Substituted 1,2,4-triazoles as intermediates in the synthesis of TYK2 inhibitors

This patent application is a continuation of U.S. patent application Ser. No. 17/713,646, filed Apr. 5, 2022; which is a continuation of U.S. patent application Ser. No. 17/243,508, filed Apr. 28, 2021; which is a continuation of U.S. patent application Ser. No. 16/938,183, filed Jul. 24, 2020; which is a continuation of International Patent Application No. PCT/US2019/057485, filed Oct. 22, 2019; which claims the benefit of, and priority to, U.S. Provisional Application No. 62/749,003, filed Oct. 22, 2018; U.S. Provisional Application No. 62/756,942, filed Nov. 7, 2018; U.S. Provisional Application No. 62/839,459, filed Apr. 26, 2019; U.S. Provisional Application No. 62/875,449, filed Jul. 17, 2019; U.S. Provisional Application No. 62/893,721, filed Aug. 29, 2019; and U.S. Provisional Application No. 62/907,354, filed Sep. 27, 2019 each of which is incorporated herein by reference in their entirety.

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for inhibiting nonreceptor tyrosine-protein kinase 2 (“TYK2”), also known as Tyrosine kinase 2.

TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

TYK2 activation by IL-23, has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 individuals with psoriasis identified associations between disease susceptibility and TYK2. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis.

TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6. Decreased TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, decreased Tyk2 activity reduced the production of Th1/Th17-related cytokines and matrix metalloproteases, and other key markers of inflammation.

TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no infiltration of CD4 T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS. This corroborates earlier studies linking increased TYK2 expression with MS susceptibility. Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

TYK2 is the sole signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.

Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder), showed a strong, and significant correlation between loss of function mutations to TYK2 and decreased prevalence of SLE in families with affected members. Genome-wide association studies of individuals with SLE versus an unaffected cohort showed highly significant correlation between the TYK2 locus and SLE.

TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects.

Studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 via STAT1-mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V7311), and the kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) resulted in failure to transform.

Thus, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and/or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases. TYK2 mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Aβ administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients.

Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata.

Accordingly, compounds that inhibit the activity of TYK2 are beneficial, especially those with selectivity over JAK2. Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side-effects associated with the inhibition of JAK2.

Accordingly there is a need to provide novel inhibitors having more effective or advantageous pharmaceutically relevant properties, like selectivity over other JAK kinases (especially JAK2).

Disclosed herein is a compound of Formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl; R 16 is —C(═O)NR 1 R 2 , —C(═N—CN)NR 1 R 2 , —P(═O)R 1 R 2 , or —C(═O)R 11 ; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; or -L-Ring A is absent; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; or -L-Ring A is absent; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein is a method of inhibiting a TYK2 enzyme in a patient or biological sample comprising contacting said patient or biological sample with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

Also disclosed herein is a method of treating a TYK2-mediated disorder comprising administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

“Aliphatic chain” refers to a linear chemical moiety that is composed of only carbons and hydrogens. In some embodiments, the aliphatic chain is saturated. In some embodiments, the aliphatic chain is unsaturated. In some embodiments, the unsaturated aliphatic chain contains one unsaturation. In some embodiments, the unsaturated aliphatic chain contains more than one unsaturation. In some embodiments, the unsaturated aliphatic chain contains two unsaturations. In some embodiments, the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds.

“Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C 1 -C 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 8 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

“Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (—CH═CH 2 ), 1-propenyl (—CH 2 CH═CH 2 ), isopropenyl [—C(CH 3 )═CH 2 ], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

“Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C 2 -C 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula —OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

“Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 5 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

“Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 .

“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogen halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 OCH 2 CH 2 OCH 3 , or —CH(CH 3 )OCH 3 . Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 15 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C 1 -C 6 heteroalkyl. Unless stated otherwise specifically in the specification, a Heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.

The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.

As used herein, the term “TYK2-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Accordingly, another embodiment relates to treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role. Such TYK2-mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.

Compounds

Described herein are compounds that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Z is a bond, —CR Z 2 —, or —(CR Z 2 —. each R Z is independently hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), L is a bond. In some embodiments of a compound of Formula (I), L is —C(═O)—.

In some embodiments of a compound of Formula (I), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (I), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (I), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (I), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (I), R 4 is —OR b . In some embodiments of a compound of Formula (I), R 4 is hydrogen.

In some embodiments of a compound of Formula (I), the compound is of Formula (Ia):

In some embodiments of a compound of Formula (I), the compound is of Formula (Ib):

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 3 is hydrogen.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), Z is a bond or —CH 2 —. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Z is —CH 2 —. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Z is a bond.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 8 is hydrogen. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 2 is C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 5 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (II) or (II′), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

R 11 is deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; X is —CR x — or —N—; R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II) or (II′), L is a bond. In some embodiments of a compound of Formula (II) or (II′), L is —C(═O)—.

In some embodiments of a compound of Formula (II) or (II′), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (II) or (II′), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (II) or (II′), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (II) or (II′), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II) or (II′), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II) or (II′), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (II′), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II) or (II′), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II) or (II′), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (II) or (II′), R 4 is —OR b . In some embodiments of a compound of Formula (II) or (II′), R 4 is hydrogen.

In some embodiments of a compound of Formula (II) or (II′), X is —CH—. In some embodiments of a compound of Formula (II) or (II′), X is —N—.

In some embodiments of a compound of Formula (II) or (II′), the compound is of Formula (IIa) or (II′a):

In some embodiments of a compound of Formula (II) or (II′), the compound is of Formula (IIb) or (II′b):

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 3 is hydrogen.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 1 is hydrogen. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 2 is C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 5 is—OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 5 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH,—OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 11 is deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 11 is deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 1 is halogen. In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R 11 is hydrogen.

Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; provided that

is not

each R B is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

or two R B on the same carbon are taken together to form an oxo;

or two R B on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more deuterium, oxo, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl;

n is 0-4;

each Y is independently C or N;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

or R 3 and R 4 are taken together to form an optionally substituted ring;

L is a bond or —C(═O)—;

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;

each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or two R A on the same carbon are taken together to form an oxo;

X is —CR x — or —N—;

R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;

Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or two R D on the same carbon are taken together to form an oxo;

R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), L is a bond. In some embodiments of a compound of Formula (III), L is —C(═O)—.

In some embodiments of a compound of Formula (III), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (III), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (III), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (III), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (III), R 4 is —OR b . In some embodiments of a compound of Formula (III), R 4 is hydrogen.

In some embodiments of a compound of Formula (III), X is —CH—. In some embodiments of a compound of Formula (III), X is —N—.

In some embodiments of a compound of Formula (III), the compound is of Formula (IIIa):

In some embodiments of a compound of Formula (III), the compound is of Formula (IIIb):

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 3 is hydrogen.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 5 is halogen, —CN,—OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 8 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 8 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 8 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), Ring B is a heterocycloalkyl or heteroaryl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),

is

and n′ is 0-3.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), each R B is independently hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R B on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), each R B is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; two R B on the same carbon are taken together to form an oxo.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), two R B on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more deuterium, oxo, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), two R B on adjacent atoms are taken together to form a heterocycloalkyl or heteroaryl; each optionally substituted with one or more deuterium, oxo, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0-2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0 or 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1 or 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1-3.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n′ is 0. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n′ is 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n′ is 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n′ is 0-2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n′ is 0 or 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n′ is 1 or 2.

Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

Ring C is a bicyclic ring system; each R C is independently hydrogen, oxo, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; m is 0-4; R 12 is —C(═O)NR 1 R 2 or -L 1 -R 13 R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; L 1 is —O—, —NH—, or —N(CH 3 )—; R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; X is —CR x — or —N—; R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IV), L is a bond. In some embodiments of a compound of Formula (IV), L is —C(═O)—.

In some embodiments of a compound of Formula (IV), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (IV), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (IV), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (IV), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (IV), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (IV), R 4 is —OR b . In some embodiments of a compound of Formula (IV), R 4 is hydrogen.

In some embodiments of a compound of Formula (IV), X is —CH—. In some embodiments of a compound of Formula (IV), X is —N—.

In some embodiments of a compound of Formula (IV), the compound is of Formula (IVa):

In some embodiments of a compound of Formula (IV), the compound is of Formula (IVb):

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 12 is —C(═O)NR 1 R 2 .

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 1 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 2 is C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 12 is -L 1 -R 13 .

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), L 1 is —NH—. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), L 1 is —O— or —NH—.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is halogen, —CN,—OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), Ring C is indole or benzimidazole.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R C is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R C is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R C is independently halogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 0. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 0 or 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 0-2. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 1 or 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 1-3.

Also disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; or two R D on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more deuterium, oxo, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl; r is 0-4; each Y is independently C or N; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (V), L is a bond. In some embodiments of a compound of Formula (V), L is —C(═O)—.

In some embodiments of a compound of Formula (V), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (V), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (V), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (V), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (V), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (V), R 4 is —OR b . In some embodiments of a compound of Formula (V), R 4 is hydrogen.

In some embodiments of a compound of Formula (V), each X is —N—. In some embodiments of a compound of Formula (V), each X is —CH—. In some embodiments of a compound of Formula (V), one X is —N— and the other is —CH—.

In some embodiments of a compound of Formula (V), the compound is of Formula (Va):

In some embodiments of a compound of Formula (V), the compound is of Formula (Vb):

In some embodiments of a compound of Formula (V), (Va), or (Vb), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 3 is hydrogen.

In some embodiments of a compound of Formula (V), (Va), or (Vb), R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 8 is hydrogen. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 2 is C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (V), (Va), or (Vb), Ring D is a heterocycloalkyl or heteroaryl.

In some embodiments of a compound of Formula (V), (Va), or (Vb)

is

and r′ is 0-3.

In some embodiments of a compound of Formula (V), (Va), or (Vb), each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), each R D is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), each R D is independently hydrogen or cycloalkyl.

In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 0. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 0-2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 0 or 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 1 or 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 1-3.

In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is 0. In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is 0-2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is 0 or 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is 1 or 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is 1-3.

Also disclosed herein is a compound of Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R E ; each R E is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R E on the same carbon are taken together to form an oxo; L 2 is a bond, —O—, or

R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

or R 3 and R 4 are taken together to form an optionally substituted ring;

L is a bond or —C(═O)—;

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;

each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or two R A on the same carbon are taken together to form an oxo;

X is —CR x — or —N—;

R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VI), L is a bond. In some embodiments of a compound of Formula (VI), L is —C(═O)—.

In some embodiments of a compound of Formula (VI), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (VI), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (VI), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (VI), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (VI), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (VI), R 4 is —OR b . In some embodiments of a compound of Formula (VI), R 4 is hydrogen.

In some embodiments of a compound of Formula (VI), X is —CH—. In some embodiments of a compound of Formula (VI), X is —N—.

In some embodiments of a compound of Formula (VI), the compound is of Formula (VIa):

In some embodiments of a compound of Formula (VI), the compound is of Formula (VIb):

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 3 is hydrogen.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 8 is hydrogen. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 2 is C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), L 2 is a bond.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), Ring E is cycloalkyl, heterocycloalkyl, or aryl; each optionally substituted with one or more R E .

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), Ring E is aryl optionally substituted with one or more R E .

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), each R E is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), each R E is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), each R E is independently halogen.

Also disclosed herein is a compound of Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

R 14 is hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), cycloalkyl, or heterocycloalkyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; X is —CR x — or —N—; R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VII), L is a bond. In some embodiments of a compound of Formula (VII), L is —C(═O)—.

In some embodiments of a compound of Formula (VII), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (VII), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (VII), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (VII), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VII), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VII), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VII), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (VII), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VII), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (VII), R 4 is —OR b . In some embodiments of a compound of Formula (VII), R 4 is hydrogen.

In some embodiments of a compound of Formula (VII), X is —CH—. In some embodiments of a compound of Formula (VII), X is —N—.

In some embodiments of a compound of Formula (VII), the compound is of Formula (VIIa):

In some embodiments of a compound of Formula (VII), the compound is of Formula (VIIb):

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 3 is hydrogen.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 5 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 14 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 alkyl(cycloalkyl). In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 14 is C 1 -C 6 alkyl or C 1 -C 6 alkyl(cycloalkyl).

Also disclosed herein is a compound of Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

R 15 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; L 3 is —O—, —NH—, or —N(CH 3 )—; L 4 is —NR 3 — or —C(═O)—; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; X is —CR x — or —N—; R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VIII), L is a bond. In some embodiments of a compound of Formula (VIII), L is —C(═O)—.

In some embodiments of a compound of Formula (VIII), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (VIII), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (VIII), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (VIII), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VIII), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VIII), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VIII), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (VIII), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VIII), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (VIII), R 4 is —OR b . In some embodiments of a compound of Formula (VIII), R 4 is hydrogen.

In some embodiments of a compound of Formula (VIII), X is —CH—. In some embodiments of a compound of Formula (VIII), X is —N—.

In some embodiments of a compound of Formula (VIII), the compound is of Formula (VIIIa):

In some embodiments of a compound of Formula (VIII), the compound is of Formula (VIIIb):

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 5 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), L 3 is —O—. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), L 3 is —NH—.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 15 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), L 4 is —NR 3 —.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 3 is hydrogen.

In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), L 4 is —C(═O)—.

A compound of Formula (IX), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

Ring F is a heterocycloalkyl or heteroaryl; each R F is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or two R F on the same carbon are taken together to form an oxo; or two R F on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more deuterium, oxo, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl; p is 0-4; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; X is —CR x — or —N—; R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IX), L is a bond. In some embodiments of a compound of Formula (IX), L is —C(═O)—.

In some embodiments of a compound of Formula (IX), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (IX), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (IX), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (IX), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IX), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IX), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IX), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (IX), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IX), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (IX), R 4 is —OR b . In some embodiments of a compound of Formula (IX), R 4 is hydrogen.

In some embodiments of a compound of Formula (IX), X is —CH—. In some embodiments of a compound of Formula (IX), X is —N—.

In some embodiments of a compound of Formula (IX), the compound is of Formula (IXa):

In some embodiments of a compound of Formula (IX), the compound is of Formula (IXb):

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 3 is hydrogen.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 8 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 8 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 8 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring F is a heterocycloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb),

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each RF is independently hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R F is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 0. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 1. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 0-2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 0 or 1. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 1 or 2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 1-3.

Also disclosed herein is a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

L 5 is a saturated or unsaturated linear aliphatic chain having 1-10 carbon atoms optionally substituted with one or more R L5 , wherein 1-5 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —P(═O)—; each R 15 is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or two R 15 on the same carbon atom are taken together to form an oxo; R 12 is —C(═O)NR 1 R 2 or -L 1 -R 13 ; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; L 1 is —O—, —NH—, or —N(CH 3 )—; R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; X is —CR x — or —N—; R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (X), L is a bond. In some embodiments of a compound of Formula (X), L is —C(═O)—.

In some embodiments of a compound of Formula (X), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (X), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (X), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (X), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (X), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (X), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (X), R 4 is —OR b . In some embodiments of a compound of Formula (X), R 4 is hydrogen.

In some embodiments of a compound of Formula (X), X is —CH—. In some embodiments of a compound of Formula (X), X is —N—.

In some embodiments of a compound of Formula (X), the compound is of Formula

In some embodiments of a compound of Formula (X), the compound is of Formula

In some embodiments of a compound of Formula (X), the compound is of Formula (Xa):

In some embodiments of a compound of Formula (X), the compound is of Formula (Xb):

In some embodiments of a compound of Formula (X), the compound is of Formula (Xa-1):

In some embodiments of a compound of Formula (X), the compound is of Formula (Xb-1):

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 3 is hydrogen.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 12 is —C(═O)NR 1 R 2 .

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 8 is hydrogen. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 2 is C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 12 is -L 1 -R 13 .

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 1 is —NH—. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 1 is —O— or —NH—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —P(═O)—. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L5 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, or —S(═O) 2 —. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, or —S(═O) 2 —. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L5 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —P(═O)—. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), each R L5 is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), each R 15 is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), each R 15 is independently deuterium or halogen.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), two R 15 on the same carbon atom are taken together to form an oxo.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is

Also disclosed herein is a compound of Formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

L 6 is a saturated or unsaturated linear aliphatic chain having 1-10 carbon atoms optionally substituted with one or more R L6 , wherein 1-5 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —P(═O)—; each R L6 is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or two R L6 on the same carbon atom are taken together to form an oxo; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; X is —CR x — or —N—; R x is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is hydrogen, halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═O)R 7 , —OC(═O)R 7 , —C(═O)OR 8 , —OC(═O)OR 8 , —C(═O)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XI), L is a bond. In some embodiments of a compound of Formula (XI), L is —C(═O)—.

In some embodiments of a compound of Formula (XI), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (XI), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (XI), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (XI), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XI), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XI), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XI), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (XI), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XI), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (XI), R 4 is —OR b . In some embodiments of a compound of Formula (XI), R 4 is hydrogen.

In some embodiments of a compound of Formula (XI), X is —CH—. In some embodiments of a compound of Formula (XI), X is —N—.

In some embodiments of a compound of Formula (XI), the compound is of Formula (XIa):

In some embodiments of a compound of Formula (XI), the compound is of Formula (XIb):

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 3 is hydrogen.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , or aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 8 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 8 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 7 is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, or —S(═O) 2 —. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with—NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, or —S(═O) 2 —. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —P(═O)—. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, —O—, —S—, —S(═O)—, —S(═O) 2 —, or —P(═O)—. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH 3 )—, or —O—. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), each R L6 is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), each R L6 is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), each R L6 is independently deuterium or halogen.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), two R L6 on the same carbon atom are taken together to form an oxo.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is

Also disclosed herein is a compound of Formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl; R 16 is —C(═O)NR 1 R 2 , —C(═N—CN)NR 1 R 2 , —P(═O)R 1 R 2 , or —C(═O)R 11 ; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; or -L-Ring A is absent; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl; R 16 is —C(═O)NR 1 R 2 , —C(═N—CN)NR 1 R 2 , —P(═O)R 1 R 2 , or —C(═O)R 11 ; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; or -L-Ring A is absent; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl; R 16 is —C(═O)NR 1 R 2 , —C(═N—CN)NR 1 R 2 , —P(═O)R 1 R 2 , or —C(═O)R 11 ; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl; R 16 is —C(═O)NR 1 R 2 , —C(═N—CN)NR 1 R 2 , —P(═O)R 1 R 2 , or —C(═O)R 11 ; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is aryl. In some embodiments of a compound of Formula (XII), Ring B is phenyl. In some embodiments of a compound of Formula (XII), Ring B is heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is 6-membered heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is pyridyl.

Also disclosed herein is a compound of Formula (XII′), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

R 16 is —C(═O)NR 1 R 2 , —C(═N—CN)NR 1 R 2 , —P(═O)R 1 R 2 , or —C(═O)R 11 ; R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII) or (XII′), L is a bond. In some embodiments of a compound of Formula (XII) or (XII′), L is —C(═O)—.

In some embodiments of a compound of Formula (XII) or (XII′), -L-Ring A is absent.

In some embodiments of a compound of Formula (XII) or (XII′), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (XII) or (XII′), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (XII) or (XII′), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (XII) or (XII′), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII) or (XII′), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII) or (XII′), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XII) or (XII′), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (XII), the compound is of Formula (XIIa):

In some embodiments of a compound of Formula (XII), the compound is of Formula (XIIb):

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 4 is —OR b . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 4 is hydrogen. In some embodiments of a compound of Formula (XII), R 4 is —P(═O)R b R b . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 4 is —S(═O) 2 R a .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each X is —N—. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc) each X is —CR X —. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), two X are —N— and the other is —CR X —. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), one X is —N— and the others are —CR X —. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each X is —CH—. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), two X are —N— and the other is —CH—. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), one X is —N— and the others are —CH—. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc),

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc),

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R X is independently hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each RX is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each RX is independently hydrogen, deuterium, or halogen.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 3 is hydrogen.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 16 is —C(═O)NR 1 R 2 or —C(═O)R 11 . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 16 is —C(═O)NR 1 R 2 . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 16 is —C(═N—CN)NR 1 R 2 . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 16 is —P(═O)R 1 R 2 . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 16 is —C(═O)R 11 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 1 and R 2 are independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 1 is hydrogen. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 2 is C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is cycloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R 11 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R 11a is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R 11a is independently deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R 11a is independently deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R 11a is independently deuterium, halogen, —CN, —OR b , —NR c R d , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R 11a is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R 11a is independently deuterium, halogen, or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NHS(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)R 7 , —NR'S(═O)(═NR 8 )R 7 , or aryl optionally substituted with one or more deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 S(═O)(═NR 8 )R 7 , or aryl optionally substituted with one or more deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , or —NR 8 C(═N—CN)R 7 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 9 R 10 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 9 R 10 or —NR 8 C(═O)NR 9 R 10 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 8 C(═N—CN)R 7 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 8 S(═O)(═NR 8 )R 7 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 8 C(═O)NR 9 R 10 or —NR 8 C(═O)R 7 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 8 C(═O)NR 9 R 10 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 8 C(═O)R 7 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is not—NR 8 C(═O)R 7 .

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is —NR 8 C(═O)NR 9 R 10 or heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 5 is heterocycloalkyl optionally substituted with one or more oxo, halogen, —OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, and aryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), the heterocycloalkyl of R 5 is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), the heterocycloalkyl of R 5 is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is unsubstituted cycloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 7 is unsubstituted heterocycloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 8 is hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 8 is hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a C 2 -C 8 heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a bicyclic heterocycloalkyl or a spiro heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azabicyclo[1.1.1]pentanyl, or 2-azaspiro[3.3]heptanyl, each optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XII), the compound is of Formula (XIIc):

wherein R 5a is deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIIc); R 5a is deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIIc); R 5a is halogen, —OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and aryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; or -L-Ring A is absent; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; L is a bond or —C(═O)—; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ; each R A is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R A on the same carbon are taken together to form an oxo; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —P(═O)R b R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or R 3 and R 4 are taken together to form an optionally substituted ring; each X is independently —CR x — or —N—; each R x is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 5 is halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 7 , —S(═O) 2 R 7 , —NO 2 , —NR 9 R 10 , —NR 8 S(═O)R 7 , —NR 8 S(═O) 2 R 7 , —S(═O) 2 NR 9 R 10 , —C(═N—CN)R 7 , —C(═O)R 7 , —OC(═N—CN)R 7 , —OC(═O)R 7 , —C(═N—CN)OR 8 , —C(═O)OR 8 , —OC(═N—CN)OR 8 , —OC(═O)OR 8 , —C(═N—CN)NR 9 R 10 , —C(═O)NR 9 R 10 , —OC(═N—CN)NR 9 R 10 , —OC(═O)NR 9 R 10 , —NR 8 C(═N—CN)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═N—OH)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)OR 8 , —NR 8 C(═O)OR 8 , —NR 8 S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R x and R 5 are taken together to form ring D optionally substituted with one or more R D ; Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R D is independently hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R D on the same carbon are taken together to form an oxo; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, cycloalkyl, or heterocycloalkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R 8 and R 9 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ; each R 11a is independently deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (XIII), Ring B is aryl. In some embodiments of a compound of Formula (XIII), Ring B is phenyl. In some embodiments of a compound of Formula (XIII), Ring B is heteroaryl. In some embodiments of a compound of Formula (XIII), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (XIII), Ring B is 6-membered heteroaryl. In some embodiments of a compound of Formula (XIII), Ring B is 6-membered pyridyl.

In some embodiments of a compound of Formula (XIII), L is a bond. In some embodiments of a compound of Formula (XIII), L is —C(═O)—.

In some embodiments of a compound of Formula (XIII), L-Ring A is absent.

In some embodiments of a compound of Formula (XIII), Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (XIII), Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A . In some embodiments of a compound of Formula (XIII), Ring A is heteroaryl optionally substituted with one or more R A .

In some embodiments of a compound of Formula (XIII), each R A is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII), each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XIII), each R A is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (XIII), the compound is of Formula (XIIIa):

In some embodiments of a compound of Formula (XIII), the compound is of Formula (XIIIb):

In some embodiments of a compound of Formula (XIII), the compound is of Formula (XIIIc):

In some embodiments of a compound of Formula (XIII), the compound is of Formula (XIIId):

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —S(═O) 2 R a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 4 is hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 4 is hydrogen or —OR b . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 4 is —OR b . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 4 is hydrogen. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 4 is —P(═O)R b R b . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 4 is —S(═O) 2 R a .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each X is —N—. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId) each X is —CR X —. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), two X are —N— and the other is —CR x —. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), one X is —N— and the others are —CR X —. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each X is —CH—. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), two X are —N— and the other is —CH—. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), one X is —N— and the others are —CH—. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R X is independently hydrogen, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R x is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R x is independently hydrogen, deuterium, or halogen.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 3 is hydrogen.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl, C 1 -C 8 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl, C 1 -C 8 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more R 11a . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 11 is cycloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R 1a is independently deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R 11a is independently deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R 11a is independently deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R 11a is independently deuterium, halogen, —CN, —OR b , —NR c R d , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R 11a is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each R 11a is independently deuterium, halogen, or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is halogen, —CN, —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —OR 8 , —NR 9 R 10 , —C(═O)R 7 , —C(═O)OR 8 , —C(═O)NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR 8 C(═O)OR 8 , —NR'S(═O)(═NR 8 )R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , —NR 8 C(═N—CN)R 7 , —NR'S(═O)(═NR 8 )R 7 , or aryl optionally substituted with one or more deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═N—CN)R 7 , —NR'S(═O)(═NR 8 )R 7 , or aryl optionally substituted with one or more deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —OR 8 , —NR 9 R 10 , —NR 8 C(═O)R 7 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR 8 C(═O)R 7 . In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is aryl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR 9 R 10 , —NR 8 C(═O)NR 9 R 10 , or —NR 8 C(═N—CN)R 7 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR 9 R 10 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR 9 R 10 or —NR 8 C(═O)NR 9 R 10 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 8 is —NR 8 C(═N—CN)R 7 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR'S(═O)(═NR 8 )R 7 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR 8 C(═O)NR 9 R 10 or —NR 8 C(═O)R 7 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR 8 C(═O)NR 9 R 10 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 8 is —NR 8 C(═O)R 7 .

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is —NR 8 C(═O)NR 9 R 10 or heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 5 is heterocycloalkyl optionally substituted with one or more oxo, halogen, —OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 8 alkynyl, cycloalkyl, heterocycloalkyl, aryl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, and aryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), the heterocycloalkyl of R 5 is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), the heterocycloalkyl of R 5 is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is unsubstituted cycloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 7 is unsubstituted heterocycloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 8 is hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 8 is hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a C 2 -C 8 heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH,—OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a bicyclic heterocycloalkyl or a spiro heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azabicyclo[1.1.1]pentanyl, or 2-azaspiro[3.3]heptanyl, each optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound described above, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound described above, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound described above, each R a is independently C 1 -C 6 alkyl.

In some embodiments of a compound described above, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound described above, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound described above, each R b is independently C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound described above, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound described above, each R b is hydrogen. In some embodiments of a compound described above, each R b is independently C 1 -C 6 alkyl.

In some embodiments of a compound described above, each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH,—OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound described above, each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound described above, each R c and R d is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound described above, each R c and R d is hydrogen. In some embodiments of a compound described above, each R c and R d is independently C 1 -C 6 alkyl.

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

wherein:

R 1 ═-Et, —CH 2 —CD 3 , or cyclopropyl; R 2 =Me, CD 3 , or Et R 3 =Isopropyl, cyclobutyl, cyclopropyl, or t-butyl.

Further Forms of Compounds Disclosed Herein

Isomers/Stereoisomers

In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.

Labeled Compounds

In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.

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

Solvates

In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Tautomers

In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Preparation of the Compounds

The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).

Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involve the administration of about 0.1 μg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 μg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject's physiological response.

By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

Methods of Treatment

The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase inhibited by the compounds and methods is TYK2.

Provided herein are compounds that are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with activity of TYK2 or mutants thereof.

Provided herein are methods for treating a disease or disorder, wherein the disease or disorder is an autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or disorders associated with transplantation, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In some embodiments, the disease or disorder is an autoimmune disorder. In some embodiments the disease or disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

In some embodiments, the disease or disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

In some embodiments the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V7311, E957D, and R1027H.

In some embodiments, the disease or disorder is associated with transplantation. In some embodiments the disease or disorder associated with transplantation is transplant rejection, or graft versus host disease.

In some embodiments the disease or disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments the disease or disorder is associated with type I interferon signaling. In some embodiments the disease or disorder is associated with IL-10 signaling. In some embodiments the disorder is associated with IL-12 signaling. In some embodiments the disease or disorder is associated with IL-23 signaling.

Provided herein are methods for treating an inflammatory or allergic condition of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

Provided herein are methods for treating other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), or osteoarthritis.

In some embodiments the inflammatory disease is a Th1 or Th17 mediated disease. In some embodiments the Th17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease is Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or diseases affecting the nose such as allergic rhinitis.

Combination Therapy

In certain instances, the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.

In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.

In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially.

In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

The compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as well as combination therapies, are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

In some embodiments, the compound of described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

Intermediate A:

To a solution of methyl 2-hydroxy-3-nitrobenzoate (10 g, 50.7 mmol) in DMF (100 mL) at room temperature was added potassium carbonate (14.02 g, 101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) and the resulting orange mixture was heated to 60° C. for 1 h. The reaction was cooled to room temperature and then crushed ice (˜100 mL) was added, followed by water to a total volume of ˜400 mL 10 causing a yellow solid to crystallize from solution. The slurry was stirred for a few minutes and then collected by vacuum filtration and the resulting initially yellow solid was rinsed with additional water (˜100 mL) until all of the yellow color was rinsed into the filtrate giving a near white solid in the funnel. Partially air-dried solid in funnel then transferred to a flask and further dried under vacuum over night to afford Ab (10.5 g, 98%) of a yellow solid as the desired product. LCMS [M+1] + =197.1.

Methyl 2-methoxy-3-nitrobenzoate (11 g, 52.1 mmol) was dissolved in a cold solution of ammonia in methanol (7 N, 250 mL) and cone. aqueous ammonium hydroxide (100 mL) was added. The flask was sealed and the resulting solution was allowed to gently stir at room temperature overnight (˜17 h). The reaction mixture was concentrated to afford Ac (1.67 g, 86%) as a yellow solid. LCMS [M+1]+=196.1.

2-methoxy-3-nitrobenzamide (6.5 g, 33.1 mmol) was slurried in dimethyl formamide dimethyl acetal (39.5 g, 331 mmol) and the mixture was heated to 95° C. giving a clear, pale yellow solution. After heating for ˜30 min at 95° C., the reaction was cooled and was concentrated on the rotovap and the resulting yellow oil was azeotroped twice with 1,2-dichloroethane (40 mL portions) to ensure complete removal of any residual dimethyl formamide dimethyl acetal. The crude oil thus obtained was immediately dissolved in 35 mL of ethanol and was immediately used in the following step.

In a separate flask was prepared a mixture of ethanol (150 mL) and acetic acid (AcOH, 35 mL) and the resulting solution was cooled in an ice bath. Once cooled, hydrazine hydrate (16.1 mL, 331 mmol) was added dropwise. At this time, the solution containing the crude dimethyl formamide dimethyl acetal adduct as prepared above was transferred dropwise over ˜15 min by cannula into the previously prepared well-stirred ice-cold mixture containing the hydrazine. During the addition, a pale yellow solid formed in the solution. After the addition was complete, the resulting cloudy yellow mixture was allowed to warm to room temperature and stir for ˜4 h. The reaction mixture at this time was concentrated on the rotovap to remove some of the ethanol, diluted with additional water and filtered to collect the solid. The solid was washed with additional portions of water, air dried in the funnel then under vacuum to afford Ad (4.0 g, 54.8%) of a pale yellow solid as the desired product. LCMS [M+1] + =221.1.

A solution of 3-(2-methoxy-3-nitrophenyl)-4H-1,2,4-triazole (5.00 g, 22.71 mmol) in DMF (20 mL) was treated with potassium carbonate (4.20 g, 30.4 mmol). After cooling the resulting mixture in an ice bath, a solution of iodomethane (4.20 g, 29.59 mmol) in DMF (5 mL) was slowly added dropwise by syringe over 2 min. After the addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to rt. After stirring at room temperature for ˜4 h, LCMS analysis indicated complete and clean conversion to the region-isomeric mixture of products in ˜2:1 ratio, respectively. The reaction was cooled in an ice bath and was diluted with water (˜50 mL) and the solution was extracted with EtOAc (3×40 mL) and the combined extracts were washed with 10% aq. LiCl (2×20 mL), water (20 mL) then brine (20 mL), concentrated and purified by CC to afford Ae (2.0 g, 38%) of the major isomer as a pale yellow solid. LCMS [M+1] + =235.1. 1 H NMR (400 MHz, methanol-d 6 ) δ 8.50 (s, 1H), 8.11 (dd, J=7.9, 1.8 Hz, 1H), 7.85 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.83 (s, 3H).

A solution of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (2.20 g, 10.77 mmol) in EtOH (50 mL) was sparged with nitrogen for a few minutes before adding 10% Pd-C (0.90 g, 0.43 mmol) followed by sparging with hydrogen from a balloon for a few minutes then allowing the mixture to stir under a balloon of hydrogen for 1.5 h at rt. The mixture was then sparged with nitrogen to deactivate the catalyst and the mixture was filtered through a pad of celite washing with additional amounts of EtOH and the resulting clear, colorless filtrate containing the product was concentrated and purified by CC to afford an off-white solid Intermediate A (1.5 g, 68%). LCMS [M+1] + =205.2. 1 H NMR (400 MHz, chloroform-d) δ 8.09 (s, 1H), 7.35 (dd, J=7.8, 1.7 Hz, 1H), 7.00 (t, J=7.8 Hz, 1H), 6.82 (dd, J=7.8, 1.7 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 2H), 3.78 (s, 3H).

Intermediate 1:

Xa (10 g, 64.1 mmol) was placed in a 1 L flask and triethylamine (8.9 mL, 64.1 mmol) was added, followed by phosphorus oxychloride (50 mL, 546 mmol). the mixture was heated to 110° C. and stirred for 120 minutes, then concentrated under reduced pressure. 200 mL of anhydrous 1,2-dichloroethane was added to the residue and the mixture sonicated and then concentrated. the residue was dissolved in THF (200 mL), deuteromethylamine (HCl salt, 2.26 g, 32 mmol) was then added, followed by N, N-diisopropylethylamine (18 mL, 103 mmol). After 1 hour the reaction was concentrated and the residue adsorbed onto celite using dichloromethane, The filtrate was re-concentrated and purified by CC to afford a yellow solid Xb (5.1 g, 37%).

To a solution of Xb (5.00 g, 23.92 mmol) and intermediate A (4.88 g, 23.92 mmol) in THF (50 mL) under N 2 was added LiHMDS (1 M, 71.80 mL, 71.80 mmol) at 0° C. resulting a mild exotherm. The reaction was stirred at r.t. for 3h. The reaction mixture was cooled to 0° C., quenched by adding satd. NH 4 Cl (aq.), diluted with water (100 mL) and extracted by EtOAc (50 mL×3). The combined organic layers were washed by brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (DCM/EtOAc=3/1) to give the desired product Intermediate 1 (6.5 g, yield: 72.2%) as a yellow solid. LCMS [M+1] + =377.1.

Intermediate 2:

A solution of 3-(2-methoxy-3-nitrophenyl)-4H-1,2,4-triazole (Ad) (5.00 g, 22.71 mmol) in DMF (20 mL) was treated with potassium carbonate (4.20 g, 30.4 mmol). After cooling the resulting mixture in an ice bath, a solution of iodomethane-d 3 (4.20 g, 29.59 mmol) in DMF (5 mL) was slowly added dropwise by syringe over 2 min. After the addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to rt. After stirring at room temperature for ˜4 h, LCMS analysis indicated complete and clean conversion to the regioisomeric mixture of products in ˜2:1 ratio, respectively. The reaction was cooled in an ice bath and was diluted with water (˜50 mL) and the solution was extracted with EtOAc (3×40 mL) and the combined extracts were washed with 10% aq. LiCl (2×20 mL), water (20 mL) then brine (20 mL), concentrated and purified by CC to afford 2Ae (2.0 g, 38%) of the major isomer as a pale yellow solid. LCMS [M+1] + =238.1.

A solution of 3-(2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole (2.20 g, 10.77 mmol) in EtOH (50 mL) was sparged with nitrogen for a few minutes before adding 10% Pd-C (0.90 g, 0.43 mmol) followed by sparging with hydrogen from a balloon for a few minutes then allowing the mixture to stir under a balloon of hydrogen for 1.5 h at rt. The mixture was then sparged with nitrogen to deactivate the catalyst and the mixture was filtered through a pad of CELITE® washing with additional amounts of EtOH and the resulting clear, colorless filtrate containing the product was concentrated and purified by CC to afford an off-white solid 2A (1.5 g, 68%). LCMS [M+1] + =208.2.

To a solution of Xb (5.00 g, 23.92 mmol) and Example 2A (4.88 g, 23.92 mmol) in THF (50 mL) under N 2 was added LiHMDS (1 M, 71.80 mL, 71.80 mmol) at 0° C. resulting a mild exotherm. The reaction was stirred at r.t. When completed, The reaction mixture was cooled to 0° C., quenched by adding satd. NH 4 Cl (aq.), diluted with water (100 mL) and extracted by EtOAc (50 mL*3). The combined organic layers were washed by brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (DCM/EtOAc=3/1) to give the desired product intermediate 2 (6.5 g, yield: 72.2%) as a yellow solid. LCMS [M+1] + =380.1.

Intermediate 3A:

To a solution of methyl 2-hydroxy-3-nitrobenzoate (7 g, 35.5 mmol) in DMF (70 mL) at room temperature was added potassium carbonate (9.8 g, 71.0 mmol) followed by addition of iodomethane-d 3 (4.42 mL, 71.0 mmol) and the resulting orange mixture was heated to 60° C. for 1 h. The reaction was cooled to room temperature and then crushed ice (˜100 mL) was added, followed by water to a total volume of ˜400 mL causing a yellow solid to crystallize from solution. The slurry was stirred for a few minutes and then collected by vacuum filtration and the resulting initially yellow solid was rinsed with additional water (˜100 mL) until all of the yellow color was rinsed into the filtrate giving a near white solid in the funnel. Partially air-dried solid in funnel then transferred to a flask and further dried under vacuum overnight to afford 3Ab (6.5 g, 86%) of a yellow solid as the desired product. LCMS [M+1] + =215.1.

methyl 2-(methoxy-d3)-3-nitrobenzoate 3Ab (6.5 g, 30.3 mmol) was dissolved in a cold solution of ammonia in methanol (7N, 140 mL) and cone. aqueous ammonium hydroxide (60 mL) was added. The flask was sealed and the resulting solution was allowed to gently stir at room temperature overnight (˜17 h). The reaction mixture was concentrated to afford 3Ac (5.8 g, 96%) as a yellow solid. LCMS [M+1] + =200.1

2-(methoxy-d3)-3-nitrobenzamide 3Ac (5.8 g, 29.1 mmol) was slurried in dimethyl formamide dimethyl acetal (38.6 mL, 291 mmol) and the mixture was heated to 95° C. giving a clear, pale yellow solution. After heating for ˜30 min at this temp the reaction was cooled and was concentrated on the rotovap and the resulting yellow oil was azeotroped twice with 1,2-dichloroethane (40 mL portions) to ensure complete removal of any residual dimethyl formamide dimethyl acetal. The crude oil thus obtained was immediately dissolved in 35 mL of ethanol and was immediately used in the following step.

In a separate flask was prepared a mixture of ethanol (150 mL) and acetic acid (AcOH, 35 mL) and the resulting solution was cooled in an ice bath. Once cooled, hydrazine hydrate (14.1 mL, 291 mmol) was added dropwise. At this time, the solution containing the crude dimethyl formamide dimethyl acetal adduct as prepared above was transferred dropwise over ˜15 min by cannula into the previously prepared well-stirred ice-cold mixture containing the hydrazine. During the addition, a pale yellow solid formed in the solution. After the addition was complete, the resulting cloudy yellow mixture was allowed to warm to room temperature and stir for ˜4 h. The reaction mixture at this time was concentrated on the rotovap to remove some of the ethanol, diluted with additional water and filtered to collect the solid. The solid was washed with additional portions of water, air dried in the funnel then under vacuum to afford 3Ad (5.0 g, 77.0%) of a pale yellow solid as the desired product. LCMS [M+1] + =224.1

A solution of 3-(2-(methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole 3Ad (5.00 g, 22.4 mmol) in DMF (20 mL) was treated with potassium carbonate (9.28 g, 67.2 mmol). After cooling the resulting mixture in an ice bath, a solution of iodomethane (1.9 mL, 30.2 mmol) in DMF (5 mL) was slowly added dropwise by syringe over 2 min. After the addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to rt. After stirring at room temperature for ˜4 h, LCMS analysis indicated complete and clean conversion to the regioisomeric mixture of products in ˜2:1 ratio, respectively. The reaction was cooled in an ice bath and was diluted with water (˜50 mL) and the solution was extracted with EtOAc (3×40 mL) and the combined extracts were washed with 10% aq. LiCI (2×20 mL), water (20 mL) then brine (20 mL), concentrated and purified by CC to afford 3Ae (2.1 g, 39.54%) of the major isomer as a pale yellow solid. LCMS [M+1] + =238.2.

A solution of 3-(2-(methoxy-d3)-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole 3Ae (1.6 g, 6.75 mmol) in EtOH (50 mL) was sparged with nitrogen for a few minutes before adding 10% Pd-C (0.8 g) followed by sparging with hydrogen from a balloon for a few minutes then allowing the mixture to stir under a balloon of hydrogen for 1.5h at rt. The mixture was then sparged with nitrogen to deactivate the catalyst and the mixture was filtered through a pad of CELITE® washing with additional amounts of EtOH and the resulting clear, colorless filtrate containing the product was concentrated and purified by CC to afford an off-white solid 3A (1.1 g, 68%).

LCMS [M+1] + =208.2. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.35 (dd, 1H), 6.99 (t, 1H), 6.83 (dd, 1H), 3.99 (s, 3H), 3.80-3.45 (m, 2H).

Intermediate 3:

To a solution of Xb (0.9 g, 4.32 mmol) and 3A (0.9 g, 4.32 mmol) in THF (15 mL) under N 2 was added LiHMDS (1 M, 13 mL, 13 mmol) at 0° C. resulting a mild exotherm. The reaction was stirred at r.t. When completed, The reaction mixture was cooled to 0° C., quenched by adding satd. NH 4 Cl (aq.), diluted with water (100 mL) and extracted by EtOAc (50 mL×3). The combined organic layers were washed by brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (DCM/EtOAc=3/1) to give the desired product intermediate 3 (1.3 g, yield: 79.26%) as a yellow solid. LCMS [M+1] + =380.2.

Example 1: 4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-(2-oxoimidazolidin-1-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 6-(3-acetyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60m g, 0.16 mmol) and 1A (41 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 1 (6 mg, yield: 8%) as a yellow solid. LM-MS: m/z=469.2[M+H] +

Step 2: 4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-(2-oxoimidazolidin-1-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of 1B (6 mg, 0.013 mmol) in methanol (3 mL) was added NaOH (1.04 mg, 0.026 mmol) The mixture was heated to 40° C. for 2 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 1 (3 mg, yield: 50%) as a yellow solid. LM-MS: m/z=428.2[M+H] + . 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.14 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.63 (dd, 1H), 7.53 (dd, 1H), 7.43 (s, 1H), 7.25 (t, 1H), 4.17-4.12 (m, 2H), 3.95 (s, 3H), 3.74 (s, 3H), 3.49-3.37 (m, 2H).

Example 2: 4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-(3-methyl-2-oxo-imidazolidin-1-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 2A (32 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product 2. (6 mg, yield: 9%) as a yellow solid. LM-MS: m/z=441.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 11.60 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 8.06-7.88 (m, 2H), 7.50 (d, 1H), 7.32 (t, 1H), 4.62-4.49 (m, 2H), 4.03 (s, 3H), 3.81 (s, 3H), 3.65-3.54 (m, 2H), 2.91 (s, 3H).

Example 3: 4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-methyl-6-(2-oxoazetidin-1-yl) pyridazine-3-carboxamide

Intermediate 1 (0.05 g, 0.133 mmol), azetidin-2-one (0.02 g, 0.282 mmol), cesium carbonate (0.086 g, 0.264 mmol), tris(dibenzylideneacetone)dipalladium (0.012 g, 0.013 mmoL) and xantphos (0.012 g, 0.021 mmol) were added to 45 mL sealed tube. 10 mL 1,4-dioxane was added to the mixture. The resulting solution was stirred at 130° C. for 1 h under N 2 atmosphere. The mixture solution was evaporated to dryness, residues was purified by flash chromatography to afford 3 (0.0121 g, 20%) as a light yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.70 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.64-7.55 (m, 2H), 7.34 (t, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.92 (t, J=4.9 Hz, 2H), 3.75 (s, 3H), 3.25 (t, J=4.8 Hz, 2H). LC-MS (ESI): m/z=412.2 [M+H] + .

Example 4: 4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-(4-oxo-5-azaspiro[2.4]heptan-5-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 4A (35 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 110° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, The residue was purified by flash Chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to afford the title compound Example 4 (24 mg, 33.33%) as a white solid. LM-MS: m/z=452.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 11.22 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 7.78 (d, 1H), 7.55 (d, 1H), 7.31 (t, 1H), 4.34 (t, 2H), 4.05 (s, 3H), 3.78 (s, 3H), 2.26 (t, 2H), 1.28-1.24 (m, 2H), 0.98-0.93 (m, 2H).

Example 5: 6-(3-cyclopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of cyclopropanamine (2.0 g, 35.03 mmol) in Acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (3.70 g, 35.03 mmol), then it was stirred at room temperature for 2 h. solid precipitation, filtered, give the desired product 5B (4.05 g, 71.1%) as a white solid, it was used in the next step without further purification. LM-MS: m/z=163.2 [M+H] +

To a solution of 5B (0.5 g, 3.07 mmol) in THF (30 ml) was added sodium hydride (0.15 g, 6.0 mmol), then it was stirred at room temperature for 2h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product 5C (0.17 g, yield: 38.67%) as a white solid. LM-MS: m/z=127.2 [M+H] +

Step 3: 6-(3-cyclopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (70 mg, 0.18 mmol) and 5C (35 mg, 0.28 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46m g, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 5 (10 mg, yield: 10%) as a yellow solid. LM-MS: m/z=467.2[M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 8.39 (s, 1H), 7.66-7.62 (m, 2H), 7.24 (t, 1H), 4.11 (t, 2H), 4.02 (s, 3H), 3.74 (s, 3H), 3.53 (t, 2H), 2.56-2.52 (m, 1H), 0.77-0.72 (m, 4H).

Example 6: 6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of propan-2-amine (2.0 g, 33.8 mmol) in Acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (3.57 g, 33.8 mmol), then it was stirred at room temperature for 2h. solid precipitation, filtered, give the desired product Example 6B (4.2 g, 75.4%) as a white solid, it was used in the next step without further purification. LM-MS: m/z=165.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 5.39-4.32 (m, 2H), 3.85 (dt, 1H), 3.65-3.58 (m, 2H), 3.58-3.49 (m, 2H), 1.15 (d, 6H).

To a solution of 6B (0.5 g, 3.0 mmol) in THF (30 ml) was added sodium hydride (0.15 g, 6.0 mmol), then it was stirred at room temperature for 2h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product Example 6C (0.17 g, yield: 44%) as a white solid. LM-MS: m/z=129.2 [M+H] + . 1H NMR (400 MHz, CDCl 3 ) δ 4.36 (s, 1H), 4.14 (dt, 1H), 3.42-3.33 (m, 4H), 1.14 (d, 3H), 1.12 (s, 3H).

Step 3: 6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide; 2,2,2-trifluoroacetic acid

To a solution of Intermediate 1 (60m g, 0.16 mmol) and 6C (41 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46m g, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 6 (5 mg, yield: 5%) as a yellow solid. LM-MS: m/z=469.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 11.47 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.54 (d, 1H), 7.34 (t, 1H), 4.21 (dd, 3H), 4.06 (s, 3H), 3.76 (s, 3H), 3.64-3.49 (m, 2H), 1.19 (d, 6H).

Example 7: 6-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 7A (36 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 7 (24 mg, yield: 30%) as a yellow solid. LM-MS: m/z=455.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 11.08 (s, 1H), 8.42 (d, 2H), 8.17 (s, 1H), 7.77 (d, 1H), 7.58 (d, 1H), 7.31 (t, 1H), 4.17 (t, 2H), 4.04 (s, 3H), 3.80 (s, 3H), 2.02 (t, 2H), 1.25 (s, 6H).

Example 8: 6-[3-(2,2-difluoroethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide; 2,2,2-trifluoroacetic acid

To a solution of 2,2-difluoroethanamine (2.0 g, 24.67 mmol) in Acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (2.60 g, 24.67 mmol), then it was stirred at room temperature for 2 h. solid precipitation, filtered, give the desired product 8B (2.80 g, 60.83%) as a white solid, it was used in the next step without further purification. LM-MS: m/z=187.2 [M+H] +

To a solution of 8B (0.5 g, 2.68 mmol) in THF (30 ml) was added sodium hydride (0.15 g, 6.0 mmol), then it was stirred at room temperature for 2h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product 8C (0.15 g, yield: 37.29%) as a white solid. LM-MS: m/z=151.2 [M+H] +

Step 3: 6-[3-(2,2-difluoroethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide; 2,2,2-trifluoroacetic acid

To a solution of intermediate 1 (80 mg, 0.21 mmol) and 8C (47 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 8. (4 mg, yield: 4%) as a yellow solid. LM-MS: m/z=491.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD): δ 7.77-7.71 (m, 2H), 7.64 (d, 1H), 7.33 (t, 1H), 6.18-5.91 (m, 1H), 4.09 (t, 1H), 4.04 (s, 3H), 3.72-3.72 (m, 4H), 3.70-3.65 (m, 2H).

Example 9: 6-[3-(2-methoxyethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of 2-methoxyethanamine (0.38 g, 5 mmol) in THF (10 mL) was added 1-chloro-2-isocyanato-ethane (0.53 g, 5 mmol), then it was stirred at room temperature for 2 h give the desired product 9B (0.81 g, 90%) as a colorless oil, it was used in the next step without further purification. LC-MS: m/z=180.6 [M+H] +

To a solution of 9 B (0.81 g, 4.5 mmol) in THF (20 ml) was added sodium hydride (0.13 g, 5.4 mmol), then it was stirred at room temperature for 4h. Quenched with water (20 mL) and extracted by EtOAc (40 mL×2). The combined organic layers were washed by brine (60 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product 9C (0.25 g, yield: 40%) as a colorless oil. LC-MS: m/z=144.2 [M+H] +

Step 3: 6-[3-(2-methoxyethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 9C (30 mg, 0.2 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (160 mg, 0.5 mmol), Pd 2 (dba) 3 (20 mg, 0.02 mmol), and xantphos (24 mg, 0.04 mmol). The mixture degassed by N 2 for 3 times and heated to 130° C. for 2 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=95/5) to give the desired product Example 9 (8.4 mg, yield: 11%) as a white solid. LM-MS: m/z=484.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.03 (s, 1H), 8.36 (s, 1H), 8.13-8.11 (m, 2H), 7.80-7.79 (d, 1H), 7.55-7.53 (d, 1H), 7.25-7.29 (m, 1H), 4.30-4.26 (q, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 3.68-3.64 (q, 2H), 3.56-3.53 (q, 2H), 3.49-3.46 (q, 2H), 3.35 (s, 3H).

Example 10: 6-[3-(3,3-difluorocyclobutyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of 3,3-difluorocyclobutanamine hydrochloride (10A) (1.0 g, 6.96 mmol) and TEA (1.94 mL, 13.93 mmol) in THF (15 mL) was added 1-chloro-2-isocyanato-ethane (0.6 mL, 6.96 mmol) via a syringe, then it was stirred at room temperature for 2 h. The mixture solution was evaporated to dryness, redissolved in EtOAc (80 mL). The organic layer was then washed with NaHCO 3 and brine, dried over Na 2 SO 4 , filtered and concentrated, then the title compound 10B (550 mg, 37.4%)was obtained as white solid, which was used in the next step without further purification. LM-MS: m/z=213.1 [M+H] +

To a solution of 10B (0.5 g, 2.35 mmol) in THF (30 mL) was added sodium hydride (0.19 g, 4.7 mmol), then it was stirred at room temperature for 2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product 10C (0.23 g, yield: 55.4%) as a white solid.

Step 3: 6-[3-(3,3-difluorocyclobutyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 10C (56 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 110° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, The residue was purified by flash Chromatography

(PE/EtOAc=50/50 then DCM/MeOH=97/3) to afford the title compound Example 10 (12 mg, yield: 13.95%) as a white solid. LM-MS: m/z=517.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.98 (s, 1H), 8.32 (s, 1H), 8.18-8.07 (m, 2H), 7.77 (d, 1H), 7.55-7.49 (d, 1H), 7.30 (d, 1H), 4.51-4.41 (m, 1H), 4.26 (t, 2H), 4.03 (s, 3H), 3.78 (s, 3H), 3.60 (t, 2H), 2.95-2.71 (m, 4H).

Example 11:6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of cyclobutanamine (1.0 g, 14.1 mmol) in acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (1.48 g, 14.1 mmol), then it was stirred at room temperature for 2h. solid precipitation, filtered, give the desired product Example 11B (1.5 g, 60.4%) as a white solid, it was used in the next step without further purification. LM-MS: m/z=177.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 4.57 (s, 2H), 4.16-4.06 (m, 1H), 3.68-3.59 (m, 2H), 3.59-3.51 (m, 2H), 2.40-2.30 (m, 2H), 1.91-1.79 (m, 2H), 1.79-1.60 (m, 2H).

To a solution of 1-(2-chloroethyl)-3-cyclobutyl-urea (1.0 g, 5.7 mmol) in THF (30 ml) was added sodium hydride (0.27 g, 11 mmol), then it was stirred at room temperature for 2h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product Example 11C (0.70 g, yield: 88%) as a white solid. LM-MS: m/z=141.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 4.43 (t, 1H), 3.50 (dd, 2H), 3.40 (dd, 2H), 2.14-2.05 (m, 4H), 1.68-1.61 (m, 2H).

Step 3: 6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of Intermediate 1 (60 mg, 0.16 mmol) and 11C (45 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product 11 (5 mg, yield: 7%) as a yellow solid. LM-MS: m/z=481.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.46 (s, 1H), 8.37 (s, 1H), 7.63 (td, 2H), 7.29 (t, 1H), 4.43 (t, 1H), 4.19-4.09 (m, 2H), 4.01 (s, 3H), 3.74 (s, 3H), 3.70-3.61 (m, 2H), 2.38-2.23 (m, 2H), 2.13 (dd, 2H), 1.77-1.68 (m, 2H).

Example 12: 6-(3-ethyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of ethylamine hydrochloride (1.0 g, 12.3 mmol) in Acetonitrile (20 mL) was added Triethylamine (2.48 g, 24.6 mmol) and 1-chloro-2-isocyanato-ethane (1.24 g, 12.3 mmol), then it was stirred at room temperature for 2 h. solid precipitation, filtered, give the desired product Example 12B (1.5 g, 81%) as a white solid, it was used in the next step without further purification.

To a solution of 12B (1.0 g, 6.6 mmol) in THF (30 ml) was added sodium hydride (0.32 g, 13 mmol), then it was stirred at room temperature for 2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product Example 12C (0.70 g, yield: 92%) as a white solid.

Step 3: 6-(3-ethyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of Intermediate 1 (60 mg, 0.16 mmol) and 12C (36 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 12 (5 mg, yield: 6%) as a yellow solid. LM-MS: m/z=455.3 [M+H] + . 1 H NMR (400 MHz, MeOD): δ 8.53 (s, 1H), 7.76 (dd, 1H), 7.63 (dd, 1H), 7.58 (s, 1H), 7.35 (d, 1H), 4.13-3.94 (m, 5H), 3.74 (s, 3H), 3.69-3.58 (m, 2H), 3.37 (d, 2H), 1.19 (t, 3H).

Example 13: 6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of 1,1,1,3,3,3-hexadeuteriopropan-2-amine (0.20 g, 3.1 mmol) in acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (0.32 g, 3.1 mmol), then it was stirred at room temperature for 2 h. solid precipitation, filtered, give the desired product 13B (0.4 g, 76%) as a white solid, it was used in the next step without further purification. LM-MS: m/z=171.2 [M+H] +

To a solution of 13B (0.2 g, 1.2 mmol) in THF (10 ml) was added sodium hydride (0.056 g, 2.4 mmol), then it was stirred at room temperature for 2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product Example 13C (0.070 g, yield: 40%) as a white solid.

Step 3: 6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (80 mg, 0.21 mmol) and 13C (57 mg, 0.42 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (140 mg, 0.42 mmol), Pd 2 (dba) 3 (57 mg, 0.063 mmol), and xantphos (72 mg, 0.126 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. f or 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 13 (7 mg, yield: 7%) as a yellow solid. LM-MS: m/z=475.3 [M+H] + . 1 H NMR (400 MHz, MeOD): δ 8.46 (s, 1H), 8.40 (d, 1H), 7.66-7.61 (m, 2H), 7.29 (t, 1H), 4.14 (dd, 3H), 4.01 (s, 3H), 3.74 (s, 3H), 3.58-3.52 (m, 2H).

Example 14: 6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[3-(1-methyl-1,2,4-triazol-3-yl)-2-(trideuteriomethoxy)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 3 (160 mg, 0.42 mmol) and 1-isopropylimidazolidin-2-one (110 mg, 0.84 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (270 mg, 0.84 mmol), Pd 2 (dba) 3 (115.3 mg, 0.126 mmol), and xantphos (145.6 mg, 0.252 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 14 (60 mg, yield: 24%) as a yellow solid. LM-MS: m/z=472.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 11.10 (s, 1H), 8.38 (s, 1H), 8.10 (d, 2H), 7.81 (d, 1H), 7.55 (d, 1H), 7.29 (d, 1H), 4.31 (s, 2H), 4.27-4.21 (m, 1H), 4.00 (s, 3H), 3.53-3.46 (m, 2H), 1.18 (d, 6H).

Example 15: 6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of Intermediate 2 (60 mg, 0.16 mmol) and 1-isopropylimidazolidin-2-one (41 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 15. (6 mg, yield: 8%) as a yellow solid. LM-MS: m/z=472.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 10.92 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.77 (dd, 1H), 7.55 (dd, 1H), 7.28 (d, 1H), 4.25 (ddd, 3H), 3.81 (s, 3H), 3.51-3.44 (m, 2H), 1.18 (d, 6H).

Example 16.4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-[3-(3-methyloxetan-3-yl)-2-oxo-imidazolidin-1-yl]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of 3-methyloxetan-3-amine (0.87 g, 10 mmol) in THF (20 mL) was added 1-chloro-2-isocyanato-ethane (1.06 g, 10 mmol), then it was stirred at room temperature for 2 h give the desired product 16B (1.82 g, 94%) as a colorless oil, it was used in the next step without further purification. LC-MS: m/z=192.6 [M+H] +

To a solution of 16B (1.82 g, 9.2 mmol) in THF (30 ml) was added sodium hydride (0.29 g, 12 mmol), then it was stirred at room temperature for 4 h. Quenched with water (20 mL) and extracted by EtOAc (40 mL×2). The combined organic layers were washed by brine (60 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product 16C (1.0 g, yield: 69%) as a white solid. LC-MS: m/z=156.2 [M+H] +

Step 3: 4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-[3-(3-methyloxetan-3-yl)-2-oxo-imidazolidin-1-yl]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (110 mg, 0.3 mmol) and 16C (63 mg, 0.4 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (300 mg, 0.9 mmol), Pd 2 (dba) 3 (30 mg, 0.03 mmol), and xantphos (35m g, 0.06 mmol). The mixture degassed by N 2 for 3 times and heated to 130° C. for 2 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=95/5) to give the desired product Example 16. (40 mg, yield: 30%) as a white solid. LM-MS: m/z=496.6 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.09 (s, 1H), 8.13-8.06 (m, 3H), 7.76 (s, 1H), 7.45 (s, 1H), 7.19 (m, 1H), 4.83-4.81 (d, 2H), 4.35-4.30 (m, 4H), 3.94 (s, 3H), 3.75 (s, 3H), 3.39 (m, 2H). 1.57 (s, 3H)

Example 17: 6-(3-isobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of 2-methylpropan-1-amine (1.0 g, 14 mmol) in acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (1.4 g, 14 mmol), then it was stirred at room temperature for 2 h. solid precipitation, filtered, give the desired product Example 17B (1.5 g, 61%) as a white solid, it was used in the next step without further purification. LM-MS: m/z=171.2 [M+H] +

To a solution of 1-(2-chloroethyl)-3-isobutyl-urea (1.2 g, 6.7 mmol) in THF (10 ml) was added sodium hydride (0.32 g, 13 mmol), then it was stirred at room temperature for 2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product Example 17C (0.5 g, yield: 50%) as a white solid.

Step 3: 6-(3-isobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (110 mg, 0.292 mmol) and 1-(2-chloroethyl)-3-isobutyl-urea (83 mg, 0.584 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (190 mg, 0.584 mmol), Pd 2 (dba) 3 (80 mg, 0.087 mmol), and xantphos (100.7 mg, 0.175 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 17 (55 mg, yield: 39%) as a yellow solid. LM-MS: m/z=483.3 [M+H] + . 1H NMR (400 MHz, CDCl 3 ) δ 11.01 (s, 1H), 8.37 (s, 1H), 8.11 (d, 2H), 7.78 (d, 1H), 7.56 (d, 1H), 7.28 (d, 1H), 4.34-4.21 (m, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 3.58-3.48 (m, 2H), 3.09 (d, 2H), 1.95-1.90 (m, 1H), 0.91 (dd, 6H).

Example 18: 6-(3-cyclopentyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of cyclopentylamine (18A) (1.0 g, 11.7 mmol) and in THF (15 mL) was added 1-chloro-2-isocyanato-ethane (1 mL, 11.7 mmol) via a syringe, then it was stirred at room temperature for 2 h. The mixture solution was evaporated to afford the title compound 18B (780 mg, 34.97%) as a colourless oil, which was used in the next step without further purification. LM-MS: m/z=191.1 [M+H] +

To a solution of T177B (0.5 g, 2.63 mmol) in THF (30 mL) was added sodium hydride (0.21 g, 5.26 mmol), then it was stirred at room temperature for 2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the title product (18C) (310 mg, 76.54%) as colourless oil. LM-MS: m/z=155.2 [M+H] +

Step 3: 6-(3-cyclopentyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 18C (49 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 110° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, The residue was purified by flash Chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to afford the title compound Example 18 (16 mg, 20.3%) as a white solid. LM-MS: m/z=495.3 [M+H]*. 1 H NMR (400 MHz, CDCl 3 ) δ 11.05 (s, 1H), 8.37 (s, 1H), 8.14-8.08 (m, 2H), 7.80 (d, 1H), 7.55 (d, 1H), 7.29 (d, 1H), 4.41-4.32 (m, 1H), 4.31-4.25 (m, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 3.57-3.45 (m, 2H), 1.88-1.82 (m, 2H), 1.74-1.69 (m, 2H), 1.66-1.50 (m, 4H).

Example 19:6-[3-(3-bicyclo[1.1.1]pentanyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of bicyclo[1.1.1]pentan-3-amine (0.5 g, 4.2 mmol) in acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (0.44 g, 4.2 mmol), then it was stirred at room temperature for 2 h. solid precipitation, filtered, give the desired product Example 19B (0.5 g, 63%) as a white solid, it was used in the next step without further purification. LM-MS: m/z=189.1 [M+H] +

To a solution of 19B (0.5 g, 2.7 mmol) in THF (10 ml) was added sodium hydride (0.13 g, 5.3 mmol), then it was stirred at room temperature for 2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). The combined organic layers were washed by brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product Example T202C (0.35 g, yield: 87%) as a white solid.

Step 3: 6-[3-(3-bicyclo[1.1.1]pentanyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (170 mg, 0.451 mmol) and 19C (103 mg, 0.677 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (293 mg, 0.902 mmol), Pd 2 (dba) 3 (123.8 mg, 0.135 mmol), and xantphos (155 mg, 0.27 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 19 (55 mg, yield: 39%) as a yellow solid. LM-MS: m/z=493.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.94 (s, 1H), 8.30 (s, 1H), 8.12 (d, 2H), 7.78 (dd, 1H), 7.54 (dd, 1H), 7.28 (d, 1H), 4.24-4.15 (m, 2H), 4.00 (s, 3H), 3.81 (s, 3H), 3.57-3.46 (m, 2H), 2.48 (s, 1H), 2.13 (s, 6H).

Example 20: 6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[3-(1-methyl-1,2,4-triazol-3-yl)-2-(trideuteriomethoxy)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 3 (60 mg, 0.16 mmol) and 20C (45 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 20 (6 mg, yield: 8%) as a yellow solid. LM-MS: m/z=484.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 10.85 (s, 1H), 8.34 (s, 1H), 8.11 (d, 2H), 7.75 (dd, 1H), 7.55 (dd, 1H), 7.27 (d, 1H), 4.62-4.47 (m, 1H), 4.27-4.11 (m, 2H), 3.99 (s, 3H), 3.65-3.52 (m, 2H), 2.26-2.03 (m, 4H), 1.70 (dt, 2H).

Example 21: 6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 2 (200 mg, 0.527 mmol) and 21C (141 mg, 1.05 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (342 mg, 1.05 mmol), Pd 2 (dba) 3 (144.6 mg, 0.158 mmol), and xantphos (182.6 mg, 0.316 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 21 (60 mg, yield: 24%) as a yellow solid. LM-MS: m/z=478.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.04-10.91 (m, 1H), 8.38 (t, 1H), 8.15-8.03 (m, 2H), 7.82-7.75 (m, 1H), 7.60-7.52 (m, 1H), 7.31-7.26 (m, 1H), 4.32-4.18 (m, 3H), 3.86-3.76 (m, 3H), 3.53-3.44 (m, 2H).

Example 22: 6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 2 (60 mg, 0.16 mmol) and 22C (45 mg, 0.32 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32 mmol), Pd 2 (dba) 3 (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N 2 for 3 times and heated to 120° C. for 4 hrs. When reaction completed, filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example 22. (6 mg, yield: 8%) as a yellow solid. LM-MS: m/z=484.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 10.97 (s, 1H), 8.35 (s, 1H), 8.11 (d, 2H), 7.79 (dd, 1H), 7.54 (dt, 1H), 7.28 (d, 1H), 4.53 (t, 1H), 4.29-4.21 (m, 2H), 3.81 (s, 3H), 3.66-3.53 (m, 2H), 2.25-2.07 (m, 4H), 1.74-1.65 (m, 2H).

To a solution of dimethyl 3-oxopentanedioate (5.0 g, 28.7 mmol) and Ni(acac) 2 (738 mg, 2.87 mmol) in dioxane (30 mL) was added NH 2 —CN (3.6 g, 86.2 mmol). The mixture was stirred at 110° C. for o.n. The reaction was cooled to r.t. The mixture was filtered and the filter cake was collected, washed with MeOH (20 mL) and concentrated in vacuo to give the desired product Example 23b (3.0 g, 56.6% yield) as a yellow solid. LCMS [M+1] + =185.0

To a solution of Example 23b (2.5 g, 13.58 mmol) in POCl 3 (15 mL) was added DIEA (2 mL) at 0° C., which was heated to 30° C. and stirred for o.n. The reaction was concentrated in vacuo. H 2 O (15 mL) and MeOH (3 mL) were added at 0° C., which was stirred at r.t. for 1 h. The mixture was filtered and the filtrate cake was collected by filtration to give Example 23c (1.5 g, 50.1% yield) as a yellow solid. LCMS [M+1] + =221.0

To a solution of Example 23c (1.2 g, 5.42 mmol) and Example 23d (1.21 g, 5.96 mmol) in EtOH (30 mL) was added conc. HCl (5 mL) and the solution was heated to reflux for o.n. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and H 2 O (50 mL), and the pH was adjusted to ˜8 with sat. NaHCO 3 . The organic layer was separated and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the product Example 23e (700 mg, 33.1% yield) as a yellow solid. LCMS [M+1] + =389.1

To a solution of Example 23e (690 mg, 1.78 mmol) in THF (30 mL) and H 2 O (10 mL) cooled at 0° C. was added LiOH·H 2 O (112 mg, 2.67 mmol) and the solution was stirred at r.t. for o.n. The reaction was concentrated in vacuo. The residue was dissolved in H 2 O (50 mL), adjusted pH ˜4 with HCl (2 mol/L), and extracted with EtOAc (100 mL). The organic layer was concentrated to afford the crude product Example 23f (750 mg, 100% crude yield) as a yellow solid. LCMS [M+1] + =375.2

To a solution of Example 23f (500 mg, 1.33 mmol) in DMF (10 mL) were added DIEA (515 mg, 3.99 mmol), HATU (610 mg, 1.60 mmol) and CD 3 —NH 2 ·HCl (110 mg, 1.59 mmol) and the solution was stirred at r.t. for 2 h. The reaction was diluted with EtOAc (50 mL), washed with brine (10 mL*3), dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the product Example 14g (510 mg, 98% yield) as a light yellow solid. LCMS [M+1] + =391.0

To a mixture of Example 23g (500 mg, 1.278 mmol), Example 23h (33 mg, 1.917 mmol) and Cs 2 CO 3 (167 mg, 2.55 mmol) in dioxane (5 mL) was added 3 rd t-Bu-Xphos-Pd (22.5 mg, 0.128 mmol). The mixture was degassed with N 2 three times, then heated to 100° C. and stirred for overnight. The reaction was concentrated in vacuo. The residue was further purified by prep-HPLC to give the desired product Example 23h (60 mg, 54.2% yield) as a white solid. LCMS [M+1] + =440.1. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 3H), 1.65-1.80 (m, 1H), 0.8-0.94 (m, 4H).

To a solution of Example 23h (50 mg, 0.11 mmol, 1.0 eq) in pyridine (2.0 mL) was added pyridine hydrofluoride (70% in pyridine, 0.5 mL) followed by NaNO 2 (10 mg, 0.15 mmol, 1.4 eq) at 0° C. very slowly and the resulting mixture was stirred for 20 min. The reaction was concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product Example 23 (13.5 mg, 28.1% yield) as a light yellow solid. LCMS [M+1] + =443.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 10.29 (s, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.61 (dd, J=7.8 Hz, J=1.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 1.95-1.91 (m, 1H), 0.79-0.77 (m, 4H).

To a solution of Example 24a (50.00 g, 287 mmol, 1.0 eq) and TEA (31.9 g, 316 mmol, 1.1 eq) in CH 3 CN (1 L) was added Example 24b (70.3 g, 293 mmol, 1.02 eq) in portions at 0° C. After addition, it was stirred for 1 h at room temperature. The solid was removed by filtration, rinsed with MTBE. The filtrate was concentrated and then diluted with MTBE. The slurry was stirred for 30 min, filtered and the filtrate was concentrated to provide Example 24c (52.47 g, crude) as brown oil.

Example 24c (52.47 g, 262 mmol, 1.0 eq) was dissolved in MTBE (600 mL) and PPh 3 (68.74 g, 262 mmol, 1.0 eq) was added. The reaction solution was stirred 16 h at room temperature and then concentrated in vacuo. To the residual sludge was added AcOH (500 mL) and H 2 O (50 mL). The vessel was equipped with a condenser and the mixture was heated to reflux for 6 h, and then concentrated in vacuo. The crude product (115.0 g, crude) was used to next step without purification.

To last step crude product Example 24d (115.0 g, 32% purity, 216 mmol, 1.0 eq) dissolved in THF (150 mL)/MeOH (50 mL)/H 2 O (50 mL) was added LiOH·H 2 O (36.3 g, 864 mmol, 4.0 eq) and the reaction mixture was stirred for 16 at room temperature. After the reaction was completed, MeOH and THF were concentrated. The residue was diluted with H 2 O (200 mL), and then extracted with EtOAc (300 mL*3). Then pH of the aqueous phase was adjusted to 3 with conc. HCl. Acidification of the water solution afforded a brown precipitate which was collected by filtration and dried in vacuo to afford Example 24e (31.5 g, 93.5% yield) as a yellow solid.

The solution of Example 24e (15.0 g, 96.15 mmol, 1.0 eq) in POCl 3 (150 mL) was stirred for 4 h at 100° C. After the reaction was completed, it was concentrated in vacuo to give Example 24f (17.4 g, crude), which was used to next step without further purification.

To a solution of Example 24g (2.30 g, 23.70 mmol, 2.0 eq) and DIEA (12.23 g, 94.79 mmol, 8.0 eq) in THF (50 mL) was added the solution of Example 24f (2.5 g, 11.85 mmol, 1.0 eq) in DCM (25 mL) dropwise at 0° C. The reaction solution was stirred for 30 min at r.t. The reaction solution was diluted with EtOAc (100 mL), washed with brine (80 mL*3), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc=1/2) to afford the product Example 24h (1.8 g, 64.4% yield) as a yellow solid. LCMS [M+1] + =236.2

To a solution of Example 24h (700 mg, 2.98 mmol, 1.0 eq) and Example 24i (611 mg, 2.98 mmol, 1.0 eq) in dry THF (15 mL) was add LiHMDS (5.96 mL, 1M, 2.0 eq) dropwise at ˜30° C. under N 2 . The reaction mixture was stirred for 30 min at r.t. The crude product was concentrated and purified by silica gel chromatography (DCM/MeOH=10/1) to afford the product Example 24j (450 mg, 37.5% yield) as a yellow solid. LCMS [M+1] + =404.2.

To the solution of Example 24j (450 mg, 1.12 mmol, 1.0 eq) in dioxane (5 mL) were added Cs 2 CO 3 (728 mg, 2.23 mmol, 2.0 eq), Example 24k (285 mg, 3.35 mmol, 3.0 eq) and 3 rd t-Bu-Xphos catalyst (99 mg, 0.11 mmol, 0.1 eq) and the reaction mixture was stirred for 4 h at 110° C. under N 2 . The reaction solution was concentrated and purified by silica gel chromatography (DCM/MeOH=10/1) to afford the product Example 24l (320 mg, 63.5% yield) as a yellow solid. LCMS [M+1] + =453.2.

To a solution of Example 24h (120 mg, 0.27 mmol, 1.0 eq) in THF (3 mL) was added CH 3 MgBr (0.27 mL, 3.0 M, 3.0 eq) dropwise at 0° C. under N 2 . The reaction solution was stirred for 30 min at r.t. The reaction solution was poured into saturated aqueous NH 4 Cl (10 mL), and extracted with DCM (10 mL*3). The combined organic layer was washed with brine (30 mL), dried by Na 2 SO 4 and concentrated. The crude product was purified by prep-HPLC to give the desired product Example 24 (8.8 mg, 8.0% yield) as an off white solid. LCMS [M+1] + =408.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 10.57 (s, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 3.96 (s, 3H), 3.71 (s, 3H), 2.81 (s, 3H), 1.09-1.03 (m, 1H), 0.86-0.83 (m, 4H).

To the solution of Example 25a (50 mg, 0.11 mmol, 1.0 eq) in THF (1 mL) was added CH 3 MgBr (0.55 mL, 1.0 M, 5.0 eq) dropwise at 0° C. under N 2 . The reaction solution was stirred for 30 min at r.t. The reaction solution was purified by prep-TLC (DCM/MeOH=12/1) to obtained crude product (27 mg) and further purified by prep-HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of 40% MeCN in water to 50% MeCN in water over a 7 min period, where both solvents contain 0.1% formic acid) to give the desired product Example 25 (6.8 mg, 14.6% yield) as a yellow solid (FA salt). LCMS [M+1] + =422.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.55 (s, 1H), 8.58 (s, 1H), 8.48 (br, 2H), 8.10 (s, 1H), 7.71 (dd, J=7.8, 1.6 Hz, 1H), 7.52 (dd, J=7.8, 1.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 3.36 (q, J=7.2 Hz, 2H), 2.11-2.04 (m, 1H), 1.17 (t, J=7.2 Hz, 3H), 0.85-0.81 (m, 4H).

To a solution of Example 26a (135 mg, 0.3 mmol) in dry THF (10 mL) was added Example 26b (1.2 mL, 1M in THF, 1.2 mmol) dropwise at 0° C. under nitrogen. After addition (about 5 min), the reaction mixture was stirred for 1 h at r.t. Then, the reaction was quenched with MeOH (1 mL) and concentrated in vacuo. The residue was purified by prep-TLC (DCM/MeOH=20/1) to afford the product Example 26 (19.5 mg, 15% yield) as an off-white solid. LCMS [M+1] + =434.3/. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.53 (s, 1H), 10.61 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.72 (dd, J=7.8 Hz, 1.6 Hz, 1H), 7.52 (dd, J=7.8 Hz, 1.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.72-3.69 (m, 4H), 2.11-2.05 (m, 1H), 1.24-1.16 (m, 4H), 0.85-0.82 (m, 4H).

To a solution of Example 057a (5 g, 21.3 mmol) and Example 027b (2.28 g, 23.4 mmol) in THF (20 mL) were added Et 3 N (3.28 g, 31.9 mmol) and EDCI (6 g, 31.9 mmmol). The mixture was stirred at r.t. overnight. The reaction mixture was washed by brine (60 mL), and extracted by DCM (60 mL*3). The combined organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure, and dried to give Example 027c (4.4 g, 95% yield) as a yellow solid. LCMS [M+1] + =234.9/236.9

To a solution of Example 027c (4.4 g, 18.7 mmol), Example 027d (CAS: 1609394-10-6, 4.2 g, 20.6 mmol) in THF (20 mL) under N 2 was added LiHMDS (1 mol/L, 28 mL, 28.05 mmol) dropwise. The mixture was stirred at r.t. for 1 h. The reaction mixture was washed by brine (60 mL), extracted by DCM (60 mL*3). The combined organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure, purified by flash C-18 column (H 2 O/CH 3 CN=3/1) to give Example 027e (2.4 g, 32% yield) as yellow oil. LCMS [M+1] + =403.1

To a solution of Example 027e (500 mg, 1.24 mmol) in THF (10 mL) under N 2 , was added Example 027f (1 mol/L, 10 mL, 12.4 mmol) in one portion. The mixture was stirred at r.t. for 1 h. The reaction mixture was washed by brine (40 mL), and extracted by EtOAc (40 mL*3). The combined organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure to get crude product (600 mg, crude) as a yellow solid, which was directly used in next step without further purification. LCMS [M+1] + =384.1

To a solution of Example 027g (100 mg, 0.26 mmol), Example 027h (33.3 mg 0.92 mmol) in 1,4-dioxane (2 mL) were added Cs 2 CO 3 (127.3 mg 0.392 mmol), Pd 2 (dba) 3 (23.9 mg 0.026 mmol), and Xant-phos (15.1 mg 0.026 mmol). The mixture was degassed by Ar, heated to 90° C. and stirred over night. The reaction mixture was diluted by DCM and filtrated. The filtrate was concentrated under reduced pressure to remove solvent, which was further purified by prep-HPLC to give Example 027 (17.5 mg, 15% yield) as a white solid. LCMS [M+1] + =433.2. 1 H NMR (400 MHz, Chloroform-d) δ 11.25 (s, 1H), 8.84 (s, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.80 (d, J=8.0, 1.6 Hz, 1H), 7.55 (d, J=8.0, 1.6 Hz, 1H), 7.27-7.29 (m, 1H), 4.00 (s, 3H), 3.76 (s, 3H), 2.54-2.60 (m, 1H), 1.67-1.56 (m, 1H), 1.26-1.29 (m, 2H), 1.04-1.10 (m, 4H), 0.87-0.93 (m, 2H).

To a suspension of Example 028a (20 g, 96.6 mmol) in MeCN (100 mL) and H 2 O (15 mL) was added LiBr (25.2 g, 289.8 mmol), DIPEA (35.4 g, 289.8 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was isolated by filtration. The crude solid was washed with MeCN (25 mL), dried under vacuum at 45° C. to give Example 028b (17.8 g, 93% yield) as a light yellow solid.

To a suspension of Example 028b (17.5 g, 88.2 mmol) and Example 028c (15.0 g, 73.5 mmol) in H 2 O (90 mL) and 2-propanol (15 mL) was added Zn(OAc) 2 (13.4 g, 73.5 mmol). The mixture was stirred at 65° C. for 15 h. The reaction mixture was cooled to room temperature and isolated by filtration. The crude solid was washed with water (45 mL) and THF (45 mL). The solid was dried under vacuum at 70° C. to give Example 028d (25.2 g, 61% yield) as a light yellow solid.

To a suspension of Example 28d (2.0 g, 5.10 mmol), CD 3 NH 2 ·HCl (431 mg, 6.12 mmol) and NMI (293 mg, 3.57 mmol) in NMP/ACN (20 mL/20 mL) were added HOBt (344 mg, 2.55 mmol) and EDCI (1.37 g, 7.13 mmol). The mixture was stirred at r.t. for 16 h. After cooling to 0° C., the mixture was aged for 2 h at 0° C. The product was isolated by filtration. The wet cake was washed with H 2 O (20 mL), and then ACN (20 mL). The solid was collected and dried under vacuum to give Example 28b (1.1 g, 57.3% yield) as a white solid. LCMS [M+1] + =377.0

To a solution of Example 28b (1.1 g, 2.92 mmol) and Example 28c (512 mg, 4.38 mmol) in 1,4-dioxane (15 mL) were added Pd 2 (dba) 3 (267 mg, 0.29 mmol), XantPhos (337 mg, 0.58 mmol) and Cs 2 CO 3 (1.9 g, 5.84 mmol). The mixture was degassed by nitrogen for 3 times and stirred at 120° C. for 4 h. The reaction was cooled to r.t. and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=85/15) to give the desired crude product Example 28d (1.08 g, 81.2% yield, ˜35% purity) as a yellow solid, which was used for the next step directly. LCMS [M+1] + =458.0

To a solution of the crude Example 28d (1.08 g, 2.36 mmol) in DCM/MeOH (10 mL) was added 6N HCl/iPrOAc (20 mL). The mixture was stirred at r.t. for 16 h. The resulting mixture was concentrated, and the residue was purified by silica gel chromatography (EtOAc/MeOH=85/15) to give the desired product Example 28e (240 mg, 28.4% yield) as a yellow solid. CMS [M+1] + =358.0

To a solution of Example 28g (200 mg, 3.51 mmol) and TEA (709 mg, 7.02 mmol) in DCM (15 mL) was slowly added a solution of Example 28f (707 mg, 3.51 mmol) in DCM (5 mL) at 0° C. The mixture was then stirred at r.t. for 1 h. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Petroleum Ether/EtOAc=92/8) to give the desired product Example 28h (470 mg, 60.4% yield) as a yellow solid. LCMS [M+1] + =223.0

To an ice-cooled solution of NaH (14.5 mg, 0.36 mmol, 60% w.t. % in mineral oil) in DMF (1 mL) under nitrogen atmosphere was added (dropwise) a solution of Example 28e (35.7 mg, 0.1 mmol) in DMF (1 mL). After 15 min, a solution of Example 28h (20.2 mg, 0.091 mmol) in DMF (1 mL) was added. After 5 min, the cooling bath was removed and the reaction was warmed to 80° C. and stirred for 2 h. The mixture was quenched by adding water, purified by prep-HPLC to give the desired product Example 28 (1.1 mg, 2.8% yield) as a yellow solid. LCMS [M+1] + =441.0. 1 H NMR (400 MHz, DMSO-d) δ 10.89 (s, 1H), 9.60 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.61 (dd, J=7.8, 1.6 Hz, 1H), 7.49 (dd, J=8.0, 1.6 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 3.99 (t, J=6.4 Hz, 4H), 3.93 (s, 3H), 3.71 (s, 3H), 2.13 (p, J=7.6 Hz, 2H).

To a solution of Example 29b (1.0 g, 7.30 mmol) in 1,4-dioxane (15 mL) was treated with Example 29a (2 mL, 24.1 mmol) and stirred at r.t. for 16 h. After the reaction was completed, the solvent was concentrated, and the residue was suspended in DCM (5 mL) and sonicated. The resulting solid was collected via filtration, and dried to afford the desired product Example 29c (665 mg, 80% yield) as a white solid. LCMS [M+1] + =115.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 5.62 (s, 2H), 3.18-3.12 (m, 4H), 1.80-1.68 (m, 4H).

To a solution of Example 29d (50 mg, 0.13 mmol) and Example 29c (22.7 mg, 0.20 mmol) in 1,4-dioxane (1 mL) were added Pd 2 (dba) 3 (12.1 mg, 0.013 mmol), XantPhos (15.3 mg, 0.026 mmol) and Cs 2 CO 3 (86.5 mg, 0.27 mmol). The mixture was sealed, degassed by nitrogen for 3 times and stirred at 110° C. for 2 h. When completed, the reaction was cooled to r.t. and filtered. The filtrate was purified directly by prep-HPLC to give the desired product Example 29 (13 mg, 21.7% yield) as a white solid. LCMS [M+1] + =455.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 9.21 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 7.96 (s, 1H), 7.62 (dd, J=7.8, 1.6 Hz, 1H), 7.49 (dd, J=8.0, 1.6 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.42-3.37 (m, 4H), 1.81 (s, 4H).

To a suspension of Example 30a (1.0 g, 2.55 mmol), CH 3 NH 2 ·HCl (206 mg, 3.06 mmol) and NMI (146 mg, 1.78 mmol) in NMP/ACN (7 mL/7 mL) were added HOBt (172 mg, 1.27 mmol) and EDCI (685 mg, 3.57 mmol). The mixture was stirred at r.t. for 16 h. After cooling to 0° C., the mixture was aged for 2 h at 0° C. The product was isolated by filtration. The wet cake was washed with H 2 O (10 mL), and then ACN (10 mL). The solid was collected and dried under vacuum to give Example 30b (417 mg, 43.9% yield) as a white solid. LCMS [M+1] + =374.0

To a solution of Example 68b (72 mg, 0.19 mmol) and Example 30c (23 mg, 0.23 mmol) in 1,4-dioxane (2 mL) were added Pd 2 (dba) 3 (17.6 mg, 0.019 mmol), XantPhos (22.3 mg, 0.038 mmol) and Cs 2 CO 3 (125.5 mg, 0.38 mmol). The mixture was degassed by nitrogen for 3 times and stirred at 110° C. for 3.5 h in a sealed tube. When completed, the reaction was cooled to r.t. and filtered. The filtrate was purified directly by prep-HPLC to give the desired product Example 30 (16 mg, 19.0% yield) as a white solid. LCMS [M+1] + =438.0. H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 9.59 (s, 1H), 9.02 (d, J=5.4 Hz, 1H), 8.54 (s, 1H), 7.99 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 3.98 (s, 4H), 3.93 (s, 3H), 3.71 (s, 3H), 2.84 (d, J=4.4 Hz, 3H), 2.13 (t, J=7.8 Hz, 2H).

A solution of Example 31a (2.0 g, 5.4 mmol), TsNH 2 (1.1 g, 6.52 mmol), K 2 CO 3 (1.1 g, 6.52 mmol) in MeOH (5 mL) was stirred at r.t. for 10 min, and then Example 31b (1.86 g, 13.6 mmol) in dry DMSO (20 mL) was added, which was stirred at 110° C. for o.n. When completed, the reaction was cooled to r.t., diluted by EtOAc, washed by water, and dried over Na 2 SO 4 . The organic layer was concentrated and purified by silica gel column (Petroleum ether/EtOAc=4/1) to give Example 031b (600 mg, 52.1% yield) as a white solid. LCMS [M+1] + =214.1. 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 3.93 (d, J=6.6 Hz, 4H), 3.76 (d, J=7.4 Hz, 2H), 2.46 (s, 3H).

A solution of Mg (676 mg, 28 mmol) in MeOH (5 mL) was stirred at r.t. for 10 min, then Example 31b (600 mg, 2.8 mmol) in MeOH (5 mL) was added, and the mixture reaction was stirred at r.t. for o.n. in a sealed tube. Another Mg (676 mg, 28 mmol) was added, and the mixture reaction was stirred at r.t. for another 6 h. The mixture was filtered, and the solid was washed by MeOH. The filtrate Example 31c was used directly for next step. LCMS [M+1] + =61.2

To a solution of Example 31c (crude in MeOH) was added (Boc) 2 O (940 mg, 5.6 mmol), which was stirred at r.t. for o.n. The mixture was filtered, and the solid was washed by MeOH. The organic layer was added additional (Boc) 2 O (940 mg, 5.6 mmol), which was stirred at r.t. for another 4 h. After reaction was completed, the mixture was concentrated and purified by silica gel column (Petroleum Ether/EtOAc=5/1) to give Example 031d (500 mg, crude, containing (Boc) 2 O) as a white solid. LCMS [M+1−56] + =104.1. 1 H NMR (400 MHz, Chloroform-d) 3.93 (d, J=6.6 Hz, 4H), 1.43 (s, 9H).

A solution of Example 31d (500 mg, 3.1 mmol) in con. HCl (1 mL) was stirred at r.t for 0.5 h. After reaction was completed, the mixture was concentrated to give Example 31c (200 mg, 67.9% yield) as a white solid, which was used for next step without further purification. LCMS [M+1] + =60.2.

To a solution of Example 31c (200 mg, 3.3 mmol) and DIEA (3.3 g, 33 mmol) in 1,4-dioxane (5 mL) was added Example 31e (230 mg, 1.67 mmol), which was stirred at r.t. for o.n. After reaction was completed, the mixture was concentrated, and directly purified by silica gel column (DCM/MeOH=10/1) to give the desired product Example 31f (230 mg, crude, containing DIEA, 67.6% yield) as colorless oil. LCMS [M] + =103.2

To a solution of Example 31f (200 mg, ˜50% purity, 0.5 mmol) and Example 31g (188 mg, 0.5 mmol) in 1,4-dioxane (5 mL) were added Pd 2 (dba) 3 (45 mg, 0.05 mmol), XantPhos (30 mg, 0.05 mmol) and Cs 2 CO 3 (489 mg, 1.5 mmol). The mixture was degassed by nitrogen for 3 times, sealed, and stirred at 110° C. for 2 h. When completed, the reaction was cooled to r.t. and filtered. The filtrate was purified directly by prep-HPLC to give the desired product Example 31 (2.2 mg, 1% yield) as a white solid. LCMS [M+1] + =442.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.90 (s, 1H), 9.60 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 3.97 (s, 4H), 3.93 (s, 3H), 3.71 (s, 3H).

To a solution of Example 32a (300 mg, 2.19 mmol) in 1,4-dioxane (5 mL) were treated with Example 32b (623 mg, 3.28 mmol) and TEA (664 mg, 6.57 mmol). The mixture was stirred at r.t. for 16 h. After completion, the mixture was concentrated, and the residue was suspended in DCM (5 mL) and sonicated. The resulting solid was collected via filtration, and dried to afford the desired product Example 32c (226 mg, 73.9% yield) as a white solid.

LCMS [M+1] + =141.0

To a solution of Example 32d (60 mg, 0.16 mmol) and Example 32c (26.7 mg, 0.19 mmol) in 1,4-dioxane (0.6 mL) were added Pd 2 (dba) 3 (14.6 mg, 0.016 mmol), XantPhos (18.4 mg, 0.032 mmol) and Cs 2 CO 3 (104 mg, 0.32 mmol). The mixture was degassed by nitrogen for 3 times and stirred at 110° C. for 16 h in a sealed tube. When completed, the reaction was cooled to r.t. and filtered. The filtrate was purified directly by prep-HPLC to give the desired product Example 32 (6.6 mg, 8.7% yield) as a white solid. LCMS [M+1] + =481.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 9.61 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 7.97 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 3.93 (s, 7H), 3.69 (s, 3H), 2.08 (t, J=7.5 Hz, 4H), 1.80-1.67 (m, 2H).

To a solution of Example 33a (500 mg, 3.65 mmol, 1.0 eq) in dioxane (6 ml) was added Example 33b (624 mg, 10.95 mmol, 3.0 eq). The reaction solution was stirred for 16 h at r.t. and concentrated. The residue was treated with DCM. The resulting solid was collected by filtration to afford Example 33c (190 mg, 52% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 5.72 (brs, 2H), 3.76 (t, J=7.6 Hz, 4H), 2.14-2.04 (m, 2H).

To a solution of Example 33d (100 mg, 0.26 mmol, 1.0 eq) and Example 33c (78.0 mg, 0.78 mmol, 3.0 eq) in dioxane (4 mL) were added Xantphos (30.1 mg, 0.05 mmol, 0.2 eq), Cs 2 CO 3 (169.5 mg, 0.52 mmol, 2.0 eq) and Pd 2 (dba) 3 ·CHCl 3 (26.9 mg, 0.03 mmol, 0.1 eq). The reaction mixture was stirred at 110° C. for 4 h under N 2 protection. The solid was filtered out and filtrate was concentrated, and the residue was purified by prep-TLC (DCM/MeOH=15/1) to afford the Example 33 (43.3 mg, 37% yield) as an off-white solid. LCMS [M+1] + =448.2. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 9.20 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 7.91 (s, 1H), 7.62 (dd, J=7.8, 1.6 Hz, 1H), 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 4.00-3.70 (m, 7H), 3.70 (s, 3H), 3.01-2.91 (m, 1H), 2.19-2.09 (m, 2H), 1.12-0.99 (m, 4H).

To a solution of Example 34a (10.0 g, 42.7 mmol, 1.0 eq) in DCM (100 mL) was added BBr 3 (11.8 g, 46.9 mmol, 1.1 eq) dropwise at 0° C. The mixture was stirred for 2 h at r.t. The mixture was quenched with MeOH (12 mL), washed with brine (50 mL*3), dried over Na 2 SO 4 , and concentrated to afford the product Example 34b (9.2 g, 98% yield) as an orange solid. LCMS [M+1] + =221.2.

To a solution of Example 34b (9.2 g, 41.8 mmol, 1.0 eq) in ACN (184 mL) were added K 2 CO 3 (11.6 g, 83.6 mmol, 2.0 eq) and CD 3 I (7.3 g, 50.2 mmol, 1.2 eq). The reaction mixture was stirred for 6 h at 80° C. After the reaction was completed, the reaction mixture was concentrated and purified by silica gel chromatography (Petroleum Ether/EtOAc=2/1) to afford the product Example 34c (3.9 g, 39% yield) as an orange solid. LCMS [M+1] + =238.2.

To a solution of Example 34c (3.9 g, 16.4 mmol, 1.0 eq) in MeOH (78 mL) was added Pd/C (780 mg) under N 2 protection. The suspension was degassed under vacuum and purged with H 2 three times. The reaction mixture was stirred at r.t. for 48 h under H 2 balloon. The solid was filtered out, and the filtrate was concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc=1/1) to afford the product Example 34d (1.9 g, 56% yield) as an off-white solid. LCMS [M+1] + =208.2.

To a solution of Example 34e (450 mg, 1.91 mmol, 1.0 eq) and Example 34d (396 mg, 1.91 mmol, 1.0 eq) in dry THF (15 mL) was added LiHMDS (3.8 mL, 1 M in THF, 2.0 eq) dropwise at ˜20° C. under N 2 protection. The reaction mixture was stirred for 0.5 h at r.t., and then the silica was added to the mixture and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to afford the product Example 34f (450 mg, 58% yield) as a yellow solid. LCMS [M+1] + =406.2.

To a solution of Example 34f (200 mg, 0.49 mmol, 1.0 eq) in THF (4 mL) was added Example 34g (3.0 mL, 1.0 M in THF, 6.0 eq) dropwise at 0° C. under N 2 protection. The mixture was stirred for 0.5 h at r.t. The reaction was poured into saturated aqueous NH 4 Cl (10 mL) and extracted with EtOAc (15 mL*3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to afford the product Example 34h (160 mg, 84% yield) as a yellow solid. LCMS [M+1] + =387.1.

To a solution of Example 34h (100 mg, 0.26 mmol, 1.0 eq) in dioxane (4 mL) were added Cs 2 CO 3 (169 mg, 0.52 mmol, 2.0 eq), Example 341 (66 mg, 0.77 mmol, 3.0 eq), Xantphos (30 mg, 0.05 mmol, 0.2 eq) and Pd 2 (dba) 3 ·CHCl 3 (27 mg, 0.03 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at 110° C. under N 2 protection. After cooled to room temperature, the solvent was removed, and the crude product was purified by prep-TLC (DCM/MeOH=15/1) to afford the product Example 34 (30.9 mg, 27% yield) as a yellow solid. LCMS [M+1] + =436.2. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 10.93 (s, 1H), 9.13 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.05-2.90 (m, 1H), 2.05-2.00 (m, 1H), 1.14-1.03 (m, 4H), 0.81 (d, J=6.4 Hz, 4H).

To a solution of Example 35a (10.0 g, 94.79 mmol, 1.0 eq) in CH 3 CN (50 mL) was added propan-2-amine (5.59 g, 94.79 mmol, 1.0 eq) at 0° C. The reaction solution was stirred for 2 h at room temperature. The resulting solid was collected by filtration to afford Example 35b (8.07 g) as a white solid. The solid was dissolved in THF (150 mL), followed by NaH (5.83 g, 60% in mineral oil, 145.8 mmol, 3.0 eq) in portions at 0° C. The mixture was stirred for 16 h at room temperature. The reaction was quenched with H 2 O and extracted with EtOAc. The combined organic layer was washed with brine, dried by Na 2 SO 4 and concentrated. The crude product was purified by silica gel chromatography (DCM/MeOH=30/1) to give the desired product Example 35c (3.50 g, 29% yield) as a white solid. 1 H NMR (300 MHz, CDCl 3 -d) δ 5.07 (s, 1H), 4.21-4.06 (m, 1H), 3.38 (s, 4H), 1.13 (d, J=6.6 Hz, 6H).

To a solution of Example 35d (10.0 g, 52.08 mmol, 1.0 eq) in DCM (200 mL) were added DIEA (33.59 g, 260.4 mmol, 5.0 eq) and HATU (23.75 g, 62.50 mmol, 1.2 eq). After stirred for 30 min, Example 35e (6.09 g, 62.50 mmol, 1.2 eq) was added to the solution. The reaction solution was stirred for 1 h at room temperature. After the reaction was completed, the solvent was removed and the crude was purified by silica gel chromatography (Petroleum Ether/EtOAc=3/1) to give the desired product Example 35f (11.5 g, 94.0% yield) as a yellow solid. LCMS [M+1] + =235.0.

To a solution of Example 35f (5.0 g, 21.28 mmol, 1.0 eq) and Example 35g (4.36 g, 21.28 mmol, 1.0 eq) in THF (100 mL) was added LiHMDS (42.55 mL, 1 M in THF, 2.0 eq) dropwise at −15° C. under N 2 . The reaction solution was stirred for 1 h at r.t. And then the silica was added to the mixture and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=50/1) to give the desired product Example 35h (4.02 g, 46.9% yield) as a yellow solid. LCMS [M+1] + =403.2.

To a solution of Example 35h (2.0 g, 4.98 mmol, 1.0 eq) in THF (100 mL) was added Example 35i (39.80 mL, 39.80 mmol, 1 M, 8.0 eq) dropwise at ˜10° C. under N 2 . The reaction solution was stirred for 1 h at r.t. The reaction solution was quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried by Na 2 SO 4 and concentrated. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to give the desired product Example 35j (1.90 g, 99.7% yield) as a yellow solid. LCMS [M+1] + =384.2.

To the solution of Example 35j (100 mg, 0.26 mmol, 1.0 eq) in dioxane (3 mL) were added Example 70c (100 mg, 0.78 mmol, 3.0 eq), Cs 2 CO 3 (170 mg, 0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) and Pd 2 (dba) 3 CHCl 3 (27 mg, 0.026 mmol, 0.1 eq). The reaction solution was stirred for 4 h at 110° C. under N 2 . The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by Prep-TLC (DCM/MeOH=15/1) to give the desired product Example 35 (31.3 mg, 25.3% yield) as an off white solid. LCMS [M+1] + =476.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 9.14 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.62 (dd, J=7.8, 1.8 Hz, 1H), 7.56 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 4.12-3.99 (m, 3H), 3.95 (s, 3H), 3.70 (s, 3H), 3.41 (t, J=8.0 Hz, 2H), 3.04-2.91 (m, 1H), 1.17-1.06 (m, 8H), 1.06-0.98 (m, 2H).

A solution of Example 38b (1.13 g, 8.2 mmol) in 1,4-dioxane (10 mL) were treated with Example 38a (1.0 g, 8.2 mmol) and TEA (2.5 g, 24.7 mmol). The mixture was stirred at r.t. for 16 h. After the reaction was completed, the solution was concentrated, and the residue was suspended in a mixed solution (Petroleum Ether/EtOAc=1/1, 10 mL), and sonicated. The resulting solid was collected via filtration, dried to afford the desired product Example 38c (1.0 g, 94.3% yield) as a white solid, which contained some TEA·HCl. LCMS [M+1] + =129.0

To a solution of Example 38d (250 mg, 0.66 mmol) and Example 38c (127 mg, 0.99 mmol) in 1,4-dioxane (4 mL) were added Pd 2 (dba) 3 (60 mg, 0.068 mmol), Xantphos (77.5 mg, 0.13 mmol) and Cs 2 CO 3 (433 mg, 1.32 mmol). The mixture was sealed, degassed by nitrogen for 3 times and stirred at 110° C. for 16 h. When completed, the reaction was cooled to r.t. and filtered. The filtrate was purified directly by prep-HPLC to give the desired product Example 38 (116 mg, 37.4% yield) as a yellow solid. LCMS [M+1] + =469.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.91 (s, 1H), 9.58 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.66 (s, 4H), 1.17 (s, 6H).

Examples 89-104 were synthesized as described for examples 1-88.

To a stirred solution of Example 110a (1.0 g, 5.78 mmol), xphos (551 mg, 1.16 mmol), Pd 2 (dba) 3 (530 mg, 0.58 mmol) and Example 110b (2.5 g, 28.9 mmol) in THF (12 mL) was added LiHMDS (32 mL, 1.0 M in THF) and the resulting reaction was heated to 65° C. and stirring continued for 2 h. The reaction was poured into water (100 mL) and extracted with EtOAc (150 mL*2) and DCM (150 mL*2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by flash chromatography on a 40 g silica gel column (PE/EtOAc=0/100) to give the desired product Example 110c (900 mg, 87.4% yield) as a brown solid. LCMS [M+1] + =180.0

To a solution of Example 110c (70 mg, 0.39 mmol) and Example 110d (100 mg, 0.26 mmol) in 1,4-dioxane (2 mL) were added Pd 2 (dba) 3 (24 mg, 0.026 mmol), xantphos (30 mg, 0.052 mmol) and Cs 2 CO 3 (170 mg, 0.52 mmol). The mixture was degassed by nitrogen for 3 times and stirred at 110° C. for 2 h. When completed, the reaction was cooled to r.t., diluted with MeOH (5 mL) and filtered. The filtrate was purified directly by Prep-HPLC to give the desired product Example 110 (22 mg, 16.1% yield) as a yellow solid. LCMS [M+1] + =527.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 9.74 (s, 1H), 9.04 (s, 1H), 8.54 (s, 1H), 7.85 (d, J=3.0 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.50 (d, J=9.1 Hz, 1H), 7.39 (dd, J=9.1, 3.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.72 (t, J=4.5 Hz, 4H), 3.69 (s, 3H), 3.04 (t, J=4.7 Hz, 4H), 2.92 (s, 1H), 1.04 (d, J=4.9 Hz, 2H), 0.97 (d, J=7.8 Hz, 2H).

To a solution of Example 114a (500 mg, 1.24 mmol, 1.0 eq) in THF (15 mL) was added EtMgBr (9.93 mL, 1.0 M in THF, 9.93 mmol, 5.0 eq) dropwise at ˜10° C. The reaction solution was stirred for 30 min at r.t. The reaction solution was poured into saturated aqueous of NH 4 Cl (20 mL) at 0° C., extracted with EtOAc (20 mL*3), the combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel flash column chromatography, eluted with DCM/MeOH (10/1) to afford desired product Example 114b (367 mg, 79.5% yield) as a yellow solid. LCMS [M+1] + =372.3.

To a solution of Example 114b (100 mg, 0.27 mmol, 1.0 eq) in dioxane (5 mL) were added Example 114c (81 mg, 0.81 mmol, 3.0 eq), Cs 2 CO 3 (175 mg, 0.54 mmol, 2.0 eq), and 3 rd t-Bu-Xphos Pd (24 mg, 0.027 mmol, 0.1 eq). The reaction was stirred for 4 h at 110° C. under N 2 . The mixture was filtered and the filtrate was concentrated. The crude product was purified by Prep-TLC (DCM/MeOH=15/1) to give the desired product Example 114 (43.7 mg, 37.3% yield) as a yellow solid. LCMS [M+1] + =436.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.03 (s, 1H), 9.16 (s, 1H), 8.81 (s, 1H), 8.57 (s, 1H), 7.90 (s, 1H), 7.63 (dd, J=7.8, 1.5 Hz, 1H), 7.54 (dd, J=7.8, 1.5 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 4.03-3.92 (m, 7H), 3.73 (s, 3H), 3.10 (q, J=7.2 Hz, 2H), 2.21-2.08 (m, 2H), 1.13 (t, J=7.2 Hz, 3H).

To a solution of dimethyl 3-oxopentanedioate (5.0 g, 28.7 mmol) and Ni(acac) 2 (738 mg, 2.87 mmol) in dioxane (30 mL) was added NH 2 —CN (3.6 g, 86.2 mmol). The mixture was stirred at 110° C. for o.n. The reaction was cooled to r.t. The mixture was filtered and the filter cake was collected, washed with MeOH (20 mL) and concentrated in vacuo to give the desired product Example 117b (3.0 g, 56.6% yield) as a yellow solid. LCMS [M+1] + =185.0

To a solution of Example 117b (2.5 g, 13.58 mmol) in POCl 3 (15 mL) was added DIEA (2 mL) at 0° C., which was heated to 30° C. and stirred for o.n. The reaction was concentrated in vacuo. H 2 O (15 mL) and MeOH (3 mL) were added at 0° C., which was stirred at r.t. for 1 h. The mixture was filtered and the filtrate cake was collected by filtration to give Example 117c (1.5 g, 50.1% yield) as a yellow solid. LCMS [M+1] + =221.0

To a solution of Example 117c (1.2 g, 5.42 mmol) and Example 117d (1.21 g, 5.96 mmol) in EtOH (30 mL) was added conc. HCl (5 mL) and the solution was heated to reflux for o.n. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and H 2 O (50 mL), and the pH was adjusted to ˜8 with sat. NaHCO 3 . The organic layer was separated and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the product Example 117e (700 mg, 33.1% yield) as a yellow solid. LCMS [M+1] + =389.11.

To a solution of Example 117e (690 mg, 1.78 mmol) in THF (30 mL) and H 2 O (10 mL) cooled at 0° C. was added LiOH·H 2 O (112 mg, 2.67 mmol) and the solution was stirred at r.t. for o.n. The reaction was concentrated in vacuo. The residue was dissolved in H 2 O (50 mL), adjusted pH ˜4 with HCl (2 mol/L), and extracted with EtOAc (100 mL). The organic layer was concentrated to afford the crude product Example 117f (750 mg, 100% crude yield) as a yellow solid. LCMS [M+1] + =375.2

To a solution of Example 117f (500 mg, 1.33 mmol) in DMF (10 mL) were added DIEA (515 mg, 3.99 mmol), HATU (610 mg, 1.60 mmol) and CD 3 —NH 2 ·HCl (110 mg, 1.59 mmol) and the solution was stirred at r.t. for 2 h. The reaction was diluted with EtOAc (50 mL), washed with brine (10 mL*3), dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the product Example 117g (510 mg, 98% yield) as a light yellow solid. LCMS [M+1] + =391.0

To a mixture of Example 117g (500 mg, 1.278 mmol), Example 117h (33 mg, 1.917 mmol) and Cs 2 CO 3 (167 mg, 2.55 mmol) in dioxane (5 mL) was added 3rd t-Bu-Xphos-Pd (22.5 mg, 0.128 mmol). The mixture was degassed with N 2 three times, then heated to 100° C. and stirred for overnight. The reaction was concentrated in vacuo. The residue was further purified by prep-HPLC to give the desired product Example 117 (60 mg, 54.2% yield) as a white solid. LCMS [M+1] + =440.1. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 3H), 1.65-1.80 (m, 1H), 0.8-0.94 (m, 4H).

To the solution of Example 118a (100 mg, 0.26 mmol, 1.0 eq) in dioxane (5 mL) were added Example 118b (95 mg, 0.78 mmol, 3.0 eq), Cs 2 CO 3 (170 mg, 0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) and Pd 2 (dba) 3 ·CHCl 3 (27 mg, 0.026 mmol, 0.1 eq). The reaction solution was stirred for 4 h at 110° C. under N 2 . The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the desired product Example 118 (21.9 mg, 17.9% yield) as a light yellow solid. LCMS [M+1] + =469.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.94 (s, 1H), 9.04 (s, 1H), 8.59 (s, 1H), 7.69 (dd, J=7.8, 1.8 Hz, 1H), 7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 3.00-2.89 (m, 1H), 1.22 (s, 9H), 1.13-1.00 (m, 4H).

To a solution of Example 119a (100 mg, 0.26 mmol) and Example 119b (44 mg, 0.39 mmol) in 1,4-dioxane (2 mL) were added Pd 2 (dba) 3 (24 mg, 0.026 mmol), xantphos (30 mg, 0.052 mmol) and Cs 2 CO 3 (170 mg, 0.52 mmol). The mixture was degassed by nitrogen for 3 times and stirred at 110° C. for 2 h. When completed, the reaction was cooled to r.t., diluted with MeOH (5 mL) and filtered. The filtrate was purified directly by Prep-HPLC to give the desired product Example 119 (19.7 mg, 16.6% yield) as a yellow solid. LCMS [M+1] + =460.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 9.40 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.05 (d, J=4.6 Hz, 1H), 7.92 (s, 1H), 7.65 (q, J=8.1, 5.8 Hz, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.04 (dt, J=8.0, 3.9 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.95 (dt, J=8.1, 3.7 Hz, 1H), 1.07 (t, J=3.7 Hz, 2H), 0.99 (dd, J=7.9, 4.5 Hz, 2H).

To a solution of Example 120a (5.37 g, 47.9 mmol, 1.0 eq) in ACN (250 mL) was added NBS (6.2 g, 52.7 mmol, 1.1 eq) at 0° C. under N 2 protection. The reaction solution was stirred at r.t. for 1 h, and then the mixture was concentrated. The residue was purified by silica gel flash column chromatography (Petroleum Ether/EtOAc=5/1) to afford the product Example 120b (6.8 g, 75% yield) as a white solid. LCMS [M+1] + =190.2.

To a solution of Example 120b (6.0 g, 31.4 mmol, 1.0 eq) in dry THF (150 mL) was added n-BuLi (44 mL, 2.5 M in THF, 110 mmol, 3.5 eq) dropwise at ˜78° C. under N 2 protection. The mixture was stirred for 5 min at the same temperature. Acetone (18.2 g, 314 mmol, 10.0 eq) in THF (50 mL) was added dropwise at ˜78° C. under N 2 protection. The mixture was warmed to r.t. and stirred for 30 min. The reaction was poured into saturated aqueous NH 4 Cl (100 mL) and extracted with EtOAc (200 mL*2). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude product was purified by silica gel flash column chromatography (Petroleum Ether/EtOAc=5/1) to afford the product Example 120c (3.5 g, 65% yield) as a green solid. LCMS [M+1] + =171.2.

To a solution of Example 120d (100 mg, 0.26 mmol, 1.0 eq,) in dioxane (3 mL) were added Cs 2 CO 3 (169 mg, 0.52 mmol, 2.0 eq), Example 120c (132 mg, 0.77 mmol, 3.0 eq), Xantphos (29 mg, 0.05 mmol, 0.2 eq) and Pd 2 (dba) 3 ·CHCl 3 (31 mg, 0.03 mmol, 0.1 eq). The reaction mixture was stirred for 3 h at 110° C. under N 2 protection. After cooled to room temperature, the solvent was removed, the crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 120 (48.4 mg, 36% yield) as an off-white solid. LCMS [M+1] + =518.4. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 10.14 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 7.97 (dd, J=10.8, 8.4 Hz, 1H), 7.80 (s, 1H), 7.73 (dd, J=7.8, 1.5 Hz, 1H), 7.62 (dd, J=7.8, 1.8 Hz, 1H), 7.49 (dd, J=8.1, 1.8 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 5.26 (s, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 3.05-2.90 (m, 1H), 1.46 (s, 6H), 1.16-0.94 (m, 4H).

To a solution of Example 121a (200 mg, 1.5 mmol, 1.0 eq) in dioxane (3 mL) was added Example 121b (265.5 mg, 4.5 mmol, 3.0 eq). The reaction solution was stirred for 16 h at r.t. and concentrated to dryness. The residue was suspended in DCM and sonicated. The resulting solid was collected by filtration to afford Example 121c (57 mg, 37% yield) as a white solid.

To a solution of Example 121d (60 mg, 0.16 mmol, 1.0 eq,) and Example 121c (49 mg, 0.48 mmol, 3.0 eq) in dioxane (2 mL) were added Cs 2 CO 3 (104.3 mg, 0.32 mmol, 2.0 eq), Xantphos (17.4 mg, 0.03 mmol, 0.2 eq) and Pd 2 (dba) 3 ·CHCl 3 (20.7 mg, 0.02 mmol, 0.1 eq). The reaction mixture was stirred at 110° C. for 4 h under N 2 protection. After cooled to room temperature, the solvent was removed, and the crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 121 (40.1 mg, 56% yield) as a yellow solid. LCMS [M+1] + =450.4. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.97 (s, 1H), 9.13 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.63 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (dd, J=7.8, 1.5 Hz, 1H), 7.39 (s, 1H), 7.26 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.86-3.73 (m, 1H), 3.70 (s, 3H), 3.00-2.88 (m, 1H), 1.16-0.95 (m, 10H).

To a solution of Example 122a (700 mg, 4.61 mmol) in THF (65 mL) was added MeMgCl (15 mL, 45 mmol) at 0° C. under argon protection. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Then the mixture was quenched by aq. NH 4 C 1 , extracted with EA (50 mL*2). The combined organic phase was washed by water, brine and dried over anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure to give Example 122b (600 mg, 85.7% yield) as brown oil, which was used for the next step directly.

To a solution of Example 122c (100 mg, 0.26 mmol,) and Example 122b (59 mg, 0.39 mmol) in 1, 4-dioxane (2.5 mL) were added Pd 2 (dba) 3 (24 mg, 0.026 mmol), Xantphos (30 mg, 0.052 mmol) and Cs 2 CO 3 (170 mg, 0.52 mmol). The mixture was degassed by nitrogen for 3 times and stirred at 110° C. for 2 h. When completed, the reaction was cooled to r.t., diluted with MeOH (5 mL) and filtered. The filtrate was purified directly by Prep-TLC (DCM/MeOH=15/1) to give the desired product Example 122 (16 mg, 11.5% yield) as a yellow solid. LCMS [M+1] + =500.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 9.90 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 2.94 (s, 1H), 1.40 (s, 6H), 1.05 (s, 2H), 0.98 (d, J=7.7 Hz, 2H).

To the solution of Example 123a (100 mg, 0.26 mmol, 1.0 eq) in dioxane (5 mL) were added Example 123b (95 mg, 0.78 mmol, 3.0 eq), Cs 2 CO 3 (170 mg, 0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) and Pd 2 (dba) 3 ·CHCl 3 (27 mg, 0.026 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at 110° C. under N 2 . The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the desired product Example 123 (26.1 mg, 21.4% yield) as a light yellow solid. LCMS [M+1] + =469.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 9.05 (s, 1H), 8.91 (brs, 1H), 8.56 (s, 1H), 7.67 (dd, J=7.8, 1.5 Hz, 1H), 7.52 (dd, J=8.1, 1.8 Hz, 1H), 7.29 (t, J=8.1 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 3.00-2.88 (m, 1H), 1.22 (s, 9H), 1.12-0.99 (m, 4H).

To a solution of Example 124b (465 mg, 5.28 mmol, 1.5 eq) in DMF (10 mL) was added Cs 2 CO 3 (2.3 g, 7.04 mmol, 2.0 eq). The reaction mixture was stirred for 10 min at r.t., followed by addition of Example 124a (500 mg, 3.52 mmol, 1.0 eq) in DMF (3 mL). The mixture was stirred for 4 h at 80° C. After cooled to room temperature, the mixture was poured into H 2 O (25 mL) and extracted with EtOAc (50 mL*2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (1/1) to afford the product Example 124c (250 mg, 32% yield) as a yellow solid. LCMS [M+1] + =211.2.

To a solution of Example 124c (250 mg, 1.19 mmol, 1.0 eq) in MeOH (30 mL) was added Pd/C (25 mg) under N 2 protection. The suspension was degassed under vacuum and purged with H 2 three times, and the reaction mixture was stirred at r.t. for 0.5 h under H 2 balloon. The solid was filtered out, and the filtrate was concentrated to afford the product Example 124d (230 mg, crude, yield: quant.) as yellow oil. LCMS [M+1] + =181.2.

To a solution of Example 124e (100 mg, 0.26 mmol, 1.0 eq,) in dioxane (3 mL) were added Cs 2 CO 3 (169.5 mg, 0.52 mmol, 2.0 eq), Example 124d (93.7 mg, 0.52 mmol, 2.0 eq) and 3 rd -t-Bu-xphos-Pd (26.7 mg, 0.03 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at 110° C. under N 2 protection. After cooled to room temperature, the solvent was removed, and the crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 124 (37.0 mg, 27% yield) as a yellow solid. LCMS [M+1] + =528.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 9.87 (s, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 7.90 (d, J=3.0 Hz, 1H), 7.76 (s, 1H), 7.67 (dd, J=7.8, 1.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.40 (dd, J=9.0, 3.0 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 5.08-4.99 (m, 1H), 3.95 (s, 3H), 3.91-3.75 (m, 4H), 3.72 (s, 3H), 3.00-2.88 (m, 1H), 2.29-2.05 (m, 1H), 2.03-1.89 (m, 1H), 1.15-0.91 (m, 4H).

To a solution of Example 125a (5.0 g, 35.2 mmol, 1.0 eq) in DMF (50 mL) was added NaSMe (18.5 g, 20% in water, 53 mmol, 1.5 eq) dropwise at 0° C. The reaction mixture was stirred for 1 h at r.t. The reaction was diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (2/1) to afford the product Example 125b (4.9 g, 82% yield) as a yellow solid. LCMS [M+1] + =171.2.

To a solution of Example 125b (4.8 g, 28 mmol, 1.0 eq) in MeOH (100 mL) were added Fe powder (7.9 g, 141 mmol, 5.0 eq), NH 4 Cl (7.5 g, 141 mmol, 5.0 eq) and AcOH (3 mL). The reaction mixture was stirred for 1 h at 80° C. The reaction mixture was basified with K 2 CO 3 (pH=7-8). The solid was filtered out, and the filtrate was concentrated. The crude product was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (2/1) to afford the product Example 125c (3.6 g, 92% yield) as red oil.

LCMS [M+1] + =141.2.

To a solution of Example 125d (5.0 g, 21 mmol, 1.0 eq) in dry THF (50 mL) was added Example 125e (105 mL, 1.0 M in THF, 105 mmol, 5.0 eq) dropwise at ˜15° C. under N 2 protection. The mixture was stirred for 0.5 h at r.t. The mixture was poured into saturated aqueous of NH 4 Cl (100 mL) and extracted with EtOAc (150 mL*2). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (10/1) to afford the product Example 125f (2.8 g, 62% yield) as yellow oil. LCMS [M+1] + =216.2

To a solution of Example 125c (500 mg, 3.57 mmol, 1.0 eq) in DMF (10 mL), was added NaH (1.43 g, 60% in mineral oil, 35.7 mmol, 10.0 eq) in portions at 0° C. After addition, the reaction was stirred for 30 min at 0° C., followed by addition of Example 125f (768 mg, 3.57 mmol, 1.0 eq) in DMF. The reaction mixture was stirred for 1 h at r.t. The reaction solution was poured into water, extracted with EtOAc (50 mL*2), and the combined organic layer dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (3/1) to afford the product Example 125g (370 mg, 32% yield) as a yellow solid. LCMS [M+1] + =320.1

To a solution of Example 125g (200 mg, 0.627 mmol, 1.0 eq) in DCM (4 mL) was added m-CPBA (434 mg, 2.51 mmol, 4.0 eq) at 0° C. The reaction mixture was stirred for 1 h at r.t. The reaction was diluted with DCM (50 mL), washed with NaOH aqueous solution (1M), Na 2 SO 3 aqueous solution and brine. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (1/1) to afford the product Example 125h (60 mg, 27% yield) as a yellow solid. LCMS [M+1] + =352.2.

To a solution of Example 125h (50 mg, 0.142 mmol, 1.0 eq) in dioxane (2 mL) were added Cs 2 CO 3 (93 mg, 0.285 mmol, 2.0 eq), Example 125i (27 mg, 0.285 mmol, 2.0 eq), Xantphos (17 mg, 0.028 mmol, 0.2 eq) and Pd 2 (dba) 3 ·CHCl 3 (15 mg, 0.014 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at 110° C. under N 2 protection. After cooled to room temperature, the solvent was removed, and the crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 125 (17 mg, 29% yield) as a yellow solid. LCMS [M+1] + =411.2. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.83 (s, 1H), 10.54 (s, 1H), 9.18 (s, 1H), 8.86-8.78 (m, 2H), 8.62 (dd, J=4.8, 2.1 Hz, 1H), 8.28 (dd, J=7.8, 2.1 Hz, 1H), 8.17 (dd, J=9.3, 1.5 Hz, 1H), 7.61 (dd, J=9.3, 4.8 Hz, 1H), 7.33 (dd, J=7.8, 4.8 Hz, 1H), 3.31 (s, 3H), 3.03-2.90 (m, 1H), 1.16-0.99 (m, 4H).

To a solution of Example 126a (1.54 g, 7.1 mmol, 1.0 eq) in DMF (20 mL), was added NaH (2.86 g, 60% in mineral oil, 71 mmol, 10.0 eq) in portions at 0° C. Example 126b (1.0 g, 7.1 mmol, 1.0 eq) in DMF was added to the solution. The reaction mixture was stirred for 1 h at r.t. The reaction was poured into water (100 mL), extracted with EtOAc (100 mL*3), and the combined organic layers were dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (3/1) to afford the product Example 126c (570 mg, 25% yield) as a yellow solid. LCMS [M+1] + =320.1

To a solution of Example 126c (740 mg, 2.32 mmol, 1.0 eq) in DCM (8 mL) was added m-CPBA (1.61 g, 9.28 mmol, 4.0 eq) at 0° C. The reaction mixture was stirred for 2 h at r.t. The reaction was diluted with DCM (20 mL), washed with NaOH aqueous solution (1M), Na 2 SO 3 aqueous solution and brine. The organic layer was dried over Na 2 SO 4 , and concentrated. The residue was purified by silica gel flash column chromatography, eluted with Petroleum Ether/EtOAc (1/1) to afford the product Example 126d (470 mg, 57% yield) as a yellow solid. LCMS [M+1] + =352.2.

To a solution of Example 126d (100 mg, 0.285 mmol, 1.0 eq) in dioxane (2 mL) were added Cs 2 CO 3 (186 mg, 0.57 mmol, 2.0 eq), Example 126e (87 mg, 0.57 mmol, 2.0 eq), BINAP (36 mg, 0.057 mmol, 0.2 eq) and Pd 2 (dba) 3 ·CHCl 3 (30 mg, 0.028 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at 110° C. under N 2 protection. After cooled to room temperature, the solvent was removed, and the crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 126 (12 mg, 9% yield) as an off-white solid. LCMS [M+1] + =468.1. 1 H NMR (300 MHz, DMSO-d 6 ) δ11.84 (s, 1H), 10.04 (s, 1H), 9.14 (s, 1H), 8.95 (s, 1H), 8.69-8.63 (m, 1H), 8.35 (dd, J=2.7, 0.9 Hz, 1H), 8.26 (dd, J=7.8, 2.4 Hz, 1H), 7.78 (dd, J=8.7, 2.4 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.32 (dd, J=7.8, 4.8 Hz, 1H), 5.09 (s, 1H), 3.31 (s, 3H), 3.01-2.88 (m, 1H), 1.45 (s, 6H), 1.12-0.97 (m, 4H).

To a solution of Example 127a (550 mg, 2.32 mmol, 1.0 eq) in DCM (10 mL) was added BBr 3 (1.15 g, 4.64 mmol, 2.0 eq) at ˜20° C. The reaction mixture was stirred for 2 h at r.t. It was quenched with NaHCO 3 aqueous solution (10 mL), extracted with DCM (20 mL*3). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to afford the product Example 127b (500 mg, crude, 96% yield) as a brown solid. LCMS [M+1] + =224.3.

To a mixture of Example 127b (500 mg, 2.24 mmol, 1.0 eq) and K 2 CO 3 (927 mg, 6.72 mmol, 3.0 eq) in ACN (10 mL) was added CD 3 I (487.2 mg, 3.36 mmol, 1.5 eq). The reaction mixture was stirred for 6 h at 80° C. After cooled to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography eluted with PE/EtOAc (1/3) to afford the product Example 127c (200 mg, 37% yield) as a yellow solid. LCMS [M+1] + =241.2.

To a solution of Example 127c (200 mg, 0.84 mmol, 1.0 eq) in MeOH (20 mL) was added Pd/C (20 mg) under N 2 protection, the suspension was degassed under vacuum and purged with H 2 three times, the reaction mixture was stirred at r.t. for 1 h under H 2 balloon. The solid was filtered out, the filtrate was concentrated to afford the product Example 127d (160 mg, 90% yield) as a yellow solid. LCMS [M+1] + =211.2.

To a solution of Example 127e (170 mg, 0.72 mmol, 1.0 eq) and Example 127d (151.2 mg, 0.72 mmol, 1.0 eq) in dry THF (6 mL) was added LiHMDS (1.4 mL, 1 M in THF, 1.44 mmol, 2.0 eq) dropwise at ˜20° C. under N 2 protection. The reaction mixture was stirred for 0.5 h at r.t., and then the silica was added to the mixture and concentrated. The residue was purified by silica gel flash column chromatography eluted with DCM/MeOH (20/1) to afford the product Example 127f (45 mg, 15% yield) as a yellow solid. LCMS [M+1] + =409.4.

To a solution of Example 127f (45 mg, 0.11 mmol, 1.0 eq) in THF (3 mL) was added Example 127g (0.9 mL, 1.0 M in THF, 0.88 mmol, 8.0 eq) dropwise at 0° C. under N 2 protection. The mixture was stirred for 0.5 h at r.t. The reaction was poured into saturated aqueous of NH 4 Cl (10 mL) and extracted with EtOAc (15 mL×3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 127f (40 mg, 93% yield) as a yellow solid. LCMS [M+1] + =390.3.

To a solution of Example 127f (40 mg, 0.10 mmol, 1.0 eq) in dioxane (3 mL) were added Cs 2 CO 3 (65.2 mg, 0.20 mmol, 2.0 eq), Example 1271 (26.2 mg, 0.30 mmol, 3.0 eq), Xantphos (11.6 mg, 0.02 mmol, 0.2 eq) and Pd 2 (dba) 3 ·CHCl 3 (10.4 mg, 0.01 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at 110° C. under N 2 protection. After cooled to room temperature, the solvent was removed, the crude product was purified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 127 (3.1 mg, 7% yield) as a yellow solid. LCMS [M+1] + =439.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 10.93 (s, 1H), 9.13 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.64 (dd, J=7.8, 1.5 Hz, 1H), 7.52 (dd, J=8.1, 1.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 3.08-2.90 (m, 1H), 2.11-1.93 (m, 1H), 1.18-0.98 (m, 4H), 0.81 (d, J=6.0 Hz, 4H).

To a solution of Example 128 (100 mg, 0.26 mmol, 1.0 eq) in dioxane (5 mL) were added Example 128b (95 mg, 0.78 mmol, 3.0 eq), Cs 2 CO 3 (170 mg, 0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) and Pd 2 (dba) 3 ·CHCl 3 (27 mg, 0.026 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at 110° C. under N 2 . The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by Prep-TLC (DCM/MeOH=15/1) to give 32.0 mg crude product (90% purity) and further purified by Prep-TLC (DCM/MeOH=15/1) to afford the desired product Example 128 (12.1 mg, 9.9% yield) as a yellow solid. LCMS [M+1] + =469.3. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 9.04 (s, 1H), 8.91 (brs, 1H), 8.56 (s, 1H), 7.67 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (d, J=6.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 3.00-2.88 (m, 1H), 1.22 (s, 9H), 1.12-0.99 (m, 4H).

A solution of Example 129b (300 mg, 2.19 mmol) in 1,4-dioxane (5 mL) was treated with Example 129a (353 mg, 3.28 mmol) and TEA (664 mg, 6.57 mmol). The mixture was stirred at r.t. for 16 hrs. After reaction completed, the solvent was concentrated, the residue was suspended in DCM (5 mL), sonicated and the resulting solid was collected via filtration, dried to afford the desired product Example 129c (253 mg, crude) as a white solid. LCMS [M+1] + =115.0.

To a solution of Example 129a (80 mg, 0.21 mmol) and Example 129c (29.3 mg, 0.26 mmol) in 1,4-dioxane (2 mL) were added Pd 2 (dba) 3 (19.6 mg, 0.021 mmol), XantPhos (24.7 mg, 0.042 mmol) and Cs 2 CO 3 (140 mg, 0.43 mmol). The mixture was sealed, degassed by nitrogen for 3 times and stirred at 110° C. for 16 h. When completed, the reaction was cooled to r.t. and filtered. The filtrate was purified directly by Prep-HPLC to give the desired product Example 129 (21.8 mg, 22.7% yield) as a white solid. LCMS [M+1] + =452.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 9.59 (s, 1H), 9.02 (d, J=5.3 Hz, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 4.09 (s, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 3.54 (s, 2H), 2.84 (d, J=4.4 Hz, 3H), 2.59 (d, J=8.4 Hz, 1H), 1.15 (d, J=6.7 Hz, 3H).

To a solution of Example 130a (200 mg, 1.92 mmol) in acetone (4 mL) was added TEA (291 mg, 2.88 mmol) at 0-5° C., and then Example 130b (311 mg, 2.88 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h under N 2 . The white solid was filtered off. To the filtration was added NH 3 —H 2 O (5 eq.). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was cooled and added Petroleum ether/EtOAc=1/1 (3 mL). The solid was collected by filtered and dried to give Example 130c (17 mg, 8% yield) as a white solid.

To a solution of Example 130d (63 mg, 0.16 mmol) in dioxane (1.5 mL) were added Example 130c (17 mg, 0.16 mmol), Pd 2 (dba) 3 (15 mg, 0.016 mmol), Xantphos (10 mg, 0.016 mmol) and Cs 2 CO 3 (108 mg, 0.33 mmol). The mixture was sealed and heated to 120° C. for 2 h. The mixture was filtrated and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give Example 130 (8.7 mg, 12% yield) as a yellow solid. LCMS [M+1] + =451.1. 1 H NMR (400 MHz, Chloroform-d) δ 11.12 (s, 1H), 8.90 (s, 1H), 8.22-8.03 (m, 3H), 7.75 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.25-7.22 (m, 1H), 4.78 (d, J=65.0 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 2.66-2.57 (m, 1H), 1.94-1.76 (m, 2H), 1.27-1.17 (m, 3H), 1.07-1.0 (m, 2H).