-1-carbonyl)azetidin-3-yl)-8-(4-(trifluoromethoxy)phenyl) pyrido[3,4-b]pyrazin-5(6H)-one; 5-(1-(2-Fluoroacryloyl)azetidin-3-yl)-3-methyl-7-(4-(trifluoromethoxy)phenyl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one; (E)-5-(I-(4-Hydroxybut-2-enoyl)azetidin-3-yl)-3-methyl-7-(4-(trifluoromethoxy)phenyl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one; (R)—N-((7-(1-Hydroxyethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; (S)—N-((7-(1-hydroxyethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; N-((7-((2-Hydroxyethyl)amino)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; Methyl 2-(1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole-6-carboxamido)acrylate; N-(3-Amino-3-oxoprop-1-en-2-yl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole-6-carboxamide; N-((7-Cyano-4-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; N-(2-(7-Cyano-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)ethyl)-N-methylacrylamide; 2-Fluoro-1-(3-(1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)azetidin-1-yl)prop-2-en-1-one; N-((8-(4-(Trifluoromethyl)phenoxy)quinolin-6-yl)methyl)acrylamide; (S)—N-((5-(1,2-Dihydroxyethyl)-8-(4-(trifluoromethyl)phenoxy)quinolin-6-yl)methyl)acrylamide; and (R)—N-((5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethyl)phenoxy)quinolin-6-yl)methyl)acrylamide;

or a pharmaceutically acceptable salt thereof. Also provided herein are, where applicable, any and all stereoisomers of the compounds depicted herein, including geometric isomers (e.g., cis/trans isomers or E/Z isomers), enantiomers, diastereomers, tautomers, or mixtures thereof in any ratio, including racemic mixtures.

In some embodiments, provided herein is a compound selected from the group consisting of:

2-chloro-N-methyl-N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]acetamide N-[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[7-(hydroxymethyl)-4-[6-(trifluoromethoxy)-3-pyridyl]-1,3-benzoxazol-6-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl]methyl]prop-2-enamide N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]quinazolin-2-yl]methyl]prop-2-enamide N-[[7-[2-fluoro-4-(trifluoromethoxy)phenyl]-4-(hydroxymethyl)-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[7-[4-(trifluoromethoxy)phenyl]oxazolo[5,4-b]pyridin-5-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]furo[3,2-d]pyrimidin-2-yl]methyl]prop-2-enamide N-methyl-N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[4-[4-(trifluoromethoxy)phenyl]-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl]methyl]prop-2-enamide 1-chloro-N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]methanesulfonamide 2-chloro-N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]acetamide N-[[5-cyano-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]prop-2-enamide N-[(1R)-1-[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]ethyl]prop-2-enamide N-[(1S)-1-[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]ethyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]ethenesulfonamide 2,3,3-trideuterio-N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-(5-isopropoxythiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[4-imidazol-1-yl-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide N-[[4-(hydroxymethyl)-7-[4-(pentafluoro-lambda6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide 2-chloro-N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]acetamide N-[[5-ethyl-8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide; N-[[4-cyano-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[5-[(1R)-1,2-dihydroxyethyl]-8-[4-(trifluoromethoxy)phenyl]quinoxalin-6-yl]methyl]prop-2-enamide; N-[[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1S)-1,2-dihydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1R)-1,2-dihydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1R)-1-hydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-[(1S)-1-hydroxyethyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[3-methyl-4-(1H-pyrazol-4-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[2-methyl-7-[4-(trifluoromethoxy)phenyl]thiazolo[5,4-d]pyrimidin-5-yl]methyl]prop-2-enamide; N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]-N-methyl-prop-2-enamide; N-[[8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide); N-methyl-N-[[8-[4-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]prop-2-enamide; N-[[3-(difluoromethyl)-4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; (R)—N-((1-(difluoromethyl)-7-(1,2-dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; (S)—N-((1-(difluoromethyl)-7-(1,2-dihydroxyethyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; N-[2-[4-cyano-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]ethyl]prop-2-enamide; N-[[8-methyl-5-[4-(trifluoromethoxy)phenyl]-7-quinolyl]methyl]prop-2-enamide; N-[[8-(hydroxymethyl)-5-[4-(trifluoromethoxy)phenyl]-7-quinolyl]methyl]prop-2-enamide; (S)—N-((8-(1,2-dihydroxyethyl)-5-(4-(trifluoromethoxy)phenyl)quinolin-7-yl)methyl)acrylamide; (R)—N-((8-(1,2-dihydroxyethyl)-5-(4-(trifluoromethoxy)phenyl)quinolin-7-yl)methyl)acrylamide; (S)—N-((5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)methyl) acrylamide; (R)—N-((5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)methyl) acrylamide; N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]-N-methyl-prop-2-enamide; N-[[5-(hydroxymethyl)-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]prop-2-enamide; N-[[5-[(1S)-1,2-dihydroxyethyl]-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]-N-methyl-prop-2-enamide; N-[[5-[(1R)-1,2-dihydroxyethyl]-8-[4-(trifluoromethoxy)phenyl]-6-quinolyl]methyl]-N-methyl-prop-2-enamide; (S)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; (R)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)acrylamide; (S)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)-N-methylacrylamide; (R)—N-((4-(1,2-dihydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)methyl)-N-methylacrylamide; N-[[3-methyl-4-methylsulfonyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[4-(3-hydroxyprop-1-ynyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; 2-fluoro-1-[3-[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]azetidin-1-yl]prop-2-en-1-one; (S)—N-((1-methyl-7-(S-methylsulfonimidoyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; (R)—N-((1-methyl-7-(S-methylsulfonimidoyl)-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; 1-[3-[9-methyl-6-[4-(trifluoromethoxy)phenyl]purin-2-yl]azetidin-1-yl]prop-2-en-1-one; 2-fluoro-N-[[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; (E)-4-hydroxy-N-[[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]-N-methyl-but-2-enamide; (R)—N-((7-(1,2-dihydroxyethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)-2-fluoro-N-methylacrylamide; (S)—N-((7-(1,2-dihydroxyethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)-2-fluoro-N-methylacrylamide; N-[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]-2-fluoro-prop-2-enamide; N-[[1-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-[[9-methyl-6-[4-(trifluoromethoxy)phenyl]purin-2-yl]methyl]prop-2-enamide; N-[[7-[(1S)-1,2-dihydroxyethyl]-1-methyl-4-[4-(trifluoromethoxy)phenyl]imidazo[4,5-c]pyridin-6-yl]methyl]prop-2-enamide; N-[[7-[(1R)-1,2-dihydroxyethyl]-1-methyl-4-[4-(trifluoromethoxy)phenyl]imidazo[4,5-c]pyridin-6-yl]methyl]prop-2-enamide; N-[[3-methyl-4-(1H-pyrazol-4-yl)-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-((7-(hydroxymethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-6-yl)methyl)acrylamide; (S)—N-((7-(3,4-dihydroxybut-1-yn-1-yl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-H-benzo[d]imidazol-6-yl)methyl)acrylamide; (R)—N-((7-(3,4-dihydroxybut-1-yn-1-yl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide; 3-methyl-5-[(prop-2-enoylamino)methyl]-7-[4-(trifluoromethoxy)phenyl]benzimidazole-4-carboxamide; N-[[4-(difluoromethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; and; N-((7-(1H-imidazol-1-yl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-6-yl)methyl)acrylamide;

or a pharmaceutically acceptable salt thereof. Also provided herein are, where applicable, any and all stereoisomers of the compounds depicted herein, including geometric isomers (e.g., cis/trans isomers or E/Z isomers), enantiomers, diastereomers, tautomers, or mixtures thereof in any ratio, including racemic mixtures.

In one aspect, provided herein is a compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of:

In some aspects, the compounds of the disclosure are isotopically labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (II-A) or formula (II-B) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (II-A) or formula (II-B) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively. These isotopically-labeled compounds would be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to TEAD. Certain isotopically-labeled compounds of formula (II-A) or formula (II-B), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (II-A) or formula (II-B) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

In some aspects, any of the ways in which compounds of formula (II-A) or formula (II-B) may be isotopically labeled, and any of the ways in which isotopically-labeled compounds of formula (II-A) or formula (II-B) may be used (as described, e.g. in the previous paragraph) also apply to compounds of formula (II-AB).

In some aspects, any of the ways in which compounds of formula (II-A) or formula (II-B) may be isotopically labeled, and any of the ways in which isotopically-labeled compounds of formula (II-A) or formula (II-B) may be used (as described, e.g. in the previous paragraph) also apply to compounds of formula (II-AB′).

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (II-A) or formula (II-B) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

In some aspects, any of the ways in which compounds of formula (II-A) or formula (II-B) may be isotopically labeled, and any of the ways in which isotopically-labeled compounds of formula (II-A) or formula (II-B) may be used (as described, e.g. in the previous paragraph) also apply to compounds of formula (II-AB).

In some aspects, any of the ways in which compounds of formula (II-A) or formula (II-B) may be isotopically labeled, and any of the ways in which isotopically-labeled compounds of formula (II-A) or formula (II-B) may be used (as described, e.g. in the previous paragraph) also apply to compounds of formula (II-AB′).

Also provided herein is a pharmaceutically acceptable salt or ester of any compound provided herein, as well as a stereoisomer, a geometric isomer, a tautomer, a solvate, a metabolite, an isotope or a prodrug of such compound or a pharmaceutically acceptable salt of such compound.

In one aspect, the present disclosure is directed to processes of preparing one or more TEAD inhibitors described herein. In some embodiments, a process of preparing a TEAD inhibitor is described herein in one or more examples.

In some embodiments, provided is a process for preparing a compound of formula (II-AB′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

L′ is *—N(R 3 )-L-** or

m, or Z-L′ is

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 -alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is

i) phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R* is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; ii) C 1-6 alkyl, optionally substituted with one or more halo; or iii) cyclobutenyl or bicyclobutanyl;

L is methylene or ethylene, wherein the methylene of L is optionally substituted with one C 1-6 alkyl;

Y is CH or C(CN), and

n and m are each independently 1 or 2;

provided that:

i) when i-1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and i-2) X 2 or X 3 is N, B of formula (II-AB′) is phenyl and R 2 is haloC 1-6 alkoxyl; and

ii) when n=1 and m=2, or n=2 and m=1, B is phenyl substituted by halomethyoxyl; and

iii) the compound of formula (II-AB′) is not any one of following:

N-((8-(4-fluorophenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

N-((8-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

N-((7-fluoro-4-(4-(trifluoromethoxy)phenyl)quinazolin-2-yl)methyl)acrylamide;

N-((8-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-6-yl)methyl)acrylamide;

1-(4-(4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)piperidin-1-yl)ethan-1-one;

4-(4-methoxyphenyl)-1-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine;

6-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-methoxyphenyl)-1-methyl-1H-imidazo[4,5-c]pyridine;

6-(1-(ethylsulfonyl)piperidin-4-yl)-1-isopropyl-4-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridine;

4-(4-methoxyphenyl)-1-methyl-6-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridine; and

N-((4-(4-fluorophenyl)-1,8-naphthyridin-2-yl)methyl)acetamide.

In addition to one or more of the compounds provided above (including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof), the disclosure also provides for compositions and medicaments comprising a compound of the present disclosure or an embodiment or aspect thereof and at least one pharmaceutically acceptable carrier. The compositions of the disclosure can be used to selectively inhibit TEAD in patients (e.g., humans).

In one aspect, the disclosure provides for pharmaceutical compositions or medicaments comprising a compound of the disclosure (or embodiments and aspects thereof including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, and prodrugs) and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the disclosure provides for preparing compositions (or medicaments) comprising compounds of the disclosure. In another aspect, the disclosure provides for administering compounds of the disclosure and compositions comprising compounds of the disclosure to a patient (e.g., a human patient) in need thereof.

The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulations for intravenous administration comprise sterile aqueous solutions of a compound of the disclosure which are prepared by dissolving solid compounds of the disclosure in water to produce an aqueous solution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, tale, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of a compound of the disclosure together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit TEAD activity as required to prevent or treat the undesired disease or disorder, such as for example, pain. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound of the disclosure administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. The daily does is, in certain aspects, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

The compounds of the present disclosure may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

The compositions comprising compounds of the disclosure (or embodiments or aspects thereof including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, and prodrugs thereof) are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. A typical formulation is prepared by mixing a compound of the present disclosure and a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). Suitable carriers, diluents and excipients are well known to those skilled in the art and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). An active pharmaceutical ingredient of the disclosure (e.g., a compound of formula (I), or an embodiment or aspect thereof) can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21S t Edition, Lippincott Williams & Wilkins, Philadelphia, PA. The particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound of the present disclosure is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.

Sustained-release preparations of a compound of the disclosure (e.g., compound of formula (II-A) or formula (II-B), or an embodiment or aspect thereof) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula (II-A) or formula (II-B), or an embodiment or aspect thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposomally entrapped compounds, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamelar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal therapy.

Sustained-release preparations of a compound of formula (II-AB) may be prepared in the same way as sustained-release preparations of a compound of formula (II-A) or formula (II-B) (as described, e.g. in the preceding paragraph).

Sustained-release preparations of a compound of formula (II-AB′) may be prepared in the same way as sustained-release preparations of a compound of formula (II-A) or formula (II-B) (as described, e.g. in the preceding paragraph).

In one example, compounds of the disclosure or an embodiment or aspect thereof may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of the disclosure (or an embodiment or aspect thereof) is formulated in an acetate buffer, at pH 5. In another aspect, the compounds of the disclosure or an embodiment thereof are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution

Formulations of a compound of the disclosure suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of the disclosure.

Compressed tablets can be prepared by compressing in a suitable machine a compound of the disclosure in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of a powdered compound of the disclosure moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of a compound of the disclosure therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use. Formulations of a compound of the disclosure intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing a compound of the disclosure in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containing about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg and about 500 mg of the compounds (or an embodiment or aspect thereof) of the disclosure compounded with a filler (e.g., lactose, such as about 90-30 mg anhydrous lactose), a disintegrant (e.g, croscarellose, such as about 5-40 mg sodium croscarmellose), a polymer (e.g. polyvinylpyrrolidone (PVP), a cellulose (e.g., hydroxypropylmethyl cellulose (HPMe), and/or copovidone, such as about 5-30 mg PVP, HPMe or copovidone), and a lubricant (e.g., magnesium stearate, such as about 1-10 mg). Wet granulation, dry granulation or dry blending may be used. In one wet granulation aspect, powdered ingredients are first mixed together and then mixed with a solution or suspension of the polymer (e.g., PVP). The resulting composition can be dried, granulated, mixed with lubricant and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the disclosure in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the compounds of the disclosure in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the compounds of the disclosure can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the compounds of the disclosure can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations can desirably include a compound which enhances absorption or penetration of a compound of the disclosure through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

For topical formulations, it is desired to administer an effective amount of a pharmaceutical composition according to the disclosure to target area, e.g., skin surfaces, mucous membranes, and the like, which are adjacent to peripheral neurons which are to be treated. This amount will generally range from about 0.0001 mg to about 1 g of a compound of the disclosure (or an embodiment or aspect thereof) per application, depending upon the area to be treated, whether the use is diagnostic, prophylactic or therapeutic, the severity of the symptoms, and the nature of the topical vehicle employed. A preferred topical preparation is an ointment, wherein about 0.001 to about 50 mg of a compound of the disclosure is used per cc of ointment base. The pharmaceutical composition can be formulated as transdermal compositions or transdermal delivery devices (“patches”). Such compositions include, for example, a backing, compound of the disclosure reservoir, a control membrane, liner and contact adhesive. Such transdermal patches may be used to provide continuous pulsatile, or on demand delivery of the compounds of the present disclosure as desired.

The formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of a compound of the disclosure.

When the binding target is located in the brain, certain aspects of the disclosure provide for a compound of the disclosure (or an embodiment or aspect thereof) to traverse the blood-brain barrier. Certain neurodegenerative diseases are associated with an increase in permeability of the blood-brain barrier, such that a compound of the disclosure (or an embodiment or aspect thereof) can be readily introduced to the brain. When the blood-brain barrier remains intact, several art-known approaches exist for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods.

Physical methods of transporting a compound of the disclosure (or an embodiment or aspect thereof) across the blood-brain barrier include, but are not limited to, circumventing the blood- brain barrier entirely, or by creating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion/convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91 :2076-2080, 1994), and implanting a delivery device in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford Pharmaceutical).

Methods of creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002/0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods of transporting a compound of formula of the disclosure (or an embodiment or aspect thereof) across the blood-brain barrier include, but are not limited to, encapsulating the a compound of the disclosure (or an embodiment or aspect thereof) in liposomes that are coupled to antibody binding fragments that bind to receptors on the vascular endothelium of the blood- brain barrier (see, e.g., U.S. Patent Application Publication No. 2002/0025313), and coating a compound of the disclosure (or an embodiment or aspect thereof) in low-density lipoprotein particles (see, e.g., U.S. Patent Application Publication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of the disclosure (or an embodiment or aspect thereof) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase permeability of the blood-brain barrier (see, e.g., U.S. Patent Application Publication Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. Patent Application Publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Application Publication No. 2003/0073713); coating a compound of the disclosure (or an embodiment or aspect thereof) with a transferrin and modulating activity of the one or more transferrin receptors (see, e.g., U.S. Patent Application Publication No. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat. No. 5,004,697).

For intracerebral use, in certain aspects, the compounds can be administered continuously by infusion into the fluid reservoirs of the CNS, although bolus injection may be acceptable. The inhibitors can be administered into the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration can be performed by use of an indwelling catheter and a continuous administration means such as a pump, or it can be administered by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitors can be injected through chronically implanted cannulas or chronically infused with the help of osmotic mini pumps. Subcutaneous pumps are available that deliver proteins through a small tubing to the cerebral ventricles. Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving a subcutaneous pump device or continuous intracerebroventricular infusion through a totally implanted drug delivery system are those used for the administration of dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models for Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143, 1987.

Representative compounds of the disclosure have been shown to modulate TEAD activity.

In some embodiments, a compound that modulates TEAD activity is a compound of formula (II-A), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein:

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from C 1-3 alkyl, —OH, oxo, C 1-3 alkoxy, and —NR d R e ; and

wherein R d and R e are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from the group consisting of H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R 1 , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl; and

wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and

wherein R d and R e are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one to five R 2 ;

R 2 is independently, at each occurrence, i) halo; ii) S(R y ) 5 , wherein each R y is halo; or iii) C 1-6 alkoxy, optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R a ,

wherein R d and R e are each independently H or C 1-6 alkyl;

R a is i) C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo; and

L is methylene, optionally substituted with one or more C 1-6 alkyl.

In some embodiments, a compound that modulates TEAD activity is a compound of formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein:

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl that is fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from C 1-3 alkyl, —OH, oxo, C 1-3 alkoxy, and —NR d R e ; and

wherein R d and RC are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from the group consisting of H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl; and

wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and

wherein R d and R e are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one to five R 2 ;

R 2 is independently, at each occurrence, i) halo; ii) S(R y ) 5 , wherein each R y is halo; or iii) C 1-6 alkoxy, optionally substituted with one or more halo;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R a ,

wherein R d and R e are each independently H or C 1-6 alkyl;

R a is i) C 2-6 alkenyl optionally substituted with one or more deuterium, C 1-6 alkyl, halo, haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo; and

n and m are each independently 1 or 2.

In some embodiments, the compound that modulates TEAD activity is a compound of formula (II-AB):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

L′ is selected from the group consisting of *—N(R 3 )-L-** and

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R 4 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R ta is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and wherein R d and RC are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein

R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R b ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and m are 1; or n and m are 2;

provided that when 1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and 2) X 2 or X 3 is N,

B of formula (II-B) is phenyl and R 2 is haloC 1-6 alkoxyl.

The compounds of the disclosure (or any embodiment or aspect thereof) are useful as a medical therapy for treating diseases and conditions mediated by TEAD activity. Such diseases and conditions include but are not limited to proliferative disorders such as cancer including acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

In a specific embodiment, compounds of the disclosure (or any embodiment or aspect thereof) can be administered as a medical therapy to treat proliferative disorders such as cancer.

In one specific aspect, compounds of the disclosure (or any embodiment or aspect thereof) are administered as a medical therapy to treat proliferative disorders such as cancer.

In another aspect, the disclosure provides for a method for treating proliferative disorders such as cancer, comprising the step of administering a therapeutically effective amount of a compound according to formula (II-A) or formula (II-B) (or an embodiment or aspect thereof) as described elsewhere herein to a subject in need thereof.

In another aspect, the disclosure provides for a method for treating any of the indications enumerated herein, comprising the step of administering a therapeutically effective amount of a compound according to formula (II-AB) (or an embodiment or aspect thereof) as described elsewhere herein to a subject in need thereof.

In another aspect, the disclosure provides for a method for treating any of the indications enumerated herein, comprising the step of administering a therapeutically effective amount of a compound according to formula (II-AB′) (or an embodiment or aspect thereof) as described elsewhere herein to a subject in need thereof.

In another aspect, the disclosure provides for a compound of formula (II-A) or formula (II-B) as described elsewhere herein (or any embodiment or aspect thereof) for modulating TEAD activity. In some embodiments, the disclosure provides for a pharmaceutically acceptable salt of a compound of formula (II-A) or formula (II-B) for modulating TEAD activity.

In another aspect, the disclosure provides for a compound of formula (II-AB) as described elsewhere herein (or any embodiment or aspect thereof) for modulating TEAD activity. In some embodiments, the disclosure provides for a pharmaceutically acceptable salt of a compound of formula (II-AB) for modulating TEAD activity.

In another aspect, the disclosure provides for a compound of formula (II-AB′) as described elsewhere herein (or any embodiment or aspect thereof) for modulating TEAD activity. In some embodiments, the disclosure provides for a pharmaceutically acceptable salt of a compound of formula (II-AB′) for modulating TEAD activity.

In another aspect, the disclosure provides for a compound of formula (II-A) or formula (II-B) as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for use in medical therapy.

In another aspect, the disclosure provides for a compound of formula (II-AB) as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for use in medical therapy.

In another aspect, the disclosure provides for a compound of formula (II-AB′) as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for use in medical therapy.

In another aspect, the disclosure provides for a method for treatment or prophylaxis of proliferative disorders such as cancer, comprising the step of administering a therapeutically effective amount of a compound according to formula (II-A) or formula (II-B) (or an embodiment or aspect thereof) as described elsewhere herein, to a subject in need thereof.

In another aspect, the disclosure provides for a method for treatment or prophylaxis of any of the indications enumerated herein, comprising the step of administering a therapeutically effective amount of a compound according to formula (II-AB) (or an embodiment or aspect thereof) as described elsewhere herein, to a subject in need thereof.

In another aspect, the disclosure provides for a method for treatment or prophylaxis of any of the indications enumerated herein, comprising the step of administering a therapeutically effective amount of a compound according to formula (II-AB′) (or an embodiment or aspect thereof) as described elsewhere herein, to a subject in need thereof.

In another aspect, the disclosure provides for a compound of formula (II-A) or formula (II-B), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of proliferative disorders such as cancer.

In another aspect, the disclosure provides for a compound of formula (II-AB), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of any of the indications enumerated herein.

In another aspect, the disclosure provides for a compound of formula (II-AB′), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of any of the indications enumerated herein.

In another aspect, the disclosure provides for the use of a compound of formula (II-A) or formula (II-B), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of proliferative disorders such as cancer.

In another aspect, the disclosure provides for the use of a compound of formula (II-AB), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of any of the indications enumerated herein.

In another aspect, the disclosure provides for the use of a compound of formula (II-AB′), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of any of the indications enumerated herein.

In another aspect, the disclosure provides for a method for treating proliferative disorders such as cancer in a mammal (e.g., a human) comprising administering a compound of formula (II-A) or formula (II-B) as described elsewhere herein or an embodiment or aspect thereof such as a pharmaceutically acceptable salt thereof to the mammal.

In another aspect, the disclosure provides for a method for treating any of the indications enumerated herein, comprising administering a compound of formula (II-AB) as described elsewhere herein or an embodiment or aspect thereof such as a pharmaceutically acceptable salt thereof to the mammal.

In another aspect, the disclosure provides for a method for treating any of the indications enumerated herein, comprising administering a compound of formula (II-AB′) as described elsewhere herein or an embodiment or aspect thereof such as a pharmaceutically acceptable salt thereof to the mammal.

In another aspect, the disclosure provides for a method for modulating TEAD activity, comprising contacting TEAD with a compound of formula (II-A) or formula (II-B), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides for a method for modulating TEAD activity, comprising contacting TEAD with a compound of formula (II-AB), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides for a method for modulating TEAD activity, comprising contacting TEAD with a compound of formula (II-AB′), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof.

It is understood that, in some embodiments, in conjunction with embodiments above or below, a compound of formula (II-AB′), (II-AB), (II-A), or (II-B) as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, may be used in a therapeutically effective amount.

In another aspect, the disclosure provides for a compound of formula (II-A) or formula (II-B), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of a disease or condition mediated by TEAD activity.

In another aspect, the disclosure provides for a compound of formula (II-AB), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of a disease or condition mediated by TEAD activity. Within aspects of this embodiment, the disease or condition is any of the indications enumerated herein.

In another aspect, the disclosure provides for a compound of formula (II-AB′), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of a disease or condition mediated by TEAD activity. Within aspects of this embodiment, the disease or condition is any of the indications enumerated herein.

In another aspect, the disclosure provides for the use of a compound of formula (II-A) or formula (II-B), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TEAD activity. Within aspects of this embodiment, the disease or condition is proliferative disorders such as cancer.

In another aspect, the disclosure provides for the use of a compound of formula (II-AB), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TEAD activity. Within aspects of this embodiment, the disease or condition is any of the diseases enumerated herein.

In another aspect, the disclosure provides for the use of a compound of formula (II-AB′), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TEAD activity. Within aspects of this embodiment, the disease or condition is any of the diseases enumerated herein.

In one aspect, compounds of the disclosure demonstrate higher potency as compared to other analogues.

The compounds of formula (II-A) or formula (II-B), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (II-A) or formula (II-B), such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (II-A) or formula (II-B), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

Any of the methods of using a compound of formula (II-A) or (II-B) described in the preceding paragraphs may also be applied to a compound of formula (II-AB).

Any of the methods of using a compound of formula (II-A) or (II-B) described in the preceding paragraphs may also be applied to a compound of formula (II-AB′).

Those additional agents may be administered separately from a composition comprising a disclosed compound, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a disclosed compound in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of formula I or formula II, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, compositions of this invention are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of a disclosed compound can be administered.

Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

In one embodiment, the treatment method includes the co-administration of a compound of formula (II-A) or formula (II-B), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and at least one cytotoxic agent. The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

Any of the treatment methods involving a compound of formula (II-A) or (II-B) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, also apply to a compound or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, of formula (II-AB).

Any of the treatment methods involving a compound of formula (II-A) or (II-B) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, also apply to a compound or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, of formula (II-AB′).

Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signalling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

“Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®., Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I ( Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG 1 λ antibody genetically modified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CR L HB 8506), MAb 455 (ATCC CR L HB8507), MAb 225 (ATCC CR L 8508), MAb 528 (ATCC CR L 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc.); and mAb 806 or humanized mAb 806 (Johns et al., J Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc.); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1/p2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CC1-779; tipifarnib (R 1 1577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In other embodiments, a compound of the present invention is administered in combination with a biologic agent, such as bevacizumab or panitumumab.

In certain embodiments, compounds of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, elotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2 a , interferon alfa-2 b , irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid.

Chemotherapeutic agents also include treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; treatments for asthma such as albuterol and montelukast sodium; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.

In another embodiment, provided are methods of using a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein, or an embodiment or aspect thereof, to treat cancer in combination with a PD-1 axis binding antagonist.

In another embodiment, provided are methods of using a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein, or an embodiment or aspect thereof, to treat cancer in combination with a PD-1 axis binding antagonist.

In another embodiment, provided are methods of using a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein, or an embodiment or aspect thereof, to treat cancer in combination with a PD-1 axis binding antagonist.

The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis—with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.

The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1, PD-L2. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one embodiment, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. Specific examples of PD-1 binding antagonists are provided infra.

The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1, B7-1. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1I binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1. In some embodiments, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1, B7-1. In one embodiment, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L1 binding antagonist is an anti-PD-L1 antibody. Specific examples of PD-L1 binding antagonists are provided infra.

The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1. In some embodiments, the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In one embodiment, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L2 binding antagonist is an immunoadhesin.

PD-1 Axis Binding Antagonists

Provided herein are methods for treating cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein. Also provided herein are methods of enhancing immune function or response in an individual (e.g., an individual having cancer) comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of formula (II-A) or formula (II-B), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein.

Provided herein are methods for treating cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein. Also provided herein are methods of enhancing immune function or response in an individual (e.g., an individual having cancer) comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of formula (II-AB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein.

Provided herein are methods for treating cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein. Also provided herein are methods of enhancing immune function or response in an individual (e.g., an individual having cancer) comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of formula (II-AB′), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein.

In such methods, the PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PDL1 binding antagonist, and/or a PDL2 binding antagonist. Alternative names for “PD-1” include CD279 and SLEB2. Alternative names for “PDL1” include B7-H1, B7-4, CD274, and B7-H. Alternative names for “PDL2” include B7-DC, Btdc, and CD273. In some embodiments, PD-1, PDL1, and PDL2 are human PD-1, PDL1 and PDL2.

In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partner(s). In a specific aspect the PD-A ligand binding partners are PDL1 and/or PDL2. In another embodiment, a PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partner(s). In a specific aspect, PDL1 binding partner(s) are PD-1 and/or B7-1. In another embodiment, the PDL2 binding antagonist is a molecule that inhibits the binding of PDL2 to its binding partner(s). In a specific aspect, a PDL2 binding partner is PD-1. The antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide or a small molecule. If the antagonist is an antibody, in some embodiments the antibody comprises a human constant region selected from the group consisting of IgG1, IgG2, IgG3 and IgG4

Anti-PD-1 Antibodies

In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PDL1 antibodies can be utilized in the methods disclosed herein. In any of the embodiments herein, the PD-1 antibody can bind to a human PD-1 or a variant thereof. In some embodiments the anti-PD-1 antibody is a monoclonal antibody. In some embodiments, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab′, Fab′-SH, Fv, scFv, and (Fab′) 2 fragments. In some embodiments, the anti-PD-1 antibody is a chimeric or humanized antibody. In other embodiments, the anti-PD-1 antibody is a human antibody.

In some embodiments, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1 106, ON0-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in WO2006/121168. Nivolumab comprises a heavy chain and a light chain sequence, wherein:

(a) the heavy chain comprises the amino acid

sequence.

(SEQ ID NO: 1)

SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK,

and

(b) the light chain comprises the amino acid

sequence:

(SEQ ID NO: 2)

LSSPVTKSFNRGEC.

In some embodiments, the anti-PD-1 antibody comprises the six HVR sequences from SEQ ID NO:1 and SEQ ID NO:2 (e.g., the three heavy chain HVRs from SEQ ID NO:1 and the three light chain HVRs from SEQ ID NO:2). In some embodiments, the anti-PD-1 antibody comprises the heavy chain variable domain from SEQ ID NO:1 and the light chain variable domain from SEQ ID NO:2.

In some embodiments, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, SCH-900475, and KEYTRUDA® is an anti-PD-1 antibody described in WO2009/114335. Pembrolizumab comprises a heavy chain and a light chain sequence, wherein:

(a) the heavy chain comprises the amino acid

sequence:

(SEQ ID NO: 3)

SLSLGK,

and

(b) the light chain comprises the amino acid

sequence:

(SEQ ID NO: 4)

ACEVTHQGLSSPVTKSFNRGEC.

In some embodiments, the anti-PD-1 antibody comprises the six HVR sequences from SEQ ID NO:3 and SEQ ID NO:4 (e.g., the three heavy chain HVRs from SEQ ID NO:3 and the three light chain HVRs from SEQ ID NO:4). In some embodiments, the anti-PD-1 antibody comprises the heavy chain variable domain from SEQ ID NO:3 and the light chain variable domain from SEQ ID NO:4.

In some embodiments, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

In some embodiments, the anti-PD-1 antibody is PDR001 (CAS Registry No. 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD1 antibody that blocks the binding of PDL1 and PDL2 to PD-1.

In some embodiments, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD1 antibody.

In some embodiments, the anti-PD-1 antibody is BGB-108 (BeiGene). In some embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene).

In some embodiments, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD1 antibody.

In some embodiments, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A 1110 is a human anti-PD1 antibody.

In some embodiments, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD1 antibody.

In some embodiments, the anti-PD-1 antibody is PF-06801591 (Pfizer).

In some embodiments, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro/AnaptysBio).

In some embodiments, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

In some embodiments, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD1 antibody that inhibits PD-1 function without blocking binding of PDL1 to PD-1.

In some embodiments, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD1 antibody that competitively inhibits binding of PDL1 to PD-1.

In some embodiments, the PD-1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from a PD-1 antibody described in WO2015/112800 (Applicant: Regeneron), WO2015/112805 (Applicant: Regeneron), WO2015/112900 (Applicant: Novartis), US20150210769 (Assigned to Novartis), WO2016/089873 (Applicant: Celgene), WO2015/035606 (Applicant: Beigene), WO2015/085847 (Applicants: Shanghai Hengrui Pharmaceutical/Jiangsu Hengrui Medicine), WO2014/206107 (Applicants: Shanghai Junshi Biosciences/Junmeng Biosciences), WO2012/145493 (Applicant: Amplimmune), U.S. Pat. No. 9,205,148 (Assigned to MedImmune), WO2015/119930 (Applicants: Pfizer/Merck), WO2015/119923 (Applicants: Pfizer/Merck), WO2016/032927 (Applicants: Pfizer/Merck), WO2014/179664 (Applicant: AnaptysBio), WO2016/106160 (Applicant: Enumeral), and WO2014/194302 (Applicant: Sorrento).

Anti-PDL1 Antibodies

In some embodiments, the PD-1 axis binding antagonist is an anti-PDL1 antibody. A variety of anti-PDL1 antibodies are contemplated and described herein. In any of the embodiments herein, the isolated anti-PDL1 antibody can bind to a human PDL1, for example a human PDL1 as shown in UniProtKB/Swiss-Prot Accession No.Q9NZQ7.1, or a variant thereof. In some embodiments, the anti-PDL1 antibody is capable of inhibiting binding between PDL1 and PD-1 and/or between PDL1 and B7-1. In some embodiments, the anti-PDL1 antibody is a monoclonal antibody. In some embodiments, the anti-PDL1 antibody is an antibody fragment selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and (Fab′) 2 fragments. In some embodiments, the anti-PDL1 antibody is a chimeric or humanized antibody. In some embodiments, the anti-PDL1 antibody is a human antibody. Examples of anti-PDL1 antibodies useful in the methods of this invention and methods of making them are described in PCT patent application WO 2010/077634 and U.S. Pat. No. 8,217,149, both of which are incorporated herein.

In some embodiments, the anti-PDL1 antibody is atezolizumab (CAS Registry Number: 1422185-06-5). Atezolizumab (Genentech), also known as MPDL3280A, is an anti-PDL1 antibody.

Atezolizumab comprises:

Atezolizumab comprises a heavy chain and a light chain sequence, wherein:

(a) the heavy chain variable region sequence

comprises the amino acid sequence:

(SEQ ID NO: 11

RHWPGGFDYWGQGTLVTVSS,

and

(b) the light chain variable region sequence

comprises the amino acid sequence:

(SEQ ID NO: 12)

GQGTKVEIKR.

Atezolizumab comprises a heavy chain and a light chain sequence, wherein:

(a) the heavy chain comprises the amino acid

sequence:

(SEQ ID NO: 13)

LSLSPG,

and

(b) the light chain comprises the amino acid

sequence:

(SEQ ID NO: 14)

THQGLSSPVTKSFNRGEC.

In some embodiments, the anti-PDL1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PDL1 antibody (Merck KGaA, Pfizer). Avelumab comprises a heavy chain and a light chain sequence, wherein:

(a) the heavy chain comprises the amino acid

sequence:

(SEQ ID NO: 15)

KSLSLSPG,

and

(b) the light chain comprises the amino acid

sequence:

(SEQ ID NO: 16)

CQVTHEGSTVEKTVAPTECS.

In some embodiments, the anti-PDL1 antibody comprises the six HVR sequences from SEQ ID NO:15 and SEQ ID NO:16 (e.g., the three heavy chain HVRs from SEQ ID NO:15 and the three light chain HVRs from SEQ ID NO:16). In some embodiments, the anti-PDL1 antibody comprises the heavy chain variable domain from SEQ ID NO:15 and the light chain variable domain from SEQ ID NO:16.

In some embodiments, the anti-PDL1 antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PDL1 antibody (MedImmune, AstraZeneca) described in WO2011/066389 and US2013/034559. Durvalumab comprises a heavy chain and a light chain sequence, wherein:

(a) the heavy chain comprises the amino acid

sequence:

(SEQ ID NO: 17)

QKSLSLSPG,

and

(b) the light chain comprises the amino acid

sequence:

(SEQ ID NO: 18)

VTHQGLSSPVTKSFNRGEC.

In some embodiments, the anti-PDL1 antibody comprises the six HVR sequences from SEQ ID NO:17 and SEQ ID NO:18 (e.g., the three heavy chain HVRs from SEQ ID NO:17 and the three light chain HVRs from SEQ ID NO: 18). In some embodiments, the anti-PDL1 antibody comprises the heavy chain variable domain from SEQ ID NO:17 and the light chain variable domain from SEQ ID NO:18.

In some embodiments, the anti-PDL1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PDL1 antibody described in WO2007/005874.

In some embodiments, the anti-PDL1 antibody is LY3300054 (Eli Lilly).

In some embodiments, the anti-PDL1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PDL1 antibody.

In some embodiments, the anti-PDL1 antibody is KN035 (Suzhou Alphamab). KN035 is single-domain antibody (dAB) generated from a camel phage display library.

In some embodiments, the anti-PDL1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety. In some embodiments, the anti-PDL1 antibody is CX-072 (CytomX Therapeutics).

In some embodiments, the PDL1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from a PDL1 antibody described in US20160108123 (Assigned to Novartis), WO2016/000619 (Applicant: Beigene), WO2012/145493 (Applicant: Amplimmune), U.S. Pat. No. 9,205,148 (Assigned to MedImmune), WO2013/181634 (Applicant: Sorrento), and WO2016/061142 (Applicant: Novartis).

In a still further specific aspect, the PD-1 or PDL1 antibody has reduced or minimal effector function. In a still further specific aspect the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further embodiment, the effector-less Fe mutation is an N297A or D265A/N297A substitution in the constant region. In some embodiments, the isolated anti-PDL1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O—linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Removal of glycosylation sites form an antibody is conveniently accomplished by altering the amino acid sequence such that one of the above-described tripeptide sequences (for N-linked glycosylation sites) is removed. The alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site another amino acid residue (e.g., glycine, alanine or a conservative substitution).

Other PD-1 Antagonists

In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 binding antagonist is AMP-224. AMP-224 (CAS Registry No. 1422184-00-6; GlaxoSmithKline/MedImmune), also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO2010/027827 and WO2011/066342.

In some embodiments, the PD-1 binding antagonist is a peptide or small molecule compound. In some embodiments, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO2012/168944, WO2015/036927, WO2015/044900, WO2015/033303, WO2013/144704, WO2013/132317, and WO2011/161699.

In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PD-1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and VISTA. In some embodiments, the PDL1 binding antagonist is CA-170 (also known as AUPM-170). In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and TIM3. In some embodiments, the small molecule is a compound described in WO2015/033301 and WO2015/033299.

In some embodiments, the treatment method includes the co-administration of a compound of formula (II-A) or formula (II-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, and at least one mitogen-activated protein kinase (MAPK) inhibitor. In some embodiments, the treatment method includes the co-administration of a compound of formula (II-A) or formula (II-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, and at least one inhibitor of the RAS/MAPK pathway. In some embodiments, the treatment method includes the co-administration of a compound of formula (II-A) or formula (II-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, and at least one epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the inhibitor of the RAS/MAPK pathway is a KRAS inhibitor, a RAF inhibitor, such as a BRAF monomer or RAF dimer inhibitor, a MEK inhibitor, an ERK inhibitor, an EGFR inhibitor, or a MAPK inhibitor, or any combination thereof. In certain embodiments, the inhibitor of the RAS/MAPK pathway is an EGFR inhibitor or a MAPK inhibitor, or a combination thereof. Examples of EGFR inhibitors, MAPK inhibitors, and/or RAS/MAPK pathway inhibitors are disclosed in Moore, A. R., Rosenberg, S. C., McCormick, F. et al. RAS-targeted therapies: is the undruggable drugged?. Nat Rev Drug Discov (2020), incorporated herein by reference and include, but are not limited to: sotorasib (AMG 510 from Amgen), MRTX849 (from Mirati Therapeutics), JNJ-74699157/ARs-3248 (from J&J Wellspring Biosciences), LY3499446 (from Eli Lilly), GDCBI 1701963 (from Boehringer Ingelheim), mRNA-5671 (from Moderna Therapeutics), G12D inhibitor (from Mirati Therapeutics), RAS(ON) inhibitors (from Revolution Medicines), BBP-454 (from BridgeBio Pharma), SP600125, PLX4032, GW5074, AZD6244, PD98059, simvastatin, alisertib, teriflunomide, NSC95397, PD325901, PD98059, lovastatin, sorafenib (NEXAVAR®*, Bayer Labs), vermurafenib (ZELBORAF®, Hoffman L a Roche Inc.), dabrafenib (TAFLINAR®, Novartis Pharmaceuticals Corportation), selumetinib (KOSELUGO™, AstraZeneca Pharmaceuticals LP), trametinib (MEKINIST®, Novartis Pharmaceuticals Corporation), ulixertinib, silimarin, sirolimus (RAPAMUNE®, PV Prism CV), lapatinib (TYKERB®*/TYVERB*, GlaxoSmithKline), crizotinib (XALKORI®, PF Prism CV), taselisib (Roche), PF-0491502, PF502, enterolactone, PLX4720, PD0325901, PD184352, SC-514, alisterib (MLN8237), SB415286, PLX4720, obtaoclax (GX15-070), pimasterib, venetoclax (ABT-199/VENCLEXTA®/VENCLYXTO®), eprenetapopt (APR-246), gemcitabine (GEMZAR®*), birinapant (TL32711), pexmetinib (ARRY-614), afuresertib, ralimetinib (LY2228820, Eli Lilly), cobimetinib (COTELLIC®, Exelixis/Genentech), prexasertib (LY2606368), erlotinib (TARCEVA®, OSI Pharmaceuticals), bevacizumab (AVASTIN®, Genentech), belvarafenib (Hanmi Pharm./Genentech, Inc.), and binimetinib (MEKTOVI®, Array Biopharma Inc.).

In some embodiments, the any of the treatment methods using compounds of formula (II-A) or formula (II-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, also apply to a compound of formula (II-AB), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing.

In some embodiments, the any of the treatment methods using compounds of formula (II-A) or formula (II-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, also apply to a compound of formula (II-AB′), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing.

As used herein “combination” refers to any mixture or permutation of one or more compounds of the disclosure (or an embodiment or aspect thereof) and one or more other compounds of the disclosure or one or more additional therapeutic agent. Unless the context makes clear otherwise, “combination” may include simultaneous or sequentially delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, “combination” may include dosage forms of a compound of the disclosure with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include routes of administration of a compound of the disclosure with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include formulations of a compound of the disclosure with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein.

In some embodiments, provided herein are compositions, methods, and kits, comprising: (i) one or more TEAD inhibitors (e.g., any one of the TEAD inhibitors described herein, including but not limited to, any one of compounds of formula (II-AB′), (II-AB), (II-A), or (II-B), or any variations or embodiments thereof), or a pharmaceutically acceptable salt thereof; and (ii) one or more KRAS inhibitors (e.g., any one of compounds of formula (K—I), (K-II), (K—III), or (K—IV) or any variations or embodiments thereof), or a pharmaceutically acceptable salt thereof. TEAD inhibitors may, in some embodiments, be referred to as YAP/TAZ-TEAD inhibitors. In some embodiments, the one or more KRAS inhibitor is a G12C KRAS inhibitor.

In some embodiments, provided herein are methods of reducing resistance of a subject to treatment with a KRAS inhibitor, wherein the method comprises administering to a subject in need thereof one or more TEAD inhibitors, such as a TEAD inhibitor provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the TEAD inhibitor is co-administered to the subject with the KRAS inhibitor. Also provided herein are kits comprising one or more TEAD inhibitors, or a pharmaceutically acceptable salt thereof, and optionally one or more KRAS inhibitors, or a pharmaceutically acceptable salt thereof, and instructions for use in reducing resistance of a subject to treatment with a KRAS inhibitor. In some embodiments, the reduction in resistance is sufficient for the subject to overcome resistance to treatment with a KRAS inhibitor. In some embodiments, the subject has experienced resistance to treatment with a KRAS inhibitor. In some embodiments, treatment with a KRAS inhibitor and a TEAD inhibitor decreases the likelihood of a subject receiving treatment with a KRAS inhibitor to develop resistance to such KRAS inhibitor.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K—I):

wherein E1 and E2 are each independently Nor CR 1 ; J is N, NR 10 , or CR 10 ; M is N, NR 13 , or CR 13 ; is a single or double bond as necessary to give every atom its normal valence; R 1 is independently H, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , cyano, or halo; R 2 is halo, C 1-6 alkyl, C 1-6 haloalkyl, OR′, N(R′) 2 , C 2 -3alkenyl, C 2 -3alkynyl, C 0-3 alkylene-C 3-8 cycloalkyl, C 0-3 alkylene-C 2 -7heterocycloalkyl, C 0-3 alkylenearyl, or C 0-3 alkyleneheteroaryl, and each R 1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3 -4cycloalkyl, C 2 -3alkenyl, C 2 -3alkynyl, aryl, or heteroaryl, or two R 1 substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R 3 is halo, C 1-3 alkyl, C 1-2 haloalkyl, C 1-3 alkoxy, C 3 -4cycloalkyl, C 2 -3alkenyl, C 2 -3alkynyl, aryl, or heteroaryl; R 4 is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or Spiro 6-11 membered ring; L is a bond, C 1-6 alkylene, —O—C 0 -5alkylene, —S—C 0 -5alkylene, or —NH—C 0 -5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH; R 4′ is H, C 1 -8-alkyl, C 2 -8alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, C 0-3 alkylene-C 3-8 -cycloalkyl, C 0-3 alkylene-C 2 -7heterocycloalkyl, C 0-3 alkylenearyl, or selected from

R 5 and R 6 are each independently H, halo, C 1-6 alkyl, C 2-5 alkynyl, C 1-6 alkylene-O—C 1-4 -alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, C 1-6 alkyleneamine, C 0 -6alkyleneamide, C 0-3 alkylene-C(O)OH, C 0-3 alkylene-C(O)OC 1-4 alkyl, C 1-6 alkylene-O-aryl, C 0-3 alkylene-C(O)C 1-4 alkylene-OH, C 0-3 alkylene-C 3-8 cycloalkyl, C 0-3 alkylene-C 2 -7heterocycloalkyl, C 0-3 alkylenearyl, or cyano, or R 5 and R 6 , together with the atoms to which they are attached, form a 4-6 membered ring; R 7 is H or C 1-3 alkyl, or R 7 and R 8 , together with the atoms to which they are attached, form a 4-6 membered ring; Q is CR 8 R 9 , C═CR 8 R 9 , C═0, C═S, or C═NR 8 ; R 8 and R 9 are each independently H, C 1-3 alkyl, hydroxy, C 1-3 alkoxy, cyano, nitro, or C 3 -6cycloalkyl, or R 8 and R 9 , taken together with the carbon atom to which they are attached, can form a 3-6 membered ring; R 10 is C 1-6 alkyl, C 0-3 alkylenearyl, C 0-3 alkyleneheteroaryl, C 0-3 alkylene-C 3-5 cycloalkyl, C 0-3 alkylene-C 2 -7heterocycloalkyl, C 1-6 alkoxy, O—C 0-3 alkylenearyl, O—C 0-3 alkyleneheteroaryl, O—C 0-3 alkylene-C 3-5 cycloalkyl, O—C 0-3 alkylenearyl, O—C 0-3 alkylene-C 2 -7heterocycloalkyl, NH—C 1 -8-alkyl, N(C 1 -8alkyl) 2 , NH—C 0-3 alkylenearyl, NH—C 0-3 alkyleneheteroaryl, NH—C 0-3 alkylene-C 3-8 -cycloalkyl, NH—C 0-3 alkylene-C 2 -7heterocycloalkyl, halo, cyano, or C 1-6 alkyleneamine; and R 13 is C 1-4 alkyl, C 1-3 haloalkyl, C 1-3 alkyleneamine, and C 3-5 cycloalkyl, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or any of the foregoing, with the proviso that (1) when J is NR 10 , M is Nor CR 13 ; (2) when M is NR 13 , J is N or CR 10 ; (3) when J is CR 10 , M is N or NR 3 ; and (4) when M is CR 13 , J is N or NR 10 .

Description of formula (K—I) can be found in US2018/0334454A1, the entirety of which is incorporated herein by reference. Formula (K—I) is described as formula (II) in US2018/0334454A1 (see, e.g., paragraphs [0033]-[0053]), which paragraphs and description of formula (II) and methods of making compounds of formula (II) are hereby incorporated herein by reference. Moieties of formula (K—I), such as J, Q, M, E 1 , E 2 , R 2 , R 3 , and R 4 are as defined in US2018/0334454A1, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K—I-A):

Description of formula (K—I-A) can be found in WO2021/081212A1, the entirety of which is incorporated herein by reference. Formula (K—I-A) is described as formula (I) in WO2021/081212A1 (see, e.g., Embodiment 1, paragraph [0037]), which paragraphs and description of formula (I) and methods of making compounds of formula (I) are hereby incorporated herein by reference. Moieties of formula (K—I-A), such as R 1 , R 2 , R 3 , and R s are as defined in WO2021/081212A1, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, a compound of formula (K—I) or (K—I-A) is sotorasib (Compound K1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Sotorasib is chemically described as 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, having the structure below:

Description of sotorasib (Compound K1) and methods of making sotorasib can be found in US2018/0334454A1, the entirety of which is incorporated herein by reference. Description of sotorasib (Compound K1) and methods of making sotorasib can be found in, e.g., Example 41, pages 210-212 of US2018/0334454A1.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K-II):

Description of formula (K-II) can be found in WO2021/124222A1, the entirety of which is incorporated herein by reference. Formula (K-II) is described as Formula (I) in WO2021/124222A1 (see, e.g., pages 5-13 and Embodiment I pages 29-32), which paragraphs and description of Formula (I) and methods of making compounds of Formula (I) are hereby incorporated herein by reference. Moieties of formula (K-II), such as A, B, C, L, and G are as defined in WO2021/124222A1, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K-II-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A, B, and C are as defined in formula (K-II). It is understood that A, B, and C of such embodiments of compounds of Formula (K-II-A) may include A, B, and C as described for Formula (K-II). Formula (K-II-A) is described as formula (Ia) in, e.g., Embodiment 21, of WO2021/124222A1, which paragraphs and description of formula (Ia) and methods of making compounds of formula (Ia) are hereby incorporated herein by reference. Moieties of formula (K-II-A), such as A, B, and C are as defined in WO2021/124222A1, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K-II-B) or (K-II-C):

wherein,

R B2 is independently selected from hydrogen, halo, C 1 -C 4 -alkyl, cyclopropyl and NH 2 ;

R B3 is independently selected from hydrogen, halo, cyclopropyl and C 1 -C 4 -alkyl;

R B4 is independently selected from hydrogen, halo and C 1 -C 4 -alkyl, or R B3 and R B4 together with the atoms to which they are attached, form a 4-6 membered ring fused to the aromatic ring to which R B3 and R B4 are attached;

R N is hydrogen, halo, C 1-4 alkyl, or halo or fluoro-C 1-4 alkyl;

R ac is selected from the group consisting of hydrogen and C 1-4 alkyl, wherein said alkyl is optionally substituted with 1 or 2 substituents selected from cyano, hydroxyl, fluoro, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl-oxy, Het b and NR 9 R 10 ;

R 9 is selected from hydrogen and C 1-4 alkyl;

R 10 is selected from hydrogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl and di-C 1-4 alkyl-amino-C 1-4 alkyl;

wherein Het b is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO 2 , wherein said heterocyclic ring Het b is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C 1-4 alkyl, hydroxy, cyano, fluoro, hydroxy-C 1-4 alkyl, C 1-4 alkoxy and fluoro-C 1-4 -alkyl, and wherein said heterocyclic ring Het b is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Het b is optionally further substituted with C 1-4 alkyl which is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C 1-4 akloxy;

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A and C are as defined in Formula (K-II). It is understood that A and C of such embodiments of compounds of Formulae (K-II-B) and (K-II-C) may include A and C as described for Formula (K-II).

Formulae (K-II-B) and (K-II-C) are described as formula (Ib*) and (Id*), respectively in, e.g., Embodiment 39 and 41, of WO2021/124222A 1, which paragraphs and description of formula (Ib*) or (Id*) and methods of making compounds of formula (Ib*) or (Id*) are hereby incorporated herein by reference. Moieties of formula (K-II-B) or (K-II-C), such as A, C, R B2 , R B3 , R B4 , R N , and R ae are as defined in WO2021/124222A1, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, a compound of formula (K-II), (K-II-A), (K-II-B), or (K-II-C) is Compound K2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound K2 is chemically described as 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one, having the structure below:

Description of Compound K2 and methods of making Compound K2 can be found in, e.g., Method 1-Synthetic Scheme on pages 111 to 114 of WO2021/124222A1.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K—III):

wherein:

X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 8 ;

Y is a bond, O, S or NR s ;

R 1 is —C(O)C(R A ) C(R B ) p or —SO 2 C(R A ) C(R B ) p ; R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9 ;

each Z is C1-C4 alkylene;

each R 3 is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl or halogen;

L is a bond, —C(O)—, or C1-C3 alkylene;

R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or

more R 6 , R 7 or R 8 ;

each R 5 is independently hydrogen or C 1 -C 3 alkyl;

R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ;

each R 7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR 5 , —C(O)N(R 5 ) 2 , —N(R s ) 2 , wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, —OR 1 , —N(R 5 ) 2 , or heteroaryl;

each R 9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;

each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

R 11 is haloalkyl;

R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R s ) 2 , or hydroxyalkyl;

each R B is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR 5 R 11 , —C(O)N(R s ) 2 , —NHC(O)C1-C3 alkyl, —CH 2 NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 ;

or when is a double bond and p is two, one R B is hydrogen and R A and one R B and the carbon atoms to which they are attached form a 4-8 membered partially saturated cycloalkyl substituted with oxo;

m is zero or an integer between 1 and 2;

p is one or two; and wherein,

when is a triple bond then R A is absent, p equals one and R B is hydroxyalkyl,

or when is a double bond then R A is present, R B is present and p equals two, wherein when R A is hydrogen or C1-C3 alkyl, at least one R B is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR 5 R 11 , —C(O)N(R s ) 2 , —NHC(O)C1-C3 alkyl, —CH 2 NHC(O)C1-C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl; or when each R B is hydrogen, then R A is deuterium, cyano, halogen, haloalkyl, —C(O)N(R 5 ) 2 , hydroxyalkyl or heteroalkyl;

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Description of formula (K—III) can be found in US2019/0144444A1, the entirety of which is incorporated herein by reference. Formula (K—III) is described as Formula (II) in US2019/0144444A1 (see, e.g., paragraphs [0169]-[0193]), which paragraphs and description of Formula (II) and methods of making compounds of Formula (II) are hereby incorporated herein by reference. Moieties of formula (K—III), such as X, Y, L, m, R 1 , R 2 , R 3 , and R 4 are as defined in US2019/0144444A1, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K—III-A):

where the piperazinyl ring is optionally substituted with R 8 ; or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 , R 3 , R 4 , R 8 , L, and m are as defined in Formula (K—III). It is understood that R 1 , R 3 , R 4 , R 1 , L, and m of such embodiments of compounds of Formula (K—III-A) may include R 1 , R 3 , R 4 , R 8 , L, and m as described for Formula (K—III). Formula (K—III-A) is described as Formula (II-B) in, e.g., paragraphs [0231]-[0241] of US2019/0144444A1, which paragraphs and description of Formula (II-B) and methods of making compounds of Formula (II-B) are hereby incorporated herein by reference. Moieties of formula (K—III-A), such as L, m, R 1 , R 2 , R 3 , and R 4 are as defined in US2019/0144444A 1, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, a compound of formula (K—III) or (K—III-A) is adagrasib (Compound K3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Adagrasib is chemically described as 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile, having the structure below:

Description of adagrasib (Compound K3) and methods of making adagrasib can be found in, e.g., Example 478 on pages 668-669 of US2019/0144444A1.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K—IV):

wherein,

R 1 is an electrophilic moiety capable of forming a covalent bond with a cysteine residue at position 12 of a K-Ras G12C mutant protein; R 2 is selected from a group consisting of H, OH, NH 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, cyclopropyl, and —NHR, wherein R is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 hydroxyalkanoyl, C 1-6 cyanoalkyl, C 1-6 alkylamino, —(C 1-6 alkenyl)NH(CH 3 )—(C 1-6 alkylenyl)N(CH 3 ) 2 , and —(C 1-3 alkylenyl)(3-7 membered-heterocyclyl);

R 3 and R 4 are each independently selected from the group consisting of H, NH 2 , halo, C 1-6 alkyl, C 1-6 haloakyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 alkylamino, and cyclopropyl;

R 5 is selected from the group consisting of H, NH 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 alkylamino, and C 3 -7 cycloalkyl, Wherein at least one of R 2 , R 3 , R 4 , and R 5 is other than H; or

R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 , together with the atoms to which they are each bonded, form a C 3 -7 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6-14 aryl, or 5- to 10-membered heteroaryl; each of which is optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy;

X is selected from the group consisting of NH 2 , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylsulfanyl, C 1-6 alkylthio, C 3 -7 cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; each of which is optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH 2 , halo, cyano, carboxy, carbamoyl, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and 4- to 7-membered heterocyclyl; wherein two geminal substituents may be taken together to form C 3 -7 spirocycloalkyl or 4- to 7-membered spiroheterocyclyl;

Y is selected from the group consisting of -L-Y 1 or Y 1 ;

Y 1 is selected from the group consisting of H, NH 2 , halo, cyano, carbamoyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with a 4- to 10-membered heterocyclyl that is optionally substituted with 1-4 Y 1a substituents, C 1-6 alkyl substituted with a C 1-6 dialkylamino substituent, C 1-6 alkyl substituted with a C 1-6 dialkylamino cyclopropyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 2-6 alkynyl, C 1-6 alkylamino, C 6-14 aryl, C 6-14 aryl substituted with a C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, a 4- to 10-membered heterocyclyl substituted with methyl, hydroxyl, and oxo;

each Y 1a is independently selected from the group consisting of halo, CJ-6 alkyl, C 1-6 alkoxy, 3- to 7-membered heterocyclyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, oxo, hydroxyl, NH 2 , cyano, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S, and N(L a );

L a is selected from the group consisting of hydrogen and C 1-3 alkyl;

U is C(R 6a );

V is C(R 6b );

W is C(R 6c ) or N;

each of R 6a , R 6b , and R 6c are independently selected from the group consisting of H, OH, NH 2 , halo, cyano, carbamoyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with a 4- to 10-membered heterocyclyl substituent, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 1-6 alkylamino, C 6-14 aryl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 3 -7 cycloalkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1, and 2;

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Description of formula (K—IV) can be found in US2021/0230142A9, the entirety of which is incorporated herein by reference. Formula (K—IV) is described as Formula (I) in US2021/0230142A9 (see, e.g., paragraphs [0113]-[0132]), which paragraphs and description of Formula (I) and methods of making compounds of Formula (I) are hereby incorporated herein by reference. Moieties of formula (K—IV), such as U, V, W, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in US2021/0230142A9, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K—IV-A):

wherein,

R 2 is selected from the group consisting of H, OH, NH 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, cyclopropyl, and —NHR, wherein R is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 hydroxyalkanoyl, C 1-6 cyanoalkyl, C 1-6 alkylamino, —(C 1-6 alkylenyl)NH(CH 3 )—(C 1-6 alkylenyl)N(CH 3 ) 2 , and —(C 1-3 alkylenyl)(3-7 membered-heterocyclyl);

R 3 and R 4 are each independently selected from the group consisting of H, NH 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 alkylamino, and cyclopropyl;

R 5 is selected from the group consisting of H, NH 2 , halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 alkylamino, and C 3 -7 cycloalkyl, wherein at least one of R 2 , R 3 , R 4 , and R 5 is other than H; or R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 , together with the atoms to which they are each bonded, form a C 3 -7 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6-14 aryl, or 5- to 10-membered heteroaryl;

each of which is optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1 -3 alkoxy, and C 1-3 haloalkoxy;

R 7 is selected from the group consisting of H, cyano, and halo; and R 8 and R 9 are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, and halo; wherein C 1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), an alkyl or aryl sulfonate leaving group, C 1-6 alkanoylamino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 6-12 dialkylamino, and C 1-6 haloalkoxy;

or

R 7 and R 8 together form a triple bond between the carbons to which they are attached, or R 7 and R 8 together with the carbons to which they are each bonded form a C 3 -7 cycloalkenyl optionally substituted with one or two halo substituents; and R 9 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, cyano, and halo; wherein C 1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: C 1-6 alkanoylamino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 6-12 dialkylamino, and C 1-6 haloalkoxy;

X is selected from the group consisting of NH 2 , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3 -7 cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; each of which is optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH 2 , halo, cyano, carboxy, carbamoyl, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and 4- to 7-membered heterocyclyl; wherein two geminal substituents may be taken together to form C 3 -7 spirocycloalkyl or 4- to 7-membered spiroheterocyclyl;

Y is selected from the group consisting of -L-Y 1 or Y 1 ;

Y 1 is selected from the group consisting of H, NH 2 , halo, cyano, carbamoyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with a 4- to 10-membered heterocyclyl that is optionally substituted with 1-4 Y 1a substituents, C 1-6 alkyl substituted with a C 1-6 dialkylamino substituent, C 1-6 alkyl substituted with a C 1-6 dialkylamino cyclopropyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 2-6 alkynyl, C 1-6 alkylamino, C 6-14 aryl, C 6-14 aryl substituted with a C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 3 -7 cycloalkyl, C 3 -7 cycloalkyl substituted with a C 1-6 dialkylamino, C 1-6 haloalkoxy, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl substituted with methyl, hydroxy, and oxo;

each Y 1a is independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered heterocyclyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 haloalkyl, oxo, hydroxy, NH 2 , cyano, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S, and N(L a );

L a is selected from the group consisting of hydrogen and C 1-3 alkyl;

U is C(R 6a );

V is C(R 6b );

W is C(R 6c ) or N;

each of R 6a , R 6b , and R 6c are independently selected from the group consisting of H, OH, NH 2 , halo, cyano, carbamoyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with a 4- to 10-membered heterocyclyl substituent, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 1-6 alkylamino, C 6-14 aryl, C 1-6 aminoalkyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, C 1-6 cyanoalkyl, C 3 -7 cycloalkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1, and 2;

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Formula (K—IV-A) is described as Formula (II) in, e.g., paragraph [0137] of US2021/0230142A9, which paragraphs and description of Formula (II) and methods of making compounds of Formula (II) are hereby incorporated herein by reference. Moieties of formula (K—IV-A), such as U, V, W, X, Y, R 1 , R 2 , R 3 , R 4 , R s , R 7 , R 8 , and R 9 are as defined in US2021/0230142A9, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a compound of formula (K-IV-B) or (K-IV-C):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein U, V, W, Y, R 2 , R 3 , R 4 , and R 5 are as defined in Formula (K—IV). It is understood that U, V, W, Y, R 2 , R 3 , R 4 , and R 5 of such embodiments of compounds of Formulae (K-IV-B) and (K-IV-C) may include U, V, W, Y, R 2 , R 3 , R 4 , and R 5 as described for Formula (K—IV). Formulae (K-IV-B) and (K-IV-C) are described as Formulae (Ib) and (IVb), respectively, in, e.g., paragraphs [0277] and [0285] of US2021/0230142A9, which paragraphs and description of Formula (Ib) or (IVb) and methods of making compounds of Formula (Ib) or (IVb) are hereby incorporated herein by reference. Moieties of formulae (K-IV-B) and (K-IV-C), such as U, V, W, Y, R 2 , R 3 , R 4 , and R 5 are as defined in US2021/0230142A9, including any variations or embodiments thereof.

In some embodiments, in conjunction with embodiments above or below, a compound of formula (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C) is Compound K4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound K2 is chemically described as 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one, having the structure below:

Description of Compound K4 and methods of making Compound K4 can be found in, e.g., Example 17 a & 17b on pages 130 to 135 of US2021/0230142A9.

In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors comprise a G12C KRAS inhibitor (e.g., any one of Compound K1, Compound K2, Compound K3, and Compound K4). G12C KRAS inhibitors are described in, for example, Hallin et al. (Cancer Discov, 2020, 10(1): 54-71), Skoulidis et al. (N. Engl. J. Med., 2021, 384(25): 2371-2381), and Hong et al. (N. Engl. J. Med., 2020, 383(13): 1207-1217), each of which is incorporated herein by reference in its entirety and specifically with respect to G12C KRAS inhibitors described therein.

In some embodiments, in conjunction with embodiments above or below, the one or more TEAD inhibitors are selected from the group consisting of compounds T1, T2, T3, and T4 as listed in Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, in conjunction with embodiments above or below, the one or more TEAD inhibitors are selected from the group consisting of the compounds listed in Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors are selected from the group consisting of compounds K1, K2, K3, and K4 as listed in Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt ofany of the foregoing.

In some embodiments, the YAP/TAZ-TEAD inhibitors are selected from the group consisting of:

N-[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy) 05 phenyl]-2,3-dihydrobenzofuran-5-yl]methyl]prop-2-enamide; N-[[4-cyano-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide; N-((5-(1,2-dihydroxyethyl)-8-(4-(trifluoromethoxy)phenyl)quinoxalin-6-yl)methyl)acrylamide; and N-[[4-(hydroxymethyl)-3-methyl-7-[4-(trifluoromethoxy)phenyl]benzimidazol-5-yl]methyl]prop-2-enamide,

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the one or more KRAS inhibitors are selected from the group consisting of:

4-(4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one; 2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroaciyloyl)piperazin-2-yl)acetonitrile; and 1-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((I-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one,

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compositions, methods, or kits, comprise one or more TEAD inhibitors (e.g., any one of the TEAD inhibitors described herein, including but not limited to, any one of compounds of formula (II-AB′), (II-AB), (II-A), (II-A-20), (II-B), or (II-B-18), or any variations or embodiments thereof) and one or more KRAS inhibitors (e.g., any one of compounds of formula (K—I), (K—I-A), (K-II), (K-II-A), (K-II-B), (K-II-C), (K—III), (K—III-A), (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C) or any variations or embodiments thereof). TEAD inhibitors may, in some embodiments, be referred to as YAP/TAZ-TEAD inhibitors. In some embodiments, in conjunction with embodiments above or below, the one or more KRAS inhibitors may be a G12C KRAS inhibitor (e.g., Compound K1, Compound K2, Compound K3, or Compound K4). Each and every combination of TEAD inhibitor and KRAS inhibitor is intended the same as if each and every combination is specifically and individually listed. Thus, for example, it is intended that any combination of: (1) a compound of formula (II-AB′), (II-AB), (II-A), (II-A-20), (II-B), or (II-B-18), or any variation or embodiment thereof; and (2) a compound of formula (K—I), (K—I-A), (K-II), (K-II-A), (K-II-B), (K-II-C), (K—III), (K—III-A), (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C), or any variation or embodiment thereof, is provided herein.

In some embodiments, the one or more TEAD inhibitors comprise a compound of formula (II-AB′), (II-AB), (II-A), or (II-A-20) (e.g., Compound T1, Compound T2, Compound T3, or Compound T4) and the one or more KRAS inhibitors comprise a compound of formula (K—I) (e.g., Compound K1). In some embodiments, the one or more TEAD inhibitors comprise a compound of formula (II-AB′), (II-AB), (II-A), or (II-A-20) (e.g., Compound T1, Compound T2, Compound T3, or Compound T4) and the one or more KRAS inhibitors comprise a compound of formula (K-II) (e.g., Compound K2). In some embodiments, the one or more TEAD inhibitors comprise a compound of formula (II-AB′), (II-AB), (II-A), or (II-A-20) (e.g., Compound T1, Compound T2, Compound T3, or Compound T4) and the one or more KRAS inhibitors comprise a compound of formula (K—III) (e.g., Compound K3). In some embodiments, the one or more TEAD inhibitors comprise a compound of formula (II-AB′), (II-AB), (II-A), or (II-A-20) (e.g., Compound T1, Compound T2, Compound T3, or Compound T4) and the one or more KRAS inhibitors comprise a compound of formula (K—IV) (e.g., Compound K4).

In some embodiments, the one or more TEAD inhibitors are selected from compounds of formula (II-AB′), (II-AB), (II-A), (II-A-20), or (II-B), and the one or more KRAS inhibitors are selected from compounds of formula (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C). In some embodiments, in conjunction with the embodiments above or below, the one or more KRAS inhibitors comprise Compound K4. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T1. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T2. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T3. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T4.

In some embodiments, the one or more TEAD inhibitors are selected from compounds of formula (II-AB′), (II-AB), (II-A), (II-A-20), or (II-B), and the one or more KRAS inhibitors are selected from compounds of formula (K—III) or (K—III-A). In some embodiments, in conjunction with the embodiments above or below, the one or more KRAS inhibitors comprise Compound K3. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T1. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T2. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T3. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T4.

In some embodiments, the one or more TEAD inhibitors are selected from compounds of formula (II-AB′), (II-AB), (II-A), (II-A-20), or (II-B), and the one or more KRAS inhibitors are selected from compounds of formula (K-II), (K-II-A), (K-II-B), or (K-III-C). In some embodiments, in conjunction with the embodiments above or below, the one or more KRAS inhibitors comprise Compound K2. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T1. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T2. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T3. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T4.

In some embodiments, the one or more TEAD inhibitors are selected from compounds of formula (II-AB′), (II-AB), (II-A), (II-A-20), or (II-B), and the one or more KRAS inhibitors are selected from compounds of formula (K—I) or (K—I-A). In some embodiments, in conjunction with the embodiments above or below, the one or more KRAS inhibitors comprise Compound K1. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T1. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T2. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T3. In some embodiments, in conjunction with the embodiments above or below, the one or more TEAD inhibitors comprise Compound T4.

In some embodiments, the one or more TEAD inhibitors are selected from compounds of Table 1, and the one or more KRAS inhibitors are selected from compounds of formula (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C). In some embodiments, the one or more KRAS inhibitors comprise Compound K4. In some embodiments, the one or more TEAD inhibitors are selected from compounds of Table 1, and the one or more KRAS inhibitors are selected from compounds of formula (K—III) or (K—III-A). In some embodiments, the one or more KRAS inhibitors comprise Compound K3. In some embodiments, the one or more TEAD inhibitors are selected from compounds of Table 1, and the one or more KRAS inhibitors are selected from compounds of formula (K-II), (K-II-A), (K-II-B), or (K-II-C). In some embodiments, the one or more KRAS inhibitors comprise Compound K2. In some embodiments, the one or more TEAD inhibitors are selected from compounds of Table 1, and the one or more KRAS inhibitors are selected from compounds of formula (K—I) or (K—I-A). In some embodiments, the one or more KRAS inhibitors comprise Compound K1.

In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors are selected from compounds of formula (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors are selected from compounds of formula (K—III) or (K—III-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors are selected from compounds of formula (K-II), (K-II-A), (K-II-B), or (K-II-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors are selected from compounds of formula (K—I) or (K—I-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors comprise Compound K4. In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors comprise Compound K3. In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors comprise Compound K2. In some embodiments, the one or more TEAD inhibitors comprise Compound T1, and the one or more KRAS inhibitors comprise Compound K1.

In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors are selected from compounds of formula (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors are selected from compounds of formula (K—III) or (K—III-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors are selected from compounds of formula (K-II), (K-II-A), (K-II-B), or (K-II-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors are selected from compounds of formula (K—I) or (K—I-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors comprise Compound K4. In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors comprise Compound K3. In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors comprise Compound K2. In some embodiments, the one or more TEAD inhibitors comprise Compound T2, and the one or more KRAS inhibitors comprise Compound K1.

In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors are selected from compounds of formula (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors are selected from compounds of formula (K—III) or (K—III-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors are selected from compounds of formula (K-II), (K-II-A), (K-II-B), or (K-II-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors are selected from compounds of formula (K—I) or (K—I-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors comprise Compound K4. In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors comprise Compound K3. In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors comprise Compound K2. In some embodiments, the one or more TEAD inhibitors comprise Compound T3, and the one or more KRAS inhibitors comprise Compound K1.

In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors are selected from compounds of formula (K—IV), (K—IV-A), (K-IV-B), or (K-IV-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors are selected from compounds of formula (K—III) or (K—III-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors are selected from compounds of formula (K-II), (K-II-A), (K-II-B), or (K-II-C). In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors are selected from compounds of formula (K—I) or (K—I-A). In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors comprise Compound K4. In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors comprise Compound K3. In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors comprise Compound K2. In some embodiments, the one or more TEAD inhibitors comprise Compound T4, and the one or more KRAS inhibitors comprise Compound K1.

In some embodiments, the one or more TEAD inhibitors are selected from the group consisting of:

stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and the one or more KRAS inhibitors are selected from the group consisting of:

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a combination, comprising one or more TEAD inhibitors (e.g., any one of the TEAD inhibitors described herein, including but not limited to, any one of compounds of formula (II-AB′), (II-AB), (II-A), or (II-B), or any variations or embodiments thereof) and one or more KRAS inhibitors (e.g., any one of compounds of formula (K—I), (K-II), (K—III), or (K—IV) or any variations or embodiments thereof). In some embodiments, the KRAS inhibitor is a G12C KRAS inhibitor.

In some aspects, provided herein is a method of treating a disease or condition mediated by KRAS activity in a subject in need thereof, comprising administering to the subject an effective amount of a combination, comprising: i) one or more TEAD inhibitors; and (ii) one or more KRAS inhibitors. In some embodiments, the disease or condition mediated by KRAS activity is cancer.

In some aspects, provided herein is a method of treating a disease or condition mediated by TEAD activity in a subject in need thereof, comprising administering to the subject an effective amount of a combination, comprising: i) one or more TEAD inhibitors; and (ii) one or more KRAS inhibitors. In some embodiments, the disease or condition mediated by TEAD activity is cancer.

In another aspect, provided herein is a method of reducing resistance of a subject to treatment comprising one or more KRAS inhibitors (e.g., any one of compounds of formula (K—I), (K-IL), (K—III), or (K—IV), or any variations or embodiments thereof), wherein the method comprises administering to the subject a therapeutically effective amount of one or more TEAD inhibitors (e.g., any one of the TEAD inhibitors described herein, including but not limited to, any one of compounds of formula (II-AB′), (II-AB), (II-A), or (II-B), or any variations or embodiments thereof).

In some embodiments, provided herein are kits, comprising (i) one or more TEAD inhibitors (e.g., any one of the TEAD inhibitors described herein, including but not limited to, any one of compounds of formula (II-AB′), (II-AB), (II-A), or (II-B), or any variations or embodiments thereof); (ii) one or more KRAS inhibitors (e.g., any one of compounds of formula (K—I), (K-II), (K—III), or (K—IV), or any variations or embodiments thereof); and (iii) instructions for administering the combination to treat cancer in a subject in need thereof. In some embodiments, the KRAS inhibitor is a G12C KRAS inhibitor.

In one aspect provided herein is a list of embodiments as enumerated below: Embodiment 1. A compound of formula (II-A) or (II-B):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R t is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R c is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t , wherein R t is independently at each occurrence halo, oxo, —OH, —CN, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl; and

wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t , wherein R t is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein

R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R b ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and m are each independently 1 or 2.

Embodiment 2. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a or —S(O) 2 R b , R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo.

Embodiment 3. The compound of embodiment 1 or 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a and R a is C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, halo and haloC 1-6 alkyl.

Embodiment 4. The compound of embodiment 1 or 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a and R a is C 1-6 alkyl, optionally substituted with one or more halo.

Embodiment 5. The compound of any one of embodiments 1 to 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein B is phenyl substituted with one or more R 2 , R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment 6. The compound of any one of embodiments 1 to 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein B is 5 to 6 membered heteroaryl substituted with one or more R 2 , R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment 7. The compound of embodiment 5 or 6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is halomethoxy.

X 1 is C or N; X 2 is CR s , wherein R s is selected from the group consisting of H, halo, C 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and X 3 is N or CH.

Embodiment 9. The compound of embodiment 8, wherein one of X 1 and X 3 is N.

Embodiment 10. The compound of embodiment 8, wherein X 1 is C and X 3 is CH.

Embodiment 11. The compound of any one of embodiments 8 to 10, wherein X 2 is CR s , wherein R s is C 1-15 alkyl, 5 to 15 membered heteroaryl, —CN, or C 1-15 alkoxy.

Embodiment 12. The compound of any one of embodiments 1 to 5, wherein X, is C; X 2 is N; and X 3 is N or CH.

Embodiment 13. The compound of any one of embodiments 1 to 12, wherein X, is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl fused to ring A.

Embodiment 14. The compound of embodiment 13, wherein the 5 to 6 membered heteroaryl fused to ring A is selected from the group consisting of:

Embodiment 15. The compound of embodiment 13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. The compound of any one of embodiments 1 to 12, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl fused to ring A.

Embodiment 17. The compound of embodiment 16, wherein the 5 to 6 membered heterocyclyl fused to ring A is

Embodiment 18. The compound of embodiment 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment 19. The compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 20. The compound of any one of embodiments 1 to 12, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl fused to ring A,

Embodiment 21. The compound of embodiment 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment 22. The compound of any one of embodiments 1 to 12, wherein X, is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl fused to ring A,

Embodiment 23. The compound of embodiment 22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment 24. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

Z is —C(O)R a and R a is C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, halo and haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment 25. The compound of embodiment 24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment 26. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

Z is —C(O)R a and R a is C 1-6 alkyl, optionally substituted with one or more halo, B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment 27. The compound of embodiment 26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment 28. The compound of any one of embodiments 1 to 27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

Embodiment 29. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment 30. A pharmaceutical composition, comprising (i) a compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

Embodiment 31. A compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in medical therapy.

Embodiment 32. A compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

Embodiment 33. A method for treating cancer in a mammal, comprising administering a compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

Embodiment 34. A compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in modulating TEAD activity.

Embodiment 35. A compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of a disease or condition mediated by TEAD activity.

Embodiment 36. The compound for the use of embodiment 35, wherein the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

Embodiment 37. The use of a compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of prophylaxis of a disease or condition that is mediated by TEAD activity.

Embodiment 38. The use of embodiment 33, wherein the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

Embodiment 39. A method for modulating TEAD activity, comprising contacting TEAD with a compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Embodiment 40. A method for treating a disease or condition mediated by TEAD activity in a mammal, comprising administering a compound as described in any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, to the mammal.

Embodiment 41. The method of embodiment 40, wherein the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

Embodiment 42. The use of a compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for modulating TEAD activity.

Embodiment 43. The use of a compound as described in any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis of a disease or condition mediated by TEAD activity.

Embodiment 44. The use of embodiment 43, wherein the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

L′ is selected from the group consisting of *—N(R 3 )-L-** and

wherein * denotes the point of attachment to Z, and ** denotes the point of attachment to

X 1 is C or N, and X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, or C 5-6 cycloalkyl fused to ring A;

wherein the 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, phenyl, and C 5-6 cycloalkyl formed by X 1 and R 1 are each independently optionally substituted with one or more R t , wherein R 1 is independently, at each occurrence, selected from the group consisting of halo, C 1-15 alkyl, haloC 1-15 alkyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; X 2 is N or CR s , wherein R s is selected from H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ;

wherein the C 1-15 alkyl and C 1-15 alkoxy of R s are each independently optionally substituted with one or more R t1 , wherein R t1 is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NR d R e , wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; and

wherein the C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, and 3 to 15 membered heterocyclyl of R s are each independently optionally substituted with one or more R t2 , wherein R t2 is independently at each occurrence selected from halo, oxo, —OH, —CN and C 1-6 alkyl; and wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN;

X 3 is N or CH;

B is phenyl or 5 to 6 membered heteroaryl; wherein the phenyl and 5 to 6 membered heteroaryl of B are each independently substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo;

R 3 is H or C 1-6 alkyl;

Z is —OH, —NR d R e , C 1-6 alkoxy, —C(O)R a , —S(O) 2 R b ,

wherein R d and R e are each independently H or C 1-6 alkyl, and wherein the C 1-6 alkyl of R d or R e is optionally substituted with one or more substituents selected from halo, oxo, —OH and —CN; R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; or

ii) C 1-6 alkyl, optionally substituted with one or more halo;

L is methylene, optionally substituted with one or more C 1-6 alkyl; and

n and mare 1; or n and mare 2;

provided that when 1) X 1 is taken together with R 1 and the atoms to which they are attached to form a phenyl, and 2) X 2 or X 3 is N,

B of formula (II-B) is phenyl and R 2 is haloC 1-6 alkoxyl.

Embodiment A2. A compound of embodiment A1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment A3. A compound of embodiment A1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment A4. The compound of any one of embodiments A1-A3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a or —S(O) 2 R b , R a and R b are each independently i) C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl; or ii) C 1-6 alkyl, optionally substituted with one or more halo.

Embodiment A5. The compound of embodiment A4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a and R a is C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, hydroxyl C 1-6 alkyl, halo and haloC 1-6 alkyl.

Embodiment A6. The compound of embodiment A5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a and R a is ethenyl optionally substituted with one or more substituents selected from deuterium and halo. Embodiment A7. The compound of embodiment A6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a and R a is C 1-6 alkyl, optionally substituted with one or more halo.

or a pharmaceutically acceptable salt thereof, wherein Z is.

Embodiment A9. The compound of any one of embodiments A1 to A8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein B is phenyl substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment A10. The compound of any one of embodiments A1 to A9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein B is phenyl substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, halomethoxy.

Embodiment 11. The compound of any one of embodiments A1 to A10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein B is

Embodiment A12. The compound of any one of embodiments A1 to A8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein B is 5 to 6 membered heteroaryl substituted with one or more R 2 , wherein R 2 is independently, at each occurrence, halo; S(R y ) 5 , wherein each R y is halo; or C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment A13. The compound of embodiment A1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is —C(O)R a and R a is C 2-6 alkenyl optionally substituted with one or more substituents selected from deuterium, C 1-6 alkyl, halo and haloC 1-6 alkyl; and B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment A14. The compound of embodiment A1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

Z is —C(O)R a and R a is C 1-6 alkyl, optionally substituted with one or more halo, B is phenyl substituted with one or more R 2 , wherein R 2 is C 1-6 alkoxy optionally substituted with one or more halo.

Embodiment A15. The compound of embodiment A2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A-20)

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment A16. The compound of embodiment A3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B-18)

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Embodiment A17. The compound of any one of embodiments A1 to A15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

Embodiment A18. The compound of any one of embodiments A1 to A17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

X 1 is C or N; X 2 is CR s , wherein R s is selected from the group consisting of H, halo, C 1-15 alkyl, hydroxylC 1-6 alkynyl, C 6-20 aryl, 5 to 15 membered heteroaryl, C 3-20 cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C 1-15 alkoxy, —NR d COR e , —CONR d R e , —SO 2 R d , —S(O)NHR d , —SO 2 NR d R e , —NR d SO 2 R e , and —NR d R e ; and X 3 is N or CH.

Embodiment A19. The compound of any one of embodiments A1-A18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein one of X 1 and X 3 is N.

Embodiment A20. The compound of any one of embodiments A1-A18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is C and X 3 is CH.

Embodiment A21. The compound of any one of embodiments A1-A20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 2 is CR s , wherein R s is C 1-15 alkyl, 5 to 15 membered heteroaryl, —CN, or C 1-15 alkoxy.

Embodiment A22. The compound of any one of embodiments A1-A18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is C; X 2 is N; and X 3 is N or CH.

Embodiment A23. The compound of any one of embodiments A1 to A22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heteroaryl fused to ring A.

Embodiment A24. The compound of embodiment A23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 5 to 6 membered heteroaryl fused to ring A is selected from the group consisting of:

Embodiment A25. The compound of any one of embodiments A1 to A22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a 5 to 6 membered heterocyclyl fused to ring A.

Embodiment A26. The compound of embodiment A25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 5 to 6 membered heterocyclyl fused to ring A is

Embodiment A27. The compound of any one of embodiments A1 to A1-A18 and A20-A22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a phenyl fused to ring A,

Embodiment A28. The compound of any one of embodiments A1 to A1-A18 and A20-A22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is taken together with R 1 and the atoms to which they are attached, to form a C 5-6 cycloalkyl fused to ring A,

Embodiment A29. The compound of any one of embodiments A1 to A15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

Embodiment A30. A pharmaceutical composition, comprising (i) a compound as described in any one of embodiments A1-A29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

Embodiment A31. A compound as described in any one of embodiments A1-A29, or a stereoisomer, tautomer, or