RU2813233C2 - Tyk2 inhibitors and their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (XII), where:

represents ring B is selected from the group consisting of phenyl and pyridyl; R¹⁶ is -C(=O)R¹¹; R³ represents hydrogen; R⁴ represents -OR^b; L represents bond; ring A is a 5-membered heteroaryl containing three nitrogen atoms, where ring A may be optionally replaced by one R^A; R^A is selected from the group consisting of C₁-C₆alkyl and C₁-C₆ deuteroalkyl; R⁵ is selected from the group consisting of -NR⁹R¹⁰, -NR⁸S(=O)R⁷, NR⁸C (=O) NR⁹R¹⁰, NR⁸C(=O)R⁷ and 4–5-membered heterocycloalkyl containing two nitrogen atoms; where heterocycloalkyl is substituted with two substituents, each of which is independently selected from the group consisting of oxo and C₁-C₆alkyl; R⁷ is selected from the group consisting of C₁-C₆alkyl and C₃-cycloalkyl; R⁸ represents hydrogen; R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, C₁-C₆alkyl and 5–6-membered heteroaryl containing one or two nitrogen atoms; wherein the heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of oxo, halogen, -CN, C₁-C₆alkyl and morpholinyl; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a 4-membered heterocycloalkyl containing one nitrogen atom optionally substituted by two substituents selected from C₁-C₆alkyl; R¹¹ is selected from the group consisting of C₁-C₆alkyl, C₁-C₆deuteroalkyl and C₃-cycloalkyl; wherein each alkyl and cycloalkyl is optionally substituted with one R^11a; R^11a is selected from halogen; R^b is selected from C₁-C₆alkyl. The invention also relates to specific compounds and a pharmaceutical composition based on these compounds and the compound of formula (XII).

EFFECT: obtaining new compounds and a pharmaceutical composition based on them which can be used in medicine in the treatment and prevention of cancer.

12 cl, 10 tbl, 203 ex

Description

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 62/749003, filed October 22, 2018; US Provisional Patent Application No. 62/756942, filed November 7, 2018; US Provisional Patent Application No. 62/839459, filed April 26, 2019; US Provisional Patent Application No. 62/875449, filed July 17, 2019; US Provisional Patent Application No. 62/893721, filed August 29, 2019; and U.S. Provisional Patent Application No. 62/907354, filed September 27, 2019, each of which is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] Described herein are compounds, methods for preparing such compounds, pharmaceutical compositions and drugs containing such compounds, and methods of using such compounds to inhibit non-receptor tyrosine protein kinase 2 (“TYK2”), also known as tyrosine kinase 2.

BACKGROUND OF THE INVENTION

[0003] TYK2 is a non-receptor tyrosine kinase that is a member of the Janus kinase (JAK) 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 signal transduction. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as type I and type III interferon receptors, and is activated by these receptors upon binding to cytokines. Cytokines involved in TYK2 activation include interferons (eg, IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin) and interleukins (eg, 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.) Activated TYK2 then proceeds to phosphorylate additional signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0004] Activation of TYK2 by IL-23 has been found to be associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study involving 2622 individuals with psoriasis identified associations between disease susceptibility and TYK2. Knockout or suppression of TYK2 with tyrphostin leads to a significant reduction in the severity of dermatitis induced by both IL-23 and IL-22.

[0005] 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 mucus hypersecretion are mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.

[0006] Reducing TYK2 activity results in joint protection from anti-collagen antibody-induced arthritis, a human model of rheumatoid arthritis. Mechanistically, decreased Tyk2 activity results in decreased production of Th1/Th17-related cytokines and matrix metalloproteinases, as well as other key markers of inflammation.

[0007] TYK2 knockout mice exhibited complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) with no infiltration of CD4 T cells into the spinal cord compared to controls, suggesting that TYK2 is essential for development of disease mediated by pathogenic CD4 cells in MS. This confirms the results of earlier studies establishing a link between increased TYK2 expression and susceptibility to MS. Loss-of-function mutations in TYK2 result in decreased demyelination and increased neuronal remyelination, further suggesting that TYK2 inhibitors have a role in the treatment of MS and other CNS demyelinating disorders.

[0008] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduces the severity of footpad thickening induced by methylated BSA injection, psoriasis-like skin inflammation induced by imiquimod, and colitis induced by sodium dextran sulfate or 2,4,6-trinitrobenzenesulfonic acid in mice.

[0009] Pooled studies of the relationships and associations of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) have demonstrated a strong and significant correlation between loss-of-function mutations in TYK2 and a decreased prevalence of SLE in families members who suffer from it. Genome-wide association studies involving individuals with SLE versus a cohort without it have demonstrated a highly significant correlation between the TYK2 locus and SLE.

[0010] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibited attenuated cytotoxic T cell responses and accelerated tumor development. However, these effects were found to be associated with effective suppression of natural killer (NK) cells and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other members of the JAK family, such as JAK3, play similar roles in the immune system, TYK2 has been proposed as a better target due to its involvement in fewer signaling pathways that are more closely coupled to each other, resulting in fewer off-targets. effects.

[0011] Studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on STAT1-mediated signaling, which is activated by IL-10-activated TYK2, to maintain survival cancer cells by increasing the expression of the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, results in decreased cell growth. Specific TYK2 activating mutations that promote cancer cell survival include mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, the kinase function of TYK2 was also determined to be essential for promoting cancer cell survival, as TYK2 enzymes having kinase-inactivating mutations (M978Y or M978F) in addition to the activating mutation (E957D) were consequently unable to mediate transformation.

[0012] Thus, selective inhibition of TYK2 has been proposed as a suitable target for patients with tumors dependent on IL-10 and/or BCL2, such as in 70% of adult T-cell leukemias. TYK2-mediated STAT3 signaling has also been shown to mediate amyloid-β peptide (Aβ)-induced neural cell death. Reduced TYK2-mediated STAT3 phosphorylation following Aβ administration resulted in decreased neuronal cell death, and increased STAT3 phosphorylation was observed in postmortem brain samples from Alzheimer's disease patients.

[0013] Inhibition of JAK-STAT signaling pathways is also involved in hair growth and reversal of hair loss associated with alopecia areata.

[0014] Accordingly, compounds that inhibit TYK2 activity, especially those that are selective for JAK2, are advantageous. Such compounds must provide a pharmacological effect beneficial for the treatment of one or more of the conditions described herein, without the side effects associated with JAK2 inhibition.

[0015] Accordingly, there is a need to develop new inhibitors that have more effective or advantageous pharmaceutically significant properties, such as selectivity over other JAK kinases (especially JAK2).

BRIEF DESCRIPTION OF THE INVENTION

[0016] Disclosed herein is a compound of formula (XII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

ring B represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

or -L-ring A is missing;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[0017] Also disclosed herein is a compound of formula (XIII) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

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

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

or -L-ring A is missing;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[0018] Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable excipient.

[0019] Also disclosed herein is a method of inhibiting the TYK2 enzyme in a patient or biological specimen, comprising contacting said patient or biological specimen with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0020] 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 transplant-associated disorder. In some embodiments, the disorder is associated with signaling through type I interferons, IL-10, IL-12, or IL-23.

INCLUSION BY REFERENCE

[0021] All publications, patents and patent applications mentioned in this description are incorporated herein by reference for the specific purposes defined herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0022] As used herein and in the accompanying claims, the singular number includes the plural entities defined unless the context clearly requires otherwise. Thus, for example, a reference to “agent” includes a plurality of such agents, and a reference to a “cell” includes a reference to one or more cells (or a plurality of cells) and equivalents thereof known to those skilled in the art, etc. When ranges are used herein to describe physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and their specific embodiments are intended to be included. The term "approximately" when referring to a number or numerical range means that the number or numerical range referred to is an approximate value within the variation of the readings in the experiment (or within the statistical uncertainty of the experiment), and thus the number or numerical range in some cases will vary by 1%-15% from the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “comprising”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition, a composition, method or process, etc. described herein “consists of” or “consists essentially of” the features described.

[0023] The following terms, as used in the specification and appended claims, have the meanings set forth below unless otherwise defined.

[0024] "Aliphatic chain" refers to a linear chemical moiety consisting of only carbon atoms and hydrogen atoms. 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 unsaturated bond. In some embodiments, an unsaturated aliphatic chain contains more than one unsaturated bond. In some embodiments, the unsaturated aliphatic chain contains two unsaturated bonds. In some embodiments, the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds.

[0025] “Alkyl” refers to an optionally substituted straight chain saturated hydrocarbon monoradical or an 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, t-amyl and hexyl, as well as longer chain alkyl groups such as heptyl, octyl, etc. A numerical range such as "C ₁ -C ₆ alkyl" whenever it appears herein means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 atoms carbon or 6 carbon atoms, although this definition also covers cases in which the term "alkyl" appears without a numerical range designation. In some embodiments, alkyl is C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl or C ₁ alkyl. Unless specifically stated otherwise in the specification, the 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, alkyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0026] "Alkenyl" refers to an optionally substituted straight chain hydrocarbon monoradical or an 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 from two to about six carbon atoms. The group may appear in a cis or trans conformation at 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 . A numerical range such as "C ₂ -C ₆ alkenyl" whenever it appears herein 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 this definition also covers cases in which the term "alkenyl" appears without a numerical range designation. In some embodiments, alkenyl is C ₂ -C ₁₀ alkenyl, C ₂ -C ₉ alkenyl, C ₂ -C ₈ alkenyl, C ₂ -C ₇ alkenyl, C ₂ -C ₆ alkenyl, C ₂ -C ₅ alkenyl, C ₂ -C ₄ alkenyl, C ₂ -C ₃ alkenyl or C ₂ alkenyl. Unless specifically stated otherwise in the specification, the 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, alkenyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0027] "Alkynyl" refers to an optionally substituted straight chain hydrocarbon monoradical or an 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-butadinyl, and the like. A numerical range such as "C ₂ -C ₆ alkynyl" whenever it appears herein 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 cases in which the term "alkynyl" appears without a numerical range designation. In some embodiments, the alkynyl is C ₂ -C ₁₀ alkynyl, C ₂ -C ₉ alkynyl, C ₂ -C ₈ alkynyl, C ₂ -C ₇ alkynyl, C ₂ -C ₆ alkynyl, C ₂ -C ₅ alkynyl, C ₂ -C ₄ alkynyl, C ₂ -C ₃ alkynyl or C ₂ alkynyl. Unless specifically stated otherwise in the specification, the 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, the alkynyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0028] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless specifically stated otherwise in the specification, the 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, the alkylene is optionally substituted with oxo, halogen, CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, the alkylene is optionally substituted with oxo, halogen, α, -CN, -CF ₃ , OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0029] "Alkoxy" refers to a radical of the formula -OR _a where R _a is an alkyl radical as defined. Unless specifically stated otherwise in the specification, the 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, the alkoxy is optionally substituted with oxo, halogen, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, alkoxy is optionally substituted with oxo, halogen, CN, -CF ₃ , OH or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0030] "Aminoalkyl" refers to an alkyl radical as defined above that is substituted with 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 includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0031] "Aryl" refers to a radical derived from a hydrocarbon ring system containing hydrogen, 6-30 carbon atoms and at least one aromatic ring. An aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (in the case of condensation with a cycloalkyl or heterocycloalkyl ring, the aryl is linked through an aromatic ring atom) or bridged ring systems. In some embodiments, aryl is 6-10 membered aryl. In some embodiments, aryl is 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, pleiaden , pyrene and triphenylene. In some embodiments, aryl is phenyl. Unless specifically stated otherwise in the specification, 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, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ , OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0032] “Cycloalkyl” refers to a stable partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (in the case of condensation with an aryl or heteroaryl ring, the cycloalkyl is linked through a non-aromatic ring atom) or bridged ring systems. Exemplary cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C ₃ -C ₁₅ cycloalkyl), three to ten carbon atoms (C ₃ -C ₁₀ cycloalkyl), three to eight carbon atoms (C ₃ -C ₈ cycloalkyl), three to six carbon atoms (C ₃ -C ₆ cycloalkyl), 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 3-6 membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-6 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, as well as bicyclo[3.3.2]decane and 7,7-dimethylbicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless specifically stated otherwise in the specification, 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, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, the 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.

[0033] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted with one or more deuterium atoms. In some embodiments, the alkyl is replaced by 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 .

[0034] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted with 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 atoms. 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.

[0035] "Halogen" or "halogen atom" refers to bromine, chlorine, fluorine or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0036] “Heteroalkyl” refers to an alkyl group in which one or more skeletal alkyl atoms are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or their combinations. The heteroalkyl is attached to the rest of the molecule at the heteroalkyl carbon atom. In one aspect, heteroalkyl is C ₁ -C ₆ heteroalkyl, where heteroalkyl consists of 1-6 carbon atoms and one or more non-carbon atoms, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl) -), sulfur or combinations thereof, where the heteroalkyl is attached to the rest of the molecule at the heteroalkyl carbon atom. 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 specifically stated otherwise, 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, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, 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.

[0037] "Hydroxyalkyl" refers to an alkyl radical as defined above that is substituted with one or more hydroxyls. In some embodiments, the alkyl is replaced by one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0038] “Heterocycloalkyl” refers to a stable 3-24 membered partially or fully saturated ring radical containing 2-23 carbon atoms and one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless specifically stated otherwise, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (in the case of condensation with an aryl or heteroaryl ring, the heterocycloalkyl is linked through a non-aromatic ring atom) or bridged ring systems ; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. Exemplary heterocycloalkyls include, but are not limited to, heterocycloalkyls having two to fifteen carbon atoms (C ₂ -C ₁₅ heterocycloalkyl), two to ten carbon atoms (C ₂ -C ₁₀ heterocycloalkyl), two to eight carbon atoms (C ₂ -C ₈ heterocycloalkyl), two to six carbon atoms (C ₂ -C ₆ heterocycloalkyl), 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 3-6 membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5-6 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-ox opiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl , piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tritianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,3-dihydroisobenzo furan-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 carbohydrates, including, without limitation, monosaccharides, disaccharides and oligosaccharides. It should be 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 heteroatoms) that form the heterocycloalkyl (ie, the skeletal atoms of the heterocycloalkyl ring). Unless specifically stated otherwise, 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, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃ , OH, -OMe, NH ₂ , or -NO ₂ . In some embodiments, 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.

[0039] “Heteroalkyl” refers to an alkyl group in which one or more skeletal alkyl atoms are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or their combinations. The heteroalkyl is attached to the rest of the molecule at the heteroalkyl carbon atom. In one aspect, heteroalkyl is C ₁ -C ₆ heteroalkyl. Unless specifically stated otherwise, 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, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃ , OH, -OMe, NH ₂ or -NO ₂ . In some embodiments, 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.

[0040] “Heteroaryl” refers to a 5- to 14-membered radical with a ring system containing hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus 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 (in the case of condensation with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is linked through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzodolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinil, 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. e. thienyl). Unless specifically stated otherwise in the specification, 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, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ , OH, -OMe, NH ₂ , or -NO ₂ . In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ , OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0041] The terms “treat,” “prevent,” “mitigate,” and “suppress,” and words derived from them, as used herein do not necessarily imply 100% or complete treatment, prevention, or amelioration or suppression. Rather, there are varying degrees of treatment, prevention, mitigation, and suppression that would be recognized by one of ordinary skill in the art as having potential benefit or therapeutic effect. In this regard, the disclosed methods may provide any amount of any level of treatment, prevention, amelioration, or suppression of a disorder in a mammal. For example, the severity of a disorder, including its associated symptoms or conditions, may be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10%. In addition, treatment, prevention, amelioration, or suppression provided by the methods disclosed herein may include treating, preventing, ameliorating, or suppressing one or more conditions or symptoms of a disorder, such as cancer or an inflammatory disease. Also for the purposes of this document, “treatment,” “prevention,” “mitigation,” or “suppression” includes delaying the onset of a disorder or its corresponding symptom or condition.

[0042] The terms "effective amount" or "therapeutically effective amount" as used herein refer to a sufficient amount of an administered compound disclosed herein that will reduce to some extent one or more symptoms of the disease or condition being treated. for example, cancer or inflammatory disease. In some embodiments, the result is a reduction in the severity and/or alleviation of signs, symptoms or causes of a disease or any other desired change in a biological system. For example, an “effective amount” for therapeutic routes of administration is the amount of a composition containing a compound disclosed herein that is required to provide clinically significant reduction in the severity of symptoms of a disease. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study.

[0043] As used herein, the term “TYK2-mediated disorders, diseases and/or conditions” as used herein means any disease or other detrimental condition in which TYK2 or a mutant variant thereof is known to play a role. Accordingly, another embodiment relates to treating or reducing the severity of one or more diseases in which TYK2 or a mutant variant 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 transplantation-associated disorders.

Connections

[0044] Described herein are compounds useful in the treatment of 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 transplant-associated disorder.

[0045] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

Z represents a bond, -CR ^Z ₂ - or -(CR ^Z ₂ ) 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted with one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 optionally independently substituted by one or more of 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 by one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[0046] In some embodiments of a compound of Formula (I), L is a bond. In some embodiments of the compounds of formula (I), L is -C(=O)-.

[0047] In some embodiments of the compound of formula (I), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (I), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is 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 .

[0048] In some embodiments of the 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 the compounds 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 the compounds of formula (I), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (I), each R ^A is independently C ₁ -C ₆ alkyl.

[0049] In some embodiments of the 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 the compound of formula (I), R ⁴ is hydrogen.

[0050] In some embodiments of a compound of formula (I), the compound has formula (Ia):

[0051] In some embodiments of a compound of formula (I), the compound has formula (Ib):

[0052] 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.

[0053] 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.

[0054] In some embodiments, compounds 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, compounds of formula (I), (Ia) or (Ib) R ¹ and R ² independently represent hydrogen or C ₁ -C ₆ deuteroalkyl. In some embodiments of the compounds of formula (I), (Ia) or (Ib), R ¹ 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.

[0055] 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 optionally independently substituted with one or more of 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.

[0056] 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 optionally independently substituted with one or more of 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.

[0057] 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 of 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.

[0058] 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 optionally independently substituted with one or more of 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 of 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.

[0059] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 of 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.

[0060] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[0061] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[0062] Also disclosed herein is a compound of formula (II) or (II'), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

R ¹¹ represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[0063] 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)-.

[0064] In some embodiments of a compound of formula (II) or (II'), ring A is heterocycloalkyl or heteroaryl; each of which is 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 5-membered heteroaryl; each of which is 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 .

[0065] In some embodiments of the 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 the compounds 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 the compounds of formula (II) or (II'), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (II) or (II'), each R ^A is independently C ₁ -C ₆ alkyl.

[0066] 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.

[0067] 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-.

[0068] In some embodiments of a compound of formula (II) or (II'), the compound has formula (IIa) or (II'a):

[0069] In some embodiments of a compound of formula (II) or (II'), the compound has formula (IIb) or (II'b):

[0070] 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 the compounds of formula (II), (II'), (IIa), (II'a), (IIb) or (II'b), R ³ is hydrogen.

[0071] In some embodiments, compounds 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, compounds 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 the compounds 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.

[0072] 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 optionally independently substituted with one or more of 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.

[0073] 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 optionally independently substituted with one or more of 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.

[0074] 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 of 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.

[0075] 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 optionally independently substituted with one or more of 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 of 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.

[0076] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 of 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.

[0077] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[0078] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[0079] 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, compounds 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 the compounds of formula (II), (II'), (IIa), (II'a), (IIb) or (II'b), R ¹¹ is halogen. In some embodiments of the compounds of formula (II), (II'), (IIa), (II'a), (IIb) or (II'b), R ¹¹ is hydrogen.

[0080] Also disclosed herein is a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; provided that does not represent

each R ^B independently represents 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 at the same carbon atom are taken together to form oxo;

or two R ^B at adjacent atoms are taken together to form cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more of 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 equals 0-4;

each Y is independently C or N;

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

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[0081] In some embodiments of a compound of Formula (III), L is a bond. In some embodiments of the compound of formula (III), L is -C(=O)-.

[0082] In some embodiments of the compound of formula (III), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (III), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (III), ring A is heteroaryl, optionally substituted with one or more R ^A .

[0083] In some embodiments of the 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 the compounds 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 the compounds of formula (III), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (III), each R ^A is independently C ₁ -C ₆ alkyl.

[0084] In some embodiments of the 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 the compound of Formula (III), R ⁴ is hydrogen or -OR ^b . In some embodiments of the compound of formula (III), R ⁴ is -OR ^b . In some embodiments of the compound of Formula (III), R ⁴ is hydrogen.

[0085] In some embodiments of the compound of formula (III), X is -CH-. In some embodiments of a compound of formula (III), X is -N-.

[0086] In some embodiments of a compound of formula (III), the compound has formula (IIIa):

Formula (IIIa).

[0087] In some embodiments of a compound of formula (III), the compound has formula (IIIb):

Formula (IIIb).

[0088] 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.

[0089] 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 optionally independently substituted with one or more of 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.

[0090] 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 optionally independently substituted with one or more of 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.

[0091] In some embodiments of a compound of formula (III), (IIIa) or (IIIb), R ⁵ is -OR ⁸ , -NR ⁹ R ¹⁰ , -NR ⁸ C(=O)R ⁷ or aryl, optionally substituted with one or more of 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.

[0092] In some embodiments of a compound of formula (III), (IIIa) or (IIIb), 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 optionally independently substituted with one or more of 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 -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 of 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.

[0093] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a cycloalkyl, optionally substituted with one or more of 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.

[0094] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[0095] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds of formula (III), (IIIa) or (IIIb) R ⁹ and R ¹⁰ independently represent 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 optionally independently substituted with one or more of 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.

[0096] In some embodiments of a compound of formula (III), (IIIa) or (IIIb), ring B is heterocycloalkyl or heteroaryl.

[0097] In some embodiments, compounds of formula (III), (IIIa) or (IIIb) represents , , , , , , , , , , , , or ; and n' equals 0-3.

[0098] 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 at the same carbon atom are taken together to form oxo. In some embodiments of the compounds 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 ; in this case, two R ^B at the same carbon atom are taken together to form oxo.

[0099] In some embodiments of compounds of formula (III), (IIIa) or (IIIb), two R ^B at adjacent atoms are taken together to form cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more of 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 compounds of formula (III), (IIIa) or (IIIb), two R ^B at adjacent atoms are taken together to form a heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more of 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.

[00100] 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 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, compounds of formula (III), (IIIa) or (IIIb) n is 1-3.

[00101] 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.

[00102] Also disclosed herein is a compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

ring C is a bicyclic ring system;

each R ^C independently represents 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 equals 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 represents -O-, -NH- or -N(CH ₃ )-;

R ¹³ represents C ₁ -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 optionally independently substituted with one or more of 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00103] In some embodiments of a compound of formula (IV), L is a bond. In some embodiments of the compound of formula (IV), L is -C(=O)-.

[00104] In some embodiments of the compound of formula (IV), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (IV), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (IV), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00105] In some embodiments of the 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 the compounds 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 the compounds of formula (IV), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (IV), each R ^A is independently C ₁ -C ₆ alkyl.

[00106] In some embodiments of the 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 the compound of formula (IV), R ⁴ is hydrogen or -OR ^b . In some embodiments of the compound of formula (IV), R ⁴ is -OR ^b . In some embodiments of the compound of formula (IV), R ⁴ is hydrogen.

[00107] In some embodiments of the compound of formula (IV), X is -CH-. In some embodiments of a compound of formula (IV), X is -N-.

[00108] In some embodiments of a compound of formula (IV), the compound has formula (IVa):

Formula (IVa).

[00109] In some embodiments of a compound of formula (IV), the compound has formula (IVb):

Formula (IVb).

[00110] In some embodiments of a compound of formula (IV), (IVa) or (IVb), R ¹² is -C(=O)NR ¹ R ² .

[00111] In some embodiments, compounds 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, compounds of formula (IV), (IVa) or (IVb) R ¹ and R ² independently represent 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.

[00112] In some embodiments of a compound of formula (IV), (IVa) or (IVb), R ¹² is -L ¹ -R ¹³ .

[00113] In some embodiments of a compound of formula (IV), (IVa) or (IVb), L ¹ is -NH-. In some embodiments of the compounds of formula (IV), (IVa) or (IVb), L ¹ represents -O- or -NH-.

[00114] 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.

[00115] 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 optionally independently substituted with one or more of 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.

[00116] 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 optionally independently substituted with one or more of 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.

[00117] 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 of 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.

[00118] 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 optionally independently substituted with one or more of 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 of 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.

[00119] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a cycloalkyl, optionally substituted with one or more of 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.

[00120] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00121] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds of formula (IV), (IVa) or (IVb) R ⁹ and R ¹⁰ independently represent 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 optionally independently substituted with one or more of 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.

[00122] In some embodiments of a compound of formula (IV), (IVa) or (IVb), ring C is an indole or a benzimidazole.

[00123] In some embodiments of the compounds of formula (IV), (IVa) or (IVb), each ^RC 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.

[00124] In some embodiments of the compounds of formula (IV), (IVa) or (IVb), each ^RC is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl . In some embodiments of the compounds of formula (IV), (IVa) or (IVb), each R ^C is independently halogen or C ₁ -C ₆ alkyl.

[00125] 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 equals 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.

[00126] Also disclosed herein is a compound of formula (V) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

or two R ^Ds on adjacent atoms are taken together to form cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more of 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 equals 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00127] In some embodiments of a compound of Formula (V), L is a bond. In some embodiments of the compounds of formula (V), L is -C(=O)-.

[00128] In some embodiments of the compound of formula (V), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (V), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (V), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00129] In some embodiments of the 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 the compounds 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 the compounds of formula (V), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (V), each R ^A is independently C ₁ -C ₆ alkyl.

[00130] In some embodiments of the 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 the compound of formula (V), R ⁴ is -OR ^b . In some embodiments of the compound of formula (V), R ⁴ is hydrogen.

[00131] In some embodiments of the compound of formula (V), each X is -N-. In some embodiments of the compounds 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-.

[00132] In some embodiments of a compound of formula (V), the compound has formula (Va):

Formula (Va).

[00133] In some embodiments of a compound of formula (V), the compound has formula (Vb):

Formula (Vb).

[00134] 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.

[00135] In some embodiments, compounds 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, compounds of formula (V), (Va) or (Vb) R ¹ and R ² independently represent hydrogen or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (V), (Va) or (Vb), R ¹ 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.

[00136] In some embodiments of a compound of formula (V), (Va), or (Vb), ring D is heterocycloalkyl or heteroaryl.

[00137] In some embodiments, compounds of formula (V), (Va) or (Vb) represents , , , , or ; and r' equals 0-3.

[00138] 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 the compounds 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 the compounds of formula (V), (Va) or (Vb), each R ^D is independently hydrogen or cycloalkyl.

[00139] 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 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 compounds of formula (V), (Va) or (Vb) r is 1-3.

[00140] 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 In embodiments of a compound of formula (V), (Va) or (Vb), r' is 1-3.

[00141] Also disclosed herein is a compound of formula (VI) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

ring E is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted by one or more R ^E ;

each R ^E independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

L ² represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00142] In some embodiments of a compound of formula (VI), L is a bond. In some embodiments of the compound of formula (VI), L is -C(=O)-.

[00143] In some embodiments of the compound of formula (VI), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (VI), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (VI), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00144] In some embodiments of the 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 the compounds 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 the compounds of formula (VI), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (VI), each R ^A is independently C ₁ -C ₆ alkyl.

[00145] In some embodiments of the 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 the compound of formula (VI), R ⁴ is -OR ^b . In some embodiments of the compound of formula (VI), R ⁴ is hydrogen.

[00146] In some embodiments of the compound of formula (VI), X is -CH-. In some embodiments of a compound of formula (VI), X is -N-.

[00147] In some embodiments of a compound of formula (VI), the compound has formula (VIa):

[00148] In some embodiments of a compound of formula (VI), the compound has formula (VIb):

[00149] 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.

[00150] In some embodiments, compounds 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, compounds of formula (VI), (VIa) or (VIb) R ¹ and R ² independently represent hydrogen or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (VI), (VIa) or (VIb), R ¹ 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.

[00151] In some embodiments of a compound of formula (VI), (VIa) or (VIb), L ² is a bond.

[00152] In some embodiments of a compound of formula (VI), (VIa) or (VIb), ring E is cycloalkyl, heterocycloalkyl, or aryl; each of which is optionally substituted with one or more R ^E .

[00153] In some embodiments of a compound of formula (VI), (VIa) or (VIb), ring E is aryl, optionally substituted with one or more R ^E .

[00154] 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.

[00155] In some embodiments of the compounds 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 .

[00156] In some embodiments of the compounds of formula (VI), (VIa) or (VIb), each R ^E independently represents a halogen.

[00157] Also disclosed herein is a compound of formula (VII) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

R ¹⁴ represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted by one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00158] In some embodiments of a compound of formula (VII), L is a bond. In some embodiments of the compound of formula (VII), L is -C(=O)-.

[00159] In some embodiments of the compound of formula (VII), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (VII), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (VII), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00160] In some embodiments of the 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 the compounds 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 the compounds of formula (VII), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (VII), each R ^A is independently C ₁ -C ₆ alkyl.

[00161] In some embodiments of the 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 the compound of formula (VII), R ⁴ is hydrogen or -OR ^b . In some embodiments of the compound of formula (VII), R ⁴ is -OR ^b . In some embodiments of the compound of formula (VII), R ⁴ is hydrogen.

[00162] In some embodiments of the compound of formula (VII), X is -CH-. In some embodiments of a compound of formula (VII), X is -N-.

[00163] In some embodiments of a compound of formula (VII), the compound has formula (VIIa):

Formula (VIIa).

[00164] In some embodiments of a compound of formula (VII), the compound has formula (VIIb):

Formula (VIIb).

[00165] 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.

[00166] 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 optionally independently substituted with one or more of 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.

[00167] 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 optionally independently substituted with one or more of 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.

[00168] 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 of 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.

[00169] 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 optionally independently substituted with one or more of 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 of 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.

[00170] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a cycloalkyl, optionally substituted with one or more of 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.

[00171] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00172] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[00173] 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).

[00174] Also disclosed herein is a compound of formula (VIII) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

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 optionally independently substituted with one or more of 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 represents -O-, -NH- or -N(CH ₃ )-;

L ⁴ represents -NR ³ - or -C(=O)-;

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

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted by one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00175] In some embodiments of a compound of formula (VIII), L is a bond. In some embodiments of the compound of formula (VIII), L is -C(=O)-.

[00176] In some embodiments of the compound of formula (VIII), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (VIII), ring A is 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (VIII), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00177] In some embodiments of the 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 the compounds 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 the compounds of formula (VIII), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (VIII), each R ^A is independently C ₁ -C ₆ alkyl.

[00178] In some embodiments of the 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 the compound of formula (VIII), R ⁴ is hydrogen or -OR ^b . In some embodiments of the compound of formula (VIII), R ⁴ is -OR ^b . In some embodiments of the compound of formula (VIII), R ⁴ is hydrogen.

[00179] In some embodiments of the compound of formula (VIII), X is -CH-. In some embodiments of a compound of formula (VIII), X is -N-.

[00180] In some embodiments of a compound of formula (VIII), the compound has formula (VIIIa):

Formula (VIIIa).

[00181] In some embodiments of a compound of formula (VIII), the compound has formula (VIIIb):

Formula (VIIIb).

[00182] 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 optionally independently substituted with one or more of 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.

[00183] 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 optionally independently substituted with one or more of 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.

[00184] 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 of 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.

[00185] 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 optionally independently substituted with one or more of 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 of 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.

[00186] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 of 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.

[00187] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00188] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds of formula (VIII), (VIIIa) or (VIIIb) R ⁹ and R ¹⁰ independently represent 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 optionally independently substituted with one or more of 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.

[00189] 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-.

[00190] 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.

[00191] In some embodiments of a compound of formula (VIII), (VIIIa) or (VIIIb), L ⁴ is -NR ³ -.

[00192] 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.

[00193] In some embodiments of a compound of formula (VIII), (VIIIa) or (VIIIb), L ⁴ is -C(=O)-.

[00194] A compound of formula (IX) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

ring F represents heterocycloalkyl or heteroaryl;

each R ^F independently represents 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 at the same carbon atom are taken together to form oxo;

or two R ^F at adjacent atoms are taken together to form cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more of 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 equals 0-4;

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

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00195] In some embodiments of a compound of formula (IX), L is a bond. In some embodiments of the compound of formula (IX), L is -C(=O)-.

[00196] In some embodiments of the compound of formula (IX), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (IX), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (IX), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00197] In some embodiments of the 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 the compounds 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 the compounds of formula (IX), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (IX), each R ^A is independently C ₁ -C ₆ alkyl.

[00198] In some embodiments of the 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 the compound of formula (IX), R ⁴ is hydrogen or -OR ^b . In some embodiments of the compound of formula (IX), R ⁴ is -OR ^b . In some embodiments of the compound of formula (IX), R ⁴ is hydrogen.

[00199] In some embodiments of the compounds of formula (IX), X is -CH-. In some embodiments of the compounds of formula (IX), X is -N-.

[00200] In some embodiments of a compound of formula (IX), the compound has formula (IXa):

Formula (IXa).

[00201] In some embodiments of a compound of formula (IX), the compound has formula (IXb):

Formula (IXb).

[00202] 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 the compounds of formula (IX), (IXa) or (IXb), R ³ is hydrogen.

[00203] 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 optionally independently substituted with one or more of 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.

[00204] 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 optionally independently substituted with one or more of 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.

[00205] 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 of 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.

[00206] 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 , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally independently substituted with one or more of 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 -NR ⁸ C(=O)R ⁷ . In some embodiments of a compound of formula (IX), (IXa) or (IXb), R ⁵ is aryl, optionally substituted with one or more of 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.

[00207] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a cycloalkyl, optionally substituted with one or more of 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.

[00208] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00209] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds of formula (IX), (IXa) or (IXb) R ⁹ and R ¹⁰ independently represent 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 optionally independently substituted with one or more of 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.

[00210] In some embodiments of a compound of formula (IX), (IXa) or (IXb), ring F is heterocycloalkyl.

[00211] In some embodiments, compounds of formula (IX), (IXa) or (IXb) represents , , or .

[00212] 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 the compounds 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.

[00213] 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, compounds of formula (IX), (IXa) or (IXb) p is 1-3.

[00214] Also disclosed herein is a compound of formula (X) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

L ⁵ is a saturated or unsaturated linear aliphatic chain having 1-10 carbon atoms, optionally substituted by one or more ^RL5 , where 1-5 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O- , -S-, -S(=O)-, -S(=O) ₂ - or -P(=O)-;

each R ^L5 independently represents 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 ^L5 at the same carbon atom are taken together to form 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 represents -O-, -NH- or -N(CH ₃ )-;

R ¹³ represents C ₁ -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 optionally independently substituted with one or more of 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00215] In some embodiments of a compound of formula (X), L is a bond. In some embodiments of the compound of formula (X), L is -C(=O)-.

[00216] In some embodiments of the compound of formula (X), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (X), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (X), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00217] In some embodiments of the 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 the compounds 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 the compounds of formula (X), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (X), each R ^A is independently C ₁ -C ₆ alkyl.

[00218] In some embodiments of the 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 the compound of formula (X), R ⁴ is hydrogen.

[00219] In some embodiments of the compounds of formula (X), X is -CH-. In some embodiments of compounds of formula (X), X is -N-.

[00220] In some embodiments of a compound of formula (X), the compound has the formula

In some embodiments of a compound of formula (X), the compound has the formula .

[00221] In some embodiments of a compound of formula (X), the compound has formula (Xa):

Formula (Xa).

[00222] In some embodiments of a compound of formula (X), the compound has formula (Xb):

Formula (Xb).

[00223] In some embodiments of the compound of formula (X), the compound has formula (Xa-1):

Formula (Xa-1).

[00224] In some embodiments of the compound of formula (X), the compound has formula (Xb-1):

Formula (Xb-1).

[00225] In some embodiments of compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1), R ³ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1), R ³ is hydrogen.

[00226] 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 .

[00227] In some embodiments, compounds 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, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) R ¹ and R ² independently represent hydrogen or C ₁ -C ₆ deuteroalkyl. In some embodiments of compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1), R ¹ is hydrogen. In some embodiments, compounds 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, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) R ² is C ₁ -C ₆ deuteroalkyl.

[00228] In some embodiments of a compound of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1), R ¹² is -L ¹ -R ¹³ .

[00229] In some embodiments, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) L ¹ is -NH-. In some embodiments, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) L ¹ is -O- or -NH-.

[00230] 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.

[00231] In some embodiments, 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 one or more R ^L5 where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O-, -S-, -S(=O)-, -S(=O ) ₂ - or -P(=O)-. In some embodiments, compounds 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 by one or more R ^L5 wherein 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )- or -O-. In some embodiments, compounds 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 by one or more R ^L5 wherein 1, 2 or 3 carbon atoms are optionally replaced by -NH- or -O-.

[00232] In some embodiments, 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, where 1 , 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O-, -S-, -S(=O)-, or -S(=O) ₂ -. In some embodiments, 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, where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )- or -O-. In some embodiments, 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, where 1, 2 or 3 carbon atoms are optionally replaced by -NH- or -O-.

[00233] In some embodiments, compounds 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 one or more R ^L5 where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O-, -S-, -S(=O)-, or -S(= O) ₂ -. In some embodiments, compounds 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 by one or more R ^L5 wherein 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )- or -O-. In some embodiments, compounds 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 by one or more R ^L5 wherein 1, 2 or 3 carbon atoms are optionally replaced by -NH- or -O-.

[00234] In some embodiments, 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, where 1 , 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O-, -S-, -S(=O)-, -S(=O) ₂ - or -P(= O)-. In some embodiments, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) L ⁵ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )- or -O-. In some embodiments, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) L ⁵ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH- or -O-.

[00235] In some embodiments of compounds 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 compounds of formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), each R ^L5 is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl. In some embodiments of compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1), each R ^L5 is independently deuterium or halogen.

[00236] In some embodiments, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) two R ^L5 at the same carbon atom are taken together to form oxo.

[00237] In some embodiments, compounds of formula (X), (Xa), (Xa-1), (Xb) or (Xb-1) L ⁵ is , or .

[00238] Also disclosed herein is a compound of formula (XI) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

L ⁶ is a saturated or unsaturated linear aliphatic chain having 1-10 carbon atoms, optionally substituted by one or more ^RL6 , where 1-5 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O- , -S-, -S(=O)-, -S(=O) ₂ -, or -P(=O)-;

each R ^L6 independently represents 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 at the same carbon atom are taken together to form oxo;

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

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

X represents -CR ^x - or -N-;

R ^x represents 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00239] In some embodiments of a compound of formula (XI), L is a bond. In some embodiments of the compounds of formula (XI), L is -C(=O)-.

[00240] In some embodiments of the compound of formula (XI), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (XI), ring A is 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (XI), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00241] In some embodiments of the 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 the compounds 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 the compounds of formula (XI), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (XI), each R ^A is independently C ₁ -C ₆ alkyl.

[00242] In some embodiments of the 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 the compound of formula (XI), R ⁴ is hydrogen or -OR ^b . In some embodiments of the compound of formula (XI), R ⁴ is -OR ^b . In some embodiments of the compound of formula (XI), R ⁴ is hydrogen.

[00243] In some embodiments of the compounds of formula (XI), X is -CH-. In some embodiments of the compounds of formula (XI), X is -N-.

[00244] In some embodiments of a compound of formula (XI), the compound has formula (XIa):

Formula (XIa).

[00245] In some embodiments of a compound of formula (XI), the compound has formula (XIb):

Formula (XIb).

[00246] 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 the compounds of formula (XI), (XIa) or (XIb), R ³ is hydrogen.

[00247] 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 optionally independently substituted with one or more of 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.

[00248] 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 optionally independently substituted with one or more of 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.

[00249] 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 of 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.

[00250] 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 optionally independently substituted with one or more of 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 -NR ⁸ C(=O)R ⁷ . In some embodiments of a compound of formula (XI), (XIa) or (XIb), R ⁵ is aryl, optionally substituted with one or more of 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.

[00251] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 of 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.

[00252] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00253] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[00254] In some embodiments, a compound of formula (XI), (XIa) or (XIb) L ⁶ is a saturated linear aliphatic chain having 1-8 carbon atoms, optionally substituted by one or more ^RL6 where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O-, -S-, -S(=O)-, or -S(=O) ₂ -. In some embodiments, a compound of formula (XI), (XIa) or (XIb) L ⁶ is a saturated linear aliphatic chain having 1-8 carbon atoms, optionally substituted by one or more R ^L6 , wherein 1, 2 or 3 carbon atoms are optional replaced by -NH-, -N(CH ₃ )- or -O-. In some embodiments, a compound of formula (XI), (XIa) or (XIb) L ⁶ is a saturated linear aliphatic chain having 1-8 carbon atoms, optionally substituted by one or more R ^L6 , wherein 1, 2 or 3 carbon atoms are optional replaced by -NH- or -O-.

[00255] In some embodiments, the compounds of formula (XI), (XIa) or (XIb) L ⁶ is a saturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH- , -N(CH ₃ )-, -O-, -S-, -S(=O)-, or -S(=O) ₂ -. In some embodiments, the compounds of formula (XI), (XIa) or (XIb) L ⁶ is a saturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N (CH ₃ )- or -O-. In some embodiments, the compounds of formula (XI), (XIa) or (XIb) L ⁶ is a saturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH- or -O -.

[00256] In some embodiments, a compound of formula (XI), (XIa) or (XIb) L ⁶ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, optionally substituted by one or more ^RL6 where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N(CH ₃ )-, -O-, -S-, -S(=O)-, -S(=O) ₂ - or -P(=O)-. In some embodiments, a compound of formula (XI), (XIa) or (XIb) L ⁶ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, optionally substituted by one or more ^RL6 , wherein 1, 2 or 3 carbon atoms are optional replaced by -NH-, -N(CH ₃ )- or -O-. In some embodiments, a compound of formula (XI), (XIa) or (XIb) L ⁶ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, optionally substituted by one or more ^RL6 , wherein 1, 2 or 3 carbon atoms are optional replaced by -NH- or -O-.

[00257] In some embodiments, compounds of formula (XI), (XIa) or (XIb) L ⁶ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH- , -N(CH ₃ )-, -O-, -S-, -S(=O)-, -S(=O) ₂ - or -P(=O)-. In some embodiments, compounds of formula (XI), (XIa) or (XIb) L ⁶ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH-, -N (CH ₃ )- or -O-. In some embodiments, the compounds of formula (XI), (XIa) or (XIb) L ⁶ is an unsaturated linear aliphatic chain having 1-8 carbon atoms, where 1, 2 or 3 carbon atoms are optionally replaced by -NH- or -O -.

[00258] In some embodiments of compounds 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 the compounds 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 compounds of formula (XI), (XIa) or (XIb), each R ^L6 is independently deuterium or halogen.

[00259] In some embodiments, compounds of formula (XI), (XIa) or (XIb) two R ^L6 at the same carbon atom are taken together to form oxo.

[00260] In some embodiments, compounds of formula (XI), (XIa) or (XIb) L ⁶ is .

[00261] Also disclosed herein is a compound of formula (XII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

ring B represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

or -L-ring A is missing;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00262] Also disclosed herein is a compound of formula (XII) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

Where:

ring B represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

or -L-ring A is missing;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00263] Also disclosed herein is a compound of formula (XII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

ring B represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00264] Also disclosed herein is a compound of formula (XII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Formula (XII),

Where:

ring B represents 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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00265] In some embodiments of the compound of formula (XII), ring B is aryl or heteroaryl. In some embodiments of the compound of formula (XII), ring B is aryl. In some embodiments of the compound of formula (XII), ring B is phenyl. In some embodiments of the compound of formula (XII), ring B is heteroaryl. In some embodiments of the compound of formula (XII), ring B is a 5- or 6-membered heteroaryl. In some embodiments of the compound of formula (XII), ring B is a 6-membered heteroaryl. In some embodiments of the compound of formula (XII), ring B is pyridyl.

[00266] Also disclosed herein is a compound of formula (XII') or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

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 represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ deuteroalkyl;

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00267] In some embodiments of a compound of formula (XII) or (XII'), L is a bond. In some embodiments of compounds of formula (XII) or (XII'), L is -C(=O)-.

[00268] In some embodiments of the compound of formula (XII) or (XII'), the -L-ring A is absent.

[00269] In some embodiments of a compound of formula (XII) or (XII'), ring A is heterocycloalkyl or heteroaryl; each of which is 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 5-membered heteroaryl; each of which is 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 .

[00270] In some embodiments of the compounds 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 the compounds 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 the compounds of formula (XII) or (XII'), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (XII) or (XII'), each R ^A is independently C ₁ -C ₆ alkyl.

[00271] In some embodiments of the compound of formula (XII), the compound has formula (XIIa):

Formula (XIIa).

[00272] In some embodiments of a compound of formula (XII), the compound has formula (XIIb):

Formula (XIIb).

[00273] In some embodiments, compounds 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 compounds 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 the compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ⁴ is hydrogen. In some embodiments of the compound of formula (XII), R ⁴ is -P(=O)R ^b R ^b . In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ⁴ is -S(=O) ₂ R ^a .

[00274] In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb), or (XIIc), each X is -N-. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), each X is -CR ^X -. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb), or (XIIc), two Xs are -N- and the remaining one is -CR ^X- . In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), one X is -N- and the others are -CR ^X -. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), each X is -CH-. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb), or (XIIc), two Xs are -N- and the remaining X is -CH-. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), one X is -N- and the others are -CH-. In some embodiments, compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc) represents . In some embodiments, compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc) represents . In some embodiments, compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc) represents or .

[00275] In some embodiments of compounds 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 compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), 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 compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), each R ^X independently represents hydrogen, deuterium or halogen.

[00276] In some embodiments, compounds of formula (XII), (XII'), (XIIa), (XIIb), or (XIIc) represents . In some embodiments, compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc) represents . In some embodiments, compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc) represents .

[00277] In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ³ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ³ is hydrogen.

[00278] 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) ^R11 . 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 the compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ¹⁶ is -C(=O)R ¹¹ .

[00279] In some embodiments, compounds 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, compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc) R ¹ and R ² independently represent hydrogen or C ₁ -C ₆ deuteroalkyl. In some embodiments, compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc) R ¹ and R ² independently represent C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ¹ is hydrogen. In some embodiments of compounds 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 compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ² is C ₁ -C ₆ deuteroalkyl. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ² is C ₁ -C ₆ alkyl.

[00280] 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 optionally independently substituted with one or more R ^11a . In some embodiments, compounds 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 optionally independently substituted with one or more R ^11a . In some embodiments, compounds 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 optionally independently substituted with one or more R ^11a . In some embodiments of compounds 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 optionally independently substituted with one or more R ^11a . In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ¹¹ is C ₁ -C ₆ alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is optionally independently substituted with one or more R ^11a . In some embodiments, compounds 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 compounds 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 compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ¹¹ is C ₁ -C ₆ deuteroalkyl. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ¹¹ is C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ¹¹ is cycloalkyl. In some embodiments of compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), R ¹¹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ deuteroalkyl, or cycloalkyl.

[00281] In some embodiments of compounds 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 compounds 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 compounds 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 compounds 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 compounds 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 compounds of formula (XII), (XII'), (XIIa), (XIIb) or (XIIc), each R ^11a independently represents deuterium, halogen, or C ₁ -C ₆ alkyl.

[00282] 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00283] 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 ⁸ 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 optionally independently substituted with one or more of 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.

[00284] 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 ⁸ 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 optionally independently substituted with one or more of 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.

[00285] 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 ⁸ 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 optionally independently substituted with one or more of 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.

[00286] 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 ⁸ S(=O)(=NR ⁸ )R ⁷ , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally independently substituted with one or more of 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.

[00287] In some embodiments, compounds of formula (XII), (XII'), (XIIa) or (XIIb) R⁵ represents -OR⁸, -NR⁹R¹⁰, -C(=O)R⁷, -C(=O)OR⁸, -C(=O)NR⁹R¹⁰, -NR⁸C(=O)NR⁹R¹⁰, -NR⁸C(=N-CN)R⁷, -NR⁸C(=O)OR⁸, -NR⁸S(=O)(=NR⁸)R⁷, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally independently substituted with one or more of oxo, deuterium, halogen, -CN, -OR^b, -NR^cR^d, -C(=O)R^a, -C(=O)OR^b, -C(=O)NR^cR^d, C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments, compounds of formula (XII), (XII'), (XIIa) or (XIIb) R⁵ represents -OR⁸, -NR⁹R¹⁰, -NR⁸C(=O)R⁷, -NR⁸C(=N-CN)R⁷, -NR⁸S(=O)(=NR⁸)R⁷, or aryl, optionally substituted with one or more of deuterium, halogen, -CN, -OR^b, -NR^cR^d, -C(=O)R^a, -C(=O)OR^b, -C(=O)NR^cR^d, C₁-C₆alkyl or C₁-C₆haloalkyl.

[00288] 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 of 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.

[00289] 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 optionally independently substituted with one or more of 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 compounds of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is aryl, optionally substituted with one or more of 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.

[00290] 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 .

[00291] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is -NR ⁹ R ¹⁰ .

[00292] 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 .

[00293] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is -NR ⁸ C(=N-CN)R ⁷ .

[00294] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is -NR ⁸ S(=O)(=NR ⁸ )R ⁷ .

[00295] 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) ^R7 .

[00296] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is -NR ⁸ C(=O)NR ⁹ R ¹⁰ .

[00297] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is -NR ⁸ C(=O)R ⁷ .

[00298] In some embodiments of the compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is not -NR ⁸ C(=O)R ⁷ .

[00299] 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 of 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 optionally independently substituted with one or more of 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.

[00300] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is heterocycloalkyl, optionally substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00301] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), R ⁵ is heterocycloalkyl, optionally substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00302] In some embodiments of a compound of formula (XII), (XII'), (XIIa), or (XIIb), R ⁵ is heterocycloalkyl, optionally substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00303] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), heterocycloalkyl R ⁵ is , , , , , or .

[00304] In some embodiments of a compound of formula (XII), (XII'), (XIIa) or (XIIb), heterocycloalkyl R ⁵ is .

[00305] 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 optionally independently substituted with one or more of 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 compounds 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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 compounds of formula (XII), (XII'), (XIIa) or (XIIb), R ⁷ is C ₁ -C ₆ alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is optionally independently substituted with one or more of 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 compounds of formula (XII), (XII'), (XIIa) or (XIIb), R ⁷ is cycloalkyl, optionally substituted with one or more of 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 compounds 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 of 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 compounds of formula (XII), (XII'), (XIIa) or (XIIb), R ⁷ is unsubstituted heterocycloalkyl.

[00306] 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[00307] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[00308] In some embodiments, compounds 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 by one or more from 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, compounds 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 of 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, compounds 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 spiroheterocycloalkyl, optionally substituted by one or more from 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, compounds 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 of which is optionally substituted with one or more of 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.

[00309] In some embodiments of a compound of formula (XII), the compound has formula (XIIc):

Formula (XIIc);

where R ^5a represents 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 optionally independently substituted with one or more of 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.

[00310] In some embodiments of the 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 optionally independently substituted with one or more of 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.

[00311] In some embodiments of the 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 optionally independently substituted with one or more of 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.

[00312] Also disclosed herein is a compound of formula (XIII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

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

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

or -L-ring A is missing;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 independently represent 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00313] Also disclosed herein is a compound of formula (XIII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Where:

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

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

R ⁴ represents 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 represents a bond or -C(=O)-;

ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R ^A ;

each R ^A independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form oxo;

each X is independently -CR ^x - or -N-;

each R ^x independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00314] Also disclosed herein is a compound of formula (XIII) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Formula (XIII),

Where:

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

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

R ⁴ represents 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 independently represents 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 optionally independently substituted with one or more of 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 optionally independently substituted with one or more of 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 a ring D, optionally substituted by one or more R ^D ;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D independently represents 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 optionally independently substituted with one or more of 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 at the same carbon atom are taken together to form 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 optionally independently substituted by one or more of 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 by one or more of 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 taken together with the atoms to which they are attached to form a heterocycloalkyl, optionally substituted by one or more of 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 represents C ₁ -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 optionally independently substituted with one or more R ^11a ;

each R ^11a independently represents 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 optionally independently substituted by one or more of 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 independently represents 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 optionally independently substituted by one or more of 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 ^c and R ^d are each 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 optionally independently substituted by one or more of 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 by one or more of 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.

[00315] In some embodiments of the compound of formula (XIII), ring B is aryl or heteroaryl. In some embodiments of the compound of formula (XIII), ring B is aryl. In some embodiments of the compound of formula (XIII), ring B is phenyl. In some embodiments of the compound of formula (XIII), ring B is heteroaryl. In some embodiments of the compound of formula (XIII), ring B is a 5- or 6-membered heteroaryl. In some embodiments of the compound of formula (XIII), ring B is a 6-membered heteroaryl. In some embodiments of the compound of formula (XIII), ring B is a 6-membered pyridyl.

[00316] In some embodiments of a compound of formula (XIII), L is a bond. In some embodiments of the compound of formula (XIII), L is -C(=O)-.

[00317] In some embodiments of the compound of formula (XIII), the L-ring A is absent.

[00318] In some embodiments of the compound of formula (XIII), ring A is heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (XIII), ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each of which is optionally substituted with one or more R ^A . In some embodiments of the compound of formula (XIII), ring A is heteroaryl, optionally substituted with one or more R ^A .

[00319] In some embodiments of the 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 the compounds 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 the compounds of formula (XIII), each R ^A is independently halogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (XIII), each R ^A is independently C ₁ -C ₆ alkyl.

[00320] In some embodiments of a compound of formula (XIII), the compound has formula (XIIIa):

Formula (XIIIa).

[00321] In some embodiments of a compound of formula (XIII), the compound has formula (XIIIb):

Formula (XIIIb).

[00322] In some embodiments of the compound of formula (XIII), the compound has formula (XIIIc):

Formula (XIIIc).

[00323] In some embodiments of a compound of formula (XIII), the compound has formula (XIIId):

Formula (XIIId).

[00324] In some embodiments, compounds 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, compounds 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 the compounds 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 the compounds of formula (XIII) or (XIIIa)-(XIIId), R ⁴ is hydrogen. In some embodiments, the compounds of formula (XIII) or (XIIIa)-(XIIId) R ⁴ is -P(=O)R ^b R ^b . In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) R ⁴ is -S(=O) ₂ R ^a .

[00325] In some embodiments of compounds of formula (XIII) or (XIIIa)-(XIIId), each X is -N-. In some embodiments of compounds of formula (XIII) or (XIIIa)-(XIIId), each X is -CR ^X -. In some embodiments of compounds of formula (XIII) or (XIIIa)-(XIIId), two Xs are -N- and the remaining one is -CR ^X- . In some embodiments of compounds of formula (XIII) or (XIIIa)-(XIIId), one X is -N- and the others are -CR ^X- . In some embodiments of compounds of formula (XIII) or (XIIIa)-(XIIId), each X is -CH-. In some embodiments of compounds of formula (XIII) or (XIIIa)-(XIIId), two Xs are -N- and the remaining X is -CH-. In some embodiments of compounds of formula (XIII) or (XIIIa)-(XIIId), one X is -N- and the others are -CH-. In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) represents . In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) represents . In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) represents or .

[00326] 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 the compounds 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 the compounds of formula (XIII) or (XIIIa)-(XIIId), each R ^X is independently hydrogen, deuterium, or halogen.

[00327] In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) represents . In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) represents . In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) represents .

[00328] In some embodiments of the compounds of formula (XIII) or (XIIIa)-(XIIId), R ³ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (XIII) or (XIIIa)-(XIIId), R ³ is hydrogen.

[00329] 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 optionally independently substituted with one or more R ^11a . In some embodiments, compounds 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 or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally independently substituted with one or more R ^11a . In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) 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 optionally independently substituted with one or more R ^11a . In some embodiments, compounds 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 optionally independently substituted with one or more R ^11a . In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) R ¹¹ represents C ₁ -C ₆ alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is optionally independently substituted with one or more R ^11a . In some embodiments, compounds 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, compounds of formula (XIII) or (XIIIa)-(XIIId) R ¹¹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or cycloalkyl. In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) R ¹¹ represents C ₁ -C ₆ deuteroalkyl. In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) R ¹¹ represents C ₁ -C ₆ alkyl. In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) R ¹¹ is cycloalkyl.

[00330] In some embodiments of the compounds of formula (XIII) or (XIIIa)-(XIIId), 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 the compounds 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 the compounds 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 the compounds 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 compounds 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 the compounds of formula (XIII) or (XIIIa)-(XIIId), each R ^11a independently represents deuterium, halogen, or C ₁ -C ₆ alkyl.

[00331] In some embodiments, compounds 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 ⁸ 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 optionally independently substituted with one or more of 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.

[00332] 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 ⁸ 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 optionally independently substituted with one or more of 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.

[00333] 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 ⁸ 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 optionally independently substituted with one or more of 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.

[00334] 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 ⁸ S(=O)(=NR ⁸ )R ⁷ , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally independently substituted with one or more of 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.

[00335] In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) R⁵ represents -OR⁸, -NR⁹R¹⁰, -C(=O)R⁷, -C(=O)OR⁸, -C(=O)NR⁹R¹⁰, -NR⁸C(=O)NR⁹R¹⁰, -NR⁸C(=N-CN)R⁷, -NR⁸C(=O)OR⁸, -NR⁸S(=O)(=NR⁸)R⁷, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally independently substituted with one or more of oxo, deuterium, halogen, -CN, -OR^b, -NR^cR^d, -C(=O)R^a, -C(=O)OR^b, -C(=O)NR^cR^d, C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments, compounds of formula (XIII) or (XIIIa)-(XIIId) R⁵ represents -OR⁸, -NR⁹R¹⁰, -NR⁸C(=O)R⁷, -NR⁸C(=N-CN)R⁷, -NR⁸S(=O)(=NR⁸)R⁷, or aryl, optionally substituted with one or more of deuterium, halogen, -CN, -OR^b, -NR^cR^d, -C(=O)R^a, -C(=O)OR^b, -C(=O)NR^cR^d, C₁-C₆alkyl or C₁-C₆haloalkyl.

[00336] 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 ⁸ S(=O)(=NR ⁸ )R ⁷ or aryl, optionally substituted with one or more of 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.

[00337] 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 optionally independently substituted with one or more of 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, the compounds 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 of 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.

[00338] 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 .

[00339] In some embodiments of a compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is -NR ⁹ R ¹⁰ .

[00340] In some embodiments of the compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is -NR ⁹ R ¹⁰ or -NR ⁸ C(=O)NR ⁹ R ¹⁰ .

[00341] In some embodiments of a compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is -NR ⁸ C(=N-CN)R ⁷ .

[00342] In some embodiments of the compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is -NR ⁸ S(=O)(=NR ⁸ )R ⁷ .

[00343] In some embodiments of the 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 .

[00344] In some embodiments of the compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is -NR ⁸ C(=O)NR ⁹ R ¹⁰ .

[00345] In some embodiments, the compounds of formula (XIII) or (XIIIa)-(XIIId) R ⁵ is -NR ⁸ C(=O)R ⁷ .

[00346] 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 of 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 optionally independently substituted with one or more of 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.

[00347] In some embodiments of a compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is heterocycloalkyl, optionally substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00348] In some embodiments of a compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is heterocycloalkyl, optionally substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00349] In some embodiments of a compound of formula (XIII) or (XIIIa)-(XIIId), R ⁵ is heterocycloalkyl, optionally substituted with one or more of 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 optionally independently substituted with one or more of 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.

[00350] In some embodiments of a compound of formula (XIII) or (XIIIa)-(XIIId), heterocycloalkyl R ⁵ is , , , , , or .

[00351] In some embodiments of a compound of formula (XIII) or (XIIIa)-(XIIId), heterocycloalkyl R ⁵ is .

[00352] 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 optionally independently substituted with one or more of 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, compounds of formula (XIII) or (XIIIa)-(XIIId) R ⁷ is C ₁ -C ₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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, compounds of formula (XIII) or (XIIIa)-(XIIId) R ⁷ is C ₁ -C ₆ alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is optionally independently substituted with one or more of 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 a cycloalkyl, optionally substituted with one or more of 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, compounds 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 of 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, compounds of formula (XIII) or (XIIIa)-(XIIId) R ⁷ is unsubstituted heterocycloalkyl.

[00353] 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[00354] In some embodiments, compounds 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 optionally independently substituted with one or more of 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, compounds 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 optionally independently substituted with one or more of 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.

[00355] In some embodiments, compounds 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 of 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, compounds 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 of 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, compounds 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 spiroheterocycloalkyl, optionally substituted by one or more of 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, compounds 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 of which is optionally substituted with one or more of 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.

[00356] In some embodiments of the 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 optionally independently substituted with one or more of 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 the compounds 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 the compounds described above, each R ^a is independently C ₁ -C ₆ alkyl.

[00357] In some embodiments of the 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 optionally independently substituted with one or more of 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 the compounds described above, each R ^b independently represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of the compounds described above, each R ^b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ deuteroalkyl. In some embodiments of the compounds described above, each R ^b independently represents hydrogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds described above, each R ^b is hydrogen. In some embodiments of the compounds described above, each R ^b is independently C ₁ -C ₆ alkyl.

[00358] In some embodiments of the compound described above, R ^c and R ^d are each 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 optionally independently substituted with one or more of 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 the compound described above, R ^c and R ^d are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of the compounds described above, R ^c and R ^d are each independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of the compound described above, R ^c and R ^d are each hydrogen. In some embodiments of the compounds described above, R ^c and R ^d are each independently C ₁ -C ₆ alkyl.

[00359] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of:

Example Structure Example Structure 1 99 2 100 3 101 4 102 5 103 6 104 7 105 8 106 9 107 10 108 eleven 109 12 110 13 111 14 112 15 113 16 114 17 115 18 116 19 117 20 118 21 119 22 120 23 121 24 122 25 123 26 124 27 125 28 126 29 127 thirty 128 31 129 32 130 33 131 34 132 35 133 36 134 37 135 38 136 39 137 40 138 41 139 42 140 43 141 44 142 45 143 46 144 47 145 48 146 49 147 50 148 51 149 52 150 53 151 54 152 55 153 56 154 57 155 58 156 59 157 60 158 61 159 62 160 63 161 64 162 65 163 66 164 67 165 68 166 69 169 70 171 71 172 72 173 73 174 74 175 75 176 76 177 77 178 78 179 79 180 80 181 81 182 82 183 83 184 84 185 85 188 86 189 87 190 88 191 89 193 90 195 91 196 92 198 93 199 94 200 95 201 96 202 97 203 98

[00360] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

And .

[00361] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, And .

[00362] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, , , , , , , , , , , , , , , , , , , , , , , , , And .

[00363] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, , , , And .

[00364] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, , , , , , , , And .

[00365] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, , , And .

[00366] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, And .

[00367] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, And .

[00368] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, And .

[00369] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, , , , And .

[00370] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

And .

[00371] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, , , , , , , , , , , , And .

[00372] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, And .

[00373] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

And .

[00374] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[00375] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of

,

Where:

R ₁ = -Et, -CH ₂ -CD ₃ or cyclopropyl;

R ₂ =Me, CD ₃ or Et;

R ₃ =isopropyl, cyclobutyl, cyclopropyl or tert-butyl.

Additional forms of the compounds disclosed herein

Isomers/stereoisomers

[00376] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers, as well as appropriate mixtures thereof. In some situations, the compounds described herein have one or more chiral centers, and each center exists in an R configuration or an S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms, as well as appropriate mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers resulting from a separate preparation, combination or interconversion step are useful for the uses 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 diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (eg, melting points, boiling points, solubility values, reactivity, etc.) and are separated by exploiting these differences. In some embodiments, diastereomers are separated using chiral chromatography or preferably using separation/separation techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent.

Labeled compounds

[00377] In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds identical to the compounds mentioned herein, except 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 commonly found in nature. Examples of isotopes that may be included in the compounds described herein, or a solvate or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, 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. The compounds described herein and their pharmaceutically acceptable salts, solvates or stereoisomers that contain the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example those containing radioactive isotopes such as ³ H and ¹⁴ C, are useful in drug and/or substrate tissue distribution assays. Tritium isotopes, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavy isotopes such as deuterium, e.g. , ² H, provides certain therapeutic benefits due to greater metabolic stability, such as 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.

[00378] In some embodiments, the compounds described herein are labeled by other methods, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

[00379] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

[00380] In some embodiments, the compounds described herein have acidic or basic groups and thereby 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 reacting the purified compound in its free form with a suitable acid or base and isolating the resulting salt separately.

[00381] Examples of pharmaceutically acceptable salts include those prepared by reacting 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, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexine-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methyl benzoate, monohydrogen phosphate, 1-naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate and xylene sulfonate.

[00382] In addition, 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, etc.; 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'-methylene-bis-(3-hydroxy-2-ene-1-carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid.

[00383] In some embodiments, compounds described herein that contain a free acid group are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Exemplary salts include alkali or alkaline earth metal salts such as 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.

[00384] Exemplary organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also involve quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization produces products that are soluble or dispersible in water or oil.

Solvates

[00385] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods for treating diseases by administering such solvates. The present invention further provides methods for treating diseases by administering such solvates in the form of pharmaceutical compositions.

[00386] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and in some embodiments are formed during a crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed if the solvent is water, or alcoholates are formed if the solvent is alcohol. Solvates of the compounds described herein can be readily prepared or formed by the processes described herein. In addition, the compounds provided herein may exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to non-solvated forms in the context of the compounds and methods provided herein.

Tautomers

[00387] 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 due to the movement of a hydrogen atom, which is accompanied by the rearrangement of a single bond and an adjacent double bond with each other. In the orders of bond arrangement for which tautomerization is possible, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

Receiving connections

[00388] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting with commercially available chemicals and/or compounds described in the chemical literature. “Commercially available chemicals” are obtained from commonly known 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, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hoppog, New York), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, New York), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, Virginia).

[00389] Suitable references and scientific works that detail the synthesis of reactants useful in the preparation of the 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 relevant references and scientific works that detail the synthesis of reactants useful in the preparation of compounds, described herein, or 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. (ed.) 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, TWG "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" by John Wiley & Sons, in 73 volumes.

[00390] Specific and similar reactants are optionally identified using the American Chemical Society's Chemical Abstracts Service indexes of known chemicals, which are available in most public and university libraries and online. Chemicals known but not commercially available in catalogs are not necessarily obtained from custom chemical synthesis firms, where many well-known chemical suppliers ( such as those listed above) provide custom synthesis services. A reference that describes the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth, “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical compositions

[00391] In certain embodiments, a compound described herein is administered as a pure chemical. In some embodiments, a compound described herein is combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) , selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, ^21st Ed. Mack Pub. Co., Easton, PA (2005)).

[00392] 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.

[00393] In certain embodiments, a compound provided herein is substantially pure in the sense that it contains less than about 5%, or less than about 1%, or less than about 0.1% other organic small molecules, such as unreacted intermediates or synthesis by-products formed, for example, at one or more stages of the synthesis process.

[00394] Pharmaceutical compositions are administered in a manner appropriate to the disease being treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the route of administration. Typically, at an appropriate dosage and treatment regimen, the composition(s) will be provided in an amount sufficient to provide a therapeutically and/or prophylactically beneficial effect ( e.g., improved clinical outcome such as more frequent complete or partial remissions, or longer disease-free survival and/or overall survival or reduction in symptom severity). Optimal doses are usually determined through experimental models and/or clinical trials. The optimal dose depends on the patient's body weight, weight, or blood volume.

[00395] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, as well as 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, pill, capsule, liquid, inhalant, nasal spray, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drops, or ear drops. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[00396] Suitable dosages and dosage schedules are determined using conventional ranging techniques known to those of ordinary skill in the art. Treatment is typically initiated at lower doses, lower than the optimal dose of the compound disclosed herein. Thereafter, the dose is increased in small steps until the optimal effect is achieved under the circumstances. In some embodiments, the method of the present invention involves administering from about 0.1 μg to about 50 mg of at least one compound described herein per kg of body weight of the subject. For a 70 kg patient, dosages ranging from about 10 μg to about 200 mg of a compound disclosed herein will more often be used, depending on the physiological response of the subject.

[00397] By way of example only, the dose of a compound described herein for methods of treating a disease described herein is from about 0.001 to about 1 mg/kg of subject body weight per day, e.g., about 0.001 mg, about 0.002 mg, approximately 0.005 mg, approximately 0.010 mg, 0.015 mg, approximately 0.020 mg, approximately 0.025 mg, approximately 0.050 mg, approximately 0.075 mg, approximately 0.1 mg, approximately 0.15 mg, approximately 0.2 mg, approximately 0, 25 mg, approximately 0.5 mg, approximately 0.75 mg, or approximately 1 mg/kg body weight per day. In some embodiments, the dosage of a compound described herein for the methods described is from about 1 to about 1000 mg/kg body weight of the subject receiving treatment per day, e.g., about 1 mg, about 2 mg, about 5 mg, about 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 500 mg, approximately 750 mg or approximately 1000 mg in a day.

Treatment options

[00398] The compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods is TYK2.

[00399] Provided herein are compounds that are TYK2 inhibitors and therefore useful for treating one or more disorders associated with the activity of TYK2 or mutant variants thereof.

[00400] Provided herein are methods of treating a disease or disorder, wherein the disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-associated disorder, the method comprising administering to a patient in need of herein, a pharmaceutical composition containing an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[00401] In some embodiments, the disease or disorder is an autoimmune disorder. In some embodiments, the disease or disorder is selected from type 1 diabetes mellitus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[00402] 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.

[00403] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a cancer of the blood system. In some embodiments, the proliferative disorder is 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, or essential thrombocytosis.

[00404] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes mellitus.

[00405] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[00406] 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 in the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[00407] In some embodiments, the disease or disorder is associated with the transplant. In some embodiments, the transplant-associated disease or disorder is graft rejection or graft-versus-host disease.

[00408] In some embodiments, the disease or disorder is associated with signaling through type I interferons, IL-10, IL-12, or IL-23. 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.

[00409] Provided herein are methods of treating an inflammatory or allergic skin condition, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquired, acne vulgaris and other inflammatory or allergic skin conditions.

[00410] Provided herein are methods of treating other diseases or conditions, such as diseases or conditions characterized by the presence of an inflammatory component, for example, treating diseases and conditions of the eye, such as allergic eye diseases, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting nose, including allergic rhinitis, and inflammatory disease that involves autoimmune reactions or that is characterized by the presence of an autoimmune component or etiology, including autoimmune hematological disorders (eg, hemolytic anemia, aplastic anemia, true erythrocyte anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (eg 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 ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or nephropathy yu minimal change), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth restriction, hypercholesterolemia, disease heart, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, pigment incontinence, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial asthma and exercise asthma), acute injury lungs, acute respiratory distress syndrome, eosinophilia, forms of hypersensitivity, anaphylaxis, nasal sinusitis, allergic eye diseases, silica-induced diseases, COPD (reduction of lesions, airway inflammation, bronchial hyperresponsiveness, remodeling or progression of disease), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, forms of cataracts, muscle inflammation in combination with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes mellitus or type 2 diabetes mellitus type, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin-A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, nonspecific ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis.

[00411] 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), cryopyrine-associated periodic syndrome (CAPS), or osteoarthritis .

[00412] 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).

[00413] In some embodiments, the inflammatory disease is Sjögren's syndrome, allergic disorders, osteoarthritis, ocular conditions such as allergic eye diseases, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or diseases affecting the nose such as allergic rhinitis.

Combination therapy

[00414] In some cases, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.

[00415] In some embodiments, the beneficial effect experienced by a patient is increased when one of the compounds described herein is administered with a second therapeutic agent (which also includes a therapy regimen) that also has a therapeutically beneficial effect.

[00416] 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 The therapeutic agent modulates different aspects of the disease, disorder or condition being treated, thereby providing a greater overall beneficial effect than would be the case with either therapeutic agent administered alone.

[00417] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply the sum of the effects of the two therapeutic agents, or the patient experiences a synergistic benefit.

[00418] In certain embodiments, various therapeutically effective doses of the compounds disclosed herein will be used in the formulation of a pharmaceutical composition and/or in treatment regimens in which the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically effective doses of drugs and other agents for use in combination treatment regimens are not necessarily determined using methods similar to those set forth herein above for the active substances themselves. In addition, the methods of prevention/treatment described herein cover the use of metronomic dosing, i.e. providing more frequent and lower doses to minimize toxic side effects. In some embodiments, a combination treatment regimen includes treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated before, during, or after treatment with a second agent described herein and continued up to any time during treatment with the second agent or after cessation 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 a second agent used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period . Combination treatment additionally includes intermittent treatments starting and ending at different times, which contribute to the clinical management of the patient.

[00419] It should be understood that the dosage regimen for treating, preventing, or reducing the severity of the condition(s) for which attenuation is required is modified according to a variety of factors (e.g., disease, disorder, or condition suffered by the subject; age, weight , sex, diet, and medical condition of the subject). Thus, in some cases, the dosing regimen actually used differs from, and in some embodiments deviates from, the dosing regimens set forth herein.

[00420] For the combination therapies described herein, the dosages of the co-administered compounds vary depending on the type of drug used together, the specific drug used, the disease or condition being treated, etc. In additional embodiments, when coadministered with a second therapeutic agent, the compound provided herein is administered simultaneously with the second therapeutic agent or sequentially.

[00421] In combination therapies, 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, multiple therapeutic agents are provided, by way of example only, in one single form or in multiple forms (eg, as a single pill or as two separate pills).

[00422] 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 onset of a disease or condition, and the timing of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic agent and are administered continuously to subjects prone to developing conditions or diseases for the purpose of preventing the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to the subject at or as soon as possible after the onset of symptoms. In specific embodiments, a compound described herein is administered at an optimal time following detection or suspicion of the onset of a disease or condition and for a period of time necessary to treat the disease. In some embodiments, the required duration of treatment varies and the duration of treatment is adjusted to meet the specific needs of each subject. For example, in specific embodiments, a compound described herein, or a composition containing the compound, is administered for at least 2 weeks, from about 1 month to about 5 years.

[00423] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with an excipient. In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutically beneficial effect, but in combination with another therapeutic agent the overall therapeutically beneficial effect for the patient is increased ).

EXAMPLES

Intermediate A

Step 1. Synthesis of compound Ab

[00424] 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 the addition of methyl iodide (6, 34 ml, 101 mmol) and the resulting orange mixture was heated to 60°C for 1 hour. The reaction mixture was cooled to room temperature and then crushed ice (~100 ml) was added followed by the addition of water to a total volume of ~400 ml 10, resulting in crystallization of a yellow solid from solution. The slurry was stirred for several minutes and then collected by vacuum filtration, and the resulting initially yellow solid was rinsed with additional water (~100 ml) until the yellow color was completely washed out into the filtrate, yielding an almost white solid in funnel. The partially air-dried solid in the funnel was then transferred to a flask and further dried under vacuum overnight to give Ab (10.5 g, 98%) a yellow solid as the desired product. LCMS [M+1] ⁺ = 197.1.

Stage 2. Synthesis of compound Ac

[00425] 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 conc. aqueous ammonium hydroxide solution (100 ml). The flask was sealed and the resulting solution was gently stirred at room temperature overnight (~17 hours). The reaction mixture was concentrated to give Ac (1.67 g, 86%) as a yellow solid. LCMS [M+1] ⁺ = 196.1.

Step 3. Synthesis of compound Ad

[00426] 2-Methoxy-3-nitrobenzamide (6.5 g, 33.1 mmol) was suspended in dimethylformamide dimethyl acetal (39.5 g, 331 mmol) and the mixture was heated to 95°C to obtain a clear, pale yellow solution. After heating for ~30 min. At 95°C, the reaction mixture was cooled and concentrated on a rotary evaporator and the resulting yellow oil was azeotroped twice with 1,2-dichloroethane (40 ml parts) to ensure complete removal of any residual dimethylformamide dimethyl acetal. The crude oil thus obtained was directly dissolved in 35 ml of ethanol and directly used in the next step.

[00427] In a separate flask, a mixture of ethanol (150 ml) and acetic acid (AcOH, 35 ml) was prepared and the resulting solution was cooled in an ice bath. After cooling, hydrazine hydrate (16.1 mL, 331 mmol) was added dropwise. At the same time, the solution containing the crude dimethylformamide dimethylacetal adduct obtained above was transferred dropwise for ~15 min. using a cannula into a previously thoroughly mixed ice mixture containing hydrazine. During addition, a pale yellow solid formed in the solution. Once addition was complete, the resulting cloudy yellow mixture was allowed to warm to room temperature and stirred for ~4 hours. During this time, the reaction mixture was concentrated on a rotary evaporator to remove some ethanol, diluted with additional water, and filtered to collect solids. The solid was washed with additional water, air dried in a funnel, then under vacuum to give Ad (4.0 g, 54.8%) as a pale yellow solid as the desired product. LCMS [M+1] ⁺ = 221.1.

Step 4. Synthesis of compound Ae

[00428] 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 using a syringe over 2 min. After addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for ~4 hours, LCMS analysis indicated complete and pure conversion to a regioisomeric mixture of products in a ratio of ~2:1, respectively. The reaction mixture was cooled in an ice bath and diluted with water (~50 ml), and the solution was extracted with EtOAc (3x40 ml), and the combined extracts were washed with 10% aq. LiCl solution (2x20 ml), water (20 ml), then brine (20 ml), concentrated and purified with CC to give Ae (2.0 g, 38%) as the main isomer as pale yellow solid matter. 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).

Step 5: Synthesis of Intermediate A

[00429] 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 bubbled with nitrogen for several minutes before adding 10% Pd-C (0.90 g, 0.43 mmol) followed by sparging hydrogen from the balloon for several minutes, then allowing the mixture to stir under hydrogen from the balloon for 1.5 hours at room temperature . The mixture was then bubbled with nitrogen to deactivate the catalyst, and the mixture was filtered through a pad of celite, washing with additional EtOH, and the resulting product, containing a clear colorless filtrate, was concentrated and purified with CC to give Intermediate A as an off-white solid (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

Step 1. Synthesis of compound Xb

[00430] 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 was sonicated and then concentrated. The residue was dissolved in THF (200 ml), then deuteromethylamine (HCl salt, 2.26 g, 32 mmol) was added followed by N,N' -diisopropylethylamine (18 ml, 103 mmol). After 1 hour, the reaction mixture was concentrated and the residue was adsorbed onto celite using dichloromethane, the filtrate was re-concentrated and purified with CC to give a yellow solid Xb (5.1 g, 37%).

Step 2. Synthesis of intermediate 1

[00431] 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 ^o C to obtain a slight exothermic effect. The reaction mixture was stirred at room temperature. for 3 hours. The reaction mixture was cooled to 0 ^o C, quenched by adding sat. NH ₄ Cl (aq) solution, diluted with water (100 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM/EtOAc=3/1) to give the desired intermediate 1 (6.5 g, yield: 72.2%) as a yellow solid. LCMS [M+1] ⁺ = 377.1.

Intermediate 2

Step 1. Synthesis of compound 2Ae

[00432] 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 using a syringe over 2 min. Once addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for ~4 hours, LCMS analysis indicated complete and pure conversion to a regioisomeric mixture of products in a ratio of ~2:1, respectively. The reaction mixture was cooled in an ice bath and diluted with water (~50 ml), and the solution was extracted with EtOAc (3x40 ml), and the combined extracts were washed with 10% aq. LiCl solution (2x20 ml), water (20 ml), then brine (20 ml), concentrated and purified with CC to give 2Ae (2.0 g, 38%) as the main isomer as pale yellow solid matter. LCMS [M+1] ⁺ = 238.1.

Step 2. Synthesis of compound 2A

[00433] 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 ) sparged with nitrogen for several minutes before adding 10% Pd-C (0.90 g, 0.43 mmol) followed by sparging with hydrogen from the cylinder for several minutes, then allowing the mixture to stir under an atmosphere of hydrogen from the cylinder for 1.5 h at room temperature The mixture was then bubbled with nitrogen to deactivate the catalyst and the mixture was filtered through a pad of CELITE® washing with additional EtOH and the resulting product containing a clear colorless filtrate was concentrated and purified with CC to give 2A as an off-white solid (1.5 g , 68%) . LCMS [M+1] ⁺ = 208.2.

Step 3. Synthesis of intermediate 2

[00434] 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 ^o C to obtain a slight exothermic effect. The reaction mixture was stirred at room temperature. After completion, the reaction mixture was cooled to 0°C, quenched by adding sat. NH ₄ Cl (aq) solution, diluted with water (100 ml) and extracted with EtOAc (50 ml*3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM/EtOAc=3/1) to give the desired intermediate 2 (6.5 g, yield: 72.2%) as a yellow solid. LCMS [M+1] ⁺ = 380.1.

Intermediate connection 3A

Stage 1. Synthesis of compound 3Ab

[00435] 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 the addition of iodomethane -d ₃ (4.42 ml, 71.0 mmol) and the resulting orange mixture was heated to 60°C for 1 hour. The reaction mixture was cooled to room temperature and then crushed ice (~100 ml) was added followed by water until total volume ~400 ml, leading to crystallization of a yellow solid from solution. The slurry was stirred for several minutes and then collected by vacuum filtration, and the resulting initially yellow solid was rinsed with additional water (~100 ml) until the yellow color was completely washed out into the filtrate, yielding an almost white solid in funnel. The partially air-dried solid in the funnel was then transferred to a flask and further dried under vacuum overnight to provide 3Ab (6.5 g, 86%) as a yellow solid as the desired product. LCMS [M+1] ⁺ = 215.1.

Stage 2. Synthesis of compound 3Ac

[00436] Methyl 2-(methoxy-d3)-3-nitrobenzoate 3Ab (6.5 g, 30.3 mmol) was dissolved in cold ammonia in methanol (7 N, 140 ml) and conc. aqueous ammonium hydroxide solution (60 ml). The flask was sealed and the resulting solution was gently stirred at room temperature overnight (~17 hours). The reaction mixture was concentrated to give 3Ac (5.8 g, 96%) as a yellow solid. LCMS [M+1] ⁺ = 200.1

Stage 3. Synthesis of compound 3Ad

[00437] 2-(Methoxy-d3)-3-nitrobenzamide 3Ac (5.8 g, 29.1 mmol) was suspended in dimethylformamide dimethyl acetal (38.6 ml, 291 mmol) and the mixture was heated to 95°C to obtain a clear pale -yellow solution. After heating for ~30 min at the same temperature, the reaction mixture was cooled and concentrated on a rotary evaporator and the resulting yellow oil was azeotroped twice with 1,2-dichloroethane (40 mL portion) to ensure complete removal of any residual dimethylformamide dimethyl acetal . The crude oil thus obtained was directly dissolved in 35 ml of ethanol and directly used in the next step.

[00438] In a separate flask, a mixture of ethanol (150 ml) and acetic acid (AcOH, 35 ml) was prepared and the resulting solution was cooled in an ice bath. After cooling, hydrazine hydrate (14.1 mL, 291 mmol) was added dropwise. At the same time, the solution containing the crude dimethylformamide dimethylacetal adduct obtained above was transferred dropwise for ~15 min. using a cannula into a previously thoroughly mixed ice mixture containing hydrazine. During addition, a pale yellow solid formed in the solution. Once addition was complete, the resulting cloudy yellow mixture was allowed to warm to room temperature and stirred for ~4 hours. During this time, the reaction mixture was concentrated on a rotary evaporator to remove some ethanol, diluted with additional water, and filtered to collect solids. The solid was washed with more water, air dried in a funnel, then under vacuum to give 3Ad (5.0 g, 77.0%) as a pale yellow solid as the desired product. LCMS [M+1] ⁺ = 224.1

Step 4. Synthesis of compound 3Ae

[00439] 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 using a syringe over 2 min. Once addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for ~4 hours, LCMS analysis indicated complete and pure conversion to a regioisomeric mixture of products in a ratio of ~2:1, respectively. The reaction mixture was cooled in an ice bath and diluted with water (~50 ml), and the solution was extracted with EtOAc (3x40 ml), and the combined extracts were washed with 10% aq. LiCl solution (2x20 ml), water (20 ml), then brine (20 ml), concentrated and purified with CC to give 3Ae (2.1 g, 39.54%) as the main isomer as pale -yellow solid. LCMS [M+1] ⁺ = 238.2.

Step 5. Synthesis of compound 3A

[00440] 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 the cylinder for a few minutes, then allowing the mixture to be stirred under an atmosphere of hydrogen from the cylinder for 1.5 h at room temperature. T. The mixture was then bubbled with nitrogen to deactivate the catalyst and the mixture was filtered through a pad of CELITE® washing with additional EtOH and the resulting product containing a clear colorless filtrate was concentrated and purified with CC to give 3A as an off-white solid (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

[00441] 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, mmol) at 0°C to obtain a slight exothermic effect. The reaction mixture was stirred at room temperature. After completion, the reaction mixture was cooled to 0°C, quenched by adding sat. NH ₄ Cl (aq) solution, diluted with water (100 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM/EtOAc=3/1) to give the desired 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-(trideuteromethyl)pyridazine -3-carboxamide

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

[00442] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (60 mg, 0.16 mmol) and 1A (41 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120 ^o C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product of Example 1 (6 mg, yield: 8%), in as a yellow solid. LM-MS: mass/charge=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-(trideuteromethyl)pyridazine -3-carboxamide

[00443] NaOH (1.04 mg, 0.026 mmol) was added to a solution of 1B (6 mg, 0.013 mmol) in methanol (3 mL). The mixture was heated to 40°C for 2 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 1 (3 mg, yield: 50%), in 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-oxoimidazolidin-1-yl)-N- (trideuteromethyl)pyridazine-3-carboxamide

[00444] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (60 mg, 0.16 mmol) and 2A (32 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided 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)pyridazin-3 -carboxamide

[00445] 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 a 45 mL sealed tube. 10 ml of 1,4-dioxane was added to the mixture. The resulting solution was stirred at 130°C for 1 hour under N ₂ atmosphere. The mixture solution was evaporated to dryness and the residue was purified by flash chromatography to give 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]heptane-5 -yl)-N-(trideuteromethyl)pyridazine-3-carboxamide

[00446] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (60 mg, 0.16 mmol) and 4A (35 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 110°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, the residue was purified by flash chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) to obtain the title compound of 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-cyclopropylurea

[00447] To a solution of cyclopropanamine (2.0 g, 35.03 mmol) in acetonitrile (20 ml) was added 1-chloro-2-isocyanatoethane (3.70 g, 35.03 mmol), then it was stirred at room temperature in for 2 hours. The solid precipitated, filtered, the desired product 5B (4.05 g, 71.1%) was obtained as a white solid, which was used in the next step without further purification. LM-MS: mass/charge =163.2 [M+H] ⁺

Stage 2. 1-Cyclopropylimidazolidin-2-one

[00448] Sodium hydride (0.15 g, 6.0 mmol) was added to a solution of 5B (0.5 g, 3.07 mmol) in THF (30 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extracted with EtOAc (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 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: mass/charge =127.2 [M+H] ⁺

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

[00449] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (70 mg, 0.18 mmol) and 5C (35 mg, 0.28 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 5 (10 mg, yield: 10%), in as a yellow solid. LM-MS: mass/charge=467.2[M+H] ⁺ . ^1H 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-isopropylurea

[00450] To a solution of propan-2-amine (2.0 g, 33.8 mmol) in acetonitrile (20 ml) was added 1-chloro-2-isocyanatoethane (3.57 g, 33.8 mmol), then stirred at room temperature for 2 hours. The solid precipitated, filtered to give the desired product as Example 6B (4.2 g, 75.4%) as a white solid and 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).

Step 2. 1-Isopropylimidazolidin-2-one

[00451] Sodium hydride (0.15 g, 6.0 mmol) was added to a solution of 6B (0.5 g, 3.0 mmol) in THF (30 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extracted with EtOAc (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product, representing is 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide;2,2,2-trifluoroacetic acid

[00452] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (60 mg, 0.16 mmol) and 6C (41 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 6 (5 mg, yield: 5%), in 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-(trideuteromethyl)pyridazine-3-carboxamide

[00453] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (60 mg, 0.16 mmol) and 7A (36 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 7 (24 mg, yield: 30%), in 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-oxoimidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl) )anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide;2,2,2-trifluoroacetic acid

Stage 1. 1-(2-Chloroethyl)-3-(2,2-difluoroethyl)urea

[00454] To a solution of 2,2-difluoroethanamine (2.0 g, 24.67 mmol) in acetonitrile (20 mL), 1-chloro-2-isocyanatoethane (2.60 g, 24.67 mmol) was added and stirred at room temperature for 2 hours. The solid precipitated, filtered to give the desired product 8B (2.80 g, 60.83%) as a white solid, which was used in the next step without further purification. LM-MS: m/z =187.2 [M+H] ⁺

Step 2. 1-(2,2-Difluoroethyl)imidazolidin-2-one

[00455] Sodium hydride (0.15 g, 6.0 mmol) was added to a solution of 8B (0.5 g, 2.68 mmol) in THF (30 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extracted with EtOAc (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 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-oxoimidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl) )anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide;2,2,2-trifluoroacetic acid

[00456] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (80 mg, 0.21 mmol) and 8C (47 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 8 (4 mg, yield: 4%), in as a yellow solid. LM-MS: m/z=491.2 [M+H] ⁺ . ^1H 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-oxoimidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino ]-N-(trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-(2-methoxyethyl)urea

[00457] To a solution of 2-methoxyethanamine (0.38 g, 5 mmol) in THF (10 ml) was added 1-chloro-2-isocyanatoethane (0.53 g, 5 mmol), then it was stirred at room temperature for 2 hours to obtain the desired product 9B (0.81 g, 90%) as a colorless oil, it was used in the next step without further purification. LC-MS: mass/charge =180.6 [M+H] ⁺

Step 2. 1-(3-Methyloxetan-3-yl)imidazolidin-2-one

[00458] Sodium hydride (0.13 g, 5.4 mmol) was added to a solution of 9 B (0.81 g, 4.5 mmol) in THF (20 mL), then stirred at room temperature for 4 hours. Quench with water (20 ml) and extract with EtOAc (40 ml x 2). The combined organic layers were washed with brine (60 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product 9C ( 0.25 g, yield: 40%) in colorless oil. LC-MS: m/z =144.2 [M+H] ⁺

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

[00459] Cesium carbonate (160 mg, 0.5 mmol) was added to a solution of intermediates 1 (60 mg, 0.16 mmol) and 9C (30 mg, 0.2 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (20 mg, 0.02 mmol) and Xantphos (24 mg, 0.04 mmol). The mixture was degassed with N ₂ 3 times and heated to 130°C for 2 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=95/5) provided the desired product as 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-oxoimidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl) )anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-(3,3-difluorocyclobutyl)urea

[00460] 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 -isocyanatoethane (0.6 ml, 6.96 mmol) using a syringe, then it was stirred at room temperature for 2 hours. 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 a white solid, which was used in the next step without additional cleaning. LM-MS: mass/charge =213.1 [M+H] ⁺

Step 2. 1-(3,3-Difluorocyclobutyl)imidazolidin-2-one

[00461] Sodium hydride (0.19 g, 4.7 mmol) was added to a solution of 10B (0.5 g, 2.35 mmol) in THF (30 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extracted with EtOAc (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 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-oxoimidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl) )anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide

[00462] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediate 1 (60 mg, 0.16 mmol) and 10C (56 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 110°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, and the residue was purified by flash chromatography.

[00463] (PE/EtOAc=50/50 then DCM/MeOH=97/3) to obtain the title compound of Example 10 (12 mg, yield: 13.95%) as a white solid. LM-MS: m/z =517.2 [M+H] ^{+. 1H} 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-cyclobutylurea

[00464] To a solution of cyclobutanamine (1.0 g, 14.1 mmol) in acetonitrile (20 ml) was added 1-chloro-2-isocyanatoethane (1.48 g, 14.1 mmol), then it was stirred at room temperature in for 2 hours. The solid precipitated, filtered, and the desired product was Example 11B (1.5 g, 60.4%) as a white solid, which was used in the next step without further purification. LM-MS: m/z =177.1 [M+H]+. ^1H 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).

Step 2. 1-Cyclobutylimidazolidin-2-one

[00465] Sodium hydride (0.27 g, 11 mmol) was added to a solution of 1-(2-chloroethyl)-3-cyclobutylurea (1.0 g, 5.7 mmol) in THF (30 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extract with EtOAc (30 ml x 2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product, representing is 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

[00466] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediates 1 (60 mg, 0.16 mmol) and 11C (45 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-ethylurea

[00467] 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-isocyanatoethane (1.24 g , 12.3 mmol), then stirred at room temperature for 2 hours. The solid precipitated, filtered to give the desired product as Example 12B (1.5 g, 81%) as a white solid and used at the next stage without additional purification.

Stage 2. 1-Ethylimidazolidin-2-one

[00468] Sodium hydride (0.32 g, 13 mmol) was added to a solution of 12B (1.0 g, 6.6 mmol) in THF (30 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extracted with EtOAc (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product, representing is Example 12C (0.70 g, yield: 92%), as a white solid.

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

[00469] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediate 1 (60 mg, 0.16 mmol) and 12C (36 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 12 (5 mg, yield: 6%), in as a yellow solid. LM-MS: m/z =455.3 [M+H]+. ^1H 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-[2,2,2-trideutero-1-(trideuteromethyl)ethyl]urea

[00470] To a solution of 1,1,1,3,3,3-hexadeuteropropan-2-amine (0.20 g, 3.1 mmol) in acetonitrile (20 ml) was added 1-chloro-2-isocyanatoethane (0. 32 g, 3.1 mmol), then stirred at room temperature for 2 hours. The solid precipitated, filtered to give the desired product 13B (0.4 g, 76%) as a white solid and used in the next step. without additional cleaning. LM-MS: m/z =171.2 [M+H]+

Step 2. 1-[2,2,2-Trideutero-1-(trideuteromethyl)ethyl]imidazolidin-2-one

[00471] Sodium hydride (0.056 g, 2.4 mmol) was added to a solution of 13B (0.2 g, 1.2 mmol) in THF (10 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extracted with EtOAc (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product, representing is example 13C (0.070 g, yield: 40%), as a white solid.

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

[00472] Cesium carbonate (140 mg, 0.42 mmol) was added to a solution of intermediate 1 (80 mg, 0.21 mmol) and 13C (57 mg, 0.42 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (57 mg, 0.063 mmol) and Xantphos (72 mg, 0.126 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 13 (7 mg, yield: 7%), in as a yellow solid. LM-MS: m/z=475.3 [M+H]+. ^1H 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-oxoimidazolidin-1-yl)-4-[3-(1-methyl-1,2,4-triazol-3-yl)-2-(trideuteromethoxy)anilino]- N-(trideuteromethyl)pyridazine-3-carboxamide

[00473] 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 was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 14 (60 mg, yield: 24%), in 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 N-(trideuteromethyl)pyridazine-3-carboxamide

[00474] 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 was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 15 (6 mg, yield: 8%), in 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-oxoimidazolidine -1-yl]-N-(trideuteromethyl)pyridazin-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-(3-methyloxetan-3-yl)urea

[00475] To a solution of 3-methyloxetan-3-amine (0.87 g, 10 mmol) in THF (20 ml) was added 1-chloro-2-isocyanatoethane (1.06 g, 10 mmol), then stirred at room temperature for 2 hours, the desired product 16B (1.82 g, 94%) was obtained as a colorless oil, which was used in the next step without further purification. LC-MS: mass/charge =192.6 [M+H] ⁺

Step 2. 1-(3-Methyloxetan-3-yl)imidazolidin-2-one

[00476] Sodium hydride (0.29 g, 12 mmol) was added to a solution of 16B (1.82 g, 9.2 mmol) in THF (30 mL), then stirred at room temperature for 4 hours. Quench with water (20 ml) and extracted with EtOAc (40 ml×2). The combined organic layers were washed with brine (60 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 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: mass/charge =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-oxoimidazolidine -1-yl]-N-(trideuteromethyl)pyridazin-3-carboxamide

[00477] Cesium carbonate (300 mg, 0.9 mmol) was added to a solution of intermediate 1 (110 mg, 0.3 mmol) and 16C (63 mg, 0.4 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (30 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol). The mixture was degassed with N ₂ 3 times and heated to 130°C for 2 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=95/5) provided the desired product as Example 16 (40 mg, yield: 30%), in as a white solid. LM-MS: m/z=496.6 [M+H] ⁺ . ^1H 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-isobutylurea

[00478] To a solution of 2-methylpropan-1-amine (1.0 g, 14 mmol) in acetonitrile (20 ml) was added 1-chloro-2-isocyanatoethane (1.4 g, 14 mmol), then stirred at room temperature for 2 hours. The solid precipitated, filtered to obtain the desired product as Example 17B (1.5 g, 61%) as a white solid, which was used in the next step without further purification. LM-MS: mass/charge =171.2 [M+H] ⁺

Step 2. 1-(2-Chloroethyl)-3-isobutylurea

[00479] Sodium hydride (0.32 g, 13 mmol) was added to a solution of 1-(2-chloroethyl)-3-isobutylurea (1.2 g, 6.7 mmol) in THF (10 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extract with EtOAc (30 ml x 2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product, representing is example 17C (0.5 g, yield: 50%), as a white solid.

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

[00480] To a solution of intermediate 1 (110 mg, 0.292 mmol) and 1-(2-chloroethyl)-3-isobutylurea (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 was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 17 (55 mg, yield: 39%), in 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

Step 1. 1-(2-Chloroethyl)-3-cyclopentylurea

[00481] To a solution of cyclopentylamine (18A) (1.0 g, 11.7 mmol) and THF (15 mL) was added 1-chloro-2-isocyanatoethane (1 mL, 11.7 mmol) using a syringe, then stirred at room temperature for 2 hours. The mixture solution was evaporated to give the title compound 18B (780 mg, 34.97%) as a colorless oil, which was used in the next step without further purification. LM-MS: mass/charge =191.1[M+H] ⁺

Stage 2. 1-Cyclopentylimidazolidin-2-one

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

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

[00482] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediate 1 (60 mg, 0.16 mmol) and 18C (49 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 110°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo and the residue was purified by flash chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the title compound of 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-oxoimidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazole -3-yl)anilino]-N-(trideuteromethyl)pyridazin-3-carboxamide

Step 1. 1-(3-Bicyclo[1.1.1]pentanyl)-3-(2-chloroethyl)urea

[00483] 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-isocyanatoethane (0.44 g, 4.2 mmol), then stirred at room temperature for 2 hours. The solid precipitated, filtered to give the desired product as Example 19B (0.5 g, 63%) as a white solid and was used in the next step without additional cleaning. LM-MS: mass/charge =189.1 [M+H] ⁺

Step 2. 1-(3-Bicyclo[1.1.1]pentanyl)imidazolidin-2-one

[00484] Sodium hydride (0.13 g, 5.3 mmol) was added to a solution of 19B (0.5 g, 2.7 mmol) in THF (10 mL), then stirred at room temperature for 2 hours. Quench with water (20 ml) and extracted with EtOAc (30 ml×2). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc/PE=1/1) to give the desired product, which is Example T202C (0.35 g, yield: 87%), as a white solid.

Step 3. 6-[3-(3-Bicyclo[1.1.1]pentanyl)-2-oxoimidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazole -3-yl)anilino]-N-(trideuteromethyl)pyridazin-3-carboxamide

[00485] 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 was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 19 (55 mg, yield: 39%), in as a yellow solid. LM-MS: m/z =493.3[M+H]+. ^1H 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 N-(trideuteromethyl)pyridazine-3-carboxamide

[00486] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediate 3 (60 mg, 0.16 mmol) and 20C (45 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 20 (6 mg, yield: 8%), in 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-oxoimidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N- (trideuteromethyl)pyridazine-3-carboxamide

[00487] 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 was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 21 (60 mg, yield: 24%), in as a yellow solid. LM-MS: m/z=478.3 [M+H] ⁺ . ^1H 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 N-(trideuteromethyl)pyridazine-3-carboxamide

[00488] Cesium carbonate (100 mg, 0.32 mmol) was added to a solution of intermediate 2 (60 mg, 0.16 mmol) and 22C (45 mg, 0.32 mmol) in 1,4-dioxane (8 mL). , Pd ₂ (dba) ₃ (43 mg, 0.048 mmol) and Xantphos (46 mg, 0.08 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) provided the desired product as Example 22 (6 mg, yield: 8%), in 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).

Example 23

Stage 1. Example 23b

[00489] In 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) added NH₂-CN (3.6 g, 86.2 mmol). The mixture was stirred at 110°C overnight. The reaction mixture was cooled to room temperature. The mixture was filtered and the filter cake was collected, washed with MeOH (20 ml) and concentrated invacuum to give the desired product as Example 23b (3.0 g, 56.6% yield) as a yellow solid. LCMS [M+1]⁺ = 185.0

Stage 2. Example 23c

[00490] 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 overnight. The reaction mixture was concentrated in vacuo . H ₂ O (15 ml) and MeOH (3 ml) were added at 0°C, which were stirred at room temperature for 1 hour. The mixture was filtered and the filter cake collected by filtration to give Example 23c (1.5 g, yield 50.1%) as a yellow solid. LCMS [M+1] ⁺ = 221.0

Stage 3. Example 23e

[00491] 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 refluxed overnight. The reaction mixture 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 using sat. NaHCO ₃ solution. The organic layer was separated and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to give the product as Example 23e (700 mg, 33.1% yield) as a yellow solid. LCMS [M+1] ⁺ = 389.1.

Stage 4. Example 23f

[00492] 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 room temperature overnight. The reaction mixture was concentrated in vacuo . The residue was dissolved in H ₂ O (50 ml), pH adjusted to ~4 with HCl (2 mol/l) and extracted with EtOAc (100 ml). The organic layer was concentrated to provide the crude product of Example 23f (750 mg, 100% yield, crude) as a yellow solid. LCMS [M+1] ⁺ = 375.2.

Stage 5. Example 23g

[00493] To a solution of Example 23f (500 mg, 1.33 mmol) in DMF (10 ml) was 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 RT for 2 hours. The reaction mixture 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 give the product Example 14g (510 mg, 98% yield) as a light yellow solid. LCMS [M+1] ⁺ = 391.0

Stage 6. Example 23h

[00494] 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 tert-Bu-Xphos -Pd ^3rd generation (22.5 mg, 0.128 mmol). The mixture was degassed with N ₂ three times, then heated to 100°C and stirred overnight. The reaction mixture was concentrated in vacuo . The residue was further purified by preparative HPLC to obtain the desired product as Example 23h (60 mg, 54.2% yield) as a white solid. LCMS [M+1] ⁺ = 440.1. ¹ H NMR (300 MHz, DMSO- d6 ) 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).

Stage 7. Example 23

[00495] 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 very slow addition of NaNO ₂ (10 mg, 0.15 mmol, 1.4 eq.) at 0°C, and the resulting mixture was stirred for 20 minutes. The reaction mixture was concentrated in vacuo . The residue was purified by preparative HPLC to obtain the desired product as Example 23 (13.5 mg, 28.1% yield) as a light yellow solid. LCMS [M+1] ⁺ = 443.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 24

Stage 1. Example 24c

[00496] 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 portionwise example 24b (70.3 g, 293 mmol, 1.02 eq.) at 0 ^o C. After addition, it was stirred for 1 hour 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 minutes, filtered and the filtrate was concentrated to give Example 24c (52.47 g, crude) as a brown oil.

Stage 2. Example 24d

[00497] 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 for 16 hours at room temperature and then concentrated in vacuo . AcOH (500 ml) and H ₂ O (50 ml) were added to the remaining precipitate. The vessel was equipped with an evaporator and the mixture was refluxed for 6 hours and then concentrated in vacuo . The crude product (115.0 g, crude material) was used in the next step without purification.

Stage 3. Example 24e

[00498] The crude product of Example 24d from the last step (115.0 g, 32% purity, 216 mmol, 1.0 eq.), dissolved in THF (150 ml)/MeOH (50 ml)/H ₂ O (50 ml), LiOH.H ₂ O (36.3 g, 864 mmol, 4.0 eq.) was added and the reaction mixture was stirred for 16 at room temperature. After completion of the reaction, MeOH and THF were concentrated. The residue was diluted with H ₂ O (200 ml) and then extracted with EtOAc (300 ml*3). The pH of the aqueous phase was then adjusted to 3 using conc. HCl. Acidification of the aqueous solution gave a brown precipitate, which was collected by filtration and dried in vacuo to give Example 24e (31.5 g, 93.5% yield) as a yellow solid.

Stage 4. Example 24f

[00499] A solution of Example 24e (15.0 g, 96.15 mmol, 1.0 eq.) in POCl ₃ (150 ml) was stirred for 4 hours at 100 ^o C. After completion of the reaction, it was concentrated in vacuo to give example 24f (17.4 g, crude material), which was used in the next step without further purification.

Stage 5. Example 24h

[00500] Into 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) add a solution of Example 24f (2.5 g, 11.85 mmol, 1.0 eq) in DCM (25 ml) drop by drop at 0^oC. The reaction solution was stirred for 30 minutes. at room temperature. The reaction solution was diluted with EtOAc (100 ml), washed with saline (80 ml*3), dried over anhydrous Na₂SO₄ and concentrated invacuum. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1/2) to give the product of Example 24h (1.8 g, 64.4% yield) as a yellow solid. LCMS [M+1]⁺ =236.2

Stage 6. Example 24j

[00501] 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 added LiHMDS ( 5.96 ml, 1M, 2.0 eq.) dropwise at -30 ^o C under N ₂ atmosphere. The reaction mixture was stirred for 30 minutes. at room temperature. The crude product was concentrated and purified by silica gel chromatography (DCM/MeOH=10/1) to give the product Example 24j (450 mg, 37.5% yield) as a yellow solid. LCMS [M+1] ⁺ = 404.2.

Stage 7. Example 24i

[00502] To a solution of Example 24j (450 mg, 1.12 mmol, 1.0 eq.) in dioxane (5 ml) was added Cs ₂ CO ₃ (728 mg, 2.23 mmol, 2.0 eq.), example 24k (285 mg, 3.35 mmol, 3.0 eq.) and the third ^generation tert -Bu-Xphos catalyst (99 mg, 0.11 mmol, 0.1 eq.), and the reaction mixture was stirred for 4 h at 110 ^o C in an atmosphere of N ₂ . The reaction solution was concentrated and purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the product of Example 24l (320 mg, 63.5% yield) as a yellow solid. LCMS [M+1] ⁺ =453.2.

Stage 5. Example 24

[00503] 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.) at drops at 0 ^o C in an atmosphere of N ₂ . The reaction solution was stirred for 30 minutes. at RT. The reaction solution was poured into a saturated aqueous solution of NH ₄ Cl (10 ml) and extracted with DCM (10 ml*3). The combined organic layer was washed with brine (30 ml), dried with Na ₂ SO ₄ and concentrated. The crude product was purified by preparative HPLC to provide the desired product as Example 24 (8.8 mg, 8.0% yield) as an off-white solid. LCMS [M+1] ⁺ = 408.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 25

Stage 1. Example 25

[00504] To a 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.) at drops at 0 ^o C in an atmosphere of N ₂ . The reaction solution was stirred for 30 minutes. at RT. The reaction solution was purified by preparative TLC (DCM/MeOH=12/1) to obtain crude product (27 mg) and further purified by preparative HPLC (Prep-C18, 5 μm XBridge column, 19 × 150 mm, W aters; gradient elution from 40% MeCN in water to 50% MeCN in water over a period of 7 minutes, both solvents containing 0.1% formic acid) to obtain the desired product, which is Example 25 (6.8 mg, yield 14.6%), as a yellow solid (FA salt). LCMS [M+1] ⁺ =422.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 26

[00505] To a solution of example 26a (135 mg, 0.3 mmol) in dry THF (10 ml) was added example 26b (1.2 ml, 1 M in THF, 1.2 mmol) dropwise at 0°C in the atmosphere nitrogen. After addition (approximately 5 minutes), the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then quenched with MeOH (1 ml) and concentrated in vacuo . The residue was purified by preparative TLC (DCM/MeOH=20/1) to give the product of Example 26 (19.5 mg, 15% yield) as an off-white solid. LCMS [M+1] ⁺ = 434.3/. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 27

Stage 1. Example 027c

[00506] To a solution of Example 057a (5 g, 21.3 mmol) and Example 027b (2.28 g, 23.4 mmol) in THF (20 mL) was added Et ₃ N (3.28 g, 31.9 mmol ) and EDCI (6 g, 31.9 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine (60 ml) and extracted with 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

Stage 2. Example 027e

[00507] 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 atmosphere LiHMDS (1 mol/L, 28 mL, 28.05 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with brine (60 ml), extracted with DCM (60 ml*3). The combined organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure, purified by flash chromatography with a C-18 column (H ₂ O/CH ₃ CN=3/1) to give example 027e (2.4 g, yield 32 %) as a yellow oil. LCMS [M+1] ⁺ = 403.1

Stage 3. Example 027g

[00508] To a solution of Example 027e (500 mg, 1.24 mmol) in THF (10 mL) under N ₂ atmosphere, Example 027f (1 mol/L, 10 mL, 12.4 mmol) was added in one portion. The mixture was stirred at RT for 1 hour. The reaction mixture was washed with brine (40 ml) and extracted with EtOAc (40 ml*3). The combined organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give the crude product (600 mg, crude) as a yellow solid, which was directly used in the next step without further purification. LCMS [M+1] ⁺ = 384.1

Stage 4. Example 027

[00509] 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) was added Cs₂CO₃(127.3 mg, 0.392 mmol), Pd₂(dba)₃(23.9 mg, 0.026 mmol) and Xantphos (15.1 mg, 0.026 mmol). The mixture was degassed with Ar, heated to 90^oC and stirred overnight. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, which was further purified by preparative HPLC to give Example 027 (17.5 mg, 15% yield) as a white solid. LCMS [M+1]⁺ = 433.2.¹H 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).

Example 28

Stage 1. Example 028b

[00510] 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 ^o C for 16 hours. 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.

Stage 2. Example 028d

[00511] 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 ^o C for 15 hours. 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.

Stage 3. Example 28b

[00512] Into 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) HOBt (344 mg, 2.55 mmol) and EDCI (1.37 g, 7.13 mmol) were added. The mixture was stirred at room temperature for 16 hours. After cooling to 0 ^o C, the mixture was kept for 2 hours at 0 ^o 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

Stage 4. Example 28d

[00513] 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) was 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 with nitrogen 3 times and stirred at 120 ^o C for 4 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=85/15) to provide the desired crude product as Example 28d (1.08 g, 81.2% yield, ~35% purity) as a yellow solid, which applied to the next stage directly. LCMS [M+1] ⁺ = 458.0

Stage 5. Example 28e

[00514] To a solution of crude Example 28d (1.08 g, 2.36 mmol) in DCM/MeOH (10 mL) was added 6 N. HCl/iPrOAc (20 ml). The mixture was stirred at RT for 16 hours. The resulting mixture was concentrated and the residue was purified by silica gel chromatography (EtOAc/MeOH=85/15) to give the desired product as Example 28e (240 mg, 28.4% yield ), as a yellow solid. CMS [M+1] ⁺ = 358.0

Stage 6. Example 28h

[00515] To a solution of Example 28g (200 mg, 3.51 mmol) and TEA (709 mg, 7.02 mmol) in DCM (15 mL), a solution of Example 28f (707 mg, 3.51 mmol) in DCM was slowly added ( 5 ml) at 0 ^o C. The mixture was then stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (petroleum ether/EtOAc = 92/8) to obtain the desired product, which is Example 28h (470 mg, 60.4% yield) as a yellow solid. LCMS [M+1] ⁺ = 223.0

Stage 7. Example 28

[00516] To an ice-cold solution of NaH (14.5 mg, 0.36 mmol, 60 wt.% in mineral oil) in DMF (1 ml) under a 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 cool bath was removed and the reaction mixture was heated to 80 ^° C. and stirred for 2 hours. The mixture was quenched with water and purified by preparative HPLC to give the desired product as Example 28 (1.1 mg, 2.8% yield), as a yellow solid. LCMS [M+1] ⁺ = 441.0. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 29

Stage 1. Example 29c

[00517] 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 room temperature for 16 hours After completion of the reaction, the solvent was concentrated and the residue was suspended in DCM (5 ml) and sonicated. The resulting solid was collected by filtration and dried to give the desired product as Example 29c (665 mg, 80% yield) as a white solid. LCMS [M+1] ⁺ = 115.0. ^1H NMR (400 MHz, DMSO- d6 ) δ 5.62 (s, 2H), _3.18-3.12 (m, 4H), 1.80-1.68 (m, 4H).

Stage 2. Example 29

[00518] 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 29 (13 mg, 21.7% yield) as a white solid. LCMS [M+1] ⁺ = 455.0. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 30

Stage 1. Example 30b

[00519] 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) HOBt (172 mg, 1.27 mmol) and EDCI (685 mg, 3.57 mmol) were added. The mixture was stirred at room temperature for 16 hours. After cooling to 0 ^o C, the mixture was kept for 2 hours at 0 ^o 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

Stage 2. Example 30

[00520] 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) was 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 with nitrogen 3 times and stirred at 110 ^o C for 3.5 hours in a sealed tube. After completion, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 30 (16 mg, 19.0% yield) as a white solid. LCMS [M+1] ⁺ = 438.0. ¹ H NMR (400 MHz, DMSO- d6 ) 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).

Example 31

Stage 1. Example 31b

[00521] 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 RT for 10 minutes, and then example 31b (1.86 g, 13.6 mmol) in dry DMSO (20 ml) was added, which was stirred at 110 ^o C overnight. Once complete, the reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and dried over Na ₂ SO ₄ . The organic layer was concentrated and purified by a 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).

Stage 2. Example 31c

[00522] A solution of Mg (676 mg, 28 mmol) in MeOH (5 ml) was stirred at RT for 10 minutes, then Example 31b (600 mg, 2.8 mmol) in MeOH (5 ml) was added and the reaction mixture was stirred at room temperature overnight in a sealed tube. More Mg (676 mg, 28 mmol) was added and the reaction mixture was stirred at room temperature for another 6 hours. The mixture was filtered and the solid was washed with MeOH. The filtrate from Example 31c was used directly for the next step. LCMS [M+1] ⁺ =61.2

Stage 3. Example 31d

[00523] To the solution of Example 31c (crude in MeOH) was added (Boc) _2O (940 mg, 5.6 mmol), which was stirred at room temperature overnight. The mixture was filtered and the solid was washed with MeOH. Additional (Boc) _2O (940 mg, 5.6 mmol) was added to the organic layer and stirred at RT for an additional 4 hours. Once the reaction was complete, the mixture was concentrated and purified using a silica gel column (petroleum ether/ EtOAc=5/1) to give Example 031d (500 mg, crude containing (Boc) _2O ) 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).

Stage 4. Example 31c

[00524] A solution of example 31d (500 mg, 3.1 mmol) in conc. HCl (1 ml) was stirred at RT for 0.5 h. After completion of the reaction, the mixture was concentrated to give Example 31c (200 mg, 67.9% yield) as a white solid, which was used for the next step without further cleaning. LCMS [M+1] ⁺ = 60.2.

Stage 5. Example 31f

[00525] 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 room temperature overnight. After completion of the reaction, the mixture was concentrated and directly purified by a silica gel column (DCM/MeOH=10/1) to obtain the desired product as Example 31f (230 mg, crude DIEA containing material, 67.6% yield) as colorless oils LCMS [M] ⁺ = 103.2

Stage 6. Example 31

[00526] 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) was 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 with nitrogen 3 times, sealed and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 31 (2.2 mg, 1% yield) as a white solid. LCMS [M+1] ⁺ = 442.2. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 32

Stage 1. Example 32c

[00527] A solution of Example 32a (300 mg, 2.19 mmol) in 1,4-dioxane (5 ml) was treated with Example 32b (623 mg, 3.28 mmol) and TEA (664 mg, 6.57 mmol) . The mixture was stirred at RT for 16 hours. Once complete, the mixture was concentrated and the residue was suspended in DCM (5 ml) and sonicated. The resulting solid was collected by filtration and dried to give the desired product as Example 32c (226 mg, 73.9% yield) as a white solid.

LCMS [M+1] ⁺ = 141.0

Stage 2. Example 32

[00528] 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 with nitrogen 3 times and stirred at 110 ^o C for 16 hours in a sealed tube. After completion, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 32 (6.6 mg, 8.7% yield) as a white solid. LCMS [M+1] ⁺ = 481.0. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 33

Stage 1. Example 33c

[00529] 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 hours at room temperature and concentrated. The residue was treated with DCM. The resulting solid was collected by filtration to give 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) .

Stage 2. Example 33

[00530] 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) was 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 hours under _N2 protection. The solid was filtered and the filtrate was concentrated and the residue was purified by preparative TLC (DCM/MeOH = 15/1) to give Example 33 (43.3 mg, 37% yield) as an off-white solid. LCMS [M+1] ⁺ = 448.2. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 34

Stage 1. Example 34b

[00531] 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 ^o C. The mixture was stirred for 2 hours at room temperature. The mixture was quenched with MeOH (12 ml), washed with brine (50 ml * 3), dried over Na ₂ SO ₄ and concentrated to obtain the product , which is example 34b (9.2 g, 98% yield), as an orange solid. LCMS [M+1] ⁺ =221.2.

Stage 2. Example 34c

[00532] To a solution of Example 34b (9.2 g, 41.8 mmol, 1.0 eq.) in ACN (184 mL) was 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 hours at 80 ^° C. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel chromatography (petroleum ether/EtOAc=2/1) to give the product of Example 34c (3.9 g, yield 39%), as an orange solid. LCMS [M+1] ⁺ = 238.2.

Stage 3. Example 34d

[00533] 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 room temperature for 48 hours in an atmosphere of H ₂ from a balloon. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 1/1) to give the product Example 34d (1.9 g, 56% yield) as an off-white solid. LCMS [M+1] ⁺ =208.2.

Stage 4. Example 34f

[00534] 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 ^o C under N ₂ protection. The reaction mixture was stirred for 0.5 hours at room temperature, and then silica was added to the mixture and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give the product Example 34f (450 mg, 58% yield) as a yellow solid. LCMS [M+1] ⁺ = 406.2.

Stage 5. Example 34h

[00535] 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.) drop by drop at 0 ^o C under N ₂ protection conditions. The mixture was stirred for 0.5 h at room temperature. The reaction mixture 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 give the product of Example 34h (160 mg, 84% yield) as a yellow solid. LCMS [M+1] ⁺ = 387.1.

Stage 6. Example 34

[00536] To a solution of example 34h (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (4 ml) was added Cs ₂ CO ₃ (169 mg, 0.52 mmol, 2.0 eq.), example 34l (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 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 34 (30.9 mg, 27% yield) as a yellow solid. LCMS [M+1] ⁺ = 436.2. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 35

Stage 1. Example 35c

[00537] 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 ^o C. The reaction solution was stirred for 2 hours at room temperature. The resulting solid was collected by filtration to give Example 35b (8.07 g) as a white solid. The solid was dissolved in THF (150 ml), then NaH (5.83 g, 60% in mineral oil, 145.8 mmol, 3.0 eq.) portionwise at 0 ^o C. The mixture was stirred for 16 hours at room temperature. The reaction mixture was quenched with H ₂ O and extracted with EtOAc. The combined organic layer was washed with brine, dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography (DCM/MeOH=30/1) to give the desired product as 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).

Stage 2. Example 35f

[00538] To a solution of Example 35d (10.0 g, 52.08 mmol, 1.0 eq.) in DCM (200 mL) was added DIEA (33.59 g, 260.4 mmol, 5.0 eq.) and HATU (23.75 g, 62.50 mmol, 1.2 eq.). After stirring 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 hour at room temperature. After completion of the reaction, the solvent was removed and the crude material was purified by silica gel chromatography (petroleum ether/EtOAc=3/1) to obtain the desired product as Example 35f (11.5 g, 94.0% yield) as a yellow solid. . LCMS [M+1] ⁺ = 235.0.

Stage 3. Example 35h

[00539] 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) LiHMDS (42.55 mL, 1 M in THF, 2.0 eq.) was added dropwise at -15 ^° C under N ₂ atmosphere. The reaction solution was stirred for 1 hour at room temperature. And then 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 as Example 35h (4.02 g, 46.9% yield) as a yellow solid. LCMS [M+1] ⁺ = 403.2.

Stage 4. Example 35j

[00540] 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.) drop by drop at -10 ^o C in an atmosphere of N ₂ . The reaction solution was stirred for 1 hour at room temperature. The reaction solution was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to give the desired product as Example 35j (1.90 g, 99.7% yield) as a yellow solid. LCMS [M+1] ⁺ =384.2.

Stage 5. Example 35

[00541] To a solution of Example 35j (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (3 ml) was 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 hours at 110 ^° C under N ₂ atmosphere. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 35 (31.3 mg, 25.3% yield) as an off-white solid. LCMS [M+1] ⁺ = 476.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 36

[00542] To a solution of Example 36a (70 mg, 0.18 mmol, 1.0 eq.) in dioxane (2 ml) was added Example 36b (48 mg, 0.55 mmol, 3.0 eq.), Cs ₂ CO ₃ (119 mg, 0.37 mmol, 2.0 eq.), Xantphos (11 mg, 0.018 mmol, 0.1 eq.) and Pd ₂ (dba) _3. CHCl ₃ (19 mg, 0.018 mmol, 0.0 eq.) 1 eq.). The reaction solution was stirred for 4 hours at 110 ^° C under N ₂ atmosphere. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 36 (30.9 mg, 39.0% yield) as an off-white solid.

LCMS [M+1] ⁺ = 435.2. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.02 (s, 1H), 10.56 (s, 1H) _, 9.12 (s, 1H), 8.56 (s, 1H), 8 .08 (s, 1H), 7.66 (dd, J =7.8, 1.5 Hz, 1H), 7.56 (dd, J =7.8, 1.5 Hz, 1H), 7, 29 (t, J =7.4 Hz, 1H), 3.95 (s, 3H), 3.70 (s, 3H), 3.06-2.94 (m, 1H), 2.83-2 .69 (m, 1H), 1.15-1.08 (m, 2H), 1.08-0.98 (m, 8H).

Example 37

[00543] To a solution of Example 37a (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (3 ml) was added Example 37b (49 mg, 0.52 mmol, 3.0 eq.), Cs ₂ CO ₃ (170 mg, 0.52 mmol, 2.0 equiv.) and tert -Bu-Xphos-Pd ^3rd generation (23 mg, 0.026 mmol, 0.1 equiv.). The reaction solution was stirred for 6 hours at 110 ^° C under N ₂ atmosphere. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 37 (21.0 mg, 18.3% yield) as a light yellow solid. LCMS [M+1] ⁺ =442.2. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 9.98 (s, 1H) _, 9.10 (s, 1H), 8.56 (s, 1H), 8 .19 (d, J =4.8 Hz, 1H), 8.01 (s, 1H), 7.69 (t, J =8.0 Hz, 2H), 7.60 (t, J =8, 0 Hz, 2H), 7.31 (t, J =8.0 Hz, 1H), 6.96-6.88 (m, 1H), 3.96 (s, 3H), 3.72 (s, 3H), 3.04-2.91 (m, 1H), 1.14-0.94 (m, 4H).

Example 38

Stage 1. Example 38c

[00544] A solution of Example 38b (1.13 g, 8.2 mmol) in 1,4-dioxane (10 ml) was treated with Example 38a (1.0 g, 8.2 mmol) and TEA (2.5 g, 24, 7 mmol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was concentrated and the residue was suspended in a mixed solution (petroleum ether/EtOAc=1/1, 10 ml) and subjected to ultrasound. The resulting solid was collected by filtration, dried to give the desired product as Example 38c (1.0 g, 94.3% yield) as a white solid which contained some TEA.HCl. LCMS [M+1] ⁺ = 129.0

Stage 2. Example 38

[00545] 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) was 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 with nitrogen 3 times and stirred at 110 ^° C for 16 hours. Once complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 38 (116 mg, 37.4% yield) as a yellow solid. LCMS [M+1] ⁺ = 469.0. ^1H NMR (400 MHz, DMSO- d6 ) 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.

Example 105

[00546] To a solution of Example 105a (100 mg, 0.26 mmol, 1.0 eq.), Example 105b (57.0 mg, 0.78 mmol, 3.0 eq.) in dioxane (3 ml) was added ₂ CO ₃ (169.5 mg, 0.52 mmol, 2.0 eq.) and tert-Bu-XPhos-Pd ^3rd generation (26.7 mg, 0.03 mmol, 0.1 eq.). The reaction mixture was stirred at 110°C for 4 hours under _N2 protection. The solid was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC (DCM/MeOH=15/1) to give Example 105 (36.1 mg, 33% yield) as a yellow solid. LCMS [M+1] ⁺ = 421.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.02 (s, 1H), 10.56 (s, 1H), 9.12 (s, 1H), 8.57 (s, 1H), 8, 07 (s, 1H), 7.66 (dd, J =7.8, 1.5 Hz, 1H), 7.55 (dd, J =7.8, 1.5 Hz, 1H), 7.28 (t, J =7.8 Hz, 1H), 3.95 (s, 3H), 3.70 (s, 3H), 3.06-2.93 (m, 1H), 2.39 (q, J =7.5 Hz, 2H), 1.16-0.96 (m, 7H).

Example 106

[00547] To a solution of Example 106a (50 mg, 0.13 mmol, 1.0 eq.) and Example 106b (13.9 mg, 0.20 mmol, 1.5 eq.) in dioxane (3 mL) was added Cs ₂ CO ₃ (84.9 mg, 0.26 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (13.5 mg, 0.013 mmol, 0.1 eq.) and Xantphos (15, 1 mg, 0.026 mmol, 0.2 eq.). The reaction mixture was stirred for 2 hours at 110 ^o C under N ₂ protection conditions. The mixture was filtered and the filtrate was concentrated in vacuo . The crude product was purified by preparative HPLC (DCM/MeOH=25/1) to give the desired product as Example 106 (5.9 mg, 10.8% yield) as a white solid. LCMS [M+1] ⁺ = 419.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.04 (s, 1H), 10.86 (s, 1H) _, 9.15 (s, 1H), 8.57 (s, 1H), 8 .17 (s, 1H), 7.67 (dd, J =7.8, 1.5 Hz, 1H), 7.59-7.56(m, 1H), 7.29 (t, J =7 .8 Hz, 1H), 6.61 (dd, J =16.8, 10.2 Hz, 1H), 6.28 (dd, J =16.8, 1.8 Hz, 1H), 5.81 (d, J =11.7 Hz,1H), 3.96 (s, 3H), 3.71 (s, 3H), 3.05-2.95 (m, 1H), 1.15-0, 95 (m, 4H).

Example 107

[00548] To a solution of Example 107a (110 mg, 0.29 mmol) and Example 107b (93 mg, 0.86 mmol) in 1,4-dioxane (2 ml) was added Pd ₂ (dba) ₃ (26 mg, 0.029 mmol), Xantphos (33 mg, 0.057 mmol) and Cs ₂ CO ₃ (187 mg, 0.57 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C for 1 hour. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 107 (24 mg, 18.5% yield) as a yellow solid. LCMS [M+1] ⁺ = 456.0. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.04 (s, 1H), 9.88 (s, 1H) _, 9.07 (s, 1H), 8.55 (s, 1H), 8 .03 (d, J =5.1 Hz, 1H), 7.97 (s, 1H), 7.66 (d, J =8.1 Hz, 1H), 7.57 (d, J =7, 8 Hz, 1H), 7.39 (s, 1H), 7.27 (t, J= 8.0 Hz, 1H), 6.74 (d, J = 4.9 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.94 (s, 1H), 2.24 (s, 3H), 1.05 (s, 2H), 0.99 (d, J = 7.6 Hz, 2H).

Example 108

[00549] To a solution of Example 108a (100 mg, 0.26 mmol) and Example 108b (44 mg, 0.39 mmol) in 1,4-dioxane (2 ml) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 108 (18 mg, 15.1% yield) as a white solid. LCMS [M+1] ⁺ = 460.0. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.01 (s, 1H), 10.15 (s, 1H) _, 9.11 (s, 1H), 8.54 (s, 1H), 8 .20 (t, J =7.5 Hz, 1H), 7.69 (s, 1H), 7.63 (q, J =8.2, 5.8 Hz, 3H), 7.28 (t, J =8.0 Hz, 1H), 6.83 (s, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.95 (s, 1H), 1.07 ( s, 2H), 1.00 (d, J =7.4 Hz, 2H).

Example 109

To a solution of example 109a (100 mg, 0.26 mmol) and example 109b (30 mg, 0.31 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol), Xantphos 30 mg, 0.052 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 109 (25 mg, 21.7% yield) as a white solid. LCMS [M+1] ⁺ = 443.0. ¹ H NMR (400 MHz, DMSO- d6 ) δ 11.04 (s, 1H), 10.34 (s, 1H), _9.10 (s, 1H), 8.77 (d, J =4, 4 Hz, 1H), 8.56 (s, 1H), 8.07 (d, J =9.1 Hz, 1H), 7.72 (s, 1H), 7.62 (dd, J =12, 0, 8.1 Hz, 2H), 7.55 (dd, J= 9.2, 4.5 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 3.93 ( s, 3H), 3.70 (s, 3H), 2.95 (t, J =7.4 Hz, 1H), 1.06 (d, J =4.1 Hz, 2H), 1.00 ( d, J= 7.4 Hz, 2H).

Example 110

Stage 1. Example 110c

[00550] Into 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 mixture was heated to 65 ^o C and stirring was continued for 2 hours. The reaction mixture 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 as Example 110c (900 mg , yield 87.4%), as a brown solid. LCMS [M+1] ⁺ = 180.0

Stage 2. Example 110

[00551] 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) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 110 (22 mg, 16.1% yield) as a yellow solid. LCMS [M+1] ⁺ = 527.0. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 111

[00552] Solution of Example 111a (100 mg, 0.26 mmol), Example 111b (96 mg, 0.76 mmol), Pd ₂ (dba) ₃ (24 mg, 0.026 mmol), Xantphos (8 mg, 0.013 mmol) and Cs ₂ CO ₃ (170 mg, 0.52 mmol) in dioxane (3 ml) were heated to 110°C for 2 hours in an Ar atmosphere. This mixture was filtered and directly purified by preparative HPLC to give Example 111 (37 mg, 30.1% yield) as a yellow solid. LCMS [M+1] ⁺ = 471.3. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H), 10.21 (s, 1H) _, 9.10 (s, 1H), 8.54 (s, 1H), 8 .14 (s, 1H), 7.64 (dd, J =13.6, 7.9 Hz, 2H), 7.27 (t, J =7.9 Hz, 1H), 7.08 (s, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 3.01-2.92 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H ), 1.11-0.96 (m, 4H).

Example 112

[00553] Solution of Example 112a (100 mg, 0.26 mmol), Example 112b (80 mg, 0.78 mmol), Pd ₂ (dba) ₃ (24 mg, 0.026 mmol), Xantphos (8 mg, 0.013 mmol) and Cs ₂ CO ₃ (170 mg, 0.52 mmol) in dioxane (3 ml) were heated to 110°C for 2 hours in an Ar atmosphere. This mixture was filtered and directly purified by preparative HPLC to give Example 112 (34 mg, 28.6% yield) as a yellow solid. LCMS [M+1] ⁺ = 456.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.12 (s, 1H), 9.91 (s, 1H) _, 9.06 (s, 1H), 8.53 (s, 1H), 8 .25 (s, 1H), 7.68 (d, J =8.0 Hz, 1H), 7.60 (d, J =7.8 Hz, 1H), 7.52 (t, J =7, 8 Hz, 1H), 7.26 (t, J =7.9 Hz, 1H), 7.15 (d, J =8.3 Hz, 1H), 6.73 (d, J =7.3 Hz , 1H), 3.92 (s, 3H), 3.69 (s, 3H), 2.98-2.89 (m, 1H), 2.28 (s, 3H), 1.09-0, 94 (m, 4H).

Example 113

[00554] Solution of Example 113a (100 mg, 0.26 mmol), Example 113b (30 mg, 0.26 mmol), Pd ₂ (dba) ₃ (24 mg, 0.026 mmol), Xantphos (8 mg, 0.013 mmol) and Cs ₂ CO ₃ (170 mg, 0.52 mmol) in DMA (3 ml) were heated to 130°C for 2 hours in an Ar atmosphere. This mixture was filtered and directly purified by preparative HPLC to give Example 113 (13 mg, 10.9% yield) as a yellow solid. LCMS [M+1] ⁺ = 457.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.04 (s, 1H), 10.21 (s, 1H) _, 9.09 (s, 1H), 8.54 (s, 1H), 7 .97 (d, J =9.1 Hz, 1H), 7.62 (dd, J =15.5, 8.4 Hz, 3H), 7.43 (d, J =9.2 Hz, 1H) , 7.25 (t, J =8.0 Hz, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 2.94 (t, J =5.6 Hz, 1H) , 1.09-0.96 (m, 4H).

Example 114

Stage 1. Example 114b

[00555] 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 ^o C. The reaction solution was stirred for 30 minutes. at RT. The reaction solution was poured into saturated aqueous NH ₄ Cl (20 ml) at 0 ^o C, extracted with EtOAc (20 ml * 3), the combined organic layers were washed with saline (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 give the desired product as Example 114b (367 mg, 79.5% yield) as a yellow solid. LCMS [M+1] ⁺ = 372.3.

Stage 2. Example 114

[00556] To a solution of Example 114b (100 mg, 0.27 mmol, 1.0 eq.) in dioxane (5 ml) was added Example 114c (81 mg, 0.81 mmol, 3.0 eq.), Cs ₂ CO ₃ (175 mg, 0.54 mmol, 2.0 equiv.) and tert -Bu-Xphos-Pd ^3rd generation (24 mg, 0.027 mmol, 0.1 equiv.). The reaction mixture was stirred for 4 hours at 110 ^o C in an atmosphere of N ₂ . The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 114 (43.7 mg, 37.3% yield) as a yellow solid. LCMS [M+1] ⁺ = 436.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 115

[00557] To a solution of Example 115a (100 mg, 0.27 mmol, 1.0 eq.) in dioxane (5 ml) was added Example 115b (103 mg, 0.81 mmol, 3.0 eq.), Cs ₂ CO ₃ (175 mg, 0.54 mmol, 2.0 eq), Xantphos (31 mg, 0.054 mmol, 0.2 eq) and Pd ₂ (dba) ₃ CHCl ₃ (28 mg, 0.027 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C in an atmosphere of N ₂ . The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 115 (40.3 mg, 32.3% yield) as a light yellow solid. LCMS [M+1] ⁺ = 464.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 10.96 (s, 1H), 8.89 (s, 1H) _, 8.56 (s, 1H), 8.15 (s, 1H), 7 .62 (dd, J =7.8, 1.5 Hz, 1H), 7.56 (dd, J =7.8, 1.5 Hz, 1H), 7.26 (t, J =7.8 Hz, 1H), 4.09-3.96 (m 3H), 3.95 (s, 3H), 3.72 (s, 3H), 3.39 (t, J = 8.1 Hz, 2H) , 3.10 (q, J =7.2 Hz, 2H), 1.19-1.03 (m, 9H).

Example 116

[00558] To a solution of Example 116a (100 mg, 0.27 mmol, 1.0 eq.) in dioxane (5 ml) was added Example 116b (69 mg, 0.81 mmol, 3.0 eq.), Cs ₂ CO ₃ (175 mg, 0.54 mmol, 2.0 eq.), Xantphos (31 mg, 0.054 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (28 mg, 0.027 mmol, 0.1 eq.). The reaction solution was stirred for 4 hours at 110 ^° C under N ₂ atmosphere. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 116 (40.7 mg, 36.0% yield) as a light yellow solid. LCMS [M+1] ⁺ = 421.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.04 (s, 1H), 10.90 (s, 1H) _, 8.88 (s, 1H), 8.56 (s, 1H), 8 .00 (s, 1H), 7.65 (dd, J =7.8, 1.5 Hz, 1H), 7.52 (dd, J =7.8, 1.5 Hz, 1H), 7, 26 (t, J =7.8 Hz, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 3.12 (q, J =7.2 Hz, 2H), 2, 07-1.96 (m, 1H), 1.13 (t, J =7.2 Hz, 3H), 0.79 (d, J =6.0 Hz, 4H).

Example 117

Stage 1. Example 117b

[00559] In 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) added NH₂-CN (3.6 g, 86.2 mmol). The mixture was stirred at 110°C overnight. The reaction mixture was cooled to room temperature. The mixture was filtered and the filter cake was collected, washed with MeOH (20 ml) and concentrated invacuum to obtain the desired product as Example 117b (3.0 g, 56.6% yield) as a yellow solid. LCMS [M+1]⁺ = 185.0

Stage 2. Example 117c

[00560] 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 overnight. The reaction mixture was concentrated in vacuo . H ₂ O (15 ml) and MeOH (3 ml) were added at 0°C, which were stirred at room temperature for 1 hour. The mixture was filtered and the filter cake collected by filtration to give Example 117c (1.5 g, yield 50.1%) as a yellow solid. LCMS [M+1] ⁺ = 221.0

Stage 3. Example 117e

[00561] 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 refluxed overnight. The reaction mixture 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 using sat. NaHCO ₃ solution. The organic layer was separated and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to give the product Example 117e (700 mg, 33.1% yield) as a yellow solid. LCMS [M+1] ⁺ = 389.11.

Stage 4. Example 117f

[00562] 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 room temperature overnight. The reaction mixture was concentrated in vacuo . The residue was dissolved in H ₂ O (50 ml), pH adjusted to ~4 with HCl (2 mol/l) and extracted with EtOAc (100 ml). The organic layer was concentrated to provide the crude product as Example 117f (750 mg, 100% yield, crude) as a yellow solid. LCMS [M+1] ⁺ = 375.2

Stage 5. Example 117g

[00563] To a solution of Example 117f (500 mg, 1.33 mmol) in DMF (10 ml) was 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 RT for 2 hours. The reaction mixture 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 give the product Example 117g (510 mg, 98% yield) as a light yellow solid. LCMS [M+1] ⁺ = 391.0

Stage 6. Example 117

[00564] 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 tert-Bu-Xphos -Pd ^3rd generation (22.5 mg, 0.128 mmol). The mixture was degassed with N ₂ three times, then heated to 100°C and stirred overnight. The reaction mixture was concentrated in vacuo . The residue was further purified by preparative HPLC to obtain the desired product as Example 117 (60 mg, 54.2% yield) as a white solid. LCMS [M+1] ⁺ = 440.1. ¹ H NMR (300 MHz, DMSO- d6 ) 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).

Example 118

[00565] To a solution of Example 118a (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (5 ml) was 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 hours at 110 ^° C under N ₂ atmosphere. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as 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).

Example 119

Stage 1. Example 119

[00566] 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) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 119 (19.7 mg, 16.6% yield) as a yellow solid. LCMS [M+1] ⁺ = 460.0. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 120

Stage 1. Example 120b

[00567] 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 conditions. The reaction solution was stirred at room temperature for 1 hour and then the mixture was concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc=5/1) to give the product Example 120b (6.8 g, 75% yield) as a white solid. LCMS [M+1] ⁺ = 190.2.

Stage 2. Example 120c

[00568] 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 conditions. The mixture was stirred for 5 minutes. 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 heated to room temperature and stirred for 30 minutes. The reaction mixture 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 give the product Example 120c (3.5 g, 65% yield) as a green solid. LCMS [M+1] ⁺ = 171.2.

Stage 3. Example 120

[00569] To a solution of Example 120d (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (3 ml) was 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 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 120 (48.4 mg, 36% yield) as an off-white solid. LCMS [M+1] ⁺ = 518.4. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 121

Stage 1. Example 121c

[00570] 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 hours at room temperature and concentrated to dryness. The residue was suspended in DCM and sonicated. The resulting solid was collected by filtration to give Example 121c (57 mg, 37% yield) as a white solid.

Stage 2. Example 121

_{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 hours under _N2 protection. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 121 (40.1 mg, 56% yield) as a yellow solid. LCMS [M+1] ⁺ = 450.4. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 122

Stage 1. Example 122b

[00571] To a solution of Example 122a (700 mg, 4.61 mmol) in THF (65 ml) was added MeMgCl (15 ml, 45 mmol) at 0 ^o C under argon protection. The reaction mixture was heated to room temperature and stirred for 16 hours. Then the mixture was quenched with aq. NH ₄ Cl solution, extracted with EA (50 ml*2). The combined organic phase was washed with 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 a brown oil, which was used directly for the next step.

Stage 1. Example 122

[00572] 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) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative TLC (DCM/MeOH=15/1) to give the desired product as Example 122 (16 mg, 11.5% yield) as a yellow solid. LCMS [M+1] ⁺ = 500.0. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 123

[00573] To a solution of Example 123a (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (5 ml) was 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 hours at 110 ^o C in an atmosphere of N ₂ . The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 123 (26.1 mg, 21.4% yield) as a light yellow solid. LCMS [M+1 ] ⁺ = 469.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 124

Stage 1. Example 124c

[00574] 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 minutes. at RT followed by the addition of Example 124a (500 mg, 3.52 mmol, 1.0 eq.) in DMF (3 ml). The mixture was stirred for 4 hours at 80 ^o C. After cooling 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 give the product as Example 124c (250 mg, 32% yield) as a yellow solid. LCMS [M+1] ⁺ = 211.2.

Stage 2. Example 124d

[00575] 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 RT for 0.5 hours under an atmosphere of H ₂ from a balloon. The solid was filtered and the filtrate was concentrated to give the product as Example 124d (230 mg, crude, yield: quantity) as a yellow oil. LCMS [M+1] ⁺ = 181.2.

Stage 3. Example 124

[00576] To a solution of Example 124e (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (3 ml) was added Cs ₂ CO ₃ (169.5 mg, 0.52 mmol, 2.0 eq.) , example 124d (93.7 mg, 0.52 mmol, 2.0 equiv.) and tert-Bu-XPhos-Pd ^3rd generation (26.7 mg, 0.03 mmol, 0.1 equiv.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 124 (37.0 mg, 27% yield) as a yellow solid. LCMS [M+1] ⁺ = 528.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 125

Stage 1. Example 125b

[00577] 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 ^o C. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture 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 give the product as Example 125b (4.9 g, 82% yield) as a yellow solid. LCMS [M+1] ⁺ = 171.2.

Stage 2. Example 125c

[00578] To a solution of Example 125b (4.8 g, 28 mmol, 1.0 eq) in MeOH (100 ml) was 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 hour at 80 ^o C. The basicity of the reaction mixture was increased with K ₂ CO ₃ (pH=7~8). The solid was filtered off and the filtrate was concentrated. The crude product was purified by silica gel flash column chromatography, eluted with petroleum ether/EtOAc (2/1) to give the product Example 125c (3.6 g, 92% yield) as a red oil.

LCMS [M+1] ⁺ = 141.2.

Stage 3. Example 125f

[00579] 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. .) drop by drop at -15 ^o C under N ₂ protection conditions. The mixture was stirred for 0.5 h at room temperature. The mixture was poured into saturated aqueous 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 give the product as Example 125f (2.8 g, 62% yield) as a yellow oil. LCMS [M+1 ] ⁺ = 216.2

Stage 4. Example 125g

[00580] 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 parts at 0°C. After addition, the reaction mixture was stirred for 30 minutes. 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 hour at RT. The reaction solution was poured into water, extracted with EtOAc (50 ml*2), and the combined organic layer was 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 give the product Example 125g (370 mg, 32% yield) as a yellow solid. LCMS [M+1] ⁺ = 320.1

Stage 5. Example 125h

[00581] 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 hour at RT. The reaction mixture was diluted with DCM (50 ml), washed with aqueous NaOH (1 M), aqueous Na ₂ SO ₃ 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 give the product as Example 125h (60 mg, 27% yield) as a yellow solid. LCMS [M+1] ⁺ = 352.2.

Stage 6. Example 125

[00582] To a solution of example 125h (50 mg, 0.142 mmol, 1.0 eq.) in dioxane (2 ml) was 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 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 125 (17 mg, 29% yield) as a yellow solid. LCMS [M +1] ⁺ =411.2. ¹ H NMR (300 MHz, DMSO- d6 ) 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).

Example 126

Stage 1. Example 126c

[00583] 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 parts 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 hour at RT. The reaction mixture 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 give the product as Example 126c (570 mg, 25% yield) as a yellow solid. LCMS [M+1] ⁺ = 320.1

Stage 2. Example 126d

[00584] 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 ^o C. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with DCM (20 ml), washed with aqueous NaOH (1 M), aqueous Na ₂ SO ₃ 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 give the product as Example 126d (470 mg, 57% yield) as a yellow solid. LCMS [M+1] ⁺ = 352.2.

Stage 3. Example 126

[00585] To a solution of Example 126d (100 mg, 0.285 mmol, 1.0 eq.) in dioxane (2 mL) was 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 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 126 (12 mg, 9% yield) as an off-white solid. LCMS [M+1] ⁺ = 468.1. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 127

Stage 1. Example 127b

[00586] 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 ^o C. The reaction mixture was stirred for 2 hours at RT. It was quenched with an aqueous solution of NaHCO ₃ (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 give the product as Example 127b (500 mg, crude, 96% yield) as a brown solid. LCMS [M+1] ⁺ = 224.3.

Stage 2. Example 127c

[00587] 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 hours at 80 ^o C. After cooling 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 give the product Example 127c (200 mg, 37% yield) as a yellow solid. LCMS [M+1] ⁺ = 241.2.

Stage 3. Example 127d

[00588] 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 room temperature for 1 hour in an atmosphere of H ₂ from a balloon. The solid was filtered off and the filtrate was concentrated to give Example 127d (160 mg, 90% yield) as a yellow solid. LCMS [M+1] ⁺ = 211.2.

Stage 4. Example 127f

[00589] 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 hours at room temperature and then silica was added to the mixture and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (20/1) to give the product as Example 127f (45 mg, 15% yield) as a yellow solid. LCMS [M+1] ⁺ = 409.4.

Stage 5. Example 127h

[00590] 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.) drop by drop at 0 ^o C under N ₂ protection conditions. The mixture was stirred for 0.5 h at RT. The reaction mixture was poured into saturated aqueous NH ₄ Cl (10 ml) and extracted with EtOAc (15 ml x 3). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product Example 127f (40 mg, 93% yield) as a yellow solid. LCMS [M+1] ⁺ = 390.3.

Stage 6. Example 127

[00591] To a solution of Example 127f (40 mg, 0.10 mmol, 1.0 eq.) in dioxane (3 ml) was added Cs ₂ CO ₃ (65.2 mg, 0.20 mmol, 2.0 eq.) , example 127l (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 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product as Example 127 (3.1 mg, 7% yield) as a yellow solid. LCMS [M+1] ⁺ = 439.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 128

[00592] To a solution of Example 128 (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (5 ml) was 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 hours at 110 ^o C in an atmosphere of N ₂ . The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to obtain 32.0 mg of crude product (90% purity) and further purified by preparative TLC (DCM/MeOH=15/1) to obtain the desired product, which is Example 128 (12.1 mg, 9.9% yield) as a yellow solid. LCMS [M+1] ⁺ = 469.3. ^1H NMR (300 MHz, DMSO- d6 ) 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).

Example 129

Stage 1. Example 129c

[00593] 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 RT for 16 hours. After completion of the reaction, the solvent was concentrated, the residue was suspended in DCM (5 ml), sonicated and the resulting solid was collected by filtration, dried to obtain the desired product, which is Example 129c (253 mg, crude) as a white solid. LCMS [M+1] ⁺ = 115.0.

Stage 2. Example 129

[00594] 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 with nitrogen 3 times and stirred at 110 ^o C for 16 hours. Once complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 129 (21.8 mg, 22.7% yield) as a white solid. LCMS [M+1] ⁺ = 452.0. ^1H NMR (400 MHz, DMSO- d6 ) 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).

Example 130

Stage 1. Example 130c

[00595] 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 ^o C, and then example 130b (311 mg, 2. 88 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour under N ₂ atmosphere. The white solid was filtered off. NH ₃ -H ₂ O (5 eq.) was added to the filtrate. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was cooled and petroleum ether/EtOAc=1/1 (3 ml) was added. The solid was collected by filtration and dried to give Example 130c (17 mg, 8% yield) as a white solid.

Stage 2. Example 130

[00596] To a solution of example 130d (63 mg, 0.16 mmol) in dioxane (1.5 ml) was 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 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative 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).

Example 131

[00597] To a solution of Example 131a (40 mg, 0.104 mmol, 1.0 eq.) and Example 131b (35.4 mg, 0.208 mmol, 2.0 eq.) in dioxane (3 mL) was added Xantphos (12.0 mg, 0.02 mmol, 0.2 eq.), Cs ₂ CO ₃ (67.8 mg, 0.208 mmol, 2.0 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (10.4 mg, 0 .01 mmol, 0.1 eq.). The reaction mixture was stirred at 110°C for 4 hours under _N2 protection. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 131 (7.4 mg, 14% yield) as a yellow solid. LCMS [M+1] ⁺ = 519.4.

^1H NMR (300 MHz, DMSO- d6 ) δ 12.33 (s, 1H), 10.27 (s, 1H) _, 9.54 (s, 1H), 9.18 (s, 1H), 8 .66 (s, 1H), 8.17 (d, J =5.1 Hz, 1H), 8.05-7.95 (m, 1H), 7.58 (d, J =8.1 Hz, 1H), 7.50 (d, J =5.1 Hz, 1H), 5.30 (s, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.08- 2.93 (m, 1H), 1.50 (s, 6H), 1.16-0.98 (m, 4H).

Example 132

[00598] To a solution of Example 132a (100 mg, 0.26 mmol) and Example 132b (43 mg, 0.39 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) , Xantphos (30 mg, 0.052 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 132 (1.3 mg, 3.5% yield) as a white solid. LCMS [M+1] ⁺ = 459.0. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H), 9.49 (s, 1H) _, 8.97 (s, 1H), 8.53 (s, 1H), 8 .30 (s, 0H), 7.65 (d, J =8.0 Hz, 1H), 7.56 (d, J =8.0 Hz, 1H), 7.27 (t, J =7, 9 Hz, 1H), 5.90 (s, 1H), 3.92 (s, 3H), 3.68 (s, 3H), 3.57 (s, 3H), 2.88 (s, 1H) , 2.17 (s, 3H), 1.03 (s, 2H), 0.95 (d, J =7.7 Hz, 2H).

Example 133

[00599] To a solution of Example 133a (180 mg, 0.47 mmol) and Example 133b (180 mg, 1.41 mmol) in 1,4-dioxane (2 ml) was added Pd ₂ (dba) ₃ (43 mg, 0.047 mmol), Xantphos (54 mg, 0.094 mmol) and Cs ₂ CO ₃ (306 mg, 0.94 mmol). The mixture was degassed with nitrogen 3 times, sealed and stirred at 120 ^° C for 16 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 133 (67.3 mg, 30.3% yield) as a white solid. LCMS [M+1] ⁺ = 476.0. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.98 (s, 1H), 9.19 (s, 1H) _, 9.02 (s, 1H), 8.54 (s, 1H), 7 .90 (s, 1H), 7.60 (d, J =7.8 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.23 (t, J =8, 0 Hz, 1H), 3.93 (s, 3H), 3.67 (s, 3H), 3.64 (s, 4H), 2.94 (s, 1H), 1.18 (s, 6H) , 1.06 (d, J =4.5 Hz, 2H), 1.00 (d, J =7.8 Hz, 2H).

Example 134

[00600] To a solution of Example 134a (130 mg, 0.35 mmol) and Example 134b (67 mg, 0.52 mmol) in 1,4-dioxane (4 ml) was added Pd ₂ (dba) ₃ (32 mg, 0.035 mmol), Xantphos (40 mg, 0.070 mmol) and Cs ₂ CO ₃ (227 mg, 0.70 mmol). The mixture was sealed, degassed with nitrogen 3 times and stirred at 110 ^o C for 16 hours. Once complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 134 (34 mg, 21.0% yield) as a yellow solid. LCMS [M+1] ⁺ = 466.0. ¹ H NMR (400 MHz, DMSO- d6 ) δ 10.86 (s, 1H) _, 9.17 (d, J =5.3 Hz, 1H), 8.55 (s, 1H), 8.27 (s, 1H), 7.62 (d, J =7.8 Hz, 1H), 7.51 (d, J =7.9 Hz, 1H), 7.25 (t, J =7.9 Hz , 1H), 4.06 (t, J =8.2 Hz, 2H), 4.02 (s, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.44 (t, J =8.1 Hz, 2H), 2.83 (d, J =4.6 Hz, 3H), 1.09 (d, J =6.7 Hz, 6H).

Example 135

[00601] To a solution of Example 135a (100 mg, 0.26 mmol) and Example 135b (43 mg, 0.39 mmol) in 1,4-dioxane (2 ml) was 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 with nitrogen 3 times and stirred at 120 ^° C for 16 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to obtain the desired product as Example 135 (41.8 mg, 35.1% yield) as a white solid (containing 0.43 FA salt, by ¹ H NMR). LCMS [M+1] ⁺ = 459.0. ^1H NMR (400 MHz, DMSO- d6 ) δ 13.32 (s, 1H), 10.96 (s, 1H) _, 9.20 (s, 1H), 8.54 (s, 1H), 7 .72 (d, J = 6.6 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.27 (t, J =8.0 Hz, 1H), 6.99 (s, 1H), 5.84 (d, J =6.6 Hz, 1H), 3.93 (s, 3H), 3.68 (s, 3H), 2.98 (d, J =7.1 Hz, 1H), 1.09 (d, J = 4.3 Hz, 2H), 1.03 (dd, J =9.6, 5.4 Hz, 2H).

Example 136

[00602] To a solution of Example 136a (100 mg, 0.26 mmol) and Example 136b (37 mg, 0.31 mmol) in 1,4-dioxane (1 ml) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 136 (4.5 mg, 3.7% yield) as a white solid. LCMS [M+1] ⁺ = 467.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.00 (s, 1H), 10.34 (s, 1H) _, 9.16 (s, 1H), 8.54 (s, 1H), 8 .40 (d, J =8.0 Hz, 1H), 8.21 (s, 1H), 7.63-7.60 (m, 3H), 7.31-7.27 (m, 2H), 3.93 (s, 3H), 3.69 (s, 3H), 2.97 (br, 1H), 1.07-1.00 (m, 4H).

Example 137

[00603] To a solution of example 137a (60 mg, 0.171 mmol, 1.0 eq.) in dioxane (2 ml) was added Cs ₂ CO ₃ (111 mg, 0.342 mmol, 2.0 eq.), example 137b (32 mg , 0.342 mmol, 2.0 eq.), BINAP (21.3 mg, 0.034 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (17.7 mg, 0.017 mmol, 0.1 eq. .). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=30/1) to give the product of Example 137 (8 mg, 11% yield) as an off-white solid. LCMS [M+1] ⁺ =410.2. ¹ H NMR (300 MHz, DMSO- d6 ) δ 11.85 (s, 1H), 10.11 (s, 1H) _, 9.16 (s, 1H), 9.03 (s, 1H),8 .66 (dd, J =4.8, 1.8 Hz, 1H), 8.30-8.22 (m, 2H), 7.76-7.68 (m, 2H), 7.31 (dd , J =7.8, 4.8 Hz, 1H), 6.99-6.91(m, 1H), 3.12, (m, 3H), 3.01-2.89 (m, 1H) , 1.12-0.97 (m, 4H).

Example 138

[00604] To a solution of Example 138a (277 mg, 0.72 mmol) and Example 138b (84 mg, 0.87 mmol) in 1,4-dioxane (4 ml) was added Pd ₂ (dba) ₃ (66 mg, 0.072 mmol), Xantphos (83 mg, 0.14 mmol) and Cs ₂ CO ₃ (470 mg, 1.44 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C for 16 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 138 (21 mg, 6.6% yield) as a yellow solid. LCMS [M+1] ⁺ = 445.0. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.06 (s, 1H), 9.60 (s, 1H) _, 8.99 (s, 1H), 8.54 (s, 1H), 7 .65 (d, J =8.0 Hz, 1H), 7.56 (d, J =8.1 Hz, 1H), 7.51 (s, 2H), 7.27 (t, J =7, 9 Hz, 1H), 6.08 (s, 1H), 3.92 (s, 3H), 3.69 (d, J =4.7 Hz, 6H), 2.89 (s, 1H), 1 .03 (s, 2H), 0.95 (s, 2H).

Example 139

[00605] To a solution of Example 139a (100 mg, 0.26 mmol) and Example 139b (37 mg, 0.31 mmol) in 1,4-dioxane (1 ml) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative TLC (MeOH/DCM=1/15) to obtain the desired product as Example 139 (14.6 mg, 12.1% yield) as a white solid. LCMS [M+1] ⁺ = 467.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.04 (s, 1H), 10.53 (s, 1H) _, 9.13 (s, 1H), 8.61 (s, 1H), 8 .54 (s, 1H), 8.07 (d, J =12.0 Hz, 1H), 7.83-7.79 (m, 2H), 7.62 (t, J =8.0 Hz, 2H), 7.33 (t, J =8.0 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.97 (br, 1H), 1.21- 1.01 (m, 4H).

Example 140

[00606] To a solution of Example 140a (100 mg, 0.26 mmol) and Example 140b (37 mg, 0.31 mmol) in 1,4-dioxane (1 ml) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 140 (12.2 mg, 10.1% yield) as a white solid. LCMS [M+1] ⁺ = 467.2. ^1H NMR (400 MHz, DMSO- d6 ) δ _11.24 (s, 1H), 10.42 (s, 1H), 9.12 (s, 1H), 8.54 (s, 1H), 7 .98 (s, 1H), 7.87 (t, J =8.0 Hz, 1H), 7.78(d, J =8.0 Hz, 1H), 7.72 (d, J =8, 0 Hz, 1H), 7.58 (d, J =8.0 Hz, 1H), 7.52 (d, J =8.0 Hz, 1H), 7.35 (t, J =8.0 Hz , 1H), 3.93 (s, 3H), 3.70 (s, 3H), 2.96 (br, 1H), 1.21-1.00 (m, 4H).

Example 141

Stage 1. Example 141c

[00607] To a solution of Example 141a (182 mg, 1.94 mmol, 1.0 eq.) in dioxane (10 ml) was added Cs ₂ CO ₃ (1.25 g, 3.87 mmol, 2.0 eq.) , example 141b (500 mg, 2.32 mmol, 1.2 eq.), BINAP (240 mg, 0.387 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (199 mg, 0.194 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. The solvent was concentrated and the crude product was purified by silica gel flash column chromatography, eluting with (DCM/MeOH=30/1) to give the product as Example 141c (490 mg, 72% yield) as a yellow solid. LCMS [M+1] ⁺ =293.1.

Stage 2. Example 141e

To a solution of Example 141c (490 mg, 1.678 mmol, 1.0 eq.) in THF (10 mL) was added Example 141d (25.17 mL, 1.0 M in THF, 25.17 mmol, 15.0 eq.) drop by drop at 0 ^o C under N ₂ protection conditions. The mixture was stirred for 1.5 hours at room temperature. After completion of the reaction, the mixture was poured into a saturated aqueous solution of NH ₄ Cl (20 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 DCM/MeOH = (30/1) to give the product Example 141e (170 mg, 37% yield) as a yellow solid. LCMS [M+1] ⁺ =274.1.

Stage 3. Example 141

[00608] To a solution of Example 141e (60 mg, 0.22 mmol, 1.0 eq.) in dioxane (2 ml) was added Cs ₂ CO ₃ (143 mg, 0.44 mmol, 2.0 eq.), example 141f (90 mg, 0.44 mmol, 2.0 eq.), 3rd generation tert-Bu-XPhos-Pd (39 mg, 0.044 mmol, 0.2 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=20/1) to give the product of Example 141 (29 mg, 29% yield) as a yellow solid. LCMS [M+1] ⁺ = 443.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.31 (s, 1H), 10.10 (s, 1H) _, 9.51 (s, 1H), 9.17 (s, 1H), 8 .66 (s, 1H), 8.35-8.32 (m, 1H), 8.19 (d, J =5.1 Hz, 1H), 7.82-7.64 (m, 2H), 7.48 (d, J =5.1 Hz, 1H), 7.02-6.92 (m, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.06 -2.95 (m, 1H), 1.67-0.97 (m, 4H).

Example 142

Stage 1. Example 142c

[00609] A mixture of Example 142a (250 mg, 2.0 mmol), Example 142b (276 mg, 2.0 mmol) and TEA (610 mg, 6.0 mmol) in 1,4-dioxane (2 ml) was stirred at room temperature overnight. The reaction mixture was filtered to obtain the desired product as Example 142c (350 mg, 51.4% yield) as a white solid. LCMS [M+1] ⁺ = 133.1. ^1H NMR (400 MHz, DMSO- d6 ) δ 5.97 (s, 2H), _3.88-3.75 (m, 4H), 3.69 (s, 3H), 1.51 (d, J =24.0 Hz, 3H).

Stage 2. Example 142

[00610] To a solution of Example 142c (40 mg, 0.31 mmol) and Example 142d (96 mg, 0.25 mmol) in 1,4-dioxane (1 ml) was added Pd ₂ (dba) ₃ (23 mg, 0.025 mmol), Xantphos (29 mg, 0.051 mmol) and Cs ₂ CO ₃ (166 mg, 0.51 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 142 (46.7 mg, 38.9% yield) as a yellow solid. LCMS [M+1] ⁺ = 473.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.90 (s, 1H), 9.89 (s, 1H) _, 9.01 (s, 1H), 8.54 (s, 1H), 7 .99 (s, 1H), 7.62 (d, J =8.0 Hz, 1H), 7.49 (d, J =8.0 Hz, 1H), 7.25 (t, J =8, 0 Hz, 1H), 4.13-4.01 (m, 4H), 3.93 (s, 3H), 3.71 (s, 3H), 1.54 (d, J = 24.0 Hz, 3H).

Example 143

Stage 1. Example 143b

[00611] A solution of Example 143a (2.0 g, 15.5 mmol) in DMSO/H ₂ O (20 ml/20 ml) was treated with NaCN (1.52 g, 31.0 mmol) and DABCO (1, 74 g, 15.5 mmol). The mixture was stirred at 60 ^° C for 6 hours. After completion of the reaction, the solvent was extracted with DCM (50 ml) and concentrated to give the crude product, which was purified directly by preparative HPLC to give the desired product as Example 143b (500 mg, yield 26.8%), as a white solid. LCMS [M+1] ⁺ = 121.0

Stage 2. Example 143

[00612] To a solution of Example 143b (60 mg, 0.5 mmol) and Example 143c (191 mg, 0.5 mmol) in dioxane (5 ml) was added Pd ₂ (dba) ₃ (50 mg, 0.05 mmol) , Xantphos (30 mg, 0.05 mmol) and Cs ₂ CO ₃ (224.5 mg, 0.75 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C overnight. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 143 (7.4 mg, 3.2% yield) as an off-white solid. LCMS [M+1] ⁺ = 468.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.14 (s, 1H), 10.90 (s, 1H), _9.16 (s, 1H), 8.60-8.51 (m, 2H), 7.85 (s, 1H), 7.76 (s, 1H), 7.67 (d, J =7.9 Hz, 1H), 7.62 (d, J =7.9 Hz, 1H), 7.34 (d, J =8.0 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.98 (s, 1H), 1.21 ( s, 1H), 1.09 (s, 2H), 1.04 (d, J =7.0 Hz, 2H).

Example 144

Stage 1. Example 144c

[00613] A mixture of Example 144a (250 mg, 2.1 mmol), Example 144b (288 mg, 2.1 mmol) and TEA (637 mg, 6.3 mmol) in 1,4-dioxane (2 ml) was stirred at room temperature overnight. The reaction mixture was filtered to obtain the desired product as Example 144c (200 mg, 76.3% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.04 (s, 2H), 4.03 (t, J =8.0 Hz, 2H), 3.86 (t, J =8.0 Hz , 2H), 3.67-3.62 (m, 1H).

Stage 2. Example 144

[00614] To a solution of Example 144c (66 mg, 0.53 mmol) and Example 144d (100 mg, 0.27 mmol) in 1,4-dioxane (2 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.027 mmol), Xantphos (31 mg, 0.053 mmol) and Cs ₂ CO ₃ (173 mg, 0.53 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C overnight. Once complete, the reaction mixture was cooled to room temperature, diluted with CH ₃ CN (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 144 (61.3 mg, 49.7% yield) as a yellow solid. LCMS [M+1] ⁺ = 466.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.91 (s, 1H), 9.96 (s, 1H), _9.02 (s, 1H), 8.54 (s, 1H), 7 .96 (s, 1H), 7.62 (d, J =8.0 Hz, 1H), 7.48 (d, J =8.0 Hz, 1H), 7.25 (t, J =8, 0 Hz, 1H), 4.27 (t, J =8.0 Hz, 2H), 4.13 (t, J =8.0 Hz, 1H), 3.93 (s, 3H), 3.75 -3.67 (m, 4H).

Example 145

[00615] To a solution of Example 145a (100 mg, 0.26 mmol) and Example 145b (98 mg, 0.78 mmol) in 1,4-dioxane (2 ml) was 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 with nitrogen 3 times and stirred at 110 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 145 (32 mg, 26.0% yield) as a white solid. LCMS [M+1] ⁺ = 474.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.03 (s, 1H), 9.92 (s, 1H), 9.08 (s, 1H), 8.54 (s, 1H), 8 .05 (s, 1H), 7.71 (s, 1H), 7.63 (d, J =8.0 Hz, 1H), 7.58 (d, J =8.3 Hz, 2H), 7 .29 (t, J =7.9 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.94 (s, 1H), 2.23 (s, 3H) , 1.05 (s, 2H), 0.99 (d, J =7.6 Hz, 2H).

Example 146

Stage 1. Example 146b

[00616] A solution of Example 146a (3.0 g, 19.2 mmol, 1.0 eq.) in POCl ₃ (30 ml) was stirred for 4 hours at 100 ^o C. After completion of the reaction, it was concentrated in vacuo to give crude product (3.0 g, crude material), which was used in the next step without further purification.

Stage 2. Example 146d

[00617] To a solution of Example 146c (1.96 g, 28.4 mmol, 2.0 eq) and DIEA (14.7 g, 113.6 mmol, 8.0 eq) in THF (30 mL) was added a solution of Example 146b (3.0 g, crude) in DCM (20 ml) dropwise at 0 ^° C. The reaction solution was stirred for 30 minutes. at RT. The reaction solution was diluted with EtOAc (100 ml), washed with brine (50 ml*3), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel flash column chromatography, eluted with petroleum ether/EtOAc (3/1) to give the product as Example 146d (400 mg, 14% yield) as a yellow solid. LCMS [M+1] ⁺ = 206.2.

Stage 3. Example 146f

[00618] To a solution of Example 146d (400 mg, 1.94 mmol, 1.0 eq.) and Example 146e (402 mg, 1.94 mmol, 1.0 eq.) in dry THF (15 mL) was added LiHMDS ( 3.88 ml, 1 M in THF, 3.88 mmol, 2.0 eq.) dropwise at 0 ^o C under N ₂ protection. The reaction mixture was stirred for 0.5 hours at room temperature. Silicon dioxide was then added to the mixture and concentrated. The residue was purified by silica gel flash column chromatography, eluting with DCM/MeOH = (20/1) to give the product Example 146f (310 mg, 42% yield) as a yellow solid. LCMS [M+1] ⁺ = 377.3.

Stage 4. Example 146

[00619] To a solution of Example 146f (290 mg, 0.77 mmol, 1.0 eq.) in dioxane (5 ml) was added Cs ₂ CO ₃ (502.0 mg, 1.54 mmol, 2.0 eq.) , example 146g (231 mg, 2.31 mmol, 3.0 eq.) and BINAP (95.9 mg, 0.15 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (82.8 mg, 0.08 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product of Example 146 (80.5 mg, 24% yield) as an off-white solid .LCMS [M+1] ⁺ = 441.3. ¹ H NMR (300 MHz, DMSO- d6 ) δ 10.92 (s, 1H), 9.61 (s, 1H), 9.05 ₍ d, J =4.8 Hz, 1H), 8.57 (s, 1H), 8.03 (s, 1H), 7.64 (dd, J =7.8, 1.8 Hz, 1H), 7.52 (dd, J =8.1, 1.8 Hz, 1H), 7.27 (t, J =7.8 Hz, 1H), 4.01 (t, J =7.8 Hz, 4H), 3.74 (s, 3H), 2.87 ( d, J =4.8 Hz, 3H), 2.23-2.08 (m, 2H).

Example 147

Step 1. 2-Chloro-3-methoxyisonicotinic acid

[00620] To a solution of 2-chloro-3-methoxypyridine (50 g, 0.348 mol) in THF（500 ml）at -78°C, LDA (1.0 M in THF, 418 ml, 0.418 mmol) was added dropwise. After addition, the mixture was stirred at -78°C for 30 minutes, then dry ice was added to the reaction mixture over 30 minutes. The reaction mixture was quenched with 5% w/v. aqueous NaOH solution (200 ml) and the aqueous layer was washed with EtOAc (200 ml×2). Organic fractions were removed and the pH of the aqueous layer was adjusted to 2 using 6 M aqueous HCl. The aqueous layer was extracted with EtOAc (30 ml×3) and the combined organic fractions were dried with Na ₂ SO ₄ , filtered and concentrated to give the title compound as a yellow solid (35 g, 53.8%).

Step 2. 2-Chloro-3-methoxyisonicotinamide

[00621] Into a solution of 2-chloro-3-methoxyisonicotinic acid (37 g, 0.197 mol), Boc ₂ O (49.84 ml, 0.217 mol) and pyridine (19.14 ml, 0.239 mol) in DCM（600 ml） NH ₄ HCO ₃ (78.0 g, 0.985 mol) was added at 0°C. After addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated on a rotary evaporator to remove some DCM and filtered to collect liquid. The filtrate was washed with H ₂ O (100 ml×2). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM/MeOH=20/1) to give the title compound in as a brown solid (24.0 g, yield: 65.3%). LM-MS: mass/charge =187.6[M+H] ⁺

Step 3. 2-Chloro-3-methoxy-4-(1H-1,2,4-triazol-3-yl)pyridine

[00622] 2-Chloro-3-methoxyisonicotinamide (24 g, 0.129 mol) was suspended in dimethylformamide dimethyl acetal (173 ml, 1.29 mol) and the mixture was heated to 95 ^o C to obtain a clear pale yellow solution. After heating for 1 hour, the reaction mixture was cooled and concentrated on a rotary evaporator and the resulting yellow oil was azeotroped twice with 1,2-dichloroethane (40 ml part) to ensure complete removal of any residual dimethylformamide dimethyl acetal. The crude oil thus obtained was directly dissolved in 50 ml of ethanol and directly used in the next step.

[00623] In a separate flask, a mixture of ethanol (500 ml) and acetic acid (AcOH, 130 ml) was prepared and the resulting solution was cooled in an ice bath. After cooling, hydrazine hydrate (64 mL, 1.29 mol) was added dropwise. At the same time, the solution containing the crude dimethylformamide dimethylacetal adduct obtained above was transferred dropwise for ~15 min. using a cannula into a previously thoroughly mixed ice mixture containing hydrazine. During addition, a pale yellow solid formed in the solution. After addition was complete, the resulting cloudy yellow mixture was allowed to warm to room temperature and stirred overnight. At this time, the reaction mixture was concentrated on a rotary evaporator to remove some ethanol, diluted with additional water, and filtered to collect solids. The solid was washed with additional parts of water, air dried in a funnel, then under vacuum to obtain 24 g (88%) of a pale yellow solid as the desired product. LM-MS: mass/charge =211.6 [M+H] ⁺

Step 4. 2-Chloro-3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine

[00624] A solution of 2-chloro-3-methoxy-4-(1H-1,2,4-triazol-3-yl)pyridine (9.00 g, 42.7 mmol) in DMF (80 ml) was treated with potassium carbonate (17.7 g, 128.1 mmol). After cooling the resulting mixture in an ice bath, a solution of iodomethane (8.1 g, 57.6 mmol) in DMF (5 ml) was slowly added dropwise using a syringe over 2 min. Once addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature overnight, LCMS analysis indicated complete and net conversion to a regioisomeric mixture of products in a ratio of ~3:1, respectively. The reaction mixture was cooled in an ice bath and diluted with water (~50 ml), and the solution was extracted with EtOAc (3x40 ml), and the combined extracts were washed with 10% aq. LiCl solution (2×20 ml), water (20 ml), then brine (20 ml), concentrated and purified by column chromatography (PE/EA = 5/1) to obtain the title compound (5.0 g, 52%) as the main isomer as a pale yellow solid. LM-MS: mass/charge =225.6[M+H] ⁺

Step 5. 3-Methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-amine

[00625] In a solution of 2-chloro-3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (5 g, 22.3 mmol), diphenylmethanimine (6.01 g, 33.45 mmol), sodium tert-butoxide (3.2 g, 33.45 mmol) and DPEphos (2.4 g, 4.46 mmol) in 1,4-dioxane (100 ml) was added Pd ₂ ( dba) ₃ (2.0 g, 2.23 mmol). The mixture was degassed with N ₂ 3 times and heated to 100°C for 1 hour. After completion of the reaction, filtration, the filtrate was removed in vacuo, DCM 50 ml, 2 M HCl 50 ml was added, stirred at room temperature for 20 minutes, the aqueous layer was washed with DCM (20 ml x 2). The pH of the aqueous layer was adjusted to 9 using 5% w/v. aqueous NaOH solution, the aqueous layer was extracted with DCM (50 ml×6) and the combined organic fractions were dried (Na ₂ SO ₄ ), filtered and concentrated and subjected to chromatography (DCM/MeOH=20/1) to obtain the title compound in as a white solid. (2.6 g, 56.8%)

Step 6. 6-Chloro-4-((3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(methyl- d ₃ )pyridazine-3-carboxamide

[00626] In a solution of 4,6-dichloro-N-(trideuteromethyl)pyridazine-3-carboxamide (3.97 g, 19.0 mmol) and 3-methoxy-4-(1-methyl-1,2,4- triazol-3-yl)pyridin-2-amine (3.00 g, 14.6 mmol) in THF (50 ml) under N ₂ was added LiHMDS (1 M, 43.80 ml, 43.80 mmol) at 0 °C with a slight exothermic effect. The reaction mixture was stirred at room temperature. After completion, the reaction mixture was cooled to 0°C, quenched by adding sat. NH ₄ Cl (aq) solution, diluted with water (100 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM/EtOAc=3/1) to give the title compound in as a yellow solid (2.70 g, 48.9%).

Step 7. 6-(3-Isopropyl-2-oxoimidazolidin-1-yl)-4-[[3-methoxy-4-(1-methyl-1,2,4-triazol-3-yl)-2-pyridyl ]amino]-N-(trideuteromethyl)pyridazine-3-carboxamide

[00627] Into a solution of 6-chloro-4-((3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-( methyl-d3)pyridazin-3-carboxamide (3.6 g, 9.5 mmol) and 1-isopropylimidazolidin-2-one (2.4 g, 19 mmol) in 1,4-dioxane (30 ml) added cesium carbonate (6.2 g, 19 mmol), Pd ₂ (dba) ₃ (2.6 g, 2.9 mmol) and Xantphos (3.3 g, 5.7 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, subjected to chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) to obtain the desired product T241 as a yellow solid (0.55 g, 12%) . ^1H NMR (400 MHz, CDCl ₃ ): δ 12.20 (s, 1H), 10.16 (s, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8. 14 (s, 1H), 7.51 (d, 1H), 4.43-4.32 (m, 1H), 4.23 (t, 2H), 4.03 (s, 3H), 4.00 (s, 3H), 3.51 (t, 2H), 1.23 (d, 6H). LM-MS: m/z =470.3 [M+H] ⁺

Example 148

Stage 1. Example 148b

[00628] To a solution of Example 148a (1.0 g, 5.21 mmol, 1.0 eq.) in DCM (15 mL) was added CD ₃ NH ₂ ⋅HCl (438 mg, 6.25 mmol, 1.2 eq. .), DIEA (3.36 g, 26.04 mmol, 5.0 eq.) and HATU (2.37 g, 6.25 mmol, 1.2 eq.). The reaction mixture was stirred for 4 hours at room temperature. The solvent was removed and the residue was purified by flash column chromatography on silica gel, eluting with PE/EtOAc (1/1) to give the product of Example 148b (670 mg, yield 61.8%) as an off-white solid. LCMS [M+1] ⁺ = 208.2.

Stage 2. Example 148d

[00629] To a solution of Example 148b (200 mg, 0.96 mmol, 1.0 eq.) and Example 148c (196 mg, 0.96 mmol, 1.0 eq.) in dry THF (5 mL) was added LiHMDS ( 1.92 ml, 1 M in THF, 1.92 mmol, 2.0 eq.) dropwise at -15°C. The reaction solution was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was removed and the residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (20/1) to give the product as Example 148d (212 mg, 58.7% yield) as a yellow solid. substances. LCMS [M+1] ⁺ = 376.3

Stage 3. Example 148

[00630] To a solution of Example 148d (100 mg, 0.27 mmol, 1.0 eq.) in dioxane (3 ml) was added Cs ₂ CO ₃ (260 mg, 0.80 mmol, 3.0 eq.), example 148e (102 mg, 0.80 mmol, 3.0 eq.) and BrettPhos ^3rd generation catalyst (48 mg, 0.05 mmol, 0.2 eq.). The reaction mixture was stirred for 6 hours at 120 ^o C in an atmosphere of N ₂ . The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product as Example 148 (26.1 mg, 21.0% yield) as a light yellow solid. LCMS [M+1] ⁺ = 468.4. ^1H NMR (300 MHz, DMSO- d6 ) δ 10.66 (s, 1H), 8.96 (s, 1H) _, 8.55 (s, 1H), 8.52 (s, 1H), 8 .46 (s, 1H), 7.94 (s, 1H), 7.56-7.48 (m, 2H), 7.22 (t, J =7.8 Hz, 1H), 3.95 ( s, 3H), 3.74 (s, 3H), 3.65 (s, 4H), 1.21 (s, 6H).

Example 149

Stage 1. Example 149c

[00631] Solution of Example 149a (200 mg, 0.90 mmol), Example 149b (95 mg, 0.91 mmol), Example 149c (26 mg, 0.18 mmol), CuI (18 mg, 0.09 mmol) and K ₃ PO ₄ (380 mg, 1.82 mmol) in 1,4-dioxane (5 ml) were stirred at 110°C overnight. The reaction mixture was diluted with CH ₃ CN (5 ml), filtered and concentrated to give the crude product as Example 149d (210 mg, quant.) as a black oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.85 (br, 1H), 7.33 (d, J =8.0 Hz, 1H), 6.43 (d, J =8.0 Hz , 1H), 5.98 (s, 2H), 4.13 (s, 2H), 3.91 (t, J =4.0 Hz, 2H), 3.61 (t, J =4.0 Hz , 2H).

Stage 2. Example 149

[00632] Pd ₂ (dba) ₃ (48 mg, 0 .05 mmol), Xantphos (60 mg, 0.10 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C overnight. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 149 (11.5 mg, 4.1% yield) as an off-white solid. LCMS [M+1] ⁺ = 541.3. ¹ H NMR (400 MHz, DMSO- d6 ) δ 11.05 (s, 1H), 10.08 (s, 1H) _, 9.09 (s, 1H), 8.54 (s, 1H), 8 .20 (s, 1H), 7.91 (s, 1H), 7.72-7.58 (m, 4H), 7.29 (t, J =8.0 Hz, 1H), 4.19 ( s, 2H), 3.96 (t, J =4.0 Hz, 2H), 3.93 (s, 3H), 3.72-3.70 (m, 5H), 2.95 (br, 1H ), 1.06-0.97 (m, 4H).

Example 150

Stage 1. Example 150c

[00633] To a solution of Example 150a (240 mg, 2.0 mmol) in dioxane (4 mL) was added Example 150b (411 mg, 3.0 mmol) and TEA (606 mg, 6.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was triturated with petroleum ether/EtOAc=1/1 (5 ml). The solid was collected by filtration and dried to give Example 150c (120 mg, 47.5% yield) as a white solid. LCMS [M+1] ⁺ = 127.1

Stage 2. Example 150

[00634] To a solution of example 150d (100 mg, 0.27 mmol) in dioxane (3 ml) was added example 150c (50 mg, 0.4 mmol), Pd ₂ (dba) ₃ (25 mg, 0.027 mmol), Xantphos (16 mg, 0.027 mmol) and Cs ₂ CO ₃ (176 mg, 0.26 mmol). The mixture was sealed and heated to 120 ^° C overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 150 (47 mg, 37.3% yield) as a yellow solid. LCMS [M+1] ⁺ = 467.2. ¹ H NMR (400 MHz, Chloroform- d ) δ 10.94 (s, 1H), 8.14-8.02 (m, 3H), 7.76 (d, J = 7.7 Hz, 1H), 7.53 (d, J =7.2 Hz, 1H), 7.26 (s,1H), 7.14 (s, 1H), 4.15 (s, 3H), 3.99 (s, 3H ), 3.81 (s, 3H), 0.69 (br, 4H).

Example 151

Stage 1. Example 151c

[00635] A solution of Example 151a (200 mg, 1.1 mmol) in 1,4-dioxane (35 ml) was treated with Example 151b (274 mg, 2.0 mmol) and TEA (300 mg, 3.0 mmol) . The mixture was stirred at RT for 16 hours. After completion of the reaction, the solvent was concentrated and the residue was suspended in DCM (5 ml) and sonicated. The resulting solid was collected by filtration and dried to obtain the desired crude product as Example 151c (300 mg, crude, 190.7% yield) as a white solid.

Stage 2. Example 151

[00636] To a solution of Example 151d (94 mg, 0.25 mmol) and Example 151c (150 mg, crude, 1.0 mmol) in dioxane (5 ml) was added Pd ₂ (dba) ₃ (91 mg, 0. 1 mmol), Xantphos (59 mg, 0.1 mmol) and Cs ₂ CO ₃ (652 mg, 2.0 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C overnight. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 151 (3.7 mg, 0.7% yield) as an off-white solid. LCMS [M+1] ⁺ = 484.2. ^1H NMR (400 MHz, Chloroform- d ) δ 11.12 (s, 1H), 8.11 (s, 1H), 7.97-7.83 (m, 3H), 7.51-7.44 (m, 1H), 4.71-4.61 (m, 2H), 4.52 (dd, J =21.4, 10.8 Hz, 2H), 4.01 (s, 3H), 3, 80 (s, 3H).

Example 152

[00637] To a solution of Example 152a (100 mg, 0.26 mmol) and Example 152b (45 mg, 0.41 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) , Xantphos (30 mg, 0.052 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 152 (10.0 mg, 8.4% yield) as a white solid. LCMS [M+1] ⁺ = 457.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.03 (s, 1H), 10.12 (s, 1H) _, 9.10 (s, 1H), 8.88 (s, 1H), 8 .54 (d, J =3.4 Hz, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.62 (d, J =9.3 Hz, 2H), 7 .29 (t, J =7.7 Hz, 1H), 3.93 (s,3H), 3.69 (s,3H), 2.96 (s, 1H), 2.37 (d, J = 3.4 Hz, 3H), 1.06 (s, 2H), 0.99 (s, 2H).

Example 153

[00638] To a solution of Example 153a (100 mg, 0.26 mmol) and Example 153b (45 mg, 0.41 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) , Xantphos (30 mg, 0.052 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130°C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 153 (20.0 mg, 17.1% yield) as a white solid. LCMS [M+1] ⁺ = 457.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H), 10.31 (s, 1H) _, 9.11 (s, 1H), 8.54 (s, 1H), 8 .30 (s, 1H), 8.15 (s, 1H), 7.65 (t, J =9.6 Hz, 2H), 7.29 (d, J =7.9 Hz, 1H), 7 .23 (s, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.97 (s, 1H), 2.37 (s, 3H), 1.08 (s, 2H), 1.02 (s,2H).

Example 154

[00639] To a solution of Example 154a (100 mg, 0.26 mmol) and Example 154b (45 mg, 0.39 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) , Xantphos (30 mg, 0.052 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130°C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 154 (40.0 mg, 34.2% yield) as a white solid. LCMS [M+1] ⁺ = 457.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.03 (s, 1H), 10.27 (s, 1H) _, 9.14 (s, 1H), 8.55 (s, 2H), 7 .78 (s, 1H), 7.65-7.57 (m,3H), 7.30 (d, J =7.9 Hz, 1H), 3.93 (s, 3H), 3.69 ( s, 3H), 2.97 (s, 1H), 2.34 (s, 3H), 1.07 (s, 2H), 1.01 (s 2H).

Example 155

Stage 1. Example 155c

[00640] To a solution of Example 155a (120 mg, 0.585 mmol, 1.0 eq.) in DMF (10 mL) was added NaH (234 mg, 60% in mineral oil, 5.85 mmol, 10.0 eq.) at parts at 0°C. After adding Example 155b (188.8 mg, 0.878 mmol, 1.5 eq.) in DMF to the mixture, the reaction mixture was stirred for 1.5 hours at RT. The reaction solution was poured into water (50 ml), extracted with EtOAc (50 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 DCM/MeOH (20/1) to give the product Example 155c (24 mg, 11% yield) as a yellow solid. LCMS [M+1] ⁺ =385.1.

Stage 2. Example 155

[00641] To a solution of Example 155c (18 mg, 0.047 mmol, 1.0 eq.) in dioxane (2 ml) was added Cs ₂ CO ₃ (30.1 mg, 0.094 mmol, 2.0 eq.), Example 155d ( 10.2 mg, 0.094 mmol, 2.0 eq.), BINAP (5.8 mg, 0.009 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ ⋅CHCl ₃ (4.9 mg, 0.005 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by preparative TLC (DCM/MeOH=20/1) to give the product of Example 155 (8.6 mg, 41% yield) as a yellow solid. LCMS [M+1] ⁺ =458.3. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.28 (s, 1H), 10.46 (s, 1H), 9.16 (d, J = 7.2 Hz, 2H), 8.66 (s, 1H), 8.20-8.11 (m, 2H), 7.54-7.46 (m, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 3.05-2.93 (m, 1H), 2.56 (s, 3H), 1.17-0.99 (m, 4H).

Example 156

Stage 1. Example 156b

[00642] To a solution of Example 156a (5.0 g, 22.73 mmol, 1.0 eq.) in DMF (100 mL) was added K ₂ CO ₃ (9.41 g, 68.18 mmol, 3.0 eq. .) and CD ₃ I (6.60 g, 45.45 mmol, 2.0 eq.) at 0°C. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc 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 (1/1) to give the product as Example 156b (1.58 g, 29.3% yield) as a yellow solid. LCMS [M+1] ⁺ = 238.2.

Stage 2. Example 156c

[00643] To a solution of Example 156b (500 mg, 2.11 mmol, 1.0 eq.) in MeOH (10 ml) was added Pd/C (200 mg) portionwise under N ₂ protection, the suspension was degassed under vacuum and purged H ₂ three times, the reaction mixture was stirred for 30 minutes. at room temperature in an H ₂ atmosphere from a cylinder. The solid was filtered off and the filtrate was concentrated to give the product as Example 156c (425 mg, crude, 97.3% yield) as a gray solid. LCMS [M+1] ⁺ = 208.2.

Stage 3. Example 156e

[00644] To a solution of Example 156c (425 mg, 2.05 mmol, 1.0 eq.) and Example 156d (429 mg, 2.05 mmol, 1.0 eq.) in dry THF (15 mL) was added LiHMDS ( 4.11 ml, 1 M in THF, 4.11 mmol, 2.0 eq.) dropwise at -15°C. The reaction solution was stirred at -15 ^° C for 30 minutes. After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel flash column chromatography, eluted with petroleum ether/EtOAc (1/2) to give the product as Example 156e (170 mg, 27.8% yield) as a yellow solid. LCMS [M+1] ⁺ = 380.3.

Stage 4. Example 156

[00645] To a solution of example 156e (100 mg, 0.26 mmol, 1.0 eq.) in dioxane (3 ml) was added example 156f (102 mg, 0.79 mmol, 3.0 eq.), Cs ₂ CO ₃ (257 mg, 0.79 mmol, 3.0 eq.), BINAP (66 mg, 0.11 mmol, 0.4 eq.) and Pd ₂ (dba)3CHCl3 (54 mg, 0.05 mmol, 0 ,2 eq.). The reaction solution was stirred for 4 hours at 120°C under N ₂ atmosphere. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to provide the desired product as Example 156 (18.0 mg, 28.2% yield) as a white solid. LCMS [M+1] ⁺ = 472.3. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.89 (s, 1H), 9.60 (s, 1H) _, 8.99 (s, 1H), 8.54 (s, 1H), 8 .01 (s, 1H), 7.62 (d, J =8.1 Hz, 1H), 7.49 (d, J =7.8 Hz, 1H), 7.24 (t, J =8, 1 Hz, 1H), 3.71 (s, 2H), 3.67 (s, 2H), 1.19 (s, 6H).

Example 157

Stage 1. Example 157c

[00646] A solution of Example 157a (200 mg, 1.4 mmol) in 1,4-dioxane (3 mL) was treated with Example 157b (374 mg, 2.8 mmol) and TEA (420 mg, 4.2 mmol) . The mixture was stirred at RT for 16 hours. After completion of the reaction, the solvent was concentrated and the residue was suspended in DCM (5 ml) and sonicated. The resulting solid was collected by filtration and dried to give the desired product as Example 157c (130 mg, 62% yield) as a white solid. LCMS [M+1] ⁺ = 151.0

Stage 2. Example 157

[00647] To a solution of Example 157d (157 mg, 0.42 mmol) and Example 157c (300 mg, 2.1 mmol) in dioxane (5 ml) was added Pd ₂ (dba) ₃ (91 mg, 0.1 mmol) , Xantphos (59 mg, 0.1 mmol) and Cs ₂ CO ₃ (325.8 mg, 1.0 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110°C overnight. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 157 (14.8 mg, 7.2% yield) as an off-white solid. LCMS [M+1] ⁺ = 491.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.90 (s, 1H), 9.84 (s, 1H) _, 9.01 (s, 1H), 8.54 (s, 1H), 7 .98 (s, 1H), 7.62 (d, J =7.7 Hz, 1H), 7.48 (d, J =7.8 Hz, 1H), 7.26 (d, J =8, 1 Hz, 1H), 6.16-6.44 (t, 1H), 4.09 (s, 2H), 3.93 (s, 5H), 3.71 (s, 3H), 3.06 ( s, 1H).

Example 158

Stage 1. Example 158c

[00648] To a solution of Example 158a (200 mg, 2.29 mmol) in dioxane (5 ml) was added Example 158b (400 mg, 2.91 mmol) and TEA (795 mg, 7.87 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc, washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The solution was concentrated to give crude Example 158c (170 mg, 57.2% yield) and used directly in the next step.

Stage 2. Example 158

[00649] To a solution of Example 158d (100 mg, 0.26 mmol) and Example 158c (120 mg, 0.92 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) , Xantphos (30 mg, 0.052 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130°C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 158 (14.0 mg, 13.1% yield) as a white solid. LCMS [M+1] ⁺ = 471.3. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.90 (s, 1H), 9.74 (s, 1H) _, 9.01 (s, 1H), 8.54 (s, 1H), 7 .99 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8, 1 Hz, 1H), 4.16 (d, J =11.1 Hz, 4H), 3.93 (s, 3H), 3.79 (s, 2H), 3.71 (s, 3H), 3 ,18 (s, 3H).

Example 159

Stage 1. Example 159c

[00650] To a solution of Example 159a (1.0 g, 4.2 mmol, 1.0 eq.) in dioxane (15 ml) was added Cs ₂ CO ₃ (2.7 g, 8.4 mmol, 2.0 eq. .), example 159b (861.8 mg, 5.04 mmol, 1.2 eq.), BINAP (523.3 mg, 0.84 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ ⋅CHCl ₃ (434.7 mg, 0.42 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110°C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the product Example 159c (1.0 g, 67% yield) as a yellow solid. LCMS [M+1] ⁺ = 369.3.

Stage 2. Example 159e

[00651] To a solution of Example 159c (1.0 g, 2.7 mmol, 1.0 eq) in THF (10 mL) was added Example 159d (40.5 mL, 1.0 M in THF, 40.5 mmol , 15.0 eq.) dropwise at 0°C under N ₂ protection conditions. The mixture was stirred for 0.5 h at room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl (70 ml) and extracted with EtOAc (100 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 flash column chromatography (DCM/MeOH=20/1) to give the product Example 159e (640 mg, 68% yield) as a yellow solid. LCMS [M+1] ⁺ = 350.2.

Stage 3. Example 159

[00652] To a solution of Example 159e (300 mg, 0.86 mmol, 1.0 eq.) in dioxane (5 ml) was added Cs ₂ CO ₃ (560 mg, 1.72 mmol, 2.0 eq.), example 159f (176 mg, 1.0 mmol, 1.2 eq.), BINAP (107.2 mg, 0.172 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ ⋅CHCl ₃ (89 mg, 0.086 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give 270 mg of crude product (90% purity) and further purified by preparative TLC (DCM/MeOH=20/1) to give the product representing is Example 159 (120 mg, 32% yield) as an off-white solid. LCMS [M+1] ⁺ = 486.4. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.89 (s, 1H), 10.28 (s, 1H) _, 9.17 (s, 1H), 9.02 (s, 1H), 8 .64 (dd, J =4.8, 1.8 Hz, 1H), 8.27 (dd, J =7.8, 1.8 Hz, 1H), 7.99 (dd, J =10.8 , 8.4 Hz, 1H), 7.58 (dd, J =8,1,2,1Hz, 1H), 7.34 (dd, J =7.8, 4.8 Hz, 1H), 5, 28 (s, 1H), 3.30 (s, 3H), 3.01-2.86 (m, 1H), 1.49 (s, 6H), 1.14-0.97 (m, 4H) .

Example 160

Step 1. 2-Chloro-3-methoxy-4-[1-(trideuteromethyl)-1,2,4-triazol-3-yl]pyridine

[00653] A solution of 2-chloro-3-methoxy-4-(1H-1,2,4-triazol-3-yl)pyridine (10.00 g, 47.5 mmol) in DMF (50 ml) was treated with carbonate potassium (13.1 g, 95.0 mmol). A solution of trideuteriodomethane (8.26 g, 57.0 mmol) in DMF (5 ml) was slowly added dropwise using a syringe over 2 min. The reaction mixture was stirred at room temperature for 4 hours, the reaction mixture was cooled in an ice bath and diluted with water (50 ml), and the solution was extracted with EtOAc (3x50 ml), and the combined extracts were washed with water (50 ml), then brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE/EtOAc=3/1) to give the title compound as a yellow solid (8.0 g, 74%).

Step 2. 3-Methoxy-4-[1-(trideuteromethyl)-1,2,4-triazol-3-yl]pyridin-2-amine

[00654] In a solution of 2-chloro-3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl) pyridine (8.0 g, 35.1 mmol), diphenylmethanimine (7 .64 g, 42.2 mmol), sodium tert-butoxide (6.75 g, 70.3 mmol) and DPEphos (1.88 g, 3.51 mmol) in 1,4-dioxane (100 ml) added Pd ₂ (dba) ₃ (3.22 g, 3.51 mmol). The mixture was degassed with N ₂ 3 times and heated to 100°C for 1 hour. After completion of the reaction, filtration, the filtrate was removed in vacuo, DCM 50 ml, 2 N was added. HCl 50 ml, stirred at room temperature for 20 min, the aqueous layer was washed with DCM (20 ml x 2). The pH of the aqueous layer was adjusted to 9 using 5% w/v. aqueous NaOH solution, the aqueous layer was extracted with DCM (50 ml×6) and the combined organic fractions were dried (Na ₂ SO ₄ ), filtered and concentrated and subjected to chromatography (DCM/MeOH=20/1) to obtain the title compound in as a white solid. (3.2 g, 43.7%)

Step 3. 6-Chloro-4-[[3-methoxy-4-(1-methyl-1,2,4-triazol-3-yl)-2-pyridyl]amino]-N-(trideuteromethyl)pyridazin-3 -carboxamide

[00655] In a solution of 4,6-dichloro-N-(trideuteromethyl)pyridazin-3-carboxamide (4.18 g, 20.0 mmol) and 3-methoxy-4-[1-(trideuteromethyl)-1,2, 4-triazol-3-yl]pyridin-2-amine (3.20 g, 15.4 mmol) in THF (50 ml) under N ₂ was added LiHMDS (1 M, 46.2 ml, 46.2 mmol) at 0°C with a slight exothermic effect. The reaction mixture was stirred at room temperature. After completion, the reaction mixture was cooled to 0°C, quenched by adding sat. NH ₄ Cl (aq) solution, diluted with water (100 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM/EtOAc=3/1) to give the title compound in as a yellow solid (2.70 g, 46.1%).

Step 4. 6-(3-Isopropyl-2-oxoimidazolidin-1-yl)-4-[[3-methoxy-4-[1-(trideuteromethyl)-1,2,4-triazol-3-yl]-2 -pyridyl]amino]-N-(trideuteromethyl)pyridazine-3-carboxamide

[00656] Into a solution of 6-chloro-4-[[3-methoxy-4-(1-methyl-1,2,4-triazol-3-yl)-2-pyridyl]amino]-N-(trideuteromethyl)pyridazine -3-carboxamide (2.8 g, 7.4 mmol) and 1-isopropylimidazolidin-2-one (1.9 g, 15 mmol) in 1,4-dioxane (30 ml) was added cesium carbonate (4.8 g , 15 mmol), Pd ₂ (dba) ₃ (2.0 g, 2.2 mmol) and Xantphos (2.6 g, 4.4 mmol). The mixture was degassed with N ₂ 3 times and heated to 120°C for 4 hours. After completion of the reaction, filtration, the filtrate was removed in vacuo, subjected to chromatography (PE/EtOAc=50/50, then DCM/MeOH=97/3) to obtain the desired product T 311 as a yellow solid (0.58 g, 17% ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.20 (s, 1H), 10.16 (s, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.51 (d, 1H), 4.43-4.32 (m, 1H), 4.23 (t, 2H), 4.00 (s, 3H), 3.51 ( t, 2H), 1.23 (d, 6H). LM-MS: m/z =473.3[M+H] ⁺

Example 161

Stage 1. Example 161b

[00657] To a solution of Example 161a (383 mg, 1.0 mmol) in dioxane (10 ml) was added NH ₂ Boc (176 mg, 1.5 mmol), Pd ₂ (dba) ₃ (91 mg, 0.1 mmol ), Xantphos (60 mg, 0.1 mmol) and Cs ₂ CO ₃ (652 mg, 2.0 mmol). The mixture was sealed and heated to 100°C for 8 hours. The mixture was cooled to room temperature, diluted with EtOAc, washed with water, dried over anhydrous Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with DCM/MeOH=(10/1) to give the product as Example 161b (401 mg, 86.4% yield) as a yellow solid. LCMS [M+1] ⁺ = 465.2.

Stage 2. Example 161c

A solution of Example 169b (401 mg, 0.86 mmol) in HCl/EtOAc (2 ml) was stirred at room temperature for 3 hours. The mixture was then concentrated and used directly in the next step.

Stage 3. Example 161

[00658] To a solution of Example 161c (40 mg, 0.1 mmol) and Example 161d (10.4 mg, 0.1 mmol) in pyridine (3 ml) was added POCl3 (77 mg, 0.5 mmol) at 0 ^o C. The reaction mixture was stirred at 0 ^o C for 10 minutes. Water (5 ml) was then added dropwise and the mixture was extracted with DCM (6 ml). The organic phase was dried over anhydrous Na ₂ SO _{4 and} concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 161 (12.1 mg, 26.9% yield) as a white solid. LCMS [M+1] ⁺ = 451.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.01 (s, 1H), 10.95 (s, 1H) _, 9.11 (s, 1H), 8.53 (s, 1H), 8 .00 (s, 1H), 7.63 (d, J =7.8 Hz, 1H), 7.51 (d, J =7.8 Hz, 1H), 7.25 (t, J =7, 9 Hz, 1H), 4.97 (s, 1H), 4.80 (s, 1H), 3.92 (s, 3H), 3.67 (s, 3H), 2.98 (s, 1H) , 2.19 (s, 1H), 1.58 (d, J =23.5 Hz, 1H), 1.21 (s, 2H), 1.10-1.00 (m, 4H).

Example 162

Stage 1. Example 162c

[00659] A solution of Example 162a (800 mg, 17.34 mmol) in 1,4-dioxane (35 ml) was treated with Example 162b (1.0 g, 7.34 mmol) and Na ₂ CO ₃ (1.2 g, 11.1 mmol). The mixture was stirred at RT for 16 hours. After completion of the reaction, the solvent was concentrated, the residue was suspended in DCM (5 ml), sonicated and the resulting solid was collected by filtration, dried to obtain the desired product, which is Example 162c (300 mg, yield 35.3%), as a white solid.

Stage 2. Example 162

[00660] To a solution of example 162d (58 mg, 0.5 mmol) and example 162c (94 mg, 0.25 mmol) in dioxane (3 ml) was added Pd ₂ (dba) ₃ (46 mg, 0.05 mmol) , Xantphos (30 mg, 0.05 mmol) and Cs ₂ CO ₃ (163 mg, 0.5 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C overnight. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to obtain the desired product as Example 162 (2.7 mg, yield: 11.8%) as an off-white solid. LCMS [M+1] ⁺ = 457.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.90 (s, 1H), 9.67 (s, 1H) _, 9.00 (s, 1H), 8.54 (s, 1H), 8 .00 (s, 1H), 7.62 (d, J= 7.6 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 8, 4 Hz, 1H), 5.62 (d, J =6.2 Hz, 1H), 4.38 (s, 1H), 4.17 (s, 2H), 3.93 (s, 3H), 3 .76-3.69 (m, 5H).

Example 163

Stage 1. Example 163c

[00661] To a solution of Example 163a (7.5 g, 43.0 mmol, 1.0 eq) in THF (100 mL) was added Example 163b (21.4 mL, 3.0 M in THF, 64.2 mmol , 1.5 eq.) dropwise at -20 ^o C under N ₂ protection conditions. The mixture was stirred at RT for 0.5 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (80 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 (petroleum ether/EtOAc=5/1) to give the product Example 163c (4.0 g, 45.8% yield) as a yellow oil. LCMS [M+1] ⁺ = 206.1.

Stage 2. Example 163d

To a solution of Example 163c (3.8 g, 18.0 mmol, 1.0 eq) in DCM (100 ml) was added MnO ₂ (40.1 g, 450 mmol, 25.0 eq) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=10/1) to give the product Example 163d (2.5 g, 66.5% yield) as an off-white solid. LCMS [M+1] ⁺ = 204.1.

Stage 3. Example 163f

[00662] To a solution of Example 163d (100 mg, 0.49 mmol, 1.0 eq.) in dioxane (2.0 mL) was added Cs ₂ CO ₃ (320 mg, 0.98 mmol, 2.0 eq.) , example 163e (41.9 mg, 0.49 mmol, 1.0 eq.), BINAP (61.3 mg, 0.098 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (50, 9 mg, 0.049 mmol, 0.1 eq.). The reaction mixture was stirred for 2 hours at 80 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc=3/1) to give the product Example 163f (60 mg, 48.4% yield) as a yellow solid. LCMS [M+1] ⁺ = 253.2.

Stage 4. Example 163i

[00663] To a solution of example 163g (28.0 g, 243.4 mmol, 1.0 eq.) in MeOH (400 ml) at 0 ^o C (ice bath) was added example 163h (16.0 g, 267.7 mmol, 1.1 eq.) drop by drop. After addition, the reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated in vacuo and then replaced with THF (80 ml*4) to remove the remaining MeOH. After removal of the solvent by evaporation, Example 163i (15.0 g, 83.8% yield) was obtained as a yellow oil.

Stage 5. Example 163k

[00664] To a solution of Example 163j (40.0 g, 279.7 mmol, 1.0 eq) in dry THF (400 mL) was added LDA (181.8 mL, 2 M in THF, 363.6 mmol, 1 .3 eq.) at -70 ^o C dropwise, which was stirred for an additional 40 minutes. at the same temperature after addition. I ₂ (92.3 g, 363.6 mmol, 1.3 eq.) in THF (100 ml) was added dropwise to the solution. After addition, the reaction mixture was heated to room temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous NH ₄ Cl (200 ml), extracted with EtOAc (200 ml * 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc=80/1) to give the desired product as Example 163k (20.0 g, 26.6% yield) as a white solid. LCMS [M+1] ⁺ = 270.1.

Stage 6. Example 163l

[00665] To a solution of Example 163k (15.0 g, 55.6 mmol, 1.0 eq) in NMP (50 mL) was added CuCN (9.9 g, 111.2 mmol, 2.0 eq) and the mixture was stirred for 5 hours at 120 ^° C. After cooling to room temperature, the mixture was diluted with EtOAc (200 ml) and filtered. The filtrate was washed with brine (50 ml*3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc=50/1) to give the desired product as Example 163l (7.5 g, 80.1% yield) as a yellow solid. LCMS [M+1] ⁺ = 169.2.

Stage 7. Example 163m

[00666] A solution of Example 163l (5.0 g, 29.8 mmol, 1.0 eq) and Example 163i (4.4 g, 59.6 mmol, 2.0 eq) in THF (150 ml) t -BuOK (7.3 g, 65.6 mmol, 2.2 eq.) was added portionwise at 0 ^° C. After addition, the mixture was heated to room temperature and stirred for 5 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc=1/1) to give the product Example 163m (2.6 g, 42.7% yield) as a white solid. LCMS [M+1] ⁺ = 225.2.

Stage 8. Example 163o

[00667] To a solution of Example 163m (1.1 g, 4.9 mmol, 1.0 eq.) in dioxane (20 ml) was added Cs ₂ CO ₃ (3.26 g, 9.8 mmol, 2.0 eq. .), example 163n (1.37 g, 5.39 mmol, 1.1 eq.), BINAP (623 mg, 0.98 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ ( 517 mg, 0.49 mmol, 0.1 eq.). The reaction mixture was stirred for 3 hours at 90 ^o C under N ₂ protection conditions. After completion of the reaction, the solvent was removed and the residue was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the product as Example 163o (1.4 g, 89.3% yield) as a yellow solid substances. LCMS [M+1] ⁺ = 326.3.

Stage 9. Example 163p

[00668] A solution of Example 163o (1.4 g, 4.29 mmol, 1.0 eq.) in TFA (20 ml) was stirred for 1 hour at 70 ^o C. After completion of the reaction, it was concentrated in vacuo. The residue was dissolved in MeOH (20 ml) and increased in basicity with NaHCO ₃ (910 mg, 8.58 mmol, 2.0 eq.). The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the product Example 163p (750 mg, 84.9% yield) as a light gray solid. [M+1] ⁺ = 206.2.

Stage 10. Example 163

[00669] To a solution of example 163f (22 mg, 0.11 mmol, 1.0 eq.) and example 163p (30 mg, 0.12 mmol, 0.9 eq.) in dioxane (2 ml) was added Cs ₂ CO ₃ (77.3 mg, 0.22 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (12.3 mg, 0.011 mmol, 0.1 eq.) and BINAP (15.0 mg , 0.022 mmol, 0.2 eq.). The reaction mixture was stirred for 3 hours at 110 ^o C under N ₂ protection conditions. The reaction solution was filtered and the filtrate was concentrated in vacuo . The crude product was purified by preparative TLC (DCM/MeOH=30/1) to provide the desired product as Example 163 (13.8 mg, 27.6% yield) as a light yellow solid. LCMS [M+1] ⁺ = 422.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.36 (s, 1H), 10.91 (s, 1H) _, 9.71 (s, 1H), 8.96 (s, 1H), 8 .67 (s, 1H), 8.14 (d, J =5.4 Hz, 1H), 7.50 (d, J =5.1 Hz, 1H), 4.00 (s, 3H), 3 .92 (s, 3H), 3.16 (q, J =7.2 Hz, 2H), 2.12-2.04 (m, 1H), 1.15 (t, J =7.2 Hz, 3H), 0.89 -0.82 (m, 4H).

Example 164

Stage 1. 2-Methylazetidine-1-carboxamide

[00670] To a solution of 2-methylazetidine hydrochloride (120 mg, 1.12 mmol), phenylcarbamate (184 mg, 1.34 mmol) in 1,4-dioxane (20 ml) was added NEt ₃ (0.5 ml, 3. 36 mmol) and stirred at RT for 16 hours. After completion of the reaction, the solvent was concentrated, the residue was suspended in DCM (5 ml), sonicated and the resulting solid was collected by filtration, dried to obtain the desired product (150 mg , 89%) as a white solid. LM-MS: mass/charge =115.1[M+H] ⁺

Stage 2.

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(2-methylazetidine-1 -carboxamido)pyridazine-3-carboxamide

Into a solution of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)

[00671] phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (244.7 mg, 0.65 mmol) and 2-methylazetidine-1-carboxamide (150 mg, 1.0 mmol) in 1 ,4-dioxane (10 ml) Pd ₂ (dba) ₃ (60 mg, 0.065 mmol), Xantphos (75 mg, 0.13 mmol) and Cs ₂ CO ₃ (635 mg, 1.95 mmol) were added. The mixture was sealed, degassed with nitrogen 3 times and stirred at 120 ^° C for 4 hours. Once complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified directly by preparative HPLC to obtain the racemic product (125 mg, yield: 42%) as a white solid. LM-MS: mass/charge =455.3[M+H] ⁺

[00672] The racemic compound was resolved by SFC to give enantiomer A (49.5 mg, RT: 3.008 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.19 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.82 (dd, 1H), 7.53 (dd, 1H), 7.31-7.24 (m, 2H), 4.53 (dd, 1H), 4.17-4.01 (m, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 2.53-2.36 (m, 1H), 1.98-1.83 (m, 1H), 1.50 (d, 3H). ee% = 100% ；LM-MS: m/z =455.3[M+H] ⁺

[00673] Enantiomer B (49.9 mg, RT: 4.240 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.13 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.80 (dd, 1H), 7.53 (d, 1H), 7.32-7.21 (m, 2H), 4.52 (dd, 1H), 4.14-4.02 (m, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 2.57-2.35 (m, 1H), 2.05-1.81 (m, 1H), 1.50 (d, 3H). ee% = 100%；LM-MS: m/z=455.3 [M+H] ⁺

Example 165

Stage 1. Example 165c

[00674] To a solution of Example 165a (270 mg, 3.1 mmol) in dioxane (5 ml) was added Example 165b (500 mg, 3.64 mmol) and TEA (795 mg, 7.87 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc, washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The solution was concentrated to give crude Example 165c (200 mg, 49.6% yield) and used directly in the next step.

Stage 2. Example 165

[00675] To a solution of Example 165d (100 mg, 0.26 mmol) and Example 165c (120 mg, 0.92 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) , Xantphos (30 mg, 0.052 mmol) and Cs ₂ CO ₃ (340 mg, 1.04 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 165 (46.0 mg, 37.6% yield) as a white solid. LCMS [M+1] ⁺ = 471.50. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.89 (s, 1H), 9.67 (s, 1H) _, 8.99 (s, 1H), 8.54 (s, 1H), 8 .01 (s, 1H), 7.62 (d, J =7.9 Hz, 1H), 7.48 (d, J =7.9 Hz, 1H), 7.24 (s, 1H), 5 .54 (s, 1H), 3.93 (s, 3H), 3.83 (br, 4H), 3.71 (s, 3H), 1.33 (s, 3H).

Example 166

Stage 1. Example 166c

[00676] To a solution of Example 166a (2.0 g, 8.0 mmol, 1.0 eq.) in dioxane (20 ml) was added Cs ₂ CO ₃ (5.2 g, 16 mmol, 2.0 eq.) , example 166b (1.36 g, 16 mmol, 2.0 eq.), BINAP (997 mg, 1.6 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (800 mg, 0 .8 mmol, 0.1 eq.). The reaction mixture was stirred for 2 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=1/1) to give the product Example 166c (1.9 g, 86% yield) as a yellow oil. LCMS [M+1] ⁺ = 284.2.

Stage 2. Example 166e

To a solution of example 166c (1.9 g, 7.0 mmol, 1.0 eq) in THF (20 ml) was added example 166d (210 ml, 1.0 M in THF, 210 mmol, 30.0 eq) drop by drop at 0 ^o C under N ₂ protection conditions. The mixture was stirred for 0.5 h at room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl (200 ml) and extracted with EtOAc (150 ml*3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=2/1) to give the product Example 166e (850 mg, 47% yield) as a yellow solid. LCMS [M+1] ⁺ = 265.2.

Stage 3. Example 166

[00677] To a solution of Example 166e (650 mg, 2.33 mmol, 1.2 eq.) in dioxane (10 ml) was added Cs ₂ CO ₃ (1.3 g, 3.88 mmol, 2.0 eq.) , example 166f (400 mg, 1.94 mmol, 1.0 eq.), BINAP (241.7 mg, 0.388 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (200.8 mg , 0.194 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to obtain 580 mg of crude product (90% purity), which was further purified by preparative HPLC (Prep-C18, 5 µm XBridge column, 19 × 150 mm, W aters; gradient elution from 35% MeCN in water to 55% MeCN in water over a period of 7 minutes, where the aqueous phase contains 10 mM NH ₄ HCO ₃ +0.5% ammonia) to obtain the example product 166 (401.4 mg, 48% yield), as a white solid. LCMS [M+1] ⁺ = 434.4. ^1H NMR (300 MHz, DMSO- d6 ) δ _12.30 (s, 1H), 10.94 (s, 1H), 9.70 (s, 1H), 9.21 (s, 1H), 8 .66 (s, 1H), 8.13 (d, J =5.1 Hz, 1H), 7.49 (d, J =5.1 Hz, 1H), 3.99 (s, 3H), 3 .86 (s, 3H), 3.11-2.96 (m, 1H), 2.15-2.04 (m, 1H), 1.19-1.03 (m, 4H), 0.92 -0.80 (m, 4H).

Example 169

Stage 1. Example 169c

[00678] To a solution of Example 169a (123 mg, 1.0 mmol) and Example 169b (206 mg, 1.5 mmol) in dioxane (3 mL) was added Na ₂ CO ₃ (212 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered, the solid was washed with DCM, and the combined filtrate was used directly in the next step.

Stage 2. Example 169d

[00679] Imidazole (350 mg, 5.0 mmol) was added to the solution of Example 169c in portions, followed by the addition of TBSCl (300 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the crude product was purified by silica gel flash column chromatography, eluting with (DCM/MeOH=30/1) to give the product as Example 169d (60 mg, 24.5% yield) as a white solid substances.

Stage 3. Example 169f

[00680] To a solution of example 169d (60 mg, 0.26 mmol) in dioxane (5 ml) was added example 169e (100 mg, 0.26 mmol), Pd ₂ (dba) ₃ (24 mg, 0.027 mmol), Xantphos (16 mg, 0.027 mmol) and Cs ₂ CO ₃ (130 mg, 0.40 mmol). The mixture was sealed and heated to 110 ^° C overnight. The mixture was filtered and concentrated under reduced pressure to give crude Example 169f (190 mg, quant.).

Stage 4. Example 169

[00681] To a solution of Example 169f (130 mg, crude, 0.22 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Prep-C18, 5 μm XBridge column, 19 × 150 mm, Waters ; gradient elution from 35% MeCN in water to 55% MeCN in water over a period of 7 min. , where the aqueous phase contains 10 mM NH ₄ HCO ₃ + 0.5% ammonia) to obtain example 169 (2 mg, 1.9% yield from 2 stages) as a white solid. LCMS [M+1] ⁺ = 471.2. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.94 (s, 1H), 8.11-8.03 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 7 .51 (d, J =8.0 Hz,1H), 4.14 (br, 2H), 4.00 (s, 3H), 3.90 (s, 2H), 3.80 (s, 5H) , 2.83 (br, 1H), 1.25 (s, 1H).

Example 171

Stage 1. Example 171c

[00682] To a solution of Example 171a (5.0 g, 26.3 mmol, 1.0 eq) in Example 171b (50 mL) was added NaH (3.15 g, 60% in mineral oil, 78.9 mmol, 3.0 eq.) in parts at 0 ^o C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (100 ml), quenched with 2 N. aqueous HCl (15 ml), washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=3/1) to give the desired product as Example 171c (4.1 g, 64.0% yield) as a light yellow solid. LCMS [M+1] ⁺ = 244.2.

Stage 2. Example 171d

[00683] A solution of Example 171c (4.1 g, 16.80 mmol, 1.0 eq) and K ₂ CO ₃ (2.55 g, 18.48 mmol, 1.1 eq) in DMF (50 ml) CD ₃ I (2.68 g, 18.48 mmol, 1.1 eq.) was added at 0 ^o C. The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc (100 ml) and washed with saline solution (50 ml*3). The organic layer was dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=3/1) to give the desired product as Example 171d (2.83 g, 64.5% yield) as a colorless oil. LCMS [M+1] ⁺ = 261.1.

Stage 3. Example 171e

[00684] To a solution of Example 171d (2.83 g, 10.84 mmol, 1.0 eq.) in AcOH (20 mL) was added conc. HCl (40 ml). The reaction solution was heated at 100 ^° C for 16 hours. After cooling to room temperature, the mixture was concentrated, diluted with H ₂ O (20 ml) and extracted with EtOAc (30 ml*3). The combined organic layer was washed with brine (50 ml), dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=3/1) to give the desired product as Example 171e (1.12 g, 54.7% yield) as a white solid. LCMS [M+1] ⁺ = 189.2.

Stage 4. Example 171f

[00685] To a solution of Example 171e (1.12 g, 5.94 mmol, 1.0 eq.) in CH ₃ CN (15 mL) was added POCl ₃ (2 mL). The reaction solution was heated at 85 ^° C for 1 hour. After cooling to room temperature, the mixture was concentrated and diluted with EtOAc (5 ml). The solution was added to a mixed solution of EtOAc (20 ml) and saturated aqueous NaHCO ₃ solution (20 ml). After separation, the aqueous layer was extracted with EtOAc (20 ml*3). The combined organic layer was washed with brine (20 ml), dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=8/1) to give the desired product as Example 171f (1.05 g, 85.4% yield) as a white solid. LCMS [M+1] ⁺ = 207.1.

Stage 5. Example 171h

To a solution of example 171f (100 mg, 0.48 mmol, 1.0 eq.) in dioxane (4 ml) was added example 171g (37 mg, 0.43 mmol, 0.9 eq.), Cs ₂ CO ₃ (315 mg, 0.97 mmol, 2.0 eq.), BINAP (30 mg, 0.048 mmol, 0.1 eq.) and Pd ₂ (dba) _3. CHCl ₃ (50 mg, 0.048 mmol, 0.1 eq. ). The reaction mixture was stirred for 4 hours at 110 ^o C in an atmosphere of N ₂ . The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (petroleum ether/EtOAc=3/1) to provide the desired product as Example 171h (40.0 mg, 32.4% yield) as a light yellow solid. LCMS [M+1] ⁺ = 256.3.

Stage 6. Example 171

[00686] To a solution of example 171h (40 mg, 0.16 mmol, 1.0 eq.) in dioxane (3 ml) was added example 171i (29 mg, 0.14 mol, 0.9 eq.), Cs ₂ CO ₃ (102 mg, 0.31 mmol, 2.0 eq.), BINAP (10 mg, 0.016 mmol, 0.1 eq.) and Pd ₂ (dba) _3. CHCl ₃ (16 mg, 0.016 mmol, 0. 1 eq.). The reaction solution was stirred for 6 hours at 110 ^° C under N ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=20/1) to provide the desired product as Example 171 (8.2 mg, 12.3% yield) as an off-white solid. LCMS [M+1 ] ⁺ = 424.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.05 (s, 1H), 10.90 (s, 1H) _, 8.89 (s, 1H), 8.57 (s, 1H), 8 .03 (s, 1H), 7.65 (dd, J =7.8, 1.8 Hz, 1H), 7.53 (dd, J =7.8, 1.8 Hz, 1H), 7, 26 (d, J =7.8 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H), 3.11 (s, 2H), 2.07-1.96 (m , 1H), 0.79 (d, J =6.0 Hz, 4H).

Example 172

Stage 1. Example 172c

[00687] To a solution of Example 172a (150 mg, 0.72 mmol, 1.0 eq.) in dioxane (5 ml) was added Example 172b (88 mg, 0.58 mmol, 0.8 eq.), Cs ₂ CO ₃ (472 mg, 1.45 mmol, 2.0 eq.), BINAP (45 mg, 0.072 mmol, 0.1 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (75 mg, 0.072 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C in an atmosphere of N ₂ . The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (petroleum ether/EtOAc=1/1) to give the desired product as Example 172c (62 mg, 26.5% yield) as a yellow solid. LCMS [M+1] ⁺ = 323.3.

Stage 2. Example 172

[00688] To a solution of Example 172c (62 mg, 0.19 mmol, 1.0 eq.) in dioxane (5 ml) was added Example 172d (33 mg, 0.19 mol, 1.0 eq.), Cs ₂ CO ₃ (126 mg, 0.39 mmol, 2.0 eq.), BINAP (24 mg, 0.039 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (20 mg, 0.019 mmol, 0.1 eq. .). The reaction mixture was stirred for 6 hours at 110 ^o C in an atmosphere of N ₂ . The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=20/1) to provide the desired product as Example 172 (16.1 mg, 18.3% yield) as a white solid. LCMS [M+1] ⁺ = 459.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.96 (s, 1H), 10.02 (s, 1H) _, 8.95 (s, 1H), 8.92 (s, 1H), 8 .67 (dd, J =4.8, 2.1 Hz, 1H), 8.34 (d, J =2.4 Hz, 1H), 8.28 (dd, J =7.8, 2.1 Hz, 1H), 7.78 (dd, J =8.7, 2.4 Hz, 1H), 7.68 (d, J =8.7 Hz, 1H), 7.33 (dd, J =7 .8, 4.8 Hz, 1H), 5.07 (s, 1H), 3.34 (s, 3H), 3.08 (s, 2H), 1.45 (s, 6H).

Example 173

Stage 1. Example 173b

[00689] To a solution of Example 173a (1.0 g, 3.7 mmol, 1.0 eq.) in aqueous NaOH (11.1 mL, 1 M, 11.1 mmol, 3.0 eq.) was added ( Boc) ₂ O (1.29 g, 5.92 mmol, 1.6 eq.) in DCM (11.1 ml). The reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction, the two phases were separated. The organic layer was washed with water (10 ml), 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 give the product as Example 173b (505 mg, 74% yield) as a yellow solid. LCMS [M+1] ⁺ = 184.2.

Stage 2. Example 173

[00690] To a solution of Example 173c (150 mg, 0.39 mmol, 1.0 eq.) in dioxane (5 ml) was added Cs ₂ CO ₃ (254.3 mg, 0.78 mmol, 2.0 eq.) , example 173b (143.5 mg, 0.78 mmol, 2.0 eq.), BINAP (48.6 mg, 0.078 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (40, 4 mg, 0.039 mmol, 0.1 eq.). The reaction mixture was stirred for 3 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to obtain a crude product of 42 mg (90% purity), which was purified by preparative HPLC (Prep-C18, 5 μm XBridge column, 19 × 150 mm, W aters; gradient elution from 35% MeCN in water to 55% MeCN in water over a period of 7 minutes, where the aqueous phase contains 10 mm NH ₄ HCO ₃ +0.5% ammonia) to obtain the product to obtain the product representing Example 173 ( 14.2 mg, yield 8%), as a white solid. LCMS [M+1] ⁺ = 431.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.48 (br, 1H), 10.97 (s, 1H), 10.22 ( _br , 1H), 9.04 (s, 1H), 8 .56 (s, 1H), 7.66-7.52 (m, 2H), 7.26 (t, J =7.8 Hz, 1H), 7.01 (br, 1H), 6.74 ( br, 2H), 3.95 (s, 3H), 3.72 (s, 3H), 2.97-2.81 (m, 1H), 1.18-0.93 (m, 4H).

Example 174

Stage 1. Example 174c

[00691] To a solution of example 174a (500 mg, 2.45 mmol) in dioxane (20 ml) was added example 174b (417 mg, 2.45 mmol), K ₂ CO ₃ (676 mg, 4.9 mmol), BINAP (304 mg, 0.49 mmol) and Pd ₂ (dba) ₃ CHCl ₃ (252 mg, 0.25 mmol). The reaction mixture was stirred at 90°C for 16 hours under N ₂ atmosphere. The reaction mixture was concentrated and the crude material was purified by silica gel flash column chromatography (petroleum ether/EtOAc=2/1) to give the product Example 174c (170 mg, 20.5% yield) as a yellow solid. LCMS [M+1] ⁺ = 338.2.

Stage 2. Example 174

[00692] To a mixture of example 174c (170 mg, 0.5 mmol) in dioxane (5 ml) was added example 174d (86 mg, 0.5 mmol), Cs ₂ CO ₃ (326 mg, 1.0 mmol), BINAP (125 mg, 0.1 mmol) and Pd ₂ (dba) ₃ CHCl ₃ (51 mg, 0.05 mmol). The reaction mixture was stirred at 110°C for 4 hours under N ₂ atmosphere. The reaction mixture was concentrated and the residue was purified by preparative TLC (DCM/EtOAc=1/2) to give the product as Example 174 (66.6 mg, 28.0% yield) as a white solid. LCMS [M+1] ⁺ = 474.3. ^1H NMR (300 MHz, DMSO- d6 ) δ12.00 (s, 1H), 10.25 (s, 1H) _, 9.02 (s, 1H), 8.95 (s, 1H), 8, 66 (dd, J = 4.8, 2.1 Hz, 1H), 8.29 (dd, J = 7.8, 2.1 Hz, 1H), 7.99 (dd, J = 10.8, 8.1 Hz, 1H), 7.60 (dd, J =8.4, 1.8 Hz, 1H), 7.35 (dd, J =7.8, 1.5 Hz, 1H), 5, 29 (s, 1H), 3.34 (s, 3H), 3.11 (q, J =7.2 Hz, 2H), 1.48 (s, 6H), 1.13 (t, J =7 ,2 Hz, 3H).

Example 175

Stage 1. Example 175c

[00693] To a solution of Example 175a (500 mg, 2.46 mmol, 1.0 eq.) in dioxane (10 ml) was added K ₂ CO ₃ (680 mg, 4.93 mmol, 2.0 eq.), example 175b (293 mg, 2.46 mmol, 1.0 eq.), Xantphos (285 mg, 0.493 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (255 mg, 0.246 mmol, 0. 1 eq.). The reaction mixture was stirred for 16 hours at 110 ^o C under N ₂ protection conditions. After completion of the reaction, the solvent was concentrated and the crude product was purified by silica gel flash column chromatography, eluted with (DCM/MeOH=30/1) to give the product as Example 175c (380 mg, 53.8% yield) as yellow solid. LCMS [M+1] ⁺ =287.1.

Stage 2. Example 175

[00694] To a solution of Example 175c (300 mg, 1.05 mmol, 1.0 eq.) in dioxane (6 ml) was added Cs ₂ CO ₃ (683.9 mg, 2.10 mmol, 2.0 eq.) , example 175d (193.5 mg, 0.94 mmol, 0.9 eq.), BINAP (130.7 mg, 0.21 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ ( 108.5 mg, 0.105 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography, eluted with (DCM/MeOH=20/1) to give 160 mg product (crude, 80% purity), which was further purified by preparative HPLC (Prep-C18, column 5 µm XBridge, 19 × 150 mm, W aters; gradient elution from 35% MeCN in water to 55% MeCN in water over a period of 7 min., where the aqueous phase contains 10 mM NH ₄ HCO ₃ + 0.5% ammonia) with yielding the product of Example 175 (58.3 mg, 12.2% yield) as a yellow solid. LCMS [M+1] ⁺ = 456.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.49 (s, 1H), 10.53 (s, 1H) _, 9.78 (s, 1H), 8.96 (s, 1H), 8 .68 (s, 1H), 8.36 (d, J =5.4 Hz, 1H), 7.92 (t, J =8.1 Hz, 1H), 7.82 (d, J =8, 4 Hz, 1H), 7.59 (d, J =7.2 Hz, 1H), 7.50 (d, J =5.1 Hz, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.17 (q, J=7.2 Hz, 2H), 1.17 (t, J =7.2 Hz, 3H).

Example 176

Stage 1. Example 176c

[00695] To a solution of Example 176a (500 mg, 2.46 mmol, 1.0 eq.) in dioxane (10 ml) was added K ₂ CO ₃ (680 mg, 4.93 mmol, 2.0 eq.), example 176b (293 mg, 2.46 mmol, 1.0 eq.), Xantphos (285 mg, 0.493 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (255 mg, 0.246 mmol, 0. 1 eq.). The reaction mixture was stirred for 16 hours at 110 ^o C under N ₂ protection conditions. The solvent was concentrated. The crude product was purified by silica gel flash column chromatography, eluted with (DCM/MeOH=30/1) to give the product Example 176c (310 mg, 44% yield) as a yellow solid. LCMS [M+1] ⁺ =287.1.

Stage 2. Example 176

[00696] To a solution of Example 176c (310 mg, 1.084 mmol, 1.0 eq.) in dioxane (6 mL) was added Cs ₂ CO ₃ (683.9 mg, 2.168 mmol, 2.0 eq.), Example 176d ( 167.8 mg, 0.975 mmol, 0.9 eq.), BINAP (130.7 mg, 0.217 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (112.2 mg, 0.108 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography, eluted with (DCM/MeOH=15/1) to give crude product 120 mg (80% purity) and further purified by preparative HPLC to give the product representing Example 176 (61 .1 mg, yield 13%), as an off-white solid. LCMS [M+1] ⁺ =423.2. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.06 (s, 1H), 10.54 (s, 1H) _, 9.19 (s, 1H), 8.97 (s, 1H), 8 .77 (dd, J =4.8, 2.1 Hz, 1H), 8.30 (dd, J =7.8, 1.8 Hz, 1H), 7.97-7.84 (m, 2H ), 7.57 (dd, J =6.6, 1.5 Hz, 1H), 7.34 (dd, J =7.8, 4.8 Hz, 1H), 3.36 (s, 3H) , 3.14 (q, J =7.2 Hz, 2H), 1.13 (t, J =7.2 Hz, 3H).

Example 177

[00697] To a solution of Example 177a (371 mg, 1.0 mmol) and Example 177b (119 mg, 1.0 mmol) in dioxane (10 ml) was added Pd ₂ (dba) ₃ (91.5 mg, 0.1 mmol), Xantphos (59.5 mg, 0.1 mmol) and Cs ₂ CO ₃ (489 mg, 1.5 mmol). The mixture was degassed with nitrogen 3 times and stirred at 100 ^° C for 3 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 177 (154.2 mg, 33.9% yield) as a pale yellow solid. LCMS [M+1] ⁺ = 455.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.27 (s, 1H), 10.37 (s, 1H) _, 8.85 (s, 1H), 8.54 (s, 1H), 7 .96 (s, 1H), 7.84 (t, J =7.8 Hz, 1H), 7.74 (dd, J =17.3, 8.3 Hz, 2H), 7.58 (d, J =7.7 Hz, 1H), 7.50 (d, J =7.2 Hz, 1H), 7.34 (d, J =8.6 Hz, 1H), 3.93 (s, 3H) , 3.73 (s, 3H), 3.09 (t, J =7.0 Hz, 2H), 1.11 (t, J =6.9 Hz, 3H).

Example 178

[00698] To a solution of Example 178a (371 mg, 1.0 mmol) and Example 178b (111 mg, 1.0 mmol) in dioxane (10 ml) was added Pd ₂ (dba) ₃ (91.5 mg, 0.1 mmol), Xantphos (59.5 mg, 0.1 mmol) and Cs ₂ CO ₃ (489 mg, 1.5 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C for 3 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 178 (8.4 mg, 1.9% yield) as a pale yellow solid. LCMS [M+1] ⁺ = 447.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.09 (s, 1H), 9.45 (s, 1H) _, 8.73 (s, 1H), 8.54 (s, 1H), 7 .66 (d, J =7.4 Hz, 1H), 7.57 (d, J =7.8 Hz, 2H), 7.27 (t, J =7.9 Hz, 1H), 5.90 (s, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.57 (s, 3H), 3.04-2.97 (m, 2H), 2.17 ( s, 3H), 1.12-1.08 (m, 3H).

Example 179

Stage 1. Example 179c

[00699] To a solution of Example 179a (650 mg, 3.19 mmol, 1.0 eq.) in dioxane (10 mL) was added NaHCO ₃ (548.7 mg, 6.38 mmol, 2.0 eq.), example 179b (354.1 mg, 0.319 mmol, 1.0 eq.), BINAP (398.7 mg, 0.638 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (331.2 mg, 0.319 mmol, 0.1 eq.). The reaction mixture was stirred for 2 hours at 100 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=2/1) to give the product Example 179c (250 mg, 28% yield) as a yellow solid substances. LCMS [M+1] ⁺ =279.2.

Stage 2. Example 179

[00700] To a solution of Example 179c (250 mg, 0.899 mmol, 1.0 eq.) in dioxane (5 mL) was added Cs ₂ CO ₃ (586 mg, 1.80 mmol, 2.0 eq.), Example 179d ( 139 mg, 0.809 mmol, 0.9 eq.), BINAP (112 mg, 0.180 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (90 mg, 0.087 mmol, 0.1 eq.) . The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography, eluted with DCM/MeOH (20/1) to give crude product 140 mg (90% purity) and further purified by preparative HPLC to give the product representing Example 179 (84, 6 mg, yield 23%), as an off-white solid. LCMS [M+1] ⁺ =415.3. ¹ H NMR (300 MHz, DMSO- d6 ) δ 11.98 (s, 1H), 9.64 (s, 1H), _8.83 (s, 1H), 8.65 (dd, J =4, 8, 1.8 Hz, 1H), 8.53 (brs, 1H), 8.27 (dd, J =7.8, 2.1 Hz, 1H), 7.31 (dd, J =7.8 , 4.8 Hz, 1H), 6.11 (s, 1H), 3.64 (s, 3H), 3.33 (s, 3H), 3.06 (q, J =7.2 Hz, 2H ), 2.24 (s, 3H), 1.11 (t, J =7.2 Hz, 3H).

Example 180

Stage 1. Example 180c

[00701] To a solution of Example 180a (1.0 g, 4.9 mmol, 1.0 eq.) in dioxane (20 mL) was added NaHCO ₃ (842.8 mg, 9.8 mmol, 2.0 eq.) , example 180b (543.9 mg, 4.9 mmol, 1.0 eq.), BINAP (610.5 mg, 0.98 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ ( 507.2 mg, 0.49 mmol, 0.1 eq.). The reaction mixture was stirred for 2 hours at 100 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed and the crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=2/1) to give the product Example 180c (380 mg, 28% yield) as a yellow solid substances. LCMS [M+1] ⁺ = 279.2.

Stage 2. Example 180

[00702] To a solution of Example 180c (340 mg, 1.22 mmol, 1.0 eq.) in dioxane (5 ml) was added Cs ₂ CO ₃ (795.4 mg, 2.44 mmol, 2.0 eq.) , example 180d (226.6 mg, 0.32 mmol, 1.1 eq.), BINAP (152.0 mg, 0.24 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ ( 126.3 mg, 0.12 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the crude product (220 mg) and further purified by preparative HPLC (Prep-C18, 5 µm XBridge column, 19 x 150 mm, W aters ; gradient elution from 35% MeCN in water to 55% MeCN in water over a period of 7 minutes, where the aqueous phase contains 10 mm NH ₄ HCO ₃ +0.5% ammonia) to obtain the product representing example 180 (61, 9 mg, yield 11%), as a white solid. LCMS [M+1] ⁺ = 448.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.38 (s, 1H), 9.61 (s, 1H) _, 9.00 (s, 1H), 8.83 (s, 1H), 8 .67 (s, 1H), 8.16 (d, J =5.4 Hz, 1H), 7.47 (d, J =5.1 Hz, 1H), 6.13 (s, 1H), 4 .01 (s, 3H), 3.92 (s, 3H), 3.68 (s, 3H), 3.08 (q, J =7.2 Hz, 2H), 2.26 (s, 3H) , 1.15 (t, J =7.2 Hz, 3H).

Example 181

Stage 1. Example 181c

[00703] To a solution of Example 181a (1 g, 10.0 mmol) in dioxane (15 mL) was added Example 181b (2 g, 14.6 mmol) and TEA (2 g, 19.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc, washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The solution was concentrated to give a crude residue, which was purified by silica gel flash column chromatography (petroleum ether/EtOAc=1/1) to give the product Example 181c (1 g, 69.8% yield) as a white solid. .

Stage 2. Example 181

[00704] To a solution of Example 181d (100 mg, 0.26 mmol) and Example 181c (38.3 mg, 0.26 mmol) in DMA (2.5 ml) was added Pd ₂ (dba) ₃ (24 mg, 0.026 mmol), Xantphos (15.6 mg, 0.026 mmol) and Cs ₂ CO ₃ (172 mg, 0.53 mmol). The mixture was degassed with nitrogen 3 times and stirred at 130 ^° C for 2 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with MeOH (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 181 (24.3 mg, 18.9% yield) as an off-white solid. LCMS [M+1] ⁺ = 484.3. ^1H NMR (400 MHz, Chloroform- d ) δ 11.33 (s, 1H), 10.08 (s, 1H), 9.43 (s, 1H), 8.96 (s, 1H), 8, 41 (s, 1H), 8.04 (d, J =7.8 Hz, 1H), 7.91 (d, J =7.8 Hz, 1H), 7.66 (t, J =7.9 Hz, 1H), 4.41 (s, 2H), 4.35 (s, 3H), 4.18 (s, 2H), 4.13 (s, 3H), 3.40 (d, J =9 .1 Hz, 1H), 2.91 (s, 6H).

Example 182

Stage 1. Example 182c

[00705] To a solution of Example 182a (400 mg, 2.65 mmol) in dioxane (5 ml) was added Example 182b (365 mg, 2.56 mmol) and TEA (795 mg, 7.87 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then used directly in the next step.

Stage 2. Example 182d

[00706] To a solution of Example 182c in dioxane was added Boc ₂ O (687 mg, 3.18 mmol) followed by Na ₂ CO ₃ (687 mg in 5 ml H ₂ O). The mixture was stirred at room temperature overnight. The mixture was then extracted with EtOAc, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by flash column chromatography on silica gel, eluted with DCM/MeOH (10/1) to give the product as Example 182d (170 mg, yield 27.8%), as a white solid.

Stage 3. Example 182f

[00707] To a solution of example 182e (75 mg, 0.2 mmol) in dioxane (5 ml) was added example 182d (46 mg, 0.2 mmol), Pd ₂ (dba) ₃ (18 mg, 0.02 mmol) , Xantphos (13 mg, 0.02 mmol) and Cs ₂ CO ₃ (130 mg, 0.4 mmol). The mixture was sealed and heated to 110 ^° C. for 3 hours. The mixture was filtered and concentrated under reduced pressure to obtain the crude material of Example 182f (200 mg, quant.), which was used directly in the next step without purification.

Stage 4. Example 182

[00708] To a solution of Example 182f (200 mg, crude, 0.2 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours, then the mixture was concentrated and purified by preparative HPLC to give Example 182 (15.7 mg, 9.5% yield) as a white solid. LCMS [M+1] ⁺ = 477.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 10.99 (s, 1H), 9.73 (s, 1H) _, 9.05 (s, 1H), 8.54 (s, 1H), 8 .33 (s, 2H), 7.74-7.62 (m, 2H), 7.48 (d, J =7.8 Hz, 1H), 7.25 (t, J =7.8 Hz, 1H), 4.04 (d, J =9.3 Hz, 2H), 3.92 (s, 4H), 3.67 (s, 3H), 3.53 (d, J =7.6 Hz, 2H), 2.93 (s, 1H), 1.48 (s, 3H), 1.15-0.99 (m, 4H).

Example 183

Stage 1. Example 183c

[00709] To a solution of example 183a (61 mg, 0.27 mmol) in dioxane (5 ml) was added example 183b (100 mg, 0.27 mmol), Pd ₂ (dba) ₃ (24 mg, 0.027 mmol), Xantphos (16 mg, 0.027 mmol) and Cs ₂ CO ₃ (173 mg, 0.53 mmol). The mixture was sealed and heated to 110 ^° C overnight. The mixture was filtered and concentrated under reduced pressure to obtain the crude material of Example 183c (170 mg), which was used directly in the next step without purification.

Stage 2. Example 183

[00710] To a solution of Example 183c (170 mg, crude, 0.27 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated and purified by preparative HPLC to give Example 183 (14.6 mg, 10.4% yield) as a yellow solid. LCMS [M+1] ⁺ = 470.2. ^1H NMR (400 MHz, _Methanol-d4 ) δ 8.48 (s, 1H), 7.86 (s, 1H), 7.69 (d, J =7.9 Hz, 1H), 7.58 (d, J =8.0 Hz, 1H), 7.29 (t, J =8.2 Hz, 1H), 4.19-4.11 (m, 4H), 4.02 (s, 3H) , 3.73 (s, 3H), 1.64 (s, 3H).

Example 184

[00711] To a solution of Example 184a (50 mg, 0.15 mmol, 1.0 eq.) in dioxane (2 ml) was added Example 184b (25 mg, 0.15 mmol, 1.0 eq.), Cs ₂ CO ₃ (96 mg, 0.29 mmol, 2.0 eq), BINAP (18 mg, 0.029 mmol, 0.2 eq) and Pd ₂ (dba) ₃ CHCl ₃ (15 mg, 0.015 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C in an atmosphere of N ₂ . The solid was filtered off and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=20/1) to provide the desired product as Example 184 (23.5 mg, 33.6% yield) as a light yellow solid. LCMS [M+1] ⁺ = 477.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.00 (s, 1H), 10.25 (s, 1H) _, 9.02 (s, 1H), 8.95 (s, 1H), 8 .66 (dd, J =4.8, 2.1 Hz, 1H), 8.29 (dd, J =7.8, 1.8 Hz, 1H), 7.99 (dd, J =10.8 , 8.4 Hz, 1H), 7.62 (d, J =7.8 Hz, 1H), 7.35 (dd, J =7.8, 4.5 Hz, 1H), 5.29 (s , 1H), 3.34 (s, 3H), 3.09 (s, 2H), 1.48 (s, 6H).

Example 185

[00712] To a solution of Example 185a (50 mg, 0.15 mmol, 1.0 eq.) in dioxane (2 ml) was added Example 185b (30 mg, 0.15 mmol, 1.0 eq.), Cs ₂ CO ₃ (96 mg, 0.29 mmol, 2.0 eq), BINAP (18 mg, 0.029 mmol, 0.2 eq) and Pd ₂ (dba) ₃ CHCl ₃ (15 mg, 0.015 mmol, 0.1 eq.). The reaction solution was stirred for 4 hours at 110 ^° C under N ₂ atmosphere. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=20/1) to provide the desired product as Example 185 (35.0 mg, 46.8% yield) as a light yellow solid. LCMS [M+1] ⁺ = 510.4. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.38 (s, 1H), 10.25 (s, 1H) _, 9.53 (s, 1H), 8.94 (s, 1H), 8 .68 (s, 1H), 8.18 (d, J =5.1 Hz, 1H), 8.00 (dd, J =10.8, 8.4 Hz, 1H), 7.59 (d, J =8.1 Hz, 1H), 7.52 (d, J =5.1 Hz, 1H), 5.29 (s, 1H), 4.01 (s, 3H), 3.93 (s, 3H), 3.11 (s, 2H), 1.50 (s, 6H).

Example 188

[00713] To a solution of Example 188a (100 mg, 0.27 mmol) and Example 188b (30 mg, 0.27 mmol) in dioxane (10 ml) was added Pd ₂ (dba) ₃ (24.6 mg, 0.027 mmol) , Xantphos (16 mg, 0.027 mmol) and Cs ₂ CO ₃ (131 mg, 0.40 mmol). The mixture was degassed with nitrogen 3 times and stirred at 110 ^° C for 4 hours. Once complete, the reaction mixture was cooled to room temperature, diluted with EtOAc (5 ml) and filtered. The filtrate was purified directly by preparative HPLC to provide the desired product as Example 188 (27.5 mg, 22.4% yield) as a pale yellow solid. LCMS [M+1] ⁺ = 445.2. ^1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H), 10.19 (s, 1H) _, 8.85 (s, 1H), 8.55 (s, 1H), 7 .97 (d, J =9.2 Hz, 1H), 7.67-7.61 (m, 3H), 7.43 (d, J =9.2 Hz, 1H), 7.25 (t, J =8.0 Hz, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 3.08 (q, J =7.6 Hz, 2H), 1.11 (t, J =7.1 Hz, 3H).

Example 189

[00714] To a solution of Example 189b (869 mg, 3.45 mmol, 1.1 eq.) in dioxane (100 ml) was added Example 189a (650 mg, 3.14 mmol, 1.0 eq.), Cs ₂ CO ₃ (2.04 g, 6.27 mmol, 2.0 eq.), BINAP (391 mg, 0.63 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (325 mg, 0.2 eq.) 31 mmol, 0.1 eq.). The reaction solution was stirred for 4 hours at 110 ^° C under N ₂ atmosphere. The solvent was concentrated and the residue was purified by silica gel flash column chromatography, eluting with DCM/MeOH (v/v = 25/1) to give the desired product as Example 189 (1.1 g, crude, 85 % purity) as a yellow solid and further purified by preparative reverse phase MPLC to provide the desired product as Example 189 (512.6 mg, 38.6% yield) as a white solid. LCMS [M+1] ⁺ = 424.4. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.05 (s, 1H), 10.90 (s, 1H) _, 8.89 (s, 1H), 8.56 (s, 1H), 8 .04 (s, 1H), 7.65 (dd, J =7.8, 1.8 Hz, 1H), 7.53 (dd, J =8.1, 1.5 Hz, 1H), 7, 26 (t, J =7.8 Hz, 1H), 3.72 (s, 3H), 3.13 (q, J =7.2 Hz, 2H), 2.10-1.94 (m, 1H ), 1.13 (t, J =7.2 Hz, 3H), 0.79 (d, J =6.0 Hz, 4H).

Example 190

Stage 1. Example 190c

[00715] To a solution of Example 190a (150 mg, 0.73 mmol, 1.0 eq.) and Example 190b (79 mg, 0.73 mmol, 1.0 eq.) in dioxane (3 mL) was added K ₂ CO ₃ (201 mg, 1.46 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (75 mg, 0.073 mmol, 0.1 eq.) and BINAP (15.0 mg, 0.15 mmol, 0.2 eq.). The reaction mixture was stirred for 16 hours at 80 ^o C under N ₂ protection conditions. The reaction solution was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=1/1) to give the desired product as Example 190c (65 mg, 32.0% yield) as a yellow solid. LCMS [M+1] ⁺ =280.2.

Stage 2. Example 190

[00716] To a solution of example 190c (60 mg, 0.22 mmol, 1.0 eq.) in dioxane (3 ml) and example 190d (37 mg, 0.22 mmol, 1.0 eq.) was added Cs ₂ CO ₃ (139.7 mg, 0.44 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (22.2 mg, 0.022 mmol, 0.1 eq.) and BINAP (25 mg, 0.044 mmol, 0.2 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative TLC (DCM/MeOH=30/1) to provide the desired product as Example 190 (9.2 mg, 10.3% yield) as a light yellow solid. LCMS [M+1] ⁺ = 416.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.94 (s, 1H), 10.41 (s, 1H), 8.94 ₍ s, 1H), 8.73 (s, 1H), 8 .67-8.59 (m, 1H), 8.29 (d, J =8.1 Hz, 1H), 8.09 (d, J =9.0 Hz, 1H), 7.49 (d, J =9.0 Hz, 1H), 7.34 (dd, J =7.8, 4.8 Hz, 1H), 3.35 (s, 3H), 3.09 (s, 2H), 2, 54 (s, 3H).

Example 191

Stage 1. Example 191c

[00717] To a solution of Example 191a (150 mg, 0.73 mmol, 1.0 eq.) and Example 191b (89.5 mg, 0.73 mmol, 1.0 eq.) in dioxane (10 mL) was added K ₂ CO ₃ (201 mg, 1.46 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (75.3 mg, 0.073 mmol, 0.1 eq.) and BINAP (90.6 mg , 0.15 mmol, 0.2 eq.). The reaction mixture was stirred for 16 hours at 80 ^o C under N ₂ protection conditions. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=40/1) to give the desired product as Example 191c (60 mg, 28.4% yield) as a yellow solid. LCMS [M+1] ⁺ = 294.2.

Stage 2. Example 191

[00718] To a solution of Example 191c (60 mg, 0.22 mmol, 1.0 eq.) and Example 191d (35 mg, 0.22 mmol, 1.0 eq.) in dioxane (3 mL) was added Cs ₂ CO ₃ (132 mg, 0.44 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (21 mg, 0.022 mmol, 0.1 eq.) and BINAP (25.4 mg, 0.044 mmol, 0.2 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative TLC (DCM/MeOH=30/1) to provide the desired product as Example 191 (19.2 mg, 22.3% yield) as a light yellow solid. LCMS [M+1] ⁺ =430.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.97 (s, 1H), 10.35 (s, 1H) _, 9.07 (s, 1H), 8.98 (s, 1H), 8 .68 (dd, J =4.8, 1.8 Hz, 1H), 8.30 (dd, J =7.8, 1.8 Hz, 1H), 7.43-7.30 (m, 2H ), 3.35 (s, 3H), 3.11 (s, 2H), 2.44 (s, 3H), 2.33 (s, 3H).

Example 193

[00719] To a solution of Example 193a (750 mg, 2.93 mmol, 1.0 eq.) in dioxane (25 ml) was added Example 193b (900 mg, 4.39 mmol, 1.5 eq.), Cs ₂ CO ₃ (1.91 g, 5.86 mmol, 2.0 eq.), BINAP (365 mg, 0.59 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (303 mg, 0.2 eq.) 29 mmol, 0.1 eq.). The reaction solution was stirred for 6 hours at 110 ^° C under N ₂ atmosphere. The reaction solution was concentrated and the residue was purified by silica gel flash column chromatography, eluted with DCM/MeOH (v/v = 20/1) to give the desired product as Example 193 (411.8 mg, yield 33.1 %), as a light yellow solid. LCMS [M+1] ⁺ = 425.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.36 (s, 1H), 10.91 (s, 1H) _, 9.71 (s, 1H), 8.96 (s, 1H), 8 .67 (s, 1H), 8.14 (d, J =5.1 Hz, 1H), 7.50 (d, J =5.1 Hz, 1H), 4.00 (s, 3H), 3 .92 (s, 3H), 3.14 (s, 2H), 2.13-2.01 (m, 1H), 0.91-0.79 (m, 4H).

Example 195

[00720] To a solution of Example 195b (700 mg, 2.73 mmol, 1.0 eq.) in dioxane (20 mL) was added Cs ₂ CO ₃ (1.8 g, 5.46 mmol, 2.0 eq.) , example 195a (847.6 mg, 4.09 mmol, 1.5 eq.), BINAP (340.2 mg, 0.55 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ ( 279.5 mg, 0.27 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give a crude product of 1.2 g, which was further purified by preparative HPLC (Prep-C18, 5 µm XBridge column, 19 x 150 mm, W aters; gradient elution from 35% MeCN in water to 55% MeCN in water over a period of 7 minutes, where the aqueous phase contains 10 mm NH ₄ HCO ₃ +0.5% ammonia) to obtain the product representing Example 195 ( 401.9 mg, 35% yield), as an off-white solid. LCMS [M+1] ⁺ = 427.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.05 (s, 1H), 10.89 (s, 1H) _, 8.89 (s, 1H), 8.56 (s, 1H), 8 .03 (s, 1H), 7.65 (dd, J =7.8, 1.5Hz, 1H), 7.53 (dd, J =7.8, 1.5Hz, 1H), 7.26 (t, J =7.8 Hz, 1H), 3.72 (s, 3H), 3.11 (s, 2H), 2.08-1.95 (m, 1H), 0.79 (d, J =6.3 Hz, 4H).

Example 196

Stage 1. Example 196b

[00721] To a solution of Example 196a (100 mg, 0.75 mmol, 1.0 eq.) in 1 M aqueous NaOH (2.25 mL, 2.25 mmol, 3.0 eq.) was added a solution of (Boc) ₂ O (261.6 mg, 1.2 mmol, 1.6 eq.) in DCM (5 ml). The reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction, the two phases were separated. The organic layer was washed with water (5 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=20/1) to give the product Example 196b (78 mg, 53% yield) as a yellow oil. LCMS [M+1] ⁺ = 198.2.

Stage 2. Example 196

[00722] To a solution of Example 196c (50 mg, 0.13 mmol, 1.0 eq.) in DMA (2 ml) was added Cs ₂ CO ₃ (84.8 mg, 0.26 mmol, 2.0 eq.) , example 196b (51 mg, 0.26 mmol, 2.0 eq.), BINAP (16.2 mg, 0.03 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (13, 5 mg, 0.01 mmol, 0.1 eq.). The reaction mixture was stirred for 2 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 ml), washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to give the product as Example 196 (9.1 mg, 16% yield) as a yellow solid. LCMS [M+1] ⁺ = 445.3. ¹ H NMR (300 MHz, DMSO- d6 ) δ 11.10(br,1H), 10.98 (s, 1H), 10.03 ( _brs , 1H), 9.04 (s, 1H), 8 .56 (s, 1H), 7.61 (d, J =8.1 Hz, 2H), 7.26 (t, J =7.8 Hz, 1H), 7.08 (brs, 1H), 6 .45 (brs, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 2.95-2.81 (m, 1H), 2.09 (s, 3H), 1, 12-0.96 (m, 4H).

Example 198

Stage 1. Example 198

[00723] To a solution of Example 198a (200 mg, 0.97 mmol, 1.0 eq.) in dioxane (5 ml) was added K ₂ CO ₃ (267.7 mg, 1.94 mmol, 2.0 eq.) , example 198b (115.4 mg, 0.97 mmol, 1.0 eq.) and Xantphos (112.3 mg, 0.194 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (100, 4 mg, 0.097 mmol, 0.1 eq.). The reaction mixture was stirred for 6 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the product Example 198c (120 mg, 43% yield) as a yellow solid.

LCMS [M+1] ⁺ = 290.2

Stage 2. Example 198

[00724] To a solution of Example 198c (60 mg, 0.21 mmol, 1.0 eq.) in dioxane (3 mL) was added Cs ₂ CO ₃ (136.9 mg, 0.42 mmol, 2.0 eq.) , example 198d (65.2 mg, 0.32 mmol, 1.5 eq.), BINAP (26.2 mg, 0.042 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (21, 7 mg, 0.021 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to give a product of 60 mg of crude product, which was further purified by preparative HPLC (Prep-C18, 5 μm XBridge column, 19 × 150 mm, W aters; gradient elution from 35% MeCN in water to 55% MeCN in water over a period of 7 minutes, where the aqueous phase contains 10 mM NH ₄ HCO ₃ +0.5% ammonia) to obtain the product representing Example 198 (15.4 mg, yield 16%), as an off-white solid. LCMS [M+1] ⁺ =461.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.29 (s, 1H), 10.40 ( _brs , 1H), 8.90 (s, 1H), 8.57 (s, 1H), 7 .99 (s, 1H), 7.92 -7.86 (m, 1H), 7.85-7.71 (m, 2H), 7.62 (dd, J = 8.1, 1.8 Hz , 1H), 7.54 (d, J =7.2 Hz, 1H), 7.38 (t, J =7.8 Hz, 1H), 3.76 (s, 3H), 3.10 (s , 2H).

Example 199

[00725] To a solution of Example 199a (60 mg, 0.204 mmol, 1.2 eq.) in dioxane (3 mL) was added Cs ₂ CO ₃ (110.8 mg, 0.34 mmol, 2.0 eq.), example 199b (35 mg, 0.17 mmol, 1.0 eq), BINAP (21.2 mg, 0.034 mmol, 0.2 eq) and Pd ₂ (dba)3CHCl3 (17.6 mg, 0.017 mmol, 0 ,1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. After cooling to room temperature, the solvent was removed. The crude product was purified by preparative TLC (DCM/MeOH=15/1) to give the product as Example 199 (19.3 mg, 24% yield) as a yellow solid. LCMS [M+1] ⁺ =462.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.48 (s, 1H), 10.52 (s, 1H) _, 9.78 (s, 1H), 8.96 (s, 1H), 8 .67 (s, 1H), 8.36 (d, J =5.1 Hz, 1H), 7.92 (t, J =8.1 Hz, 1H), 7.82 (d, J =8, 4 Hz, 1H), 7.59 (d, J =6.9 Hz, 1H), 7.50 (d, J =5.4 Hz, 1H), 3.94 (s, 3H), 3.13 (s, 2H).

Example 200

Stage 1. Example 200b

[00726] To a solution of Example 200a (3.2 g, 18.93 mmol, 1.0 eq.) in EtOH (20 mL) and H ₂ O (4 mL) was added NaOH (908 mg, 22.72 mmol, 1 .2 eq.) at room temperature. The mixture was stirred for 1 hour at 50°C. After completion of the reaction, the solvent was removed. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=20/1) to give the product Example 200b (1.2 g, 33.9% yield) as a white solid. LCMS [M+1] ⁺ = 187.2.

Stage 2. Example 200c

[00727] A solution of Example 200b (1.2 g, 6.45 mmol, 1.0 eq) in DMF-DMA (3.07 g, 25.8 mmol, 4.0 eq) was stirred for 2 hours. at 95 ^o C. After completion of the reaction it was concentrated under vacuum. The residue was dissolved in AcOH (5 ml) and EtOH (20 ml), and N ₂ H ₄ .H ₂ O (3.2 g, 80% in water, 51.6 mmol, 8.0 eq.) was added dropwise at 0 ^o C. The reaction mixture was stirred for 2 hours at room temperature. Once complete, the mixture was concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the product Example 200c (600 mg, 44.4% yield) as a white solid. LCMS [M+1] ⁺ = 211.2.

Stage 3. Example 200d

[00728] To a solution of Example 200c (600 mg, 2.86 mmol, 1.0 eq) in DMF (10 ml) was added K ₂ CO ₃ (789 mg, 5.72 mmol, 2.0 eq) and CD ₃ I (621 mg, 4.29 mmol, 1.5 eq.) at 0 ^o C. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with EtOAc 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 (v/v = 1/3) to give the product Example 200d (550 mg, 84.8% yield) as yellow solid matter. LCMS [M+1] ⁺ = 228.2.

Stage 4. Example 200f

[00729] To a solution of Example 200d (550 mg, 2.42 mmol, 1.0 eq.) in dioxane (10 ml) was added Cs ₂ CO ₃ (1.57 g, 4.84 mmol, 2.0 eq.) , example 200e (399 mg, 2.9 mmol, 1.2 eq.), BINAP (302 mg, 0.48 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ .CHCl ₃ (251 mg, 0 .24 mmol, 0.1 eq.). The reaction mixture was stirred for 3 hours at 110 ^o C under N ₂ protection conditions. After completion of the reaction, the solvent was removed and the residue was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the product Example 200f (505 mg, 63.5% yield) as a yellow solid. LCMS [M+1] ⁺ = 329.3.

Stage 5. Example 200g

[00730] A solution of Example 200f (505 mg, 1.54 mmol, 1.0 eq.) in TFA (20 ml) was stirred for 1 hour at 70 ^° C. After completion of the reaction, it was concentrated in vacuo. The residue was dissolved in MeOH (20 ml) and increased in basicity with NaHCO ₃ (910 mg, 8.58 mmol, 2.0 eq.). The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH=20/1) to give the product as Example 200g (180 mg, 56.3% yield) as a light gray solid. [M+1] ⁺ = 209.4.

Stage 6. Example 200

[00731] To a solution of Example 200g (40 mg, 0.19 mmol, 1.0 eq.) and Example 200h (59.1 mg, 0.23 mmol, 1.2 eq.) in dioxane (2 ml) was added Cs ₂ CO ₃ (125 mg, 0.38 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (19.9 mg, 0.019 mmol, 0.1 eq.) and BINAP (23.9 mg , 0.038 mmol, 0.2 eq.). The reaction mixture was stirred for 3 hours at 110 ^o C under N ₂ protection conditions. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative TLC (DCM/MeOH=30/1) to provide the desired product as Example 200 (19.6 mg, 23.9% yield) as a light yellow solid. LCMS [M+1] ⁺ = 428.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.36 (s, 1H), 10.90 (s, 1H) _, 9.71 (s, 1H), 8.96 (s, 1H), 8 .67 (s, 1H), 8.14 (d, J =5.1 Hz, 1H), 7.50 (d, J =5.1 Hz, 1H), 3.92 (s, 3H), 3 .14 (s, 2H), 2.06-2.08 (m, 1H), 0.83-0.88 (m, 4H).

Example 201

Stage 1. Example 201c

[00732] A solution of Example 201a (1.7 g, 8.21 mmol, 1.0 eq) and Example 201b (1.39 g, 8.21 mmol, 1.0 eq) in dioxane (25 ml) added NaHCO ₃ (1.38 g, 16.4 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (850 mg, 0.82 mmol, 0.1 eq.) and BINAP (15, 0 mg, 1.64 mmol, 0.2 eq.). The reaction mixture was stirred for 16 hours at 100 ^o C under N ₂ protection conditions. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=1/1) to give the desired product as Example 201c (1.01 g, 36.2% yield) as a light brown solid. LCMS [M+1] ⁺ = 341.3.

Stage 2. Example 201

[00733] To a solution of Example 201c (78.7 mg, 0.23 mmol, 1.2 eq.) and Example 201d (40 mg, 0.19 mmol, 1.0 eq.) in dioxane (2 mL) was added Cs ₂ CO ₃ (125 mg, 0.38 mmol, 2.0 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (19.9 mg, 0.019 mmol, 0.1 eq.) and BINAP (23.9 mg , 0.038 mmol, 0.2 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C under N ₂ protection conditions. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative TLC (DCM/MeOH=30/1) to provide the desired product as Example 201 (18.9 mg, 19.3% yield) as a light yellow solid. LCMS [M+1] ⁺ =513.4. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.38 (s, 1H), 10.24 (s, 1H) _, 9.53 (s, 1H), 8.94 (s, 1H), 8 .67 (s, 1H), 8.18 (d, J =5.4 Hz, 1H), 8.00 (dd, J =10.8, 8.4 Hz, 1H), 7.60 (dd, J =8.4, 1.8 Hz, 1H), 7.51(d, J =5.1 Hz, 1H), 5.29 (s, 1H), 3.93 (s, 3H), 3, 11 (s, 2H), 1.50 (s, 6H).

Example 202

[00734] To a solution of Example 202b (750 mg, 2.20 mmol, 1.0 eq.) in dioxane (25 ml) was added Example 202a (546 mg, 2.64 mmol, 1.2 eq.), Cs ₂ CO ₃ (1.43 g, 4.40 mmol, 2.0 eq.), BINAP (274 mg, 0.44 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (228 mg, 0. 22 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C in an atmosphere of N ₂ . The solvent was concentrated; the residue was purified by silica gel flash column chromatography, eluted with DCM/MeOH (v/v = 20/1) to give the desired product as Example 202 (401.3 mg, 35.67% yield). as a light yellow solid. LCMS [M+1] ⁺ = 512.4. ^1H NMR (300 MHz, DMSO- d6 ) δ 11.15 (s, 1H), 10.11 (s, 1H) _, 8.87 (s, 1H), 8.57 (s, 1H), 7 .96 (dd, J =10.8, 8.4 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J =8.4, 1.5 Hz, 2H), 7. 63 (dd, J =7.8, 1.8 Hz, 1H), 7.49 (dd, J =8.1, 1.8 Hz, 1H), 7.28 (t, J =7.8 Hz , 1H), 5.26 (s, 1H), 3.76 (s, 3H), 3.08 (s, 2H), 1.46 (s, 6H).

Example 203

Stage 1. Example 203b

[00735] To a solution of Example 203a (50.0 g, 0.446 mol, 1.0 eq.) in ACN (1000 ml) was added NBS (87.0 g, 0.491 mol, 1.1 eq.) at 0°C in protection conditions No. ₂ . The reaction solution was stirred for 1 hour at room temperature. The solvent was concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc=5/1) to give the product Example 203b (68.1 g, 80.3% yield) as a white solid. LCMS [M+1] ⁺ = 191.2.

Stage 2. Example 203c

[00736] To a solution of Example 211b (10.0 g, 52.63 mmol, 1.0 eq) in THF (200 mL) was added n-BuLi (73.68 mL, 2.5 M in hexane, 184.21 mmol, 3.5 eq.) dropwise at -78°C under N ₂ atmosphere. The reaction mixture was stirred for 30 minutes. at the same temperature; a solution of acetone- d ₆ (16.84 g, 263.16 mmol, 5.0 eq.) in THF (30 ml) was added dropwise at -78 ^° C. The reaction mixture was stirred for 30 minutes. at RT and then quenched with saturated aqueous NH ₄ Cl (200 ml) and extracted with EtOAc (300 ml*3). The combined organic layers were washed with brine (500 ml), 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 give the desired product as Example 203c (5.9 g, 64.0% yield) as a yellow solid. LCMS [M+1] ⁺ = 177.2.

Stage 3. Example 203e

[00737] To a solution of Example 203d (2.0 g, 9.66 mmol, 1.0 eq) in dioxane (50 mL) was added Example 203c (1.71 g, 9.66 mol, 1.0 eq) , NaHCO ₃ (1.62 g, 19.32 mmol, 2.0 eq.), BINAP (1.2 g, 1.93 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (1 .0 g, 0.97 mmol, 0.1 eq.). The reaction mixture was stirred for 16 hours at 100 ^o C in an atmosphere of N ₂ . The solvent was concentrated and the residue was purified by silica gel flash column chromatography, eluting with petroleum ether/EtOAc (1/1) to give the desired product as Example 203e (960 mg, 28.7% yield) as a yellow solid. . LCMS [M+1] ⁺ = 347.3.

Stage 4. Example 203

[00738] To a solution of Example 203e (860 mg, 2.48 mmol, 1.0 eq.) in dioxane (40 ml) was added Example 203f (512 mg, 2.97 mol, 1.2 eq.), Cs ₂ CO ₃ (1.62 g, 4.96 mmol, 2.0 eq.), BINAP (309 mg, 0.50 mmol, 0.2 eq.) and Pd ₂ (dba) ₃ CHCl ₃ (257 mg, 0. 25 mmol, 0.1 eq.). The reaction mixture was stirred for 4 hours at 110 ^o C in an atmosphere of N ₂ . The solvent was concentrated and the residue was purified by silica gel flash column chromatography, eluting with DCM/MeOH (20/1) to give the desired product as Example 203 (425.0 mg, 35.5% yield) as crude white solid. LCMS [M+1] ⁺ = 483.3. ^1H NMR (300 MHz, DMSO- d6 ) δ 12.00 (s, 1H), 10.24 (s, 1H) _, 9.02 (s, 1H), 8.94 (s, 1H), 8 .66 (dd, J =4.8, 1.8 Hz, 1H), 8.29 (dd, J =7.8, 1.8 Hz, 1H), 7.99 (dd, J =10.8 , 8.1 Hz, 1H), 7.60 (dd, J =8.4, 2.1 Hz, 1H), 7.35 (dd, J =7.8, 4.8 Hz, 1H), 5 .25 (s, 1H), 3.34 (s, 3H), 3.09 (s, 2H).

Example A: TYK2 JH2 Domain Binding Assay

[00739] DiscoverX's KINOME scan ™ is a popular kinase profiling platform frequently used in academia and industry, as demonstrated by publications, so the present inventors selected this platform as a primary cell-free screening assay to determine relative binding activity and targeting chemical SARs .

[00740] DiscoverX's proprietary KINOME scan ™ uses proprietary active site-dependent competitive binding assays to determine how compounds bind to kinases. KINOME scan ™ is based on a competitive binding assay that quantifies the ability of a compound to compete with an immobilized ligand targeting the active site. The assay is performed by combining three components: DNA-labeled kinase; immobilized ligand and test compound. The ability of a test compound to compete with an immobilized ligand is measured using quantitative PCR of a DNA tag.

[00741] Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to produce affinity resins for kinase assays. Ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reaction mixtures were constructed by combining TYK2 (JH2 pseudokinase domain), ligand affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stock solutions in 100% DMSO. All tested compounds were submitted to DiscoverX in DMSO at a concentration of 10 mM. Kd values were determined using 11-point 3-fold dilution series of compounds with three DMSO controls. Each compound was tested in duplicate. All compounds for Kd measurements were dispensed by acoustic transfer (non-contact dispensing) into 100% DMSO. The compounds were then diluted directly into the assays so that the final DMSO concentration was 0.9%. All reactions were carried out in a 384-well polypropylene plate. In each case, the final volume was 0.02 ml. Assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. Kinase concentrations in the eluates were measured using qPCR.

[00742] The amount of kinase measured by qPCR (signal; y-axis) is plotted against the corresponding nM compound concentration on a log10 scale (x-axis). Binding constants (Kd) were calculated using a standard dose-response curve using the Hill equation:

[00743] The Hill slope was set to -1.

[00744] The curves were fitted using nonlinear least squares fitting using the Levenberg-Marquardt algorithm.

[00745] The results are shown in Table 1.

TABLE 1 Example Kd for binding to TYK2 (JH2 domain) (nM) Example Kd for binding to TYK2 (JH2 domain) (nM) Example Kd for binding to TYK2 (JH2 domain) (nM) 1 A 42 B 82 A 2 A 43 C 83 A 3 C 44 B 84 A 4 A 45 A 85 A 5 A 46 A 86 A 6 A 47 A 87 A 7 A 48 A 88 A 8 A 49 A 89 A 9 A 50 A 90 A 10 A 51 A 91 A eleven A 52 A 92 A 12 A 53 A 93 A 13 A 54 A 94 A 14 A 55 B 95 A 15 A 56 B 96 A 16 A 57 B 97 A 17 A 58 C 98 A 18 A 59 B 99 A 19 A 60 B 100 A 20 A 61 B 101 A 21 A 62 C 102 A 22 A 63 A 103 A 23 A 64 A 104 C 24 B 65 C 116 A 25 A 66 B 108 A 26 A 67 A 118 D 27 A 68 A 123 D 28 A 69 A 126 A 29 A 70 B 127 A thirty A 71 A 145 A 32 A 72 A 147 A 33 A 73 C 159 A 34 A 74 A 163 A 35 A 75 A 166 A 36 A 76 B 195 A 37 A 77 B 200 A 38 A 78 A 198 A 39 C 79 A 199 A 40 A 80 A 202 A 41 B 81 A 201 A

A is less than or equal to 1 nM;

B is greater than 1 nM and less than or equal to 5 nM;

C is greater than 5 nM and less than or equal to 10 nM;

D is greater than 10 nM.

Example of B. pSTAT4 induced by IL-12 in human PBMCs

[00746] Freshly isolated human PBMCs were resuspended in RPMI 1640 medium with 10% FBS. Cells were seeded in a round-bottomed 96-well plate at a concentration of 200,000 cells/well. Test compound in a 10-point dilution series (highest dose 10 μM, 1:5 dilution) was added to the wells using a liquid dispenser (Tecan D300e) and incubated for 1 hour at 37°C. Human recombinant IL-12 protein (R&D Systems) was then added to the wells at a final concentration of 10 ng/ml and incubated for 15 minutes at 37°C. Cell lysates were prepared and analyzed using the Phospho STAT4 (Tyr693) kit (Meso Scale Discovery) according to the manufacturer's protocol.

[00747] To calculate the suppression score: relative pSTAT4 signal in each well = pSTAT4 signal in each well - average pSTAT4 signal at baseline.

% Inhibition = (average pSTAT4 signal in IL-12 treated wells - relative pSTAT4 signal in each well containing compound) / average pSTAT4 signal in IL-12 treated wells * 100%.

[00748] The curve was plotted as % inhibition (y-axis) versus compound concentration (x-axis) and fitted to a normalized effect versus log inhibitor concentration equation with a variable slope using GraphPad Prism 7.0.

The control is BMS-986165: .

[00749] The results are shown in Table 2.

TABLE 2 Suppression of p-STAT4 induced by IL12 in human PBMCs Suppression of p-STAT4 induced by IL12 in human PBMCs Example IC ₅₀ for p-STAT4 (nM) Relative IC ₅₀ to control Example IC ₅₀ for p-STAT4 (nM) Relative IC ₅₀ to control 1 + 17.4 47 + 10.6 2 + 10.1 48 + 2.6 3 ++ 146.6 49 + 5.1 4 + 15.6 50 + 21.8 5 + 20.8 51 + 4.1 6 + 4.4 52 + 5.6 7 ++ 59.8 54 + 3.1 8 + 13.7 55 ++ 260.4 9 + 22.9 56 ++ 53.8 10 + 6.4 57 +++ 208.9 eleven + 3.6 59 +++ 188.6 12 + 4.5 60 ++++ >196.1 13 + 2.9 61 +++ 224.8 14 + 2 62 +++ 630.4 15 + 2.7 63 ++ 202.1 16 + 3.4 64 ++ 143.1 17 + 7.8 67 + 17.3 18 + 5.4 68 + 10.2 19 + 3 69 + 6.7 20 + 3.6 71 ++ 28.5 21 + 4.3 72 + 9.1 22 + 3.4 74 + 13.6 23 ++ 51.9 77 ++ 52.7 24 ++ 32.4 78 + 58.9 25 ++ 32.5 79 ++ 10.6 26 + eleven 80 + 3.7 27 + 3 82 + 4.3 28 + 3.3 84 + 6 29 + 10.2 85 ++ 613.9 thirty + 1.7 86 + 9.7 31 + 4.7 87 + 18.7 32 + 9.3 88 + 6 33 + 10.6 89 + 8 34 + 6.4 91 + 8.3 36 + 44.9 94 + 16.1 37 + 2 95 + 18 39 ++ 45.4 96 + 18.7 40 ++ 46.9 98 + 24.2 41 +++ 468.6 99 + 9.2 42 ++ 147.9 100 + 19.7 43 ++++ > 3039 103 + 10.8 44 ++ 77

+ less than or equal to 100 nM;

++ greater than 100 nM and less than or equal to 1 µM;

+++ greater than 1 µM and less than or equal to 10 µM;

++++ more than 10 µM.

Example of C. pSTAT3 or pSTAT5 induced by INFα in human PBMCs

[00750] Freshly isolated human PBMCs were resuspended in RPMI 1640 medium with 10% FBS. Cells were seeded in a round-bottomed 96-well plate at a concentration of 200,000 cells/well. Test compound in a 10-point dilution series (highest dose 10 μM, 1:5 dilution) was added to the wells using a liquid dispenser (Tecan D300e) and incubated for 1 hour at 37°C. Human recombinant INFα protein (R&D Systems) was then added to the wells at a final concentration of 5000 units/ml and incubated for 15 minutes at 37°C. Cell lysates were prepared and analyzed using the Phospho STAT3 Cell Assay Kit (Tyr705) (Cisbio) or the Phospho STAT5 Kit (Tyr693) (Meso Scale Discovery) according to the manufacturer's protocol.

[00751] To calculate the suppression score: relative pSTAT signal in each well = pSTAT signal in each well - average pSTAT signal at baseline.

[00752] % Inhibition = (average pSTAT signal in INFα-treated wells - relative pSTAT signal in each well containing compound) / average pSTAT signal in INFα-treated wells * 100%.

[00753] The curve was plotted as % inhibition (y-axis) versus compound concentration (x-axis) and fitted to a normalized effect versus log inhibitor concentration equation with a variable slope using GraphPad Prism 7.0.

[00754] The results are shown in Table 3.

TABLE 3 Example IC ₅₀ for p-STAT3 (nM) IC ₅₀ for p-STAT5 (nM) Relative IC ₅₀ to control 1 B 6.4 2 B 2.7 3 C >61.7 4 B 19.0 5 B 13.9 6 A 10.6 7 B 18.7 8 A 8.0 9 B 21.7 10 A 14.9 eleven A 6.3 12 A 7.4 13 A 2.2 14 A 1.9 15 A 5.0 16 A 4.8 23 B 6.6 24 B 14.2 25 B 8.4 26 B 10.5 27 A 1.5 28 A 7.8 37 A 2.2 38 A 4.1 39 B 14.6 40 B 14.2 41 C 575.0 42 C 224.3 43 C 135.5 44 C 374.8 49 A 6.5 51 A 12.8 54 A 9.3 55 B 15.5 56 C 89.5 57 C 230.5 59 C 122.2 60 D >61.7 61 C 113.5 62 C 544.7 63 B 79.9 64 B 91.6 67 B 9.4 68 A 4.5 69 A 8.5 71 B 10.0 72 B 15.7 74 A 7.0 77 C 145.8 79 B 49.7 80 A 3.7 82 A 5.6 84 A 5.2 86 B 17.0 87 B 28.6 89 A 5.4 107 A 5.3 108 A 2.9 109 A 5.5 110 A 1.5 111 A 1.4 112 A 1.8 113 A 2.2 114 A 4.7 115 A 53.8 116 A 2.8 119 A 14.1 120 A 1.1 121 A 9.1 122 A 2.7 124 A 3.1 125 A 14.4 126 A 4.8 127 A 10.7 128 C >1000 129 A 9.6 130 A 9.3 131 A 2.1 132 A 4.3 133 A 18.8 135 C >1000 136 A 3.3 137 A 6.1 138 A 20.8 139 A 2.3 140 A 0.8 141 A 3.2 142 A 4 143 A 3.8 144 A 24.2 145 A 2.5 147 A 5.8 148 A 3 149 A 2.6 150 A 9.7 151 A 16.3 152 A 2.8 153 A 4.8 154 A 3.0 155 A 3.8 156 A 4.4 157 A 9.5 158 A 7.2 159 A 1.6 160 A 5.5 161 A 6.1 163 A 1.7 164 A 3.9 165 B 206 166 A 3.0 169 A 49.3 171 A 1.2 172 A 1.7 173 B 113.7 174 A 0.8 175 A 0.3 176 A 1.8 177 A 0.4 178 A 1.2 179 A 5.8 180 A 1.3 184 A 0.8 185 A 0.3 188 A 0.6 189 A 0.8 190 A 6.3 191 A 5.4 193 A 1.4 195 A 1.6 196 B 784 198 A 0.3 199 A 0.2 200 A 1.9 201 A 0.2 202 A 0.3 203 A 0.7

A is less than or equal to 100 nM;

B is greater than 100 nM and less than or equal to 1 µM;

C is greater than 1 µM and less than or equal to 10 µM;

D is greater than 10 µM.

Example D: JH2 JAK1 and JAK2 JH1 Domain Binding Assay

[00755] Similar to the method for binding to JH2 TYK2 described above, the binding assay to the JH2 domains of JAK1 and JH1 JAK2 was performed using KINOME scan ™ from DiscoverX, but with a change in the kinase domain. These assays were performed to compare the binding selectivity of test compounds to the JH2 domains of JAK1 and JH1 of JAK2. The results are shown in Table 4.

TABLE 4 Example Kd for binding to JAK1 (JH2 domain) (nM) Kd for binding to JAK2 (JH1 domain) (nM) Control A C 147 A D 38 A C 116 A C 166 A C 159 A C 163 A B 195 A C 200 A C 198 A D 199 A D 202 A B 201 A B

A is less than or equal to 100 nM;

B is greater than 100 nM and less than or equal to 1 µM;

C is greater than 1 µM and less than or equal to 10 µM;

D is greater than 10 µM.

Example of E. pSTAT5 induced by GM-CSF and pSTAT5 induced by IL-2 in human PBMCs

[00756] Similar to the method for pSTAT4 induced by IL-12 in human PBMCs described above, these assays were performed to test whether the test compounds cross-reacted with the JAK1, JAK2 and JAK3 signaling pathways in human PBMCs. The procedure is as described, changing the stimuli to 10 ng/ml GM-CSF or 20 ng/ml IL-2. The data is shown in Table 5.

TABLE 5 Example IC ₅₀ for pSTAT5 induced by GM-CSF (nM) IC ₅₀ for pSTAT5 induced by IL-2 (nM) Control C B 195 C C 200 D C 198 C B 199 C B 202 B B 201 B B 203 C B

A is less than or equal to 100 nM;

B is greater than 100 nM and less than or equal to 1 µM;

C is greater than 1 µM and less than or equal to 10 µM;

D is greater than 10 µM.

Example F: Pharmacokinetic Studies

[00757] The pharmacokinetic parameters of the test compounds were assessed in male C57BL/6 mice, Sprague-Dawley rats, beagle dogs and cynomolgus monkeys administered by gavage and IV injection. The composition for each test compound is summarized in Table 6. Animals were fasted overnight before administration. Plasma samples were collected predose and 0.5, 1, 3, 6, 9, 12, and 24 hours postdose. Samples were analyzed by LC/MS/MS, and the concentration of the test compound at each time point was determined using linear regression. Pharmacokinetic parameters were calculated from plasma concentrations using Phoenix WinNonlin. The results of the analysis of PK parameters are summarized in Tables 7-10.

TABLE 6. Drug Formulations Used for Each Test Compound in Different Species Example Route of administration Mouse Rat Dog Monkey Control Oral A A A A IV B B B B 195 Oral A A A A IV C B B B 200 Oral A A A A IV C B B B 198 Oral A D D IV B C C 199 Oral A D IV B C 202 Oral D A A IV C B B 201 Oral A D D IV B C C 203 Oral D IV C Composition A: 0.5% methylcellulose Composition B: 5% DMSO/5% Solutol/90% Saline Composition C: 10% DMSO+10% Solutol+80% (20% SBE-β-CD) Composition D: 10% DMSO+10% HS-15+40% PEG400+40% (30% SBE-β-CD)

TABLE 7. Pharmacokinetic parameters of the tested compounds in C57BL/6 mice Example Route of administration and dose C ₀ or C _max (ng/ml) AUC
(h ng ml ^-1 ) T _1/2 (h) T _max (h) F% CL (ml kg-1 min-1) Vdss (l/kg) Control Oral (10 mg/kg) 4699 8871 2.96 0.25 86.7 I.V. (2 mg/kg) 3220 2045 2.19 15.6 1.56 195 Oral (10 mg/kg) 4295 16678 2.110 0.500 41.7 I.V. (2 mg/kg) 2950 7994 2.46 4.16 0.688 200 Oral (10 mg/kg) 4193 19295 2,010 0.250 85.1 I.V. (2 mg/kg) 2391 4475 4.62 7.35 1.5 202 Oral (10 mg/kg) 1899 6395 3.27 0.500 66.6 I.V. (2 mg/kg) 3343 1911 0.97 17.3 0.785

TABLE 8. Pharmacokinetic parameters of the tested compounds in Sprague-Dawley rats Example Route of administration and dose C ₀ or C _max (ng/ml) AUC (h·ng·ml ^-1 ) T _1/2 (h) _Tmax (h) F % CL (ml kg-1 min-1) Vdss (l/kg) Control Oral (5 mg/kg) 792±260 3197±600 2.93± 1.2 1.0±0.87 32.6±5.4 I.V. (1 mg/kg) 1743±276 1966±166 2.42± 1.7 8.41±0.7 0.933± 0.12 195 Oral (5 mg/kg) 1255±226 7444±1396 2.37± 0.32 1.67±0.58 46.7±8.8 I.V. (1 mg/kg) 2153±123 3188±603 2.14± 0.12 4.96± 0.91 0.824±0.11 200 Oral (5 mg/kg) 948±43 3657±684 4.22±3.6 1.00 42.7± 8.0 I.V. (1 mg/kg) 1033±47 1714±19 1.58± 0.21 9.42±0.022 1.24± 0.065 198 Oral (5 mg/kg) 261±35 1187±53 2.85±2.8 1.00± 0.87 16.9±0.76 I.V. (1 mg/kg) 1202±70 1405±29 1.22± 0.12 11.8± 0.22 1.10±0.065 199 Oral (5 mg/kg) 140±32 650±34 1.66± 0.37 1.33± 0.58 18.4± 1.0 I.V. (1 mg/kg) 414±56 705±140 1.74± 0.20 23.3± 4.9 3.27±0.87 202 Oral (5 mg/kg) 50.1±11 210±60 1.29±0.24 4.00± 2.0 8.35±2.4 I.V. (1 mg/kg) 1975±101 504±58 0.323±0.035 33.1± 4.0 0.653± 0.03 201 Oral (5 mg/kg) 185±138 499±502 1.14±0.2 0.42± 0.14 18.7± 18.9 I.V. (1 mg/kg) 1186±116 533±225 0.759±0.60 34.3± 12 1.31± 0.42

TABLE 9. Pharmacokinetic parameters of the tested compounds in Beagle dogs Example Route of administration and dose C ₀ or C _max (ng/ml) AUC (h·ng·ml ^-1 ) T _1/2 (h) T _max (h) F % CL (ml kg-1 min-1) Vdss (l/kg) Control Oral (2 mg/kg) 222±46 1312±579 6.21±2.9 1.67±0.58 35.5±15 I.V. (1 mg/kg) 559±34 1902±349 4.43±0.87 8.85±1.7 2.27±0.23 195 Oral (2 mg/kg) 285± 285 1517±1334 5.73±2.02 1.33±0.58 26.2±23.0 I.V. (1 mg/kg) 185±8.4 2899±453 6.69±0.39 5.31±0.93 3.04± 0.27 200 Oral (2 mg/kg) 247±17 2619±258 8.51±1.6 1.33±0 82.9± 8.2 I.V. (0.5 mg/kg) 29.7±14 790± 196 11.5±1.6 8.17±2.6 8.37± 1.39 198 Oral (2 mg/kg) 68.8±18 253± 48 1.42±0.24 1.67±0.58 54.0±10 I.V. (1 mg/kg) 182± 47.6 234± 94 4.29±1.25 68.6±28 23.1± 4.59 199 Oral (2 mg/kg) 23.4±4 67.6±25 1.36±0.05 1.33±0.6 10.7±3.9 I.V. (1 mg/kg) 334±96 315± 188 1.78±0.59 63.2±30 5.62± 1.13 202 Oral (2 mg/kg) 156±53 555± 154 1.59±0.15 1.00 55.0±15 I.V. (1 mg/kg) 469±255 504± 49 1.74±0.28 32.7±3.1 4.21± 0.19 201 Oral (2 mg/kg) 103±28 442± 81 5.05±0.47 2.0±0 38.5± 7.1 I.V. (1 mg/kg) 458± 336 575± 158 4.54±1.26 29.3±8.01 7.41± 2.64

TABLE 10. Pharmacokinetic parameters of test compounds in cynomolgus monkeys (NA: undetectable) Example Route of administration and dose C ₀ or C _max (ng/ml) AUC (h·ng·ml ^-1 ) T _1/2 (h) T _max (h) F% CL (ml kg ^-1 min ^-1 ) Vdss (l/kg) Control Oral (2 mg/kg) 247± 136 3192±1629 10.6±3.8 5.33±1.2 27.8±14 I.V. (1 mg/kg) 1417±264 5739±1168 7.54±1.6 2.79±0.74 1.20± 0.042 195 Oral (2 mg/kg) 663± 497 5420±3250 5.80±0.73 4.0±0 16.6±9.95 I.V. (1 mg/kg) 1286± 106 16326±664 7.65±0.56 0.898±0.04 0.624± 0.03 200 Oral (2 mg/kg) 384±22 4060±251 8.60±0.73 2.0±0 27.7± 1.7 I.V. (1 mg/kg) 677±81 7316±202 9.35±1.57 1.87±0.21 1.45± 0.18 198 Oral (2 mg/kg) 246± 124 1228±435 1.28±0.18 4±0 59.4±21.1 I.V. (1 mg/kg) 667±82 1034±159 1.45±0.22 16.1±2.4 1.94±0.03 201 Oral (2 mg/kg) 13.9±2 67.9± 21 3.08±0.66 2.33±1.5 4.67± 1.5 23.2±4.3 1.47±0.1 I.V. (1 mg/kg) 849±50 726± 134 1.81±0.76 203 Oral (2 mg/kg) N.A. N.A. N.A. N.A. N.A. I.V. (1 mg/kg) 787±61 595± 48 0.951±0.22 27.6±1.9 0.931±0.01

Example E: Pharmaceutical Compositions

Example E1. Composition for parenteral use

[00758] To prepare a pharmaceutical composition for parenteral use suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO and then mixed with 10 ml of 0.9% sterile saline. The mixture is formulated into a unit dosage form suitable for administration by injection.

Example E2. Composition for oral administration

[00759] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein is mixed with 750 mg of starch. The mixture is formulated into an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.

Example E3. Composition for sublingual use (solid lozenge)

[00760] To prepare a pharmaceutical composition for buccal delivery, such as a solid lozenge, mix 100 mg of a compound described herein with 420 mg of powdered sugar mixed with 1.6 ml of light corn syrup, 2.4 ml of distilled water and 0 .42 ml mint extract. The mixture is stirred gently and poured into a mold to form a lozenge suitable for buccal administration.

[00761] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or changes are intended to be included within the scope of the disclosure and the scope of the appended claims.

Claims (46)

1. Compound of formula (XII): Where: represents ring B is selected from the group consisting of phenyl and pyridyl; R ¹⁶ is -C(=O)R ¹¹ ; R ³ represents hydrogen; R ⁴ represents -OR ^b ; L represents bond; ring A is a 5-membered heteroaryl containing three nitrogen atoms, where ring A may be optionally replaced by one R ^A ; R ^A is selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ deuteroalkyl; R ⁵ is selected from the group consisting of -NR ⁹ R ¹⁰ , -NR ⁸ S(=O)R ⁷ , NR ⁸ C (=O) NR ⁹ R ¹⁰ , NR ⁸ C(=O)R ⁷ and 4-5 -membered heterocycloalkyl containing two nitrogen atoms; where heterocycloalkyl is substituted with two substituents, each of which is independently selected from the group consisting of oxo and C ₁ -C ₆ alkyl; R ⁷ is selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -cycloalkyl; R ⁸ represents hydrogen; R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl and 5-6 membered heteroaryl containing one or two nitrogen atoms; wherein the heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of oxo, halogen, -CN, C ₁ -C ₆ alkyl and morpholinyl; or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-membered heterocycloalkyl containing one nitrogen atom optionally substituted by two substituents selected from C ₁ -C ₆ alkyl; R ¹¹ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ deuteroalkyl and C ₃ -cycloalkyl; wherein each alkyl and cycloalkyl is optionally substituted with one R ^11a ; R ^11a is selected from halogen; R ^b is selected from C ₁ -C ₆ alkyl. 2. A compound according to claim 1, where the compound has the formula (XIIa): Formula (XIIa); Where: represents 3. Connection according to claim 1 or 2, where: R ¹¹ is selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ deuteroalkyl. 4. Connection according to any one of paragraphs. 1-3, where: R ⁵ represents -NR ⁸ C (=O) NR ⁹ R ¹⁰ , where R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, C1-C ₆ alkyl and 5-6 membered heteroaryl containing one or two atoms nitrogen; wherein the heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of oxo, halogen, -CN, C ₁ -C ₆ alkyl and morpholinyl. 5. Connection according to any one of paragraphs. 1-3, where: R ⁵ represents a 4-5 membered heterocycloalkyl containing two nitrogen atoms; where the heterocycloalkyl is substituted with two substituents, each of which is independently selected from the group consisting of oxo and C ₁ -C ₆ alkyl. 6. Connection according to any one of paragraphs. 1-3, where: R ⁵ is -NR ⁸ C (=O) NR ⁹ R ¹⁰ . 7. Connection according to clause 6, where: R ⁹ and R ¹⁰ are taken together with the nitrogen atom to which they are attached to form a 4-membered heterocycloalkyl containing one nitrogen atom, where the heterocycloalkyl is optionally substituted with two substituents selected from C ₁ -C ₆ alkyl. 8. Connection according to any one of paragraphs. 1-3, where: R ⁵ is -NR ⁸ C(=O)R ⁷ . 9. Connection according to clause 8, where: R ⁷ represents C ₃ -cycloalkyl. 10. A connection selected from the group consisting of: 11. A connection selected from the group consisting of: 12. A pharmaceutical composition having inhibitory activity against TYK2, containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-11 and a pharmaceutically acceptable excipient.