TW202511266A - Tyk2 inhibitors and uses thereof - Google Patents

Abstract

Described herein are compounds that are TYK2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of TYK2 activity.

Description

TYK2 inhibitors and their uses

The present disclosure relates to compounds that bind to the pseudokinase domain (JH2) of non-receptor tyrosine protein kinase 2 (TYK2). The disclosed compounds can inhibit certain interleukin signaling, such as IL-12, IL-23 and IFNα signaling. Additional aspects of the present disclosure include pharmaceutical compositions comprising the compounds described herein, methods of using the compounds to treat certain diseases, and intermediates and processes suitable for synthesizing the compounds.

TYK2 is a non-receptor tyrosine kinase 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 essential for interleukin signaling. TYK2 binds to the cytoplasmic domains of type I and type II interleukin receptors and interferon type I and type III receptors and is activated by these receptors upon interleukin binding. Interleukins involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-γ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin)) and interleukins (e.g., IL-6, IL-10, IL-12, IL-23, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like interleukin, and LIF). Subsequently, activated TYK2 in turn phosphorylates other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

The compounds described herein are regulators of the JAK kinase family. More specifically, the compounds disclosed herein are inhibitors of TYK2. In some embodiments, the compounds are selective for TYK2 relative to other JAKs. For example, the compounds can specifically bind to the pseudokinase domain (JH2) of TYK2, thereby enhancing the selectivity for JAK family members. In some embodiments, the compounds disclosed herein can be allosteric regulators or non-competitive inhibitors of TYK2. In additional embodiments, the compounds described herein can be used to treat diseases or disorders mediated by TYK2. In some embodiments, the compounds disclosed herein penetrate the blood-brain barrier and interact with the central nervous system.

In one aspect, described herein is a compound of formula (I): Formula (I), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5-membered or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted by p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted C1 _{-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl , unsubstituted} or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 _{-C 6} deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(=O)R ¹⁶ , -CO ₂ R 16 , -C(=O)N(R ¹⁶ ) ² , -S(=O)R ¹⁷ , -SO ₂ R ₁₇ or -SO ₂ N(R ¹⁶ ) ₂ ; or two ^{R 8s} attached to the same carbon atom are combined to form =O, =S or =NH; Z is -NR ¹⁰ -, -O-, -S-, -S(=O)- or -SO ₂ -; R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heterocyclic ring ^X1 , ^X2 and ^X3 are each independently ^CR11 or N; each ^R11 is independently hydrogen, halogen, unsubstituted or substituted C1- _C6 alkyl, unsubstituted or substituted _C2 -C6 _{alkenyl, unsubstituted or substituted C2-C6 alkynyl ,} unsubstituted or substituted _{C1 -C6 fluoroalkyl} , unsubstituted or substituted _{C1 - C6 heteroalkyl} , unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, ^-OR17 , -C(=O) ^R16 , _-CO2R16 , -C(=O)N( ^R16 ) ² , -N( ^R16 ) _{2 ,} -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; B ¹ is N or CR ^12a ; B ² is N or CR ^12b ; R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; R ¹ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; R ² is ring B, which is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if ring B is substituted, ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C _{or two R 16 on adjacent} ^{atoms of Ring} _{B ;} ^​ _​ ^​ _​ ^{​ ​ ​ ​} _​ ^​ _​ ^​ _​ or R ¹³ is combined with the intervening atoms to which it is attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; or R ² is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C R ¹⁵ is hydrogen, C 1 -C ₆ alkyl or C 1 -C 6 fluoroalkyl; or R 14 and R 15 are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted ₄ -membered _{to 6 -} membered monocyclic heterocyclic ring; or ^{R 1} and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; R ⁴ is hydrogen, C ₁ -C ⁶ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ or R ⁴ and R ^12a are combined with the _intervening atoms to which they are attached to form a substituted or unsubstituted C ₅ -C ₆ cycloalkyl group; R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C _{3 -C 6} cycloalkyl or _a monocyclic heterocyclic ring; each R ⁶ and R ⁷ is independently hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C _{1 -C 6 deuterium alkyl, C 1 -C 6} fluoroalkyl, C _{3 -C 6} cycloalkyl, a monocyclic heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(═O)R ¹⁷ , -SR ¹⁶ , -S(═O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; or one R ⁶ and one R ⁷ attached to the same carbon atom are combined with the carbon atom to which they are attached to form C═O, unsubstituted or substituted C ₃ -C ₆ cycloalkane or unsubstituted or substituted 3- to 6-membered heterocycloalkyl, wherein when the C ₃ -C ₆ cycloalkane or 3- to 6-membered heterocycloalkyl is substituted, the C ₃ -C ₆ cycloalkane or 3- to 6-membered heterocycloalkyl is substituted with m instances of R ³ , wherein: m is 0, 1, 2, 3, 4, 5 or 6; and each R wherein ^{R 3} is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) 2 , -N(R ¹⁶ ) 2 , -NR 16 C(=O)R 17 , -SR ₁₆ , -S(=O)R ₁₇ , -SO ² R ¹⁷ or -SO ² N(R ¹⁶ ) ₂ ; wherein if R ³ is attached to a nitrogen atom, then R ³ is hydrogen, deuterium, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C ₆ deuterioalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR 17 , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C( ^=O )N(R 16 ) 2 , -N(R 16 ) _{2 , -NR 16 C(=O)R 17} , -SR 16 , -S(=O)R ₁₇ , -SO 2 R 17 or -SO 2 N(R ₁₆ ) 2 _-C6 fluoroalkyl, unsubstituted or substituted C1- _C6 heteroalkyl, -C(=O) _R16 ^, _-CO2R16 , -C(=O)N( ^R16 ) ² , -S(=O) ^R17 , _-SO2R17 or ^-SO2N ( ^R16 ) _{2 ;} provided that at least one ^R6 and _one ^R7 attached to the same carbon atom are combined with the carbon atom to which they are attached to form a substituted cyclopropyl, an unsubstituted or substituted _C4 - _C6 cycloalkane or an unsubstituted or substituted 3-membered to 6-membered heterocycloalkyl; each ^R16 is independently hydrogen, substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted _C1 - _C6 fluoroalkyl, substituted or unsubstituted _C1 -C _{R 16} is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl, a substituted or unsubstituted C 3 -C 7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heteroalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently a substituted or unsubstituted C ₁ -C ₆ alkyl, a substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, a substituted or unsubstituted C ₁ -C ₆ heteroalkyl, a substituted or unsubstituted C ₃ -C wherein each of the _substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle and substituted heterocycle is substituted with one or more R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH _{2 CN, -OR 18 , -CH 2} OR 18 , -CO 2 R ¹⁸ , -CH ₂ CO ₂ R ^{18 , -C} (═O) ^N ( _R ¹⁸ _{) 2 , -CH2C} (=O) ^N ( ^R18 ) ₂ , -N(R18 _{) 2} , ^-CH2N ( ^R18 ) ₂ , -NR18C(=O)R18, _-CH2NR18C (= ^O ) ^R18 , -NR18SO2R19, -CH2NR18SO2R19, -SR18 ^{, -CH2SR18} , ^-S (=O) _R19 , _-CH2S (=O) _R19 , _{-SO2R19 ,} ^-CH2SO2R19 , _{-SO2N (} ^R18 ₎₂ ^{, or -CH2SO2N} _{( R18)2 ; each} ^{R18 is independently selected from} hydrogen, _C1 - ^C or two R 18 groups are combined with the N atom to which they are attached to form a N-containing ^heterocyclic ring; _each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C _{1 -C 6} heteroalkyl, C ₃ -C ₆ cycloalkyl, C _{2 -C 6} heterocycloalkyl, phenyl, benzyl, _{5 -} membered heteroaryl and 6-membered heteroaryl; n is 1, ₂ or _{3; p is 1, 2, 3 or 4} ; and q is 0, 1, 2, 3 or 4.

In some embodiments, the compound is a compound of formula (IA): Formula (IA), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: m is 0, 1, 2, 3, 4, 5 or 6; r and t are each independently 0, 1 or 2, with the proviso that the sum of t and r is at least 2; and ^V1 is ^-NR3- , -O-, -S-, -S(=O)- or _-SO2- .

In some embodiments, the compound is a compound of formula (IB): Formula (IB), or a pharmaceutically acceptable salt, tautomer or solvate thereof.

In some embodiments, the compound is a compound of formula (IC): Formula (IC), or a pharmaceutically acceptable salt, tautomer or solvate thereof.

In some embodiments, the compound is a compound of formula (ID): Formula (ID), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: ^A1 and ^A2 are each independently N or C; ^A3 is S, O, N, ^NR8 , ^CR8 or C=O; ^A4 and ^A5 are each independently S, O, N, ^NR8 or ^CR8 ; wherein at least one of ^A1 and ^A2 is C, or at least one of ^A3 , ^A4 and ^A5 is ^CR8 .

Any combination of the groups described above for the various variables is encompassed herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

Also described herein are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt, tautomer or solvate thereof and a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

Described herein are compounds of formula (I), or pharmaceutically acceptable salts, tautomers, or solvates thereof, useful for treating TYK2-mediated disorders. Described herein are compounds of formula (I), or pharmaceutically acceptable salts, tautomers, or solvates thereof, useful for treating inflammatory or autoimmune diseases. In some embodiments, the disease is selected from: multiple sclerosis, such as relapsing or relapsing-remitting multiple sclerosis; stroke; epilepsy; encephalomyelitis, such as acute diffuse encephalomyelitis; polyneuropathy, such as chronic inflammatory demyelinating polyneuropathy; encephalitis, such as autoimmune encephalitis; or a neuromyelitis optica spectrum disorder, such as neuromyelitis optica.

Any of the foregoing aspects is another embodiment, wherein an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvent thereof is: (a) administered systemically to a mammal; and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered to a mammal by injection; and/or (g) administered topically to a mammal; and/or (h) administered by ocular administration; and/or (i) administered rectally to a mammal; and/or (j) administered non-systemically or topically to a mammal.

In any of the foregoing aspects are other embodiments comprising a single administration of an effective amount of the compound, including other embodiments in which the compound is administered to the mammal once a day or multiple times a day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, the compounds provided herein are administered orally to a human.

An article of manufacture is provided, which includes a packaging material; a compound described herein or a pharmaceutically acceptable salt thereof within the packaging material; and a label indicating that the compound or composition or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvent thereof is used to modulate TYK2; or to treat, prevent or ameliorate one or more symptoms of a disease or condition that would benefit from modulation of TYK2.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following examples. However, it should be understood that the detailed description and specific examples, although indicating specific embodiments, are given only as illustrations, because various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art based on this detailed description.

Cross-references to Related Applications

This application claims the benefit of U.S. Provisional Application No. 63/504,693, filed May 26, 2023, which is incorporated herein by reference in its entirety.

TYK2 activation has been associated with a variety of diseases and disorders, including inflammatory diseases and disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer.

Specifically, IL-23 activation of TYK2 is associated with inflammatory diseases such as inflammatory bowel disease (IBD), Crohn's disease, chylous diarrhea, and ulcerative colitis. As a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behcet's disease. Tyk 2 is also associated with diseases and conditions of the skin such as psoriasis, vitiligo, atopic dermatitis, scleroderma, or of the eye such as Sjögren's syndrome, uveitis, and dry eye.

TYK2 is associated with respiratory diseases and conditions 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 the TYK2/STAT6 pathway.

TYK2 has also been implicated in autoimmune diseases and conditions, such as multiple sclerosis (MS), lupus, and systemic lupus erythematosus (SLE). Loss-of-function mutations in TYK2 result in reduced demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders. Various type I IFN signaling pathways that depend on TYK2 signaling have implicated TYK2 in SLE and other autoimmune diseases and conditions.

TYK2 is associated with arthritis, including chondroitinib and rheumatoid arthritis. Reduced TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis.

TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice exhibit impaired cytotoxic T cell responses and accelerated tumor development. These effects are primarily due to potent inhibition of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for treating autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 is an excellent target because it participates in fewer and more closely related signaling pathways, resulting in fewer off-target effects. However, studies of T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2/STAT1 signaling to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2 (but not other JAK family members) reduces cell growth. Therefore, selective inhibition of TYK2 has been shown to be a suitable target for patients with IL-10 and/or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases.

TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by the amyloid-β (Αβ) peptide. Reduced TYK2 phosphorylation of STAT3 leads to reduced neuronal cell death following administration of Αβ, and increased STAT3 phosphorylation has been observed in postmortem brains of Alzheimer's patients.

Inhibition of the JAK-STAT signaling pathway has also been implicated in hair growth and reversal of hair loss associated with alopecia areata.

There is a continuing need to provide novel inhibitors with more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased mobility across the blood-brain barrier or with increased activity or increased selectivity over other JAK kinases, particularly JAK2. In some embodiments, the present disclosure provides inhibitors of TYK2 that exhibit increased mobility across the blood-brain barrier. In some embodiments, TYK2 inhibitors exhibit selectivity over JAK1, JAK2, and/or JAK3. In some embodiments, compounds with this selectivity, particularly over JAK2, provide a pharmacological response that advantageously treats one or more of the diseases or conditions described herein without the side effects associated with JAK2 inhibition. For example, compounds with increased activity or increased selectivity over other JAK kinases, particularly JAK2. The present disclosure relates to compounds that bind to the pseudokinase domain (JH2) of non-receptor tyrosine protein kinase 2 (TYK2) and inhibit certain interleukin signaling, particularly IL-23 and IFNα signaling; to pharmaceutical compositions comprising the compounds; to methods of using the compounds to treat certain autoimmune diseases, multiple sclerosis (MS), lupus and systemic lupus erythematosus (SLE), and other CNS demyelination disorders; and to intermediates and processes useful for synthesizing the compounds.

In some embodiments, the TYK2 inhibitors described herein are used to treat a disease or condition in a mammal.

The compounds described herein, including their pharmaceutically acceptable salts, tautomers and solvates, are inhibitors of TYK2. In some embodiments, the compounds described herein are selective for TYK2 relative to other JAKs. In some embodiments, the compounds described herein selectively/specifically bind to the pseudokinase domain (JH2) of TYK2. In some embodiments, the compounds described herein bind to heterotopic sites of TYK2. In additional embodiments, the compounds described herein may be suitable for treating TYK2-mediated diseases or disorders. In some embodiments, the compounds described herein exhibit improved blood-brain barrier penetration relative to previously disclosed TYK2 inhibitors.

In one aspect, the present disclosure provides a compound of formula (I): Formula (I), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5-membered or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted by p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted C1 _{-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl , unsubstituted} or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 _{-C 6} deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(=O)R ¹⁶ , -CO ₂ R 16 , -C(=O)N(R ¹⁶ ) ² , -S(=O)R ¹⁷ , -SO ₂ R ₁₇ or -SO ₂ N(R ¹⁶ ) ₂ ; or two ^{R 8s} attached to the same carbon atom are combined to form =O, =S or =NH; Z is -NR ¹⁰ -, -O-, -S-, -S(=O)- or -SO ₂ -; R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heterocyclic ring ^X1 , ^X2 and ^X3 are each independently ^CR11 or N; each ^R11 is independently hydrogen, halogen, unsubstituted or substituted C1- _C6 alkyl, unsubstituted or substituted _C2 -C6 _{alkenyl, unsubstituted or substituted C2-C6 alkynyl ,} unsubstituted or substituted _{C1 -C6 fluoroalkyl} , unsubstituted or substituted _{C1 - C6 heteroalkyl} , unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, ^-OR17 , -C(=O) ^R16 , _-CO2R16 , -C(=O)N( ^R16 ) ² , -N( ^R16 ) _{2 ,} -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; B ¹ is N or CR ^12a ; B ² is N or CR ^12b ; R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; R ¹ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; R ² is ring B, which is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if ring B is substituted, ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C _{or two R 16 on adjacent} ^{atoms of Ring} _{B ;} ^​ _​ ^​ _​ ^{​ ​ ​ ​} _​ ^​ _​ ^​ _​ or R ¹³ is combined with the intervening atoms to which it is attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; or R ² is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C R ¹⁵ is hydrogen, C 1 -C ₆ alkyl or C 1 -C 6 fluoroalkyl; or R 14 and R 15 are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted ₄ -membered _{to 6 -} membered monocyclic heterocyclic ring; or ^{R 1} and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; R ⁴ is hydrogen, C ₁ -C ⁶ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ or R ⁴ and R ^12a are combined with the _intervening atoms to which they are attached to form a substituted or unsubstituted C ₅ -C ₆ cycloalkyl group; R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C _{3 -C 6} cycloalkyl or _a monocyclic heterocyclic ring; each R ⁶ and R ⁷ is independently hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C _{1 -C 6 deuterium alkyl, C 1 -C 6} fluoroalkyl, C _{3 -C 6} cycloalkyl, a monocyclic heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(═O)R ¹⁷ , -SR ¹⁶ , -S(═O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; or one R ⁶ and one R ⁷ attached to the same carbon atom are combined with the carbon atom to which they are attached to form C═O, unsubstituted or substituted C ₃ -C ₆ cycloalkane or unsubstituted or substituted 3- to 6-membered heterocycloalkyl, wherein when the C ₃ -C ₆ cycloalkane or 3- to 6-membered heterocycloalkyl is substituted, the C ₃ -C ₆ cycloalkane or 3- to 6-membered heterocycloalkyl is substituted with m instances of R ³ , wherein: m is 0, 1, 2, 3, 4, 5 or 6; and each R wherein ^{R 3} is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) 2 , -N(R ¹⁶ ) 2 , -NR 16 C(=O)R 17 , -SR ₁₆ , -S(=O)R ₁₇ , -SO ² R ¹⁷ or -SO ² N(R ¹⁶ ) ₂ ; wherein if R ³ is attached to a nitrogen atom, then R ³ is hydrogen, deuterium, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C ₆ deuterioalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR 17 , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C( ^=O )N(R 16 ) 2 , -N(R 16 ) _{2 , -NR 16 C(=O)R 17} , -SR 16 , -S(=O)R ₁₇ , -SO 2 R 17 or -SO 2 N(R ₁₆ ) 2 _-C6 fluoroalkyl, unsubstituted or substituted C1- _C6 heteroalkyl, -C(=O) _R16 ^, _-CO2R16 , -C(=O)N( ^R16 ) ² , -S(=O) ^R17 , _-SO2R17 or ^-SO2N ( ^R16 ) _{2 ;} provided that at least one ^R6 and _one ^R7 attached to the same carbon atom are combined with the carbon atom to which they are attached to form a substituted cyclopropyl, an unsubstituted or substituted _C4 - _C6 cycloalkane or an unsubstituted or substituted 3-membered to 6-membered heterocycloalkyl; each ^R16 is independently hydrogen, substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted _C1 - _C6 fluoroalkyl, substituted or unsubstituted _C1 -C _{R 16} is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl, a substituted or unsubstituted C 3 -C 7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heteroalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently a substituted or unsubstituted C ₁ -C ₆ alkyl, a substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, a substituted or unsubstituted C ₁ -C ₆ heteroalkyl, a substituted or unsubstituted C ₃ -C wherein each of the _substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle and substituted heterocycle is substituted with one or more R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH _{2 CN, -OR 18 , -CH 2} OR 18 , -CO 2 R ¹⁸ , -CH ₂ CO ₂ R ^{18 , -C} (═O) ^N ( _R ¹⁸ _{) 2 , -CH2C} (=O) ^N ( ^R18 ) ₂ , -N(R18 _{) 2} , ^-CH2N ( ^R18 ) ₂ , -NR18C(=O)R18, _-CH2NR18C (= ^O ) ^R18 , _-NR18SO2R19 , -CH2NR18SO2R19, -SR18 ^{, -CH2SR18} , ^-S (=O) _R19 , _-CH2S (=O) _R19 , _-SO2R19 , ^-CH2SO2R19 , _{-SO2N (} ^R18 ₎₂ ^{, or -CH2SO2N} _{( R18)2 ; each} ^{R18 is independently selected from} hydrogen, _C1 - ^C or two R 18 groups are combined with the N atom to which they are attached to form a N-containing ^heterocyclic ring; _each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C _{1 -C 6} heteroalkyl, C ₃ -C ₆ cycloalkyl, C _{2 -C 6} heterocycloalkyl, phenyl, benzyl, _{5 -} membered heteroaryl and 6-membered heteroaryl; n is 1, ₂ or _{3; p is 1, 2, 3 or 4} ; and q is 0, 1, 2, 3 or 4.

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, each R ⁶ and R ⁷ are independently: hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl, C ₃ -C ₆ cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; or one R ⁶ and one R 7 are connected to the same carbon atom. ⁷ is combined with the carbon atom to which it is attached to form C=O, unsubstituted or substituted C ₃ -C ₆ cycloalkane or unsubstituted or substituted 3-membered to 6-membered heterocycloalkyl, wherein when the C ₃ -C ₆ cycloalkane or 3-membered to 6-membered heterocycloalkyl is substituted, the C ₃ -C ₆ cycloalkane or 3-membered to 6-membered heterocycloalkyl is substituted by m instances of R ³ , wherein: m is 0, 1, 2, 3, 4, 5 or 6; and each R ³ is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R 16 ) 2 wherein if R ³ is attached to ^the nitrogen atom, R 3 ^is hydrogen, deuterium, ^{unsubstituted} or substituted C ¹ _-C 6 alkyl, unsubstituted or substituted C ^{1 -C 6 deuterated alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, -C(=O)R 16} _{, -CO 2 R 16} ^, _{-C ( = O )} N(R ¹⁶ _{) 2 , -S(=O)R 17 ,} ^-SO _{2 R} ^{17 or} -SO ₂ N( ^{R 16 )} ₂ ; The proviso is that at least one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form a substituted cyclopropyl group, an unsubstituted or substituted C ₄ -C ₆ cycloalkane, or an unsubstituted or substituted 3- to 6-membered heterocycloalkyl group.

In some embodiments, one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form C=O, unsubstituted or substituted C ₃ -C ₆ cycloalkane, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl. In some embodiments, one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form an unsubstituted or substituted C ₃ -C ₆ cycloalkane or an unsubstituted or substituted 3- to 6-membered heterocycloalkyl. In some embodiments, one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form an unsubstituted or substituted 3- to 6-membered heterocycloalkyl. In some embodiments, one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form a 3-membered to 6-membered heterocycloalkyl. In some embodiments, one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form a 4-membered heterocycloalkyl. In some embodiments, one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form an oxacyclobutane. In some embodiments, one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form a 3-oxacyclobutane.

In some embodiments, the compound is further defined by Formula (IA): Formula (IA), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: m is 0, 1, 2, 3, 4, 5 or 6; r and t are each independently 0, 1 or 2, with the proviso that the sum of t and r is at least 2; ^V1 is ^-NR3- , -O-, -S-, -S(=O)- or _-SO2- ; Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5- or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted with p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C _{1 -C 6} heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ₁₆ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) ² , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ₁₇ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ² _R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to ^the nitrogen atom, then R ^{R 8} is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -S(=O)R ¹⁷ , -SO ₂ ^{R 17 or} -SO ₂ N(R ¹⁶ ) ₂ ; or two R ^8s attached to the same carbon atom are combined to form =O, =S or =NH; Z is -NR R ^{10 is} hydrogen, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C 1 -C _{6 fluoroalkyl, C 3 -C 6 cycloalkyl or a} monocyclic heterocyclic ring; X ¹ , X ^{2 and X 3} _are each independently ^{CR 11} _or N; each R ¹¹ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C _{6 6} heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; B ¹ is N or CR ^12a ; B ² is N or CR ^12b ; R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C _-6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted _C1 - _C6 fluoroalkyl, unsubstituted or substituted _C1 - _C6 heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, ^-OR17 , -C(=O)R16, _-CO2R16 , -C(=O)N( ^R16 ) ² , -N( ^R16 ) ² , ^-NR16C (=O) _R17 , ^-SR16 , -S( ₌ O) ^R17 _{, -SO2R17 or -SO2N(R16)2 ; R1} ^{is hydrogen ,} _C1 ^- _C6 alkyl or _C1 - _C6 fluoroalkyl; R ² is Ring B, and Ring B is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if Ring B is substituted, Ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ or R ² _is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R 14 is hydrogen, _{unsubstituted} or substituted C 1 -C ^{6 alkyl, unsubstituted} or substituted C 2 -C ₆ alkyl, or -C(=O)R ¹⁴ ; or R ¹⁴ is hydrogen, unsubstituted or substituted C 1 -C ₆ alkyl, or -C(=O)R 14 ; or R 14 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, or -C(=O)R ¹⁴ ; or R ¹⁴ is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, or -C(=O)R 14 ; or R ¹⁴ is hydrogen, unsubstituted or substituted C ^{1 -C 6} alkyl, or -C(=O)R ¹⁴ ; or R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, or _-C (=O) R ₁₅ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; or R 14 and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 4-membered to _{6 - membered monocyclic} heterocyclic ring; or R ¹ and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; ^{each R} wherein ^{R 3} is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) 2 , -N(R ¹⁶ ) 2 , -NR 16 C(=O)R 17 , -SR ₁₆ , -S(=O)R ₁₇ , -SO ² R ¹⁷ or -SO ² N(R ¹⁶ ) ₂ ; wherein if R ³ is attached to a nitrogen atom, then R ³ is hydrogen, deuterium, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C ₆ deuterioalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR 17 , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C( ^=O )N(R 16 ) 2 , -N(R 16 ) _{2 , -NR 16 C(=O)R 17} , -SR 16 , -S(=O)R ₁₇ , -SO 2 R 17 or -SO 2 N(R ₁₆ ) 2 _R4 ^is hydrogen _{, C1} -C6 alkyl, ^C1 -C6 _heteroalkyl , C1- _C6 deuterated alkyl, C1- ^C6 _fluoroalkyl or ^C3 _-C6 ^cycloalkyl ; ^or R4 and _R12a are combined ^with the intervening ^atoms _to which they are _attached to form _a substituted or unsubstituted _{C5 -C6 cycloalkyl} ^{; R5} is hydrogen, _{C1 - C6 alkyl} , _{C1 - C6} fluoroalkyl _{, C3 - C6} each R ¹⁶ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic ₃ -membered to ₈ -membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3-membered to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ₂ CN, -OR ¹⁸ , -CH ₂ OR ¹⁸ , -CO ₂ R ¹⁸ , -CH ₂ CO ₂ ^{R 18} , -C(=O)N(R ¹⁸ ) ₂ , -CH ₂ C(=O)N(R ¹⁸ ) ₂ , -N(R ¹⁸ ) ₂ , -CH ₂ N(R ¹⁸ ) ₂ , -NR ¹⁸ C(=O)R ¹⁸ , -CH ₂ NR ¹⁸ C(=O)R ¹⁸ , -NR ¹⁸ SO ₂ R ¹⁹ , -CH ₂ NR ¹⁸ SO ₂ R ¹⁹ , -SR ¹⁸ , -CH ₂ SR ¹⁸ , -S(=O)R ¹⁹ , -CH ₂ S(=O)R ¹⁹ , -SO ₂ R ¹⁹ , -CH ₂ SO ₂ R ¹⁹ , -SO ₂ N(R ¹⁸ ) ₂ or -CH ₂ SO ₂ N(R ¹⁸ ) ₂ ; Each R ^{R 18} is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁸ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; n is 1, 2 or 3; p is 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4.

In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0 or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, V ¹ is -NR ³ -, -O-, -S-, -S(=O)-, or -SO ₂ -. In some embodiments, V ¹ is -NR ³ -, -O-, or -S-. In some embodiments, V ¹ is -NR ³ - or -O-. In some embodiments, V ¹ is -NR ³ - or -S-. In some embodiments, V ¹ is -O- or -S-. In some embodiments, V ¹ is -NR ³ -. In some embodiments, V ¹ is -O-. In some embodiments, V ¹ is S-.

In some embodiments, each R ³ is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ , or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ³ is attached to a nitrogen atom, then R ³ is hydrogen, deuterium, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C 6 _6- deuterioalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, -C(═O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(═O)N(R ¹⁶ ) ₂ , -S(═O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ . In some embodiments, each R ³ is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(═O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(═O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(═O)R ¹⁷ , -SR ¹⁶ , -S(═O)R ¹⁷ , -SO ₂ R ¹⁷ , or -SO ₂ N(R ¹⁶ ) ₂ . In some embodiments, each R ³ is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , or -NR ¹⁶ C(=O)R ¹⁷ . In some embodiments, each R ³ is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , or -N(R ¹⁶ ) ₂ . In some embodiments, each R ³ is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, or C ₁ -C ₆ fluoroalkyl.

In some embodiments, r and t are each independently 0, 1, or 2, with the proviso that the sum of t and r is at least 1. In some embodiments, r and t are each independently 0, 1, or 2, with the proviso that the sum of t and r is at least 2. In some embodiments, r and t are each independently 0, 1, or 2, with the proviso that the sum of t and r is 2. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 0 or 2. In some embodiments, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0 or 1. In some embodiments, t is 0 or 2. In some embodiments, t is 1 or 2. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, r and t are both 1.

In some embodiments, the compound is further defined by Formula (IB): Formula (IB), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5- or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted with p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted C1- _{C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl ,} unsubstituted or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 _{-C 6} deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(=O)R ¹⁶ , -CO ₂ R 16 , -C(=O)N(R ¹⁶ ) ² , -S(=O)R ¹⁷ , -SO ₂ R ₁₇ or -SO ₂ N(R ¹⁶ ) ₂ ; or two ^{R 8s} attached to the same carbon atom are combined to form =O, =S or =NH; Z is -NR ¹⁰ -, -O-, -S-, -S(=O)- or -SO ₂ -; R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heterocyclic ring ^X1 , ^X2 and ^X3 are each independently ^CR11 or N; each ^R11 is independently hydrogen, halogen, unsubstituted or substituted C1- _C6 alkyl, unsubstituted or substituted _C2 -C6 _{alkenyl, unsubstituted or substituted C2-C6 alkynyl ,} unsubstituted or substituted _{C1 -C6 fluoroalkyl} , unsubstituted or substituted _{C1 - C6 heteroalkyl} , unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, ^-OR17 , -C(=O) ^R16 , _-CO2R16 , -C(=O)N( ^R16 ) ² , -N( ^R16 ) _{2 ,} -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; B ¹ is N or CR ^12a ; B ² is N or CR ^12b ; R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; R ¹ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; R ² is ring B, which is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if ring B is substituted, ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C _{or two R 16 on adjacent} ^{atoms of Ring} _{B ;} ^​ _​ ^​ _​ ^{​ ​ ​ ​} _​ ^​ _​ ^​ _​ or R ¹³ is combined with the intervening atoms to which it is attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; or R ² is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C R ¹⁵ is hydrogen, C 1 -C ₆ alkyl or C 1 -C 6 fluoroalkyl; or R 14 and R 15 are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted ₄ -membered _{to 6 -} membered monocyclic heterocyclic ring; or ^{R 1} and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; R ⁴ is hydrogen, C ₁ -C ⁶ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ or R ⁴ and R ^12a are combined with the _intervening atoms to which they are attached to form a substituted or unsubstituted C ₅ -C ₆ cycloalkyl group; R ⁵ is hydrogen _{, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl , C 3 -C 6 cycloalkyl} or a monocyclic heterocyclic ring; each R ¹⁶ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3-membered to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₁ -C ₆ fluoroalkyl group, a substituted or unsubstituted C ₁ -C ₆ heteroalkyl group, a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted monocyclic heteroaryl group; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more ^R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ₂ CN, -OR ¹⁸ , -CH 2 OR 18 , -CO 2 R 18 , -CH ₂ CO ₂ R ¹⁸ , -C(═O) _N (R 18 ^{) 2} , -CH ₂ C(═O ₎ N(R ¹⁸ ) ₂ , -N(R ¹⁸ ) ₂ , -CH ₂ ^{N(R 18 )} _{2 ,} -NR ¹⁸ C(=O)R ¹⁸ , -CH ₂ NR ¹⁸ C(=O)R ¹⁸ , -NR ¹⁸ SO ₂ R ¹⁹ , -CH ₂ NR ¹⁸ SO ₂ R ¹⁹ , -SR ¹⁸ , -CH ₂ SR ¹⁸ , -S(=O)R ¹⁹ , -CH ₂ S(=O)R ¹⁹ , -SO ₂ R ¹⁹ , -CH ₂ SO ₂ R ¹⁹ , -SO ₂ N(R ¹⁸ ) ₂ or -CH ₂ SO ₂ N(R ¹⁸ ) ₂ ; each R ¹⁸ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C 6 _6- membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁸ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; p is 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4.

In some embodiments, Z is -NR ¹⁰ -, -O-, -S-, -S(=O)-, or -SO ₂ -. In some embodiments, Z is -NR ¹⁰ -, -O-, or -S-. In some embodiments, Z is -NR ¹⁰ -, or -O-. In some embodiments, Z is -NR ¹⁰ -, or -S-. In some embodiments, Z is -O-, or -S-. In some embodiments, Z is -NR ¹⁰ -, In some embodiments, Z is -O-, In some embodiments, Z is -S-.

In some embodiments, R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl, C ₃ -C ₆ cycloalkyl or monocyclic heterocyclic ring. In some embodiments, R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl or C ₃ -C ₆ cycloalkyl. In some embodiments, R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl or C ₁ -C ₆ fluoroalkyl. In some embodiments, R ¹⁰ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments, R ¹⁰ is hydrogen or methyl. In some embodiments, R ¹⁰ is hydrogen. In some embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some embodiments, R ¹⁰ is methyl.

In some embodiments, ^X1 , ^X2 , and ^X3 are each independently N or ^CR11 . In some embodiments, ^X1 , ^X2 , and ^X3 are each N. In some embodiments, ^X1 , ^X2 , and ^X3 are each independently ^CR11 . In some embodiments, ^X1 is N or ^CR11 . In some embodiments, ^X1 is N. In some embodiments, ^X1 is ^CR11 . In some embodiments, ^X2 is N or ^CR11 . In some embodiments, ^X2 is N. In some embodiments, X2 is ^CR11 . In ^some embodiments, ^X3 is N or ^CR11 . In some embodiments, ^X3 is N. In some embodiments, ^X3 is ^CR11 . In some embodiments, ^X1 , ^X2 , and ^X3 are each independently N or CH. In some embodiments, ^X1 , ^X2 , and ^X3 are each N. In some embodiments, ^X1 , ^X2 , and ^X3 are each independently CH. In some embodiments, ^X1 is N or CH. In some embodiments, ^X1 is N. In some embodiments, ^X1 is CH. In some embodiments, ^X2 is N or CH. In some embodiments, ^X2 is N. In some embodiments, ^X2 is CH. In some embodiments, ^X3 is N or CH. In some embodiments, ^X3 is N. In some embodiments, ^X3 is CH.

In some embodiments, each R ¹¹ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C 6 alkenyl, unsubstituted or substituted C 2 -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or _substituted carbocycle, unsubstituted or substituted heterocycle, _-CN , -OH, -OR ¹⁷ , -C(=O)R 16 , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ² , -NR ₁₆ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ² R ₁₇ ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ . In some embodiments, each R ¹¹ is independently hydrogen, halogen, or unsubstituted or substituted C ₁ -C ₆ alkyl. In some embodiments, each R ¹¹ is independently hydrogen or halogen. In some embodiments, each R ¹¹ is independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl. In some embodiments, each R ¹¹ is independently halogen or unsubstituted or substituted C ₁ -C ₆ alkyl. In some embodiments, each R ¹¹ is hydrogen. In some embodiments, each R ¹¹ is independently halogen. In some embodiments, each R ¹¹ is independently unsubstituted or substituted C ₁ -C ₆ alkyl.

In some embodiments, ^B1 is ^CR12a and ^B2 is ^CR12b ; or ^B1 is N and ^B2 is ^CR12b ; or ^B1 is ^CR12a and ^B2 is N; or ^B1 is N and B2 is N. In some embodiments, ^B1 is ^CR12a and ^B2 is ^CR12b . In some embodiments, ^B1 is N; and ^B2 is ^CR12b . In some embodiments, ^B1 is ^CR12a and ^B2 is N. In some embodiments, B1 is N; ^{and B2} is N. In some embodiments, ^{B1 is CR12a} and ^B2 is ^CR12b ; or ^B1 is N and ^B2 is ^CR12b .

In some embodiments, R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted _or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR ¹⁷ , -C(=O)R ₁₆ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) ² , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ^{17 , -SR 16} _, -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ .

In some embodiments, R ^12a and R ^12b are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -SO ₂ R ¹⁷ , or -SO ₂ N(R ¹⁶ ) ₂ . In some embodiments, R ^12a and R ^12b are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , or -SO ₂ N(R ¹⁶ ) ₂ . In some embodiments, R ^12a and R ^12b are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , or -N(R ¹⁶ ) _2. In some embodiments, R ^12a and R ^12b are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, -CN, -OH, -OR ¹⁷ , or -N(R ¹⁶ ) _2. In some embodiments, R ^12a and R 12b are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, or -CN. In some embodiments, R ^12a and R ^12b are each independently hydrogen, halogen, ^C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or -CN. In some embodiments, R ^12a and R ^12b are each independently hydrogen or halogen. In some embodiments, R ^12a and R ^12b are each independently hydrogen, fluorine or chlorine. In some embodiments, R ^12a and R ^12b are each independently hydrogen or fluorine. In some embodiments, R ^12a and R ^12b are each independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl. In some embodiments, R ^12a and R ^12b are each hydrogen.

In some embodiments, B ¹ and B ² are each independently CH, CF or N. In some embodiments, B ¹ and B ² are each independently CH or N.

In some embodiments, ^B1 is CH or CF and ^B2 is CH or CF; or ^B1 is N and ^B2 is CH or CF; or ^B1 is CH or CF and ^B2 is N; or ^B1 is N and ^B2 is N. In some embodiments, ^B1 is CH and ^B2 is CH; or ^B1 is N and ^B2 is CH; or ^B1 is CH and ^B2 is N; or ^B1 is N and ^B2 is N. In some embodiments, ^B1 and ^B2 are each CH. In some embodiments, ^B1 is CH. In some embodiments, ^B2 is CH.

In some embodiments, R ¹ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl. In some embodiments, R ¹ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments, R ¹ is hydrogen or C ₁ -C ₄ alkyl. In some embodiments, R ¹ is hydrogen, methyl, ethyl, propyl, isopropyl or butyl. In some embodiments, R ¹ is hydrogen or methyl. In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is methyl.

In some embodiments, R ² is Ring B, which is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if Ring B is substituted, Ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R 16 , -C(=O)N(R ¹⁷ ) or -C(=O)R 16 . or _{R 2} ^is -C( ^=O )R ₁₄ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ₁₄ ; R ¹⁴ is hydrogen, ^{unsubstituted} or substituted C 1 -C _{6 alkyl} , ^{unsubstituted} or substituted C ² -C ₆ alkyl, or a plurality of R ¹³ groups on adjacent atoms of ring B are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; or R ² is -C(=O)R 14 , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R ¹⁴ is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C ₂ -C 6 alkyl, or a plurality of R 13 groups on adjacent atoms of ring B are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted ^5- membered or 6-membered monocyclic carbocyclic ring or an unsubstituted or substituted 5-membered or ₆ -membered _{monocyclic heterocyclic} ring; R ₁₅ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; or R 14 and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 4-membered to _{6 - membered monocyclic} heterocyclic ring; or ^{R 1 and R 15} are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring.

In some embodiments, R ² is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ , or -C(=O)OR ¹⁴ . In some embodiments, R ² is -C(=O)R ¹⁴ or -C(=O)NR ¹⁴ R ¹⁵ . In some embodiments, R ² is -C(=O)R ¹⁴ or -C(=O)NR ¹⁴ R ¹⁵ . In some embodiments, R ² is -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ . In some embodiments, R ² is -C(=O)R ¹⁴ . In some embodiments, R ² is -C(=O)NR ¹⁴ R ¹⁵ . In some embodiments, R ² is -C(=O)OR ¹⁴ .

In some embodiments, R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle or unsubstituted or substituted bicyclic heterocycle. In some embodiments, R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted monocyclic carbocycle. In some embodiments, R ¹⁴ is unsubstituted or substituted monocyclic carbocycle. In some embodiments, R ¹⁴ is unsubstituted or substituted C ₃ -C ₈ cycloalkyl. In some embodiments, R 14 is unsubstituted or substituted C ₃ -C ₄ cycloalkyl. In some embodiments, R ¹⁴ is unsubstituted or substituted cyclopropyl. In some embodiments, R ^{14 is} cyclopropyl.

In some embodiments, R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₃ -C ₆ cycloalkyl or monocyclic heterocyclic. In some embodiments, R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl or C ₃ -C ₆ cycloalkyl. In some embodiments, R ⁵ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl or C ₃ -C ₄ cycloalkyl. In some embodiments, R ⁵ is hydrogen or C ₁ -C ₄ alkyl. In some embodiments, R ⁵ is hydrogen or methyl. In some embodiments, R ⁵ is hydrogen.

In some embodiments, the compound is further defined by formula (IC): Formula (IC), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5-membered or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted by p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted C1 _{-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl , unsubstituted} or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 or two R 8 attached to the same carbon atom are combined to form =O, =S or =NH; X ₃ is CR 11 or N, wherein: R ^{11 is} independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C 2 -C ₆ carbocyclic ring, unsubstituted or substituted heterocyclic ring _, -C(=O)R ¹⁶ , -CO 2 R ¹⁶ , -C(=O)N(R ¹⁶ ) 2 , -S(=O)R ¹⁷ , -SO ₂ R 17 or -SO ₂ N(R ¹⁶ ) ₂ ; or two R ⁸ attached to the same carbon atom are combined to form =O, =S or =NH; X ³ is CR ¹¹ or N, wherein: R ¹¹ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R 16 , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) ² , -N(R ¹⁶ ) ₂ , -NR ₁₆ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ^{17 ,} -SO ₂ ^{R 17 or} -SO ₂ N(R ¹⁶ ) ₂ ; R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C 6 each R ¹⁶ is independently hydrogen, substituted or unsubstituted C _{1 -C 6} alkyl, substituted or unsubstituted C ₁ -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic _3- to _{8 -} membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ₁₆ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C 6 heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to ^8- membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ₂ CN, -OR ¹⁸ , -CH ₂ OR ¹⁸ , -CO ₂ R ¹⁸ , -CH ₂ CO ₂ ^{R 18} , -C(=O)N(R ¹⁸ ) ₂ , -CH ₂ C(=O)N(R ¹⁸ ) ₂ , -N(R ¹⁸ ) ₂ , -CH ₂ N(R ¹⁸ ) ₂ , -NR ¹⁸ C(=O)R ¹⁸ , -CH ₂ NR ¹⁸ C(=O)R ¹⁸ , -NR ¹⁸ SO ₂ R ¹⁹ , -CH ₂ NR ¹⁸ SO ₂ R ¹⁹ , -SR ¹⁸ , -CH ₂ SR ¹⁸ , -S(=O)R ¹⁹ , -CH ₂ S(=O)R ¹⁹ , -SO ₂ R ¹⁹ , -CH ₂ SO ₂ R ¹⁹ , -SO ₂ N(R ¹⁸ ) ₂ or -CH ₂ SO ₂ N(R ¹⁸ ) ₂ ; Each R ^{R 18} is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁸ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; and p is 1, 2, 3 or 4.

In some embodiments, Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5- or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted with p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _{C6 alkyl} , unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted C2- _{C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl} , unsubstituted or substituted _C1 - _C6 fluoroalkyl, unsubstituted or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 or _{two R 8} attached to ^the _same carbon ^atom _are combined ^{to form =} _{O ,} ⁼ _S or ⁼ _{NH .}

In some embodiments, ring A is an unsubstituted or substituted 5-membered or 6-membered heterocycloalkyl ring, wherein A ¹ and A ² are independently N or C. In some embodiments, ring A is an unsubstituted or substituted 5-membered heterocycloalkyl ring, wherein A ¹ and A ² are independently N or C. In some embodiments, ring A is an unsubstituted or substituted 6-membered heterocycloalkyl ring, wherein A ¹ and A ² are independently N or C.

In some embodiments, Ring A is an unsubstituted or substituted 5- or 6-membered heteroaryl ring, wherein ^A1 and ^A2 are independently N or C. In some embodiments, Ring A is unsubstituted or substituted pyrrole, unsubstituted or substituted furan, unsubstituted or substituted thiophene, unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted oxazole, unsubstituted or substituted isoxazole, unsubstituted or substituted thiazole, unsubstituted or substituted isothiazole, unsubstituted or substituted triazole, unsubstituted or substituted oxadiazole, unsubstituted or substituted thiadiazole, unsubstituted or substituted tetrazole, unsubstituted or substituted triazolone, unsubstituted or substituted pyridine, unsubstituted or substituted pyrazole, unsubstituted or substituted pyrimidine, unsubstituted or substituted pyrimidine, unsubstituted or substituted pyrimidine, unsubstituted or substituted pyrimidine, unsubstituted or substituted pyrimidine, unsubstituted or substituted pyrimidine, or unsubstituted or substituted pyrimidine. In some embodiments, Ring A is an unsubstituted or substituted imidazole or an unsubstituted or substituted triazole. In some embodiments, Ring A is an unsubstituted or substituted imidazole. In some embodiments, Ring A is an unsubstituted or substituted triazole.

In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is or In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is .

In some embodiments, the compound is further defined by Formula (ID): Formula (ID), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: ^A1 and ^A2 are each independently N or C; ^A3 is S, O, N, ^NR8 , ^CR8 or C=O; ^A4 and ^A5 are each independently S, O, N, ^NR8 or ^CR8 ; wherein at least one of ^A1 and ^A2 is C, or at least one of ^A3 , ^A4 and ^A5 is ^CR8 ; ^X3 is ^CR11 or N, wherein: ^R11 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted _C1 - _C6 fluoroalkyl, unsubstituted or substituted C _R ^{4 is hydrogen} , _{C 1 -C 6} alkyl, C ¹ _{-C 6 heteroalkyl} , C ¹ _-C ^{6 deuterated} _{alkyl , C} ¹ _{-C 6} ^fluoroalkyl _or ^C _{3 -C} ⁶ _{cycloalkyl ;} ^{each R R 16} is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted _monocyclic heteroaryl; or two R 16 on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ₁₇ is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C ₆ heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently substituted or unsubstituted C 1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C _{3 -C7} cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more ^Rs groups independently selected from the group consisting of deuterium, halogen, _C1 - _C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, _-CH2CN , ^-OR18 , _-CH2OR18 , ^-CO2R18 , ^-CH2CO2R18 , _-C (=O ₎ ^N ( ^R18 _{) 2 , -CH2C} (=O)N( ^R18 ) ₂ , -N(R18 _{) 2} , ^-CH2N ( ^R18 ) ₂ , -NR18C(=O)R18, _-CH2NR18C (= ^O ) ^R18 , -NR18SO2R19, -CH2NR18SO2R19, ^{-SR18 , -CH2SR18} , ^-S (=O) _R19 , _-CH2S (=O) _R19 , _{-SO2R19 ,} ^-CH2SO2R19 , _{-SO2N (} ^R18 ₎₂ ^{, or -CH2SO2N} _{( R18)2 ; each} ^{R18 is independently selected from} hydrogen, _C1 - ^C or two R 18 groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; _each ^{R 19 is} _{independently} selected from C ₁ -C ₆ alkyl, C _{1 -C 6 heteroalkyl} , C _{3 -C 6} cycloalkyl, C _{2 -C 6} heterocycloalkyl, phenyl, benzyl _, 5 _- membered heteroaryl and 6 _- membered heteroaryl.

In some embodiments, R ⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ deuterated alkyl. In some embodiments, R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl or C ₃ -C ₆ cycloalkyl. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl or C ₃ -C ₆ cycloalkyl. In some embodiments, R ⁴ is C ₁ -C ₄ alkyl, C ₁ -C ₄ deuterated alkyl or C ₃ -C ₆ cycloalkyl. In some embodiments, R ⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ deuterated alkyl. In some embodiments, R ⁴ is C ₁ -C ₄ alkyl. In some embodiments, R ⁴ is methyl, ethyl, propyl, isopropyl or butyl. In some embodiments, R ⁴ is methyl or ethyl. In some embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is ethyl. In some embodiments, R ⁴ is C ₃ -C ₄ cycloalkyl. In some embodiments, R ⁴ is cyclopropyl. In some embodiments, R ⁴ is C ₁ -C ₄ deuterated alkyl. In some embodiments, R ⁴ is trideuterated methyl or 2,2,2-trideuterated ethyl-1-yl. In some embodiments, R ⁴ is 2,2,2-trideuterated ethyl-1-yl.

In some embodiments, ^A1 is C; ^A2 is N or C; ^A3 is N, ^CR8 or C=O; ^A4 is N, ^NR8 , S or ^CR8 ; and ^A5 is N, ^NR8 , S or ^CR8 . In some embodiments, ^A1 is C; ^A2 is C; ^A3 is N; ^A4 is ^NR8 or ^CR8 ; and ^A5 is N or ^NR8 .

In some embodiments: ^A1 is C; ^A2 is C; ^A3 is N; ^A4 is ^NR8 , O or S; and ^A5 is ^CR8 ; or A1 is C; ^A2 is C; ^A3 is N; ^A4 is NR8, O or S; and ^A5 is N; or A1 is C; ^A2 is C; ^A3 is ^NR8 , O or S; ^A4 is ^N ; and ^A5 is N; or A1 is C; ^A2 is C; ^A3 is ^NR8 , O or S; ^A4 is N; and ^A5 is CR8; or ^A1 is N; A2 is C; ^A3 is N; ^A4 is N; and ^A5 is ^CR8 ; or ^A1 is C; A2 is C; ^A3 is N; ^A4 is N; and ^A5 is ^NR8 ; or ^A1 is C; A2 is C; ^{A3 is} N; ^A4 is N; and A5 is NR8; or ^A4 is ^N ; and A5 is CR8; ¹ is C; A ² is N; A ³ is N; A ⁴ is CR ⁸ ; and A ⁵ is N; or A ¹ is C; A ² is N; A ³ is N; A ⁴ is N; and A ⁵ is N; or A 1 is N; A ² is C; A ³ is N; A ⁴ is N; and A ⁵ is N; or A 1 is C; A ² is N; A ³ is N; A ⁴ is CR 8; and A ⁵ is CR ⁸ ; or A ¹ is C; A ² is N; A ³ is N; A ⁴ is N; and A ⁵ is CR 8; or A ¹ is C; A ² is N; A 3 is N; A ⁴ is N; and A ⁵ is CR ⁸ ; or A ¹ is C; A 2 is N; A ³ is CR ⁸ ; A ⁴ is N; and A ⁵ is CR ⁸ ; or A ¹ is C; A ² is N; A ³ is CR ⁸ ; A 4 is N; and A ⁵ is CR ⁸ ; and ^A5 is N; or ^A1 is N; ^A2 is C; ^A3 is N; A4 is ^CR8 ; and ^A5 is ^CR8 ; or ^A1 is C; ^A2 is C; ^A3 is N; ^A4 is ^CR8 ; and ^A5 is ^NR8 , O or S; or ^A1 is C; ^A2 is C; ^A3 is ^NR8 , O or S; A4 is ^CR8 ; and ^A5 is N; or ^A1 is ^C ; ^A2 is N; ^A3 is C=O; ^A4 is ^NR8 ; and ^A5 is N; or ^A1 is C; ^A2 is C; ^A3 is ^N or ^CR8 ; ^A4 is ^NR8 ; and ^A5 is N; or ^A1 is C; A2 is N; ^A3 is ^CR8 ; ^{A4 is} N; and A ⁵ is N.

In some embodiments: ^A1 is C; ^A2 is C; ^A3 is N; ^{A4 is CR8; and A5 is NR8} , O or S; or ^A1 is C; ^A2 is C; ^A3 is ^N or ^CR8 ; ^A4 is ^NR8 ; and ^A5 is N.

In some embodiments, each R ⁸ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C 6 alkenyl, unsubstituted or substituted C 2 -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C _{1 -C 6} heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR ¹⁷ , -C(=O)R 16 _, -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) ² , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O) ^{R 17 ,} -SR ₁₆ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; or two R ⁸ attached to the same carbon atom are combined to form =O, =S or =NH. In some embodiments, each R ⁸ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted carbocyclic ring, or unsubstituted or substituted heterocyclic ring; wherein if R ⁸ is attached to a nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted carbocyclic ring, or unsubstituted or substituted heterocyclic ring; or two R ⁸ attached to the same carbon atom are combined to form =0. In some embodiments, each R ⁸ is independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl. In some embodiments, each R ⁸ is hydrogen or methyl.

In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0, 1, or 3. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0, 2, or 3. In some embodiments, p is 0 or 1. In some embodiments, p is 0 or 2. In some embodiments, p is 0 or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1 or 3. In some embodiments, p is 2 or 3. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0; and Ring A is thus unsubstituted.

In some embodiments, the compound is selected from: 1: N- (4-((2',5'-dimethyl-2',5'-dihydrospiro[oxacyclobutane-3,4'-[1,2,3]triazolo[4,5-c][1,7]oxadiazine]-6'-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 2 : N- (5-(propionyl-3,3,3-d3)-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c][1,7]oxadiazine-4,3'-oxacyclobutane]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 3 : N -(5-propionyl-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c][1,7]oxadiazine-4,3'-oxadiazine]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 4 : N- (4-((2',5'-dimethyl-2',5'-dihydrospiro[oxadiazine-3,4'-[1,2,3]triazolo[4,5-c]quinoline]-6'-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 5 : N -(5-(propionyl-3,3,3-d3)-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c]quinoline-4,3'-oxacyclobutane]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; and 6 : N- (4-((2',5'-dimethyl-2',5'-dihydrospiro[oxacyclobutane-3,4'-[1,2,3]triazolo[4,5-c][1,7]oxadiazine]-6'-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide. Or a pharmaceutically acceptable salt, tautomer or solvent thereof.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt, tautomer or solvate thereof and a pharmaceutically acceptable excipient.

In another aspect, the present disclosure provides a method for treating a disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, tautomer or solvate thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the disease or condition is a TYK2-mediated disease or condition. In some embodiments, the disease or condition is an inflammatory disease or condition or an autoimmune disease or condition. In some embodiments, the disease or condition is an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is a neuroinflammatory disease or condition. In some embodiments, the disease or condition is a neurodegenerative disease or condition. In some embodiments, the disease or condition is selected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is multiple sclerosis. In some embodiments, multiple sclerosis is relapsing or relapsing remitting. In some embodiments, the disease or condition is a neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is neuromyelitis optica. In some embodiments, the disease or condition is encephalomyelitis. In some embodiments, the disease or condition is acute diffuse encephalomyelitis. In some embodiments, the disease or condition is polyneuropathy. In some embodiments, the disease or condition is chronic inflammatory demyelination polyneuropathy. In some embodiments, the disease or condition is encephalitis. In some embodiments, the disease or condition is autoimmune encephalitis. In some embodiments, the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, tinea, tinea arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eyes, intestinal disease, Crohn's disease, ulcerative colitis, chylous diarrhea, Behcet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

In some embodiments, the compounds described herein have the following structure: .

In some embodiments, n, R ² , R ⁴ , R ¹⁰ , V ¹ , X ¹ , X ² , X ³ , A ¹ , A ² , Ring A, R ⁸ , and p are as described herein. In some embodiments, n, R ² , R ⁴ , R ⁶ , R ⁷ , R ¹⁰ , X ¹ , X ² , X ³ , A ¹ , A ² , Ring A, R ⁸ , and p are as described in Table 1.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be selected by one skilled in the art to yield stable moieties and compounds.

Exemplary compounds described herein include those described in the following table: Table 1 :

The compounds in Table 1 are named as follows: 1 : N- (4-((2',5'-dimethyl-2',5'-dihydrospiro[oxacyclobutane-3,4'-[1,2,3]triazolo[4,5-c][1,7]oxadiazine]-6'-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 2 : N- (5-(propionyl-3,3,3-d3)-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c][1,7]oxadiazine-4,3'-oxacyclobutane]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 3 : N -(5-propionyl-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c][1,7]oxadiazine-4,3'-oxadiazine]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 4 : N- (4-((2',5'-dimethyl-2',5'-dihydrospiro[oxadiazine-3,4'-[1,2,3]triazolo[4,5-c]quinoline]-6'-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 5 : N -(5-(propionyl-3,3,3-d3)-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c]quinolin-4,3'-oxacyclobutane]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; and 6 : N- (4-((2',5'-dimethyl-2',5'-dihydrospiro[oxacyclobutane-3,4'-[1,2,3]triazolo[4,5-c][1,7]oxadiazine]-6'-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide.

In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds described in Table 1.

In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, the compounds described herein may exist in unsolvated form as well as solvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered disclosed herein.

As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic at the concentration or amount employed, i.e., the substance can be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

The term "pharmaceutically acceptable salt" refers to a form of the therapeutically active agent consisting of a cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, a form of the therapeutically active agent consisting of an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, eds., Handbook of Pharmaceutical Salts : Properties , Selection and Use , Weinheim/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutical salts are generally more soluble and can dissolve more rapidly in gastric and intestinal fluids than non-ionic species and can therefore be used in solid dosage forms. Furthermore, since their solubility generally varies with pH, selective dissolution in one part of the digestive tract or another is possible, and this ability can be manipulated as a matter of delayed and sustained release characteristics. Furthermore, since salt-forming molecules can be equilibrated in neutral form, delivery through biological membranes can be modulated.

In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I) with an acid. In some embodiments, the compound of formula (I) (i.e., the free base form) is alkaline and reacts with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-hydroxyglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); caprylic acid (decanoic acid); caprylic acid (caproic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclohexylamine sulfonic acid; dodecyl sulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactocyanate; Saccharic acid; gentianic acid; glucoheptanoic acid (D); gluconic acid (D); glucuronic acid (D); glutaric acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; citric acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; niacin; oleic acid; oxalic acid; palmitic acid; bis(hydroxynaphthoic acid); phosphoric acid; propionic acid; pyroglutamine (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid ( p ); and undecylenic acid.

In some embodiments, the compound of formula (I) is prepared as a chloride salt, a sulfate salt, a bromide salt, a methanesulfonate salt, a maleate salt, a citrate salt, or a phosphate salt.

In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of formula (I) with a base. In some embodiments, the compound of formula (I) is acidic and reacts with a base. In these cases, the acidic protons of the compound of formula (I) are replaced by metal ions, such as lithium, sodium, potassium, magnesium, calcium or aluminum ions. In some cases, the compounds described herein are coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, sulfamethoxazole, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine and the like. Acceptable inorganic bases for forming salts with compounds including acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

It should be understood that references to pharmaceutically acceptable salts include solvent addition forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of a solvent and is formed during a crystallization process with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are preferably prepared or formed during the processes described herein. In addition, the compounds provided herein exist in non-solvated as well as solvated forms, as appropriate.

The methods and formulations described herein include the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structure of formula (I) and active metabolites of such compounds having the same type of activity.

In some embodiments, sites on the organic groups (e.g., alkyl groups, aromatic rings) of the compounds of formula (I) are susceptible to various metabolic reactions. Incorporation of suitable substituents on the organic groups will reduce, minimize, or eliminate such metabolic pathways. In certain embodiments, suitable substituents that reduce or eliminate the susceptibility of aromatic rings to metabolic reactions are, by way of example only, halogens, deuterium, alkyl groups, halogenalkyl groups, or deuterated alkyl groups.

In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioisotope) or labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, such as, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ³² P, and ³³ P. In one aspect, isotopically labeled compounds described herein (e.g., compounds into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated) are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium confers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

In some embodiments, the compound of formula (I) has one or more stereogenic centers, and each stereogenic center exists independently in the R or S configuration. In some embodiments, the compound of formula (I) exists in the R configuration. In some embodiments, the compound of formula (I) exists in the S configuration. The compounds presented herein include all non-mirror isomers, individual mirror isomers, atropisomers and diastereomeric forms and suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and suitable mixtures thereof.

If desired, individual stereoisomers are obtained by methods such as stereoselective synthesis and/or separation of stereoisomers by chiral chromatography columns, or separation of non-mirror image isomers by crystallization and recrystallization of non-chiral or chiral chromatography columns or in appropriate solvents or mixtures of solvents. In certain embodiments, compounds of formula (I) 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 non-mirror image isomers/salts, separating the non-mirror image isomers and recovering the optically pure individual mirror image isomers. In some embodiments, individual mirror image isomers are resolved using covalent non-mirror image derivatives of the compounds described herein. In another embodiment, non-mirror image isomers are separated by separation/resolution techniques based on solubility differences. In other embodiments, stereoisomers are separated by chromatography or by forming non-mirror image isomer salts and by recrystallization or chromatography or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

In some embodiments, the compounds described herein are prepared in the form of prodrugs. "Prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally applicable because they are easier to administer than the parent drug in some cases. It can be used by the organism, for example, by oral administration, while the parent drug is not. In addition or alternatively, compared to the parent drug, the prodrug also has improved solubility in the pharmaceutical composition. In some embodiments, the design of the prodrug increases effective water solubility. Examples of prodrugs (but not limited to) are compounds described herein, which are administered in the form of esters ("prodrugs"), but then undergo metabolic hydrolysis to obtain active entities. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, in which the peptide is metabolized to reveal the active portion. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes.

Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkoxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, e.g., Design of Prodrugs, Bundgaard, A., ed., Elseview, 1985, and Method in Enzymology, Widder, K. et al., eds.; Academic, 1985, Vol. 42, pp. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, eds., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, the hydroxyl groups in the compounds disclosed herein are used to form prodrugs, wherein the hydroxyl groups are incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers and the like. In some embodiments, the hydroxyl groups in the compounds disclosed herein are prodrugs, wherein the hydroxyl groups are subsequently metabolized in vivo to give the carboxylic acid groups. In some embodiments, the carboxyl groups are used to provide esters or amides (i.e., prodrugs), which are subsequently metabolized in vivo to give the carboxylic acid groups. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

Prodrug forms of the compounds described herein are included within the scope of the claims, wherein the prodrug is metabolized in vivo to produce the compound of formula (I) described herein. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

In some embodiments, any of the hydroxyl, amine and/or carboxylic acid groups are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

In additional or additional embodiments, the compounds described herein, when administered to an organism in need thereof, are metabolized to produce metabolites, which are then used to produce a desired effect, including a desired therapeutic effect.

A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolism" as used herein refers to the sum of processes (including but not limited to hydrolysis reactions and enzyme-catalyzed reactions) by which a specific substance is changed by an organism. Thus, an enzyme can produce specific structural changes to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while UDP-glucuronyl transferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatic cells in vitro and analyzing the resulting compounds.

In some cases, heterocycles can exist in tautomeric forms. In such cases, it is understood that the structures of the compounds are shown or named in one tautomeric form, but can be shown or named in alternative tautomeric forms. Alternative tautomeric forms are expressly included in the present disclosure, such as the structures depicted below. For example, pyridone can exist in the following tautomeric forms: ; all of which are encapsulated within the group, "substituted pyridine". Similarly, triazolone can exist in the following tautomeric forms, including the zwitterionic form: ; they are all encapsulated within the group, "substituted 5-membered heteroaryl". Similarly, pyrazidinone can exist in the following tautomeric forms, including the zwitterionic form: ; they are all encapsulated within the group, "substituted 6-membered heteroaryl". Similarly, pyrazoles, triazoles, pyrimidines and their analogs are known to undergo interconversion; for the purposes of this disclosure, all interconverting isomers (including charged and zwitterionic isomers) are considered within the scope of this disclosure. General Synthesis of Compounds of the Disclosure

The compounds of formula (I) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

Unless otherwise indicated, known methods of mass spectrometry, NMR, and HPLC were used.

The compounds are prepared using standard organic chemistry techniques, such as those described in, for example, March's Advanced Organic Chemistry, 6th edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions.

In some embodiments, the compounds described herein are prepared as described in Scheme A. Scheme A : The variables are defined as in formula (I).

In some embodiments, a free amino group of B is used to nucleophilically replace one of the chloro groups of intermediate A to obtain intermediate C. In some embodiments, such as when intermediate A is a thiabendium compound (B ¹ = N), this substitution can be performed with a suitable Lewis acid (such as Zn(OAc) ₂ ). In other embodiments, such as when intermediate B is a pyridine compound (B ¹ = CH), this substitution is performed by deprotonating the amino group with a suitable base (such as LDA). In still other embodiments, intermediate C can be obtained by a cross-coupling reaction of intermediates A and B. The cross-coupling reaction may be an organometallic cross-coupling, such as Suzuki-Miyaura reaction, Buchwald-Hartwig reaction, Heck reaction, Ullman coupling, Chan-Lam coupling and the like. Finally, in some embodiments, intermediate C is converted into final compound D (e.g., compound 1) via a cross-coupling reaction. The cross-coupling reaction may be an organometallic cross-coupling, such as Suzuki-Miyaura reaction, Buchwald-Hartwig reaction, Heck reaction, Ullman coupling, Chan-Lam coupling and the like.

In some embodiments, the compounds are prepared as described in the Examples .

Unless otherwise stated, the following terms used in this application have the definitions given below. The term "including" and other forms such as "include", "includes" and "included" are used without limitation. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

As used herein, _C1 - _Cx includes _C1 - _C2 , _C1 - _{C3 , ... C1} - _Cx . By way of example only, a group represented as " _C1 - _C6 " indicates that there are one to six carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, " _C1 - _C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, and tertiary butyl.

"Alkyl" refers to an aliphatic hydrocarbon group. Alkyl groups are branched or straight chains. In some embodiments, "alkyl" has 1 to 10 carbon atoms, i.e., C ₁ -C ₁₀ alkyl. Numerical ranges such as "1 to 10" whenever appearing herein refer to each integer within the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to (and including) 10 carbon atoms, although this definition also covers the existence of the term "alkyl" without a specified numerical range. In some embodiments, the alkyl group is C ₁ -C ₆ alkyl. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl or tertiary butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dibutyl, tertiary butyl, pentyl, neopentyl or hexyl.

"Alkylene" refers to a divalent alkyl group. Any of the above monovalent alkyl groups may be an alkylene group formed by extracting a second hydrogen atom from an alkyl group. In some embodiments, the alkylene group is a C ₁ -C ₆ alkylene group. In other embodiments, the alkylene group is a C ₁ -C ₄ alkylene group. Typical alkylene groups include, but are not limited to, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, and the like. In some embodiments, the alkylene group is -CH ₂ -.

"Alkoxy" means an (alkyl)O- group wherein alkyl is as defined herein.

The term "alkylamine" refers to a -N(alkyl) _x H _y radical, wherein x is 0 and y is 2, or wherein x is 1 and y is 1, or wherein x is 2 and y is 0.

"Hydroxyalkyl" refers to an alkyl group in which one hydrogen atom is replaced by a hydroxyl group. In some embodiments, the hydroxyalkyl group is a C ₁ -C ₄ hydroxyalkyl group. Typical hydroxyalkyl groups include, but are not limited to, -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ CH ₂ OH, and the like.

"Aminoalkyl" refers to an alkyl group in which one hydrogen atom is replaced by an amine group. In some embodiments, the aminoalkyl group is a C ₁ -C ₄ aminoalkyl group. Typical aminoalkyl groups include, but are not limited to, -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ CH _{2 CH 2 NH 2} and the like.

The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR ₂ , where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl group. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH=CHCH ₃ , -C(CH ₃ )=CHCH ₃ , and -CH ₂ CH=CH ₂ .

The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon bond is present. In one embodiment, the alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or an alkyl group. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH ₃ , -C≡CCH ₂ CH ₃ , -CH ₂ C≡CH.

The term "heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C ₁ -C ₆ heteroalkyl group.

The term "aromatic" refers to a planar ring with a delocalized π electron system containing 4n+2π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl groups ("aryl", e.g., phenyl) and heterocyclic aryl groups (or "heteroaryl" or "heteroaromatic") (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the main chain of the ring are all carbon atoms. The term thus distinguishes carbocycles from "heterocyclic" rings or "heterocycles" in which the main chain of the ring contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl groups.

As used herein, the term "aryl" refers to an aromatic ring wherein each atom forming the ring is a carbon atom. In one aspect, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is phenyl, naphthyl, dihydroindenyl, indenyl, or tetrahydronaphthyl. In some embodiments, the aryl group is a C ₆ -C ₁₀ aryl group. Depending on the structure, the aryl group is a monoradical or a diradical (i.e., an aryl radical).

The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic group in which the atoms forming the ring (i.e., the backbone atoms) are carbon atoms. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl includes groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl is selected from the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norinyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl group is a C ₃ -C ₆ cycloalkyl group. In some embodiments, the cycloalkyl group is a C ₃ -C ₄ cycloalkyl group.

The term "halogen", or alternatively, "halogen" or "halide" means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine or bromine.

The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, the fluoroalkyl group is a C ₁ -C ₆ fluoroalkyl group.

The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in one or more rings, wherein each heteroatom in the one or more rings is selected from O, S and N, wherein each heterocycloalkyl has 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocycloalkyls (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring systems, and aromatic heterocycloalkyls include rings having 5 to 10 atoms in their ring systems. Heterocyclo groups include benzofused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, oxazolinyl, oxazolinyl, sulfoxazolinyl, sulfoxazolinyl, piperidine, aziridinyl, aziridinyl, oxazolinyl, sulfidinyl, homopiperidinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexanyl, 1,3-dioxolane, pyrrolyl, oxazolinyl, dithianyl, dithiothiophene, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, indolin-2-one, isoindol-1-one, isoindol-1,3- dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindoline-1,3-disulfinyl, benzo[d]oxazol-2(3H)-one, 1H-benzo[d]imidazol-2(3H)-one, benzo[d]thiazol-2(3H)-one and quininyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrifonzyl, tetrazolyl, furanyl, thienyl, isoozolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, oxazolyl, indazolyl, indolizyl, oxazolyl, pyrimidinyl, trioxazolyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, oxadiazolyl and furopyridinyl. The aforementioned radicals are C-linked (or C-bonded) or N -linked where possible. For example, radicals derived from pyrrole include both pyrrole-1-yl ( N -linked) or pyrrole-3-yl (C-linked). In addition, radicals derived from imidazole include imidazole-1-yl or imidazole-3-yl (both N -linked) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (all C-linked). Heterocyclic radicals include benzofused ring systems. Non-aromatic heterocyclic rings are optionally substituted with one or two pendant oxy (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocyclic ring is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group including one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryl groups and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrrocyanyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyrimidinyl, triazolyl, oxadiazolyl, thiadiazolyl and furazanyl. Monocyclic heteroaryl groups include indole, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolone, pyrimidine ... , quinoline, isoquinoline, benzophenone, benzophenone, quinazoline, quinoxaline, 1,8-benzophenone and pteridine. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C ₁ -C ₉ heteroaryl. In some embodiments, the monocyclic heteroaryl is a C ₁ -C ₅ heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C ₆ -C ₉ heteroaryl.

"Heterocycloalkyl" refers to a cycloalkyl group including at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl group is fused with an aryl group or a heteroaryl group. In some embodiments, the heterocycloalkyl group is oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, oxazolidinyl, thiooxazolidinyl, piperidinyl, piperidin-2-onyl, pyrrolidine-2,5-disulfinyl, pyrrolidine-2,5-dione, pyrrolidone, imidazolidinyl, imidazolidin-2-onyl or thiazolidin-2-onyl. In one embodiment, the heterocycloalkyl group is _C2 - _C10 heterocycloalkyl. In another embodiment, the heterocycloalkyl is C ₄ -C ₁₀ heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and is 3, 4, 5, 6, 7 or 8-membered. In some embodiments, the heterocycloalkyl is monocyclic and is 3, 4, 5 or 6-membered. In some embodiments, the heterocycloalkyl is monocyclic and is 3 or 4-membered. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term "bond" or "single bond" refers to a chemical bond between two atoms or moieties when the atoms joined by the bond are considered part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is not present, thereby forming a bond between the remaining identified groups.

The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is a generally recognized chemical entity embedded in or attached to a molecule.

The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups selected individually and independently from the following: halogen, -CN, _-NH2 , -NH(alkyl), -N(alkyl) ₂ , -OH, _-CO2H , _-CO2alkyl , -C(=O) _NH2 , -C(=O)NH(alkyl), -C(=O)N(alkyl) ₂ , _-S (=O) _2NH2 , -S(=O) _2NH (alkyl), -S(=O) _2N (alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfene, arylsulfene, alkylsulfene and arylsulfene. In some other embodiments, the optionally selected substituents are independently selected from halogen, -CN, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OH, -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), -C(=O)NH ₂ , -C(=O)NH(C ₁ -C ₄ alkyl), -C(=O)N(C ₁ -C ₄ alkyl) ₂ , -S(=O) ₂ NH ₂ , -S(=O) ₂ NH(C ₁ -C ₄ alkyl), -S(=O) ₂ N(C ₁ -C ₄ alkyl) ₂ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C 4 In some embodiments, the optional substituents are independently selected from _halogen , -CN, -NH _{2 ,} -OH, -NH(CH _{3 ), -N(CH 3 ) 2} , -CH ₃ , -CH ₂ CH ₃ , -CHF ₂ , _{-CF 3 ,} -OCH ₃ , _{-OCHF 2} and _{-OCF 3 .} In some embodiments, the substituted groups are substituted with one or both of the previous groups. In some embodiments, the optional substituents on aliphatic carbon atoms (non- _cyclic or cyclic ₎ include pendoxy ₍ =O).

In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more ^{R groups} independently selected from the group consisting of deuterium, halogen, C 1 -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁸ , -CO 2 R 18 , -C(═O)N(R 18 ) 2 , -N(R 18 ) 2 , -NR 18 C(═O)R 19 , -SR 18 , -S(═O)R 19 , -SO ₂ R ¹⁹ , or -SO 2 N(R ¹⁸ ) 2 ; each R 18 is independently selected from hydrogen, C ₁ -C _{6 alkyl} , monocyclic carbocycle, monocyclic heterocycle, -CN, -OR 18 , -CO ² R ¹⁸ , -C(═O)N(R ^{18 ) 2} _, -N(R 18 ) 2 , -NR ₁₈ C(═O)R ¹⁹ , -SR 18 , -S(═O)R ¹⁹ , -SO ₂ R ¹⁹ , or -SO ₂ N(R ¹⁸ ) ₂ The invention relates to a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ fluoroalkyl group, _a C ₁ -C ₆ heteroalkyl group, a C 3 -C 6 cycloalkyl group, a C ₂ -C ₆ heterocycloalkyl group, a phenyl group, a benzyl group, a 5-membered heteroaryl group and a 6-membered heteroaryl group; or two R ¹⁸ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ¹⁹ is independently selected from a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ fluoroalkyl group, a C ₁ -C ₆ heteroalkyl group, a C 3 _{-C 6} cycloalkyl group, a C ₂ -C ₆ heterocycloalkyl group, a phenyl group, a benzyl group, a 5-membered heteroaryl group and a 6-membered heteroaryl group.

As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the individual being treated.

As used herein, the term "modulate" means interacting directly or indirectly with a target so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.

As used herein, the term "degrader" refers to a bifunctional compound that binds to and/or inhibits both TYK2 kinase and E3 ubiquitin ligase, thereby causing ubiquitination and subsequent degradation of TYK2 kinase. Specifically, in some cases, the degrader is a bifunctional or proteolytic targeting chimeric (PROTAC®) protein degrader compound, which can be used as a modulator of targeted ubiquitination of TYK2 protein, which is then degraded and/or inhibited by the bifunctional compound. In some cases, such bifunctional molecules act by recruiting TYK2 kinase to E3 ubiquitin ligase for ubiquitination and subsequent degradation of TYK2 kinase. The degrader comprises a TYK2 binding portion (e.g., a group comprising a compound described herein) optionally bound to the E3 ubiquitin ligase portion via a linker.

As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to the desired site of biological action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

As used herein, the term "co-administration" or similar terms is meant to encompass the administration of selected therapeutic agents to a single patient, and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an agent or compound administered that is sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and/or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to produce a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies, as appropriate.

As used herein, the term "enhance" or "enhancing" means to increase or prolong the potency or duration of a desired effect. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the potency or duration of the effect of other therapeutic agents on a system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of other therapeutic agents in the desired system.

As used herein, the term "pharmaceutical combination" means a product resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredient, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously, concurrently or consecutively in separate entities without specific time intervals, wherein such administration provides an effective level of both compounds in the patient's body. The latter also applies to mixture therapy, such as administration of three or more active ingredients.

The terms "product" and "set" are used synonymously.

The term "individual" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (such as chimpanzees and other apes and monkey species); farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

As used herein, the term "treat", the term "treating" or the term "treatment" includes prophylactically and/or therapeutically alleviating, relieving or ameliorating at least one symptom of a disease or condition; preventing additional symptoms; inhibiting a disease or condition, such as arresting the development of a disease or condition; relieving a disease or condition; causing regression of a disease or condition; reducing secondary symptoms resulting from a disease or condition; or cessation of symptoms of a disease or condition. Pharmaceutical Compositions

In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, isomer or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the compounds described herein are formulated into a pharmaceutical composition. The pharmaceutical composition is formulated into a pharmaceutically used preparation using one or more pharmaceutically acceptable inactive ingredients that promote the processing of the active compound in a known manner. The appropriate formulation depends on the selected route of administration. A general overview of the pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

In some embodiments, the compounds or pharmaceutical compositions disclosed herein are useful for treating diseases or conditions mediated by TYK2. In some embodiments, the pharmaceutical compositions are effective in treating diseases or conditions in which TYK2 is overexpressed or overactivated. In some embodiments, the pharmaceutical compositions are effective in treating diseases or conditions that benefit from reduced TYK2 activity or expression.

In some embodiments, the pharmaceutical composition is suitable for treating a disease or disorder associated with high levels of interferons driven by TYK2, such as interferons (e.g., IFN-α, IFN-β, IFN-γ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitins) and interleukins (e.g., IL-6, IL-10, IL-12, IL-23, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like interferon, and LIF). In some embodiments, the disease or disorder is an inflammatory disease or disorder, an autoimmune disease or disorder, a respiratory disease or disorder, type 1 diabetes, and interferon pathologies (e.g., Alcardi-Goutieres syndrome), or a combination thereof.

In some embodiments, the pharmaceutical composition is suitable for treating an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is an autoinflammatory disease or condition, a host-mediated inflammatory disease or condition, an injury-related inflammatory disease or condition, an infection-related inflammatory disease or condition, an inflammatory disease or condition mediated by excessive proliferation (e.g., cancer, fibrosis). In some embodiments, the inflammatory disease or condition or an infection-related inflammatory disease or condition is a respiratory disease or condition. In some embodiments, the respiratory disease or condition is associated with a virus in a microbial infection. In some embodiments, the respiratory disease or condition is an immune response to a virus or microbial infection. In some embodiments, the respiratory disease or condition is associated with a coronavirus, such as MERS-CoV, SARS-CoV-1, or SARS-CoV-2. In some embodiments, the pharmaceutical composition is effective in reducing symptoms associated with COVID-19 or an immune response associated therewith.

In some embodiments, the pharmaceutical composition is suitable for treating an autoimmune disease or condition. In some embodiments, the autoimmune disease or condition is rheumatoid arthritis, multiple sclerosis, tinea pedis, tinea pedis arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eyes, intestinal disease, Crohn's disease, ulcerative colitis, chylous diarrhea, Behcet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, the autoimmune disease or condition is lupus or systemic lupus erythematosus. In some embodiments, the autoimmune disease or condition is tinea pedis. In some embodiments, the autoimmune disease or condition is irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IBS-D). In some embodiments, the autoimmune disease or condition is dry eye or uveitis. In some embodiments, the autoimmune disease or condition is Crohn's disease. In some embodiments, the autoimmune disease or condition is atopic dermatitis.

In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in the form of a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by any method that enables the compound to be delivered to the site of action. Such methods include, but are not limited to, delivery via enteral (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. By way of example only, the compounds described herein can be administered topically to the area in need of treatment by, for example, topical application such as a cream or ointment. Other examples of topical administration of the compounds of the invention include eye drops, eye creams, gels or hydrogels, implants, transdermal patches, or drug depots. In some embodiments, the pharmaceutical composition is administered orally (e.g., in the form of a liquid formulation, tablet, capsule, sprayable liquid, aerosolized liquid, dry powder spray).

In some embodiments, pharmaceutical compositions suitable for oral administration are presented in discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; in powder or granule form; in the form of a solution or suspension in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, tablet, or paste.

Pharmaceutical compositions for oral use include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form (such as powder or granules), optionally mixed with a binder, an inert diluent or lubricant, a surfactant or a dispersant. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets are coated or scored and formulated to provide a slow or controlled release of active ingredients therein. All formulations for oral administration should be in a dosage suitable for this administration. Insertable capsules can contain active ingredients, which are mixed with fillers such as lactose, binders such as starch and/or lubricants such as talc or magnesium stearate and stabilizers selected as appropriate. In soft capsules, active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycol. In some embodiments, stabilizers are added. The dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquers and suitable organic solvents or solvent mixtures as appropriate. Dyes or pigments may be added to tablets or dragee coatings for identification or characterization of different combinations of active compound doses.

In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Injectable formulations may be presented in unit dose forms, e.g., ampoules, or multi-dose containers, with added preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. The composition may be in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be in powder form or stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier (e.g., physiological saline or sterile pyrogen-free water) prior to use. Ready-to-use injection solutions and suspensions may be prepared from the aforementioned types of sterile powders, granules and tablets.

Pharmaceutical compositions can also be formulated as reservoir preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously). Thus, the compound can be formulated, for example, with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or with an ion exchange resin, or as a poorly soluble derivative, for example, as a poorly soluble salt.

The pharmaceutical composition can be administered topically, that is, by non-systemic administration. This includes applying the disclosed compound to the epidermis or buccal cavity in vitro, and dropping the compound into the ear, eye, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetrating the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eyes, ears or noses. For topical administration, the active ingredient may comprise 0.001% to 10% w/w of the formulation, for example 1% to 2% by weight.

Pharmaceutical compositions for administration by inhalation are conveniently delivered by an insufflator, a nebulizer pressurized canister, or other suitable means of delivering an aerosol spray. The pressurized canister may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparation may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dose form, for example, in capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

It should be understood that in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents known in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents. TYK2 and Central Nervous System ( CNS ) Disorders

TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. TYK2 binds to the cytoplasmic domains of type I and type II interferon receptors and interferon type I and type III receptors and is activated by these receptors upon interferon binding. Interferons involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-γ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitins) and interleukins (e.g., IL-6, IL-10, IL-12, IL-23, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like interferon, and LIF).

Mice containing the rs3456443 loss-of-function (LoF) mutation in the pseudokinase domain of TYK2 exhibit reduced disease risk for EAE, with evidence showing that this is due to attenuated IL-12, IL-23, and type 1 IFN signaling (see Dendrou et al., Sci Transl Med (2016)). Interleukin-induced pSTAT phosphorylation in naive human immune cells by the rs3456443 genotype demonstrated wild-type-heterozygous-homozygous dose responses to IFN-α/β, IL-23, and IL-12, confirming this as a TYK2 LoF mutation. This LoF mutation of TYK2 results in reduced demyelination and increased remyelination of neurons, which supports the role of TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

In addition, increased levels of IL-12 and IL-23 have been found in MS lesions, and IFN-γ and IL-17 are upregulated in active MS plaques (see Windhagen et al., J Exp Med (1996); Li et al., Brain (2007); Tzartos et al., Am J Path (2008)). IL-12 and IL-23 are extensively implicated in the pathogenesis of EAE: IL-12 p40 neutralizing mAb prevents clinical EAE; mice genetically deficient in IL-12 p40 or IL-23 p19 are resistant to EAE; and systemic injection of recombinant IL-12 or intracerebral injection of IL-23 encoding adenoviral vectors causes clinical relapse of EAE. Therefore, the use of TYK2 inhibitors may interrupt this important pathology in MS and other CNS disorders.

TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide, demonstrating its role in the potential treatment of Alzheimer's Disease (AD). Reduced TYK2 phosphorylation of STAT3 leads to reduced neuronal cell death following Aβ administration, and increased STAT3 phosphorylation has been observed in postmortem brains of Alzheimer's disease patients. (See Wan et al., J. Neurosci. (2010) 30(20):6873-6881).

In some embodiments, certain TYK2 inhibitors described herein penetrate the blood-brain barrier. In some embodiments, certain TYK2 inhibitors described herein have an average brain: plasma ratio of at least 0.3. In some embodiments, certain TYK2 inhibitors described herein have an average brain: plasma ratio greater than 0.3. In some embodiments, certain TYK2 inhibitors described herein have an average brain: plasma ratio of at least 0.5. In some embodiments, certain TYK2 inhibitors described herein have an average brain: plasma ratio greater than 0.5. In some embodiments, certain TYK2 inhibitors described herein have an average brain: plasma ratio of about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0 or more.

In some embodiments, the compounds of the present disclosure are suitable for neuroinflammatory diseases and conditions. In some embodiments, neuroinflammatory diseases and conditions include but are not limited to multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis or neuromyelitis optica spectrum disorders. In some embodiments, the compounds of the present disclosure are suitable for treating multiple sclerosis (MS). In some embodiments, MS is relapsing MS or relapsing remitting MS (RRMS). In some embodiments, the compounds of the present disclosure are suitable for treating neuromyelitis optica spectrum disorders, such as neuromyelitis optica. In some embodiments, the compounds of the present disclosure are suitable for treating encephalomyelitis, including acute diffuse encephalomyelitis. In some embodiments, the compounds of the present disclosure are suitable for treating polyneuropathy, such as chronic inflammatory demyelinating polyneuropathy. In some embodiments, the compounds of the present disclosure are suitable for treating encephalitis, including autoimmune encephalitis.

In one aspect, the present disclosure provides a method for treating a disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, tautomer or solvate thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the disease or condition is a TYK2-mediated disease or condition. In some embodiments, the disease or condition is an inflammatory disease or condition or an autoimmune disease or condition. In some embodiments, the disease or condition is an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is a neuroinflammatory disease or condition. In some embodiments, the disease or condition is a neurodegenerative disease or condition. In some embodiments, the disease or condition is selected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is multiple sclerosis. In some embodiments, multiple sclerosis is relapsing or relapsing remitting. In some embodiments, the disease or condition is a neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is neuromyelitis optica. In some embodiments, the disease or condition is encephalomyelitis. In some embodiments, the disease or condition is acute diffuse encephalomyelitis. In some embodiments, the disease or condition is polyneuropathy. In some embodiments, the disease or condition is chronic inflammatory demyelination polyneuropathy. In some embodiments, the disease or condition is encephalitis. In some embodiments, the disease or condition is autoimmune encephalitis. In some embodiments, the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, tinea, tinea arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eyes, intestinal disease, Crohn's disease, ulcerative colitis, chylous diarrhea, Behcet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. Administration and treatment regimens

In one embodiment, the compounds described herein, or pharmaceutically acceptable salts, tautomers, or solvates thereof, are used in the preparation of a medicament for treating a disease or condition in a mammal that would benefit from modulation of TYK2 activity. The method for treating any disease or condition described herein in a mammal in need of such treatment involves administering to the mammal a pharmaceutical composition comprising at least one compound described herein, or pharmaceutically acceptable salts, active metabolites, prodrugs, or pharmaceutically acceptable solvates thereof, in a therapeutically effective amount.

In certain embodiments, compositions containing the compounds described herein are administered for preventive and/or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous therapy, the patient's health, weight, and response to drugs, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and/or dose ranging clinical trials.

In preventive applications, a composition containing a compound described herein is administered to a patient susceptible to or at risk for a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's health, weight, and similar factors. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health and response to drugs, and the diagnosis of the treating physician. In one aspect, prophylactic treatment comprises administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof to prevent recurrence of symptoms of the disease or condition.

In certain embodiments where the patient's condition does not improve, the compound is administered chronically, i.e., for an extended period of time, including for the duration of the patient's life, in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition, at the physician's discretion.

Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, in certain embodiments, the dose or frequency of administration, or both, is reduced as needed to maintain the improved disease, disorder, or condition. However, in certain embodiments, patients require long-term intermittent treatment to prevent any recurrence of symptoms.

The amount of a given agent corresponding to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, and the identity of the individual or host to be treated (e.g., weight, sex), but is still determined according to the specific circumstances surrounding the specific agent being administered, the route of administration, the condition being treated, and the individual or host being treated.

However, in general, dosages used for adult treatment are typically in the range of 0.01 mg-2000 mg per day. In one embodiment, the desired dosage is preferably presented in a single dose or divided doses (e.g., two, three, four or more sub-doses per day) administered simultaneously or at appropriate intervals.

In one embodiment, a suitable daily dose of a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kilogram of body weight. In some embodiments, the daily dose or amount of active substance in the dosage form is lower or higher than the range indicated herein based on many variables related to individual treatment regimens. In various embodiments, the daily dose and unit dose vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the physician.

Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to determination of LD ₅₀ and ED _50. The dose ratio between toxicity and therapeutic efficacy is the therapeutic index, and it can be expressed as the ratio between LD ₅₀ and ED _50. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and/or therapeutically effective unit doses for mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within a range of circulating concentrations that include the ED ₅₀ with minimal toxicity. In certain embodiments, the daily dosage range and/or unit dose varies within this range depending upon the dosage form employed and the route of administration utilized.

Any of the foregoing aspects are further embodiments, wherein an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered to a mammal by injection; and/or (e) administered topically to a mammal; and/or (f) administered non-systemically or topically to a mammal.

Within any of the foregoing aspects are other embodiments comprising a single administration of an effective amount of the compound, including other embodiments wherein (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times a day.

Any of the foregoing aspects are other embodiments comprising multiple administrations of an effective amount of the compound, including the following other embodiments: (i) the compound is administered continuously or intermittently in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a mammal every 12 hours; (v) the compound is administered to a mammal every 24 hours. In other or alternative embodiments, the method comprises a drug holiday, in which the administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced; at the end of the drug holiday, the administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Combination Therapy

In certain cases, it may be desirable to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but in combination with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administration of one of the compounds described herein with another agent (which also includes a treatment regimen) that also has therapeutic benefit.

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

In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be additive between the two treatments, or the patient may experience a synergistic benefit.

For the combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

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

The compounds described herein, or their pharmaceutically acceptable salts, and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administering the compositions containing the compounds varies. Thus, in one embodiment, the compounds described herein are used as preventive and are continuously administered to an individual prone to manifesting a condition or disease in order to prevent the disease or condition from occurring. In another embodiment, the compounds and compositions are administered to an individual during or as soon as possible after the onset of symptoms. In a particular embodiment, the compounds described herein are administered as soon as feasible after the onset of a detected or suspected disease or condition, and are continued for the duration required to treat the disease. In some embodiments, the duration required for treatment is different, and the duration of treatment is adjusted to suit the specific needs of each individual. Examples

Unless otherwise indicated, as used above and throughout the specification of the present disclosure, the following abbreviations should be understood to have the following meanings: Abbreviations: ACN acetonitrile CAN ammonium nitrate DCM dichloromethane DIBAL diisobutylaluminum hydroxide DIPEA N,N-diisopropylethylamine DMA dimethylacetamide DMF N,N-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid ES electrospray FBS fetal bovine serum GST glutathione S-transferase HEK human embryonic kidney HEPES 4-(2-hydroxyethyl)-1-piperidiniumethanesulfonic acid HMDS bis(trimethylsilyl)amide HPLC High pressure liquid chromatography HTRF Homogeneous time-difference fluorescence IC ₅₀ Half maximal inhibitory concentration IFN Interferon IL Interleukin IPA Isopropyl alcohol JAK Janus kinase LCMS Liquid chromatography-mass spectrometry MDI Metered dose inhaler MW Microwave NMR Nuclear magnetic resonance SEAP Secreted embryonic alkaline phosphatase STAT Signal transducer and transcription activator T3P Propanephosphonic anhydride TBAF Tetrabutylammonium fluoride TBDMS Tert-butyldimethylsilyl TBDPS Tert-butyldiphenylsilyl TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TYK Non-receptor tyrosine-protein kinase

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. I. Synthesis of Compounds Example 1 : Preparation of N- ( 4 - chloro - 5- ( propionyl - 3,3,3 - d3 ) pyridin - 2 - yl ) cyclopropanecarboxamide ( A - 1 ) :

Step 1 : 4,6 - dichloro - N - methoxy - N - methylnicotinamide ( A - 1b ) : To a stirred solution of A - 1a (20.0 g, 104.0 mmol) in DCM (50.0 mL) at 0 °C, TEA (43.6 mL, 313.0 mmol) and HATU (39.6 g, 104 mmol) were added. N,O-dimethylhydroxylamine hydrochloride (15.9 g, 260.0 mmol) was then added thereto and the reaction mixture was stirred at room temperature for 16 h. After the starting material was completely consumed, water (100 mL) was added and extracted with DCM (100×2 mL). The combined organic extracts were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-15% EtOAc in heptane) to give 4,6-dichloro-N-methoxy-N-methylnicotinamide A - 1b (18.0 g) as a colorless liquid. LCMS (ES) m/z ; 235.1 [M+H] ⁺ .

Step -2 : 1- ( 4,6 - dichloropyridin - 3 - yl ) ethan - 1 - one ( A - 1c ) : To a stirred solution of A-1b ( 15 g , 63.8 mmol) in anhydrous THF (50.0 mL) was added 3M solution of MeMgBr in _Et2O (45 mL, 134 mmol) at 0°C and the reaction mixture was allowed to warm to room temperature over 20 min. After complete consumption of the starting material, it was quenched by addition of saturated _NH4Cl solution (100 mL) and extracted with EtOAc (100 mL×2). The combined extracts were washed with water (100 mL), brine (100 mL), _dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in heptane) to give the desired compound 1-(4,6-dichloropyridin-3-yl)ethan-1-one A - 1c (10.0 g) as a thick yellow liquid. LCMS (ES) m/z ; 190.1 [M+H] ⁺ .

Step -3 : 3- ( 6 - chloro - 4 - methoxypyridin - 3 - yl ) -3 - oxopropionic acid methyl ester ( A - 1d ) : To a stirred solution of A - 1c (10 g, 52.6 mmol) in dimethyl carbonate (150 mL) was added NaH (60% suspension) (6.31 g, 158 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material, it was quenched by adding 2 N HCl aqueous solution (20 mL) and extracted with EtOAc (100 mL×2). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-15% EtOAc in heptane) to give the desired compound 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropanoic acid methyl ester A - 1d (8.6 g) as a yellow solid. LCMS (ES) m/z ; 244.1 [M+H] ⁺ .

Step -4 : Methyl 2- ( 6 - chloro - 4 - methoxynicotinyl ) propionate - 3,3,3 - d3 ( A - 1e ) : To a stirred solution of A - 1d (8.6 g, 35.3 mmol) in DMF (50.0 mL) was added potassium carbonate (5.37 g, 38.8 mmol) at 0 ° C, and stirred for 5 min. Then , iodomethane- _d3 (2.45 mL, 38.8 mmol) was added dropwise thereto at 0°C, and the reaction mixture was stirred at room temperature for 6 h. After completion, water (80 mL) was added thereto and extracted with EtOAc (3×70 mL). The combined organic extracts were washed with brine (100 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash using a gradient elution of 0-8% EtOAc in heptane to give methyl 2-(6-chloro-4-methoxynicotinyl)propanoate-3,3,3- d3A - 1e (5.6 g) as an off-white solid. LCMS (ES) m/z ; 261.1 [M+H] ⁺ .

Step -5 : 1- ( 6 - chloro - 4 - hydroxypyridin - 3 - yl ) propan - 1 - one - 3,3,3 - d3 ( A - 1f ) : To a solution of A - 1e (5.6 g, 21.5 mmol) in AcOH ( 40 mL) was added hydrogen chloride (80 mL) at room temperature . The reaction mixture was then stirred at 130 °C for 16 h. After completion (as indicated by LCMS), it was quenched with water (100 mL) and extracted with EtOAc (100×2 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient of 0-20% EtOAc in heptane) to give 1-(6-chloro-4-hydroxypyridin-3-yl)propan-1-one-3,3,3- d3A - 1f (3.8 g). LCMS (ES) m/z ; 189.6 [M+H] ⁺ .

Step -6 : 1- ( 4,6 - dichloropyridin - 3 - yl ) propan - 1 - one - 3,3,3 - d3 ( A - 1g ) : To a solution of A - 1f (3.8 g, 20.1 mmol) in ACN ( 15 mL) was added _POCl3 (7 mL) at room temperature. The reaction mixture was then heated to 85 °C for 1 h . After complete consumption of the starting material, volatiles were removed under reduced pressure and saturated _NaHCO3 solution (20 mL) was added to the residue. Extraction was performed with EtOAc (3×30 mL); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in heptane) to give 11-(4,6-dichloropyridin-3-yl)propan-1-one-3,3,3-d3 ( A - 1g ) (2.6 g). LCMS (ES) m/z ; 207.1 [M+H] ⁺ .

Step -7 : N- ( 4 - chloro - 5- ( propionyl - 3,3,3 - d3 ) pyridin - 2 - yl ) cyclopropanecarboxamide ( A - 1 ) : Argon was blown through a stirred suspension of A - 1g (3.0 g , 14.5 mmol ), cyclopropanecarboxamide ( 1.11 g, 13.0 mmol) and _Cs2CO3 (9.44 g, 29.0 mmol) in 1,4 _- dioxane (50.0 mL) for 15 min. Then, rac-BINAP (0.9 g, 1.45 mmol) and _Pd2 (dba)3- _CHCl3 (1.5 g, 1.45 mmol) were added thereto. The reaction mixture was then heated at 110 °C in a sealed tube for 2 h. Upon completion, it was cooled to room temperature and filtered through a celite bed. It was washed with EtOAc (50 mL×2) and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of heptane containing 0-25% EtOAc) to give the desired compound N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide A - 1 (1.8 g) as a yellow solid. LCMS (ES) m/z ; 256.6 [M+H] ⁺ . Example 2 : N- ( 4 - chloro - 5 - propionylpyridin - 2 - yl ) cyclopropanecarboxamide ( A - 2 ) :

Step - 1 : 1- ( 4,6 - dichloropyridin - 3 - yl ) propan - 1 - one ( A - 2a ) : A - 2a (0.4 g) was synthesized by following the procedure described for the synthesis of A - 2 (Step - 1) using A - 1b (2.0 g, 8.51 mmol) and EtMgBr (3 M solution in _Et2O ) (5.67 mL, 17.0 mmol) as starting materials. LCMS (ES) m/z ; 204.0 [M+H] ⁺ .

Step - 2 : N- ( 4 - chloro - 5 - propionylpyridin - 2 - yl ) cyclopropanecarboxamide ( A - 2 ) : A - 2 ( 0.7 g) was synthesized by following the procedure described for the synthesis of A - 1 (step - 7) using A - 2a (2.3 g, 11.3 mmol) as starting material . LCMS ( ES) m/z ; 252.9 [ M + H ] ⁺ . Example 3 : Preparation of 2,5 - dimethyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] quinolin - 6 - amine ( I - 1 ) :

Step -1 : 5 - Bromo - 2 - methyl - 2H - 1,2,3 - triazole - 4 - carbaldehyde ( I - 1b ) : To a stirred solution of I - 1a (10 g, 41.6 mmol) in THF (100 mL) was added a 2 M solution of isopropylmagnesium chloride in THF (22.8 mL, 45.6 mmol) at -30°C, and stirred at the same temperature for 1 h. DMF (16.08 mL, 208 mmol) was then added thereto at -30°C. The reaction mixture was allowed to slowly warm to room temperature over 1 h. Upon completion, it was quenched by adding a saturated NH ₄ Cl solution (30 mL) and extracted with EtOAc (75 mL×3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The crude material was purified by Combi-Flash (using a gradient elution, 0-10% EtOAc in heptane) to give the desired compound 5-bromo-2-methyl-2H-1,2,3-triazole- ₄ -carbaldehyde I - 1b (6 g) as an off-white solid. ^1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H); 4.26 (s, 3H).

Step -2 : 1- ( 5 - Bromo - 2 - methyl - 2H - 1,2,3 - triazol - 4 - yl )-N - methylmethanamine ( I - 1c ) : To a stirred solution of I - 1b (15 g, 78.9 mmol ) in MeOH ( 150 mL) at 0° C , TEA (22.0 mL, 158 mmol) and methylamine hydrochloride (10.7 g, 158 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. It was then cooled to 0°C and _NaBH4 (3.58 g, 94.8 mmol) was added portionwise thereto. The reaction mixture was allowed to warm to room temperature over 2 h. After completion (indicated by LCMS), saturated NaHCO ₃ solution (30 mL) was added thereto and washed with EtOAc (20 mL×2). The NaHCO ₃ aqueous solution containing 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylmethanamine I - 1c was used in the next step without further purification. LCMS (ES) m/z ; 205.0 [M+1H] ⁺ .

Step -3 : (( 5 - bromo - 2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) methyl ) ( methyl ) carbamic acid tributyl ester ( I - 1d ) : A solution of ( Boc ) _2O (33.6 mL, 146.2 mmol) in THF ( 60 mL) was added to an _aqueous NaHCO3 solution containing I - 1c , and the reaction mixture was stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and water (50 mL) was added thereto. Extraction was performed using EtOAc (50 mL×2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous _Na2SO4 , _filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash using a gradient of 0-50% EtOAc in hexanes to afford tert-butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate I - 1d (6.0 g) as a colorless thick oil. LCMS (ES) m/z ; 305.1 [M+H] ⁺ .

Step -4 : (( 5- ( 2 - fluoro - 3 - nitrophenyl ) -2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) methyl ) ( methyl ) carbamic acid tributyl ester ( I - 1e ) : Argon was blown through a stirred suspension of I - 1d (6.0 g, 19.6 mmol) , 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane cyclopentane (6.56 g, 26.6 mmol) and KF (5.2 g, 49.2 mmol) in THF (20.0 mL) for 15 min. Then Pd(OAc) ₂ (0.18 g, 0.82 mmol) and dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphine (0.67 g, 1.64 mmol) were added thereto. The reaction mixture was stirred at 70° C. in a sealed tube for 16 h. Then it was cooled to room temperature, filtered through a celite bed and washed with EtOAc (50 mL×2). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in hexanes) to give the desired compound ((5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester I - 1e (6.0 g) as a yellow semisolid. LCMS (ES) m/z ; 366.1 [M+H] ⁺ .

Step -5 : 2,5 - dimethyl - 6 - nitro - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] quinoline ( I - 1f ) : To a stirred solution of I - 1e ( 6.0 g , 16.4 mmol ) in DCM (70.0 mL) was added TFA (35.0 mL ) at 0°C under nitrogen atmosphere , and the reaction mixture was then stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion, volatiles were removed under reduced pressure and saturated NaHCO ₃ solution (50 mL) was added to the residue. Extraction was performed with EtOAc (2×50 mL); the combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-40% EtOAc in hexanes) to give 2,5-dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline I - 1f (3.0 g) as an orange solid. LCMS (ES) m/z ; 246.0 [M+H] ⁺ .

Step - 6 : 2,5 - dimethyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] quinolin - 6 - amine ( I - 1 ) : To a stirred solution of I - 1f ( 3.0 g, 12.24 mmol ) in MeOH (40.0 mL) was added 10% Pd / C ( 520 mg ) at room temperature. It was then stirred under hydrogen atmosphere ( _H2 balloon) for 2 h. After completion, the catalyst was filtered through a diatomaceous earth bed and washed with MeOH (30 mL×2). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-55% EtOAc in hexanes) to give the desired compound 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine I - 1 (1.2 g) as a light yellow solid. LCMS (ES) m/z ; 216.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.95-6.89 (m, 2H); 6.68 (dd, J ₁ = 1.2 Hz, J ₂ = 7.6 Hz, 1H); 5.03 (s, 2H); 4.17 (s, 3H); 4.15 ( s , 2H); 2.41 ( s , 3H ) . Example 4 : Preparation of 2,5 - dimethyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiazin - 6 - amine ( I - 2 ) :

Step -1 : (( 5- ( 2 - chloro - 3 - fluoropyridin - 4 - yl ) -2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) methyl )( methyl ) carbamic acid tributyl ester ( I - 2a ) : Argon was blown through a solution of I-1d ( 5.0 g , 16.4 mmol), (2 - chloro-3 - fluoropyridin-4-yl)boronic acid (boronic acid) (2.87 g, 16.4 mmol) and CsF (7.47 g, 49.2 mmol) in THF (25 mL) for 15 min. Tri-tributylphosphonium tetrafluoroborate (0.475 g, 1.64 mmol) and _Pd2 (dba) ₃ (1.5 g, 1.64 mmol) were added thereto. The reaction mixture was then stirred at 50 °C in a sealed tube for 16 h. Upon completion, the reaction mixture was cooled to room temperature, filtered through a celite bed and washed with EtOAc (50 mL x 2). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-5% MeOH in DECM) to give ((5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester I - 2a (5.1 g) as a brown solid. LCMS (ES) m/z ; 356.1 [M+H] ⁺ .

Step -2 : 6 - Chloro - 2,5 - dimethyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ][ 1,7 ] oxazolidine ( I - 2b ) : A 4 M solution of HCl in 1,4 - dioxane ( 30 mL ) was added to I - 2a ( 2.9 g, 8.15 mmol ) at 0°C, and the reaction mixture was stirred at room temperature for 1 h. After completion, the volatiles were removed under reduced pressure and dried (co-evaporated with 1,4-dioxane). 1,4 -dioxane (10 mL) and DIPEA (6.81 mL, 39.1 mmol) were added thereto at room temperature. The reaction mixture was then stirred at 85 °C for 5 h. Upon completion, volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-35% EtOAc in hexanes) to give the desired compound 6-chloro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]oxadiazole I - 2b (1.5 g) as an off-white solid. LCMS (ES) m/z ; 236.1 [M+H] ⁺ .

Step -3 : N- ( 2,5 - dimethyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiin - 6 - yl ) cyclopropanecarboxamide ( I - 2c ) : Hydrogen was blown through a stirred suspension of I- 2b ( 1.5 g , 6.36 mmol) , cyclopropanecarboxamide (0.81 g, 9.55 mmol ) and _Cs2CO3 (4.15 g , 12.7 mmol) in 1,4- _dioxane (10 mL) for 15 min. Then, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-dibenzopyran-4-yl]diphenyl phosphate (0.37 g, 0.636 mmol) and Pd ₂ (dba) ₃ (0.58 g, 0.636 mmol) were added thereto. The reaction mixture was stirred in a sealed tube at 130° C. for 16 h. Then it was cooled to room temperature, filtered through a celite bed and washed with EtOAc (50 mL×2). The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-80% EtOAc in hexanes) to give N-(2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]oxadinin-6-yl)cyclopropanecarboxamide I - 2c (1.1 g) as a light yellow solid. LCMS (ES) m/z ; 285.1 [M+H] ⁺ .

Step -4 : 2,5 - dimethyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiazin - 6 - amine ( I - 2 ) : To a stirred solution of I - 2c (1.0 g, 3.52 mmol ) in THF (12 mL) was added an aqueous solution of LiOH ( 0.42 g, 17.6 mmol, in 5 mL of water) at room temperature. It was then stirred at 50°C for 16 h. After completion, it was cooled to room temperature and water (20 mL) was added thereto. Extraction was performed with 10% MeOH in DCM (50 mL×2); the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-10% MeOH in DCM) to give the desired compound 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]oxadiazin-6-amine I - 2 (0.31 g) as an off-white solid. LCMS (ES) m/z; 217.2 [M+H] ⁺ . ¹ H NMR ( 400 MHz, DMSO- d ₆ ) δ ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (d, J = 5.2 Hz, 1H); 6.82 (d, J = 5.2 Hz, 1H); 5.86 (s, 2H); 4.21 (s, 3H); 4.20 (s, 2H); 2.45 ( s , 3H ) . Example 5 : Preparation of 2 - cyclopropyl - 5 - methyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiazin - 6 - amine ( I - 3 ) :

Step -1 : 4,5 - Dibromo - 2 - cyclopropyl - 2H - 1,2,3 - triazole ( I - 3b ) : Argon was blown through a stirred suspension of I- 3a ( 20.0 g , 88.2 mmol), cyclopropylboronic acid (13.6 g, 159.0 mmol ) and _{Na2CO3 (} 18.7 g, 176.0 mmol) in DCE (200 mL) and 2-MeTHF ( 200 mL) for 15 min. Then, Cu(OAc) ₂ (12.8 g, 70.5 mmol) and 2,2'-bipyridine (11.0 g, 70.5 mmol) were added thereto. The reaction mixture was stirred at 70°C in a sealed tube for 16 h. It was then cooled to room temperature, filtered through a celite bed and washed with EtOAc (50 mL x 3). The combined filtrate was washed with 200 mL of 1 N HCl, brine (50 mL), dried over anhydrous _Na2SO4 , filtered _and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-5% EtOAc in hexane) to give the desired compound 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole I - 3a (8.0 g) as a yellow liquid. ¹ H NMR (400 MHz, DMSO) δ 4.13-4.16 (m, 1H); 1.05-1.12 (m, 2H); 0.74-0.77 (m, 2H).

Step -2 : 5 - Bromo - 2 - cyclopropyl - 2H - 1,2,3 - triazole - 4 - carbaldehyde ( I - 3c ) : I - 3c (3.5 g) was synthesized by following the procedure described for the synthesis of I - 1 (step-1) using I - 3b (5.0 g, 18.75 mmol) as starting material. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.02 (s, 1H); 4.15-4.09 (m, 1H); 1.47-1.43 (m, 2H); 1.23-1.17 (m, 2H).

Step -3-4 : (( 5 - bromo - 2 - cyclopropyl - 2H - 1,2,3 - triazol - 4 - yl ) methyl ) ( methyl ) carbamic acid tributyl ester ( I - 3e ) : I - 3e (2.2 g) was synthesized by following the procedure described for the synthesis of I - 1 (steps-2 and 3) using I - 3c (2.5 g , 11.6 mmol) and methylamine hydrochloride (1.56 g, 23.1 mmol) as starting materials. LCMS (ES) m/z ; 331.1 [M+H] ⁺ .

Step - 5 : (( 5- ( 2 - chloro - 3 - fluoropyridin - 4 - yl ) -2 - cyclopropyl - 2H - 1,2,3 - triazol - 4 - yl ) methyl )( methyl ) carbamic acid tributyl ester ( I - 3f ) : I - 3e (3.0 g) was synthesized by following the procedure described for the synthesis of I - 2 (step- 1 ) using I - 3e (5.3 g, 16.0 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (7.01 g, 40.0 mmol) as starting materials. LCMS (ES) m/z ; 382.0 [M+H] ⁺ .

Step -6 : 6 - Chloro - 2 - cyclopropyl - 5 - methyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxazolidine ( I - 3g ) : TFA ( 3.0 mL ) was added to a solution of I - 3f (3.0 g, 7.86 mmol ) in DCM (30.0 mL) at 0 ° C , and the reaction mixture was stirred at room temperature for 1 h. After completion, volatiles were removed under reduced pressure and dried (co-evaporated with 1,4-dioxane). 1,4-dioxane (20.0 mL) and DIPEA (7.92 mL, 39.1 mmol) were added thereto at room temperature. The reaction mixture was then stirred at 85°C for 3 h. Upon completion, volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-15% EtOAc in heptane) to give the desired compound 6-chloro-2-cyclopropyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]oxadiazole I - 3g (1.0 g) as a yellow solid. LCMS (ES) m/z ; 262.0 [M+H] ⁺ .

Step - 7 : N- ( 2 - cyclopropyl - 5 - methyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ][ 1,7 ] oxadiazin - 6 - yl ) cyclopropanecarboxamide ( I - 3h ) : I - 3h ( 0.8 g ) was synthesized by following the procedure described for the synthesis of I - 2 ( step - 3 ) using I - 3g (1.0 g , 3.82 mmol) and cyclopropanecarboxamide (0.49 g, 5.73 mmol) as starting materials. LCMS (ES) m/z ; 311.2 [M+H] ⁺ .

Step -8 : 2 - Cyclopropyl - 5 - methyl - 4,5 - dihydro - 2H- [ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiazin - 6 - amine ( I - 3 ) : I - 3 ( 0.4 g) was synthesized by following the procedure described for the synthesis of I - 2 (Step-4) using I - 3h ( 0.8 g, 2.58 mmol) as starting material. LCMS ( ES) m/z ; 243.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (d, J = 4.8 Hz, 1H); 6.79 (d, J = 4.8 Hz, 1H); 5.86 (s, 2H); 4.18 (s, 2H); 4.15-4.12 (m, 1H); 2.41 (s, 3H); 1.23-1.18 (m, 2H); 1.12-1.07 (m, 2H). Example 6 : Preparation of 2 ' , 5' - dimethyl - 2 ' , 5' - dihydrospiro [ oxacyclobutane - 3,4 ' - [ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiazine ] -6' - amine ( I - 4 ) : ​ ​ ​ ​

Step - 1 : N- ( 3- ( 5 - bromo - 2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) cyclohexane - 3 - yl ) -2 - methylpropane - 2 - sulfenamide ( I - 4b ) : To a stirred solution of I - 4a (10 g, 41.5 mmol ) in anhydrous THF (100 mL) at -30 ° C, a solution of 2 M n-BuLi in cyclohexane (18.7 mL, 37.5 mmol) was added and stirred at -78 ° C for 30 min. Then, 2-methyl-N-(cyclohexane-3-ylidene)propane-2-sulfenamide (7.28 g, 41.5 mmol) was added thereto at -78°C. The reaction mixture was stirred at the same temperature for another 30 min. After completion, it was quenched by the addition of saturated NH ₄ Cl solution (50 mL) and extracted with EtOAc (75 mL×3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Combi-Flash (using gradient elution, 0-30% EtOAc in hexanes) to give the desired compound N-(3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxadiazol-3-yl)-2-methylpropane-2-sulfenamide I-4b (9.0 g) as an off-white solid. LCMS (ES) m/z ; 337.1 [M+H] ⁺ .

Step -2 : 3- ( 5 - bromo - 2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) oxadiazol - 3 - amine ( I - 4c ) : To a stirred solution of I- 4b ( 9.0 g , 26.7 mmol) in MeOH (100 mL) was added a solution of 4 M HCl in 1,4 - dioxane (30 mL) at 0°C, and the reaction mixture was stirred for 15 min. After the starting material was completely consumed, a saturated NaHCO ₃ solution (30 mL) was added thereto and washed with EtOAc (20 mL×3). The aqueous NaHCO ₃ solution containing 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxadiazol-3-amine I - 4c was used in the next step without further purification. LCMS (ES) m/z ; 230.9 [MH] ⁺ .

Step -3 : ( 3- ( 5 - bromo - 2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) oxadiazol - 3 - yl ) carbamic acid tributyl ester ( I - 4d ) : A solution of ( Boc ) _2O ( 12.2 mL, 53.2 mmol) in THF (60 mL) was added to an _{aqueous NaHCO3} solution containing I - 4c , and the reaction mixture was stirred at room temperature for 16 h. After completion, water (50 mL) was added thereto and extracted with EtOAc (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous _Na2SO4 , _filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-40% EtOAc in hexanes) to afford tert-butyl (3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxacyclobutan-3-yl)carbamate I - 4d (8.0 g) as an off-white solid. LCMS (ES) m/z ; 333.1 [M+H] ⁺ .

Step -4 : ( 3- ( 5- ( 2 - chloro - 3 - fluoropyridin - 4 - yl ) -2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) oxacyclobutan - 3 - yl ) carbamic acid tributyl ester ( I - 4e ) : I - 4e (1.0 g ) was synthesized by following the procedure described for the synthesis of I - 2 ( step -1) using I - 4d (3.0 g, 9.0 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (3.95 g, 22.5 mmol) as starting materials. LCMS (ES) m/z ; 384.1 [M+H] ⁺ .

Step -5 : 6' - Chloro - 2' - methyl - 2 ', 5' - dihydrospiro [ oxacyclobutane - 3,4 ' -[ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiazole ] ( I - 4f ) : I - 4f ( 4.74 g ) was synthesized by following the procedure described for the synthesis of I - 3 (Step-6) using I - 4e (6.9 g, 18.0 mmol) as the starting material. LCMS (ES) m / z ; 264.1 [M+H] ⁺ .

Step -6 : 6' - Chloro - 2 ', 5' - dimethyl - 2 ', 5' - dihydrospiro [ oxacyclobutane - 3,4 '-[ 1,2,3]triazolo[4,5-c][1,7]oxadiazine] (I-4g): To a stirred solution of I-4f ( 2.5 g , 9.48 mmol ) in DMF ( 20.0 mL ) was added NaH ( 60 % suspension ) ( 0.57 g , 14.2 mmol ) at 0°C and stirred for 30 min . Then, iodomethane (0.71 mL, 11.4 mmol) was added dropwise thereto at 0°C, and the reaction mixture was stirred at room temperature for 1 h. After complete consumption of the starting material, water (50 mL) was added and extracted with _Et2O (3×50 mL). The combined organic extracts were dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by _Combi -Flash (using a gradient elution of 0-10% EtOAc in hexanes) to give 6'-chloro-2',5'-dimethyl-2',5'-dihydrospiro[oxacyclobutane-3,4'-[1,2,3]triazolo[4,5-c][1,7]oxadiazole] I - 4g (2.5 g) as a light yellow solid. LCMS (ES) m/z ; 278.1 [M+H] ⁺ .

Step -7 : N- ( 2 ', 5' - dimethyl - 2 ', 5' - dihydrospiro [ oxacyclobutane - 3,4 '-[ 1,2,3 ] triazolo [ 4,5 - c ][ 1,7 ] oxadiazine ]-6'- yl ) cyclopropanecarboxamide ( I - 4h ) : I - 4h ( 1.8 g ) was synthesized by following the procedure described for the synthesis of I-2 ( step - 3) using I - 4g ( 2.5 g , 9.0 mmol ) and cyclopropanecarboxamide (1.53 g, 18.0 mmol) as starting materials . LCMS (ES) m/z ; 327.0 [M+H] ⁺ .

Step -8 : 2 ', 5' - dimethyl - 2 ', 5' - dihydrospiro [ oxacyclobutane - 3,4 '-[ 1,2,3 ] triazolo [ 4,5 - c ] [ 1,7 ] oxadiazine ] -6' - amine ( I - 4 ) : I - 1 ( 1.0 g ) was synthesized by following the procedure described for the synthesis of I-2 ( Step - 4 ) using I - 4h (1.8 g, 5.52 mmol) as the starting material. LCMS (ES) m/z ; 259.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.83 (d, J = 5.2 Hz, 1H); 6.81 (d, J = 5.2 Hz, 1H); 6.06 (s, 2H); 4.79 (d, J = 6.4 Hz, 2H); 4.60 (d, J = 6.4 Hz, 2H); 4.27 (s, 3H) ; 2.24 ( s , 3H ). Example 7 : Preparation of 2,3,4,5 - tetramethyl - 4,5 - dihydro - 3H - imidazo [ 4,5 - c ] quinolin - 6 - amine ( I - 5 ) :

Step - 1 : N- ( 3- ( 4 - bromo - 1,2 - dimethyl - 1H - imidazol - 5 - yl ) oxadiazol - 3 - yl ) -2 - methylpropane - 2 - sulfenamide ( I - 5b ) : I - 5b (3.25 g ) was synthesized by following the procedure described for the synthesis of I - 4 (step-1) using I - 5a (5.0 g, 19.7 mmol) and 2-methyl-N-(oxadiazol-3-ylidene)propane-2-sulfenamide (3.97 mL, 29.5 mmol) as starting materials. LCMS (ES) m/z ; 350.1 [M+H] ⁺ .

Step - 2 : 3- ( 4 - bromo - 1,2 - dimethyl - 1H - imidazol - 5 - yl ) oxadiazol - 3 - amine ( I - 5c ) : I - 5c (16.0 g) was synthesized by following the procedure described for the synthesis of I - 4 (step-2) using I - 5b (13.0 g, 37.1 mmol) as the starting material. LCMS (ES) m/z ; 246.0 [M+H] ⁺ .

Step -3 : ( 3- ( 4 - bromo - 1,2 - dimethyl - 1H - imidazol - 5 - yl ) oxacyclobutan - 3 - yl ) carbamic acid tributyl ester ( I - 5d ) : I - 5d (10.0 g) was synthesized by following the procedure described for the synthesis of I - 4 (step 3) using I - 5c (16.0 g, 65.0 mmol) as the starting material. LCMS (ES) m/z ; 346.1 [M+H] ⁺ .

Step - 4 : ( 3- ( 4- ( 2 - chloro - 3 - fluoropyridin - 4 - yl ) -1,2 - dimethyl - 1H - imidazol - 5 - yl ) oxacyclobutan - 3 - yl ) carbamic acid tributyl ester ( I - 5e ) : I - 5e ( 2.0 g) was synthesized by following the procedure described for the synthesis of I - 2 (step-1) using I - 5d (2.5 g, 7.22 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (3.17 g, 18.1 mmol) as starting materials. LCMS (ES) m/z ; 397.1 [M+H] ⁺ .

Step -5 : 6 - Chloro - 2,3 - dimethyl - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ][ 1,7 ] oxadiazine - 4,3' - oxacyclobutane ] ( I - 5f ) : I - 5f ( 0.9 g ) was synthesized by following the procedure described for the synthesis of I - 3 ( Step-6 ) using I - 5e (2.0 g, 5.04 mmol) as the starting material. LCMS (ES) m/z ; 277.1 [M+H] ⁺ .

Step -6 : 6 - Chloro - 2,3,5 - trimethyl - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ][ 1,7 ] oxadiazine - 4,3' - oxacyclobutane ] ( I - 5g ) : I - 5g ( 0.7 g ) was synthesized by following the procedure described for the synthesis of I - 4 (Step-6 ) using I- 5f ( 0.7 g , 2.53 mmol) as the starting material. LCMS (ES) m/z ; 291.0 [M+H] ⁺ .

Step -7 : N- ( 2,3,5 - trimethyl - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ] [ 1,7 ] oxadiazine - 4,3' - oxacyclobutane ] -6 - yl ) cyclopropanecarboxamide ( I - 5h ) : I - 5h (0.4 g ) was synthesized by following the procedure described for the synthesis of I - 2 ( step -3) using I - 5g ( 0.7 g, 2.41 mmol) and cyclopropanecarboxamide ( 0.41 g, 4.82 mmol) as starting materials . LCMS (ES) m/z ; 340.2 [M+H] + ^.

Step -8 : 2,3,5 - trimethyl - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ][ 1,7 ] oxadiazine - 4,3' - oxacyclobutane ] -6 - amine ( I - 5 ) : I - 5 ( 0.23 g ) was synthesized by following the procedure described for the synthesis of I - 2 ( step -4 ) using I - 5h (0.35 g, 1.03 mmol) as the starting material. LCMS ( ES) m / z ; 272.1 [M+ H ] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.69 (d, J = 5.2 Hz, 1H); 6.69 (d, J = 4.8 Hz, 1H); 5.69 (s, 2H); 4.85 (d, J = 6.8 Hz, 2H); 4.65 (d, J = 6.4 Hz, 2H); 3.86 (s, 3H); 2.40 (s, 3H); 2.28 (s, 3H). Example 8 : Preparation of 2 ' , 5' - dimethyl - 2 ' , 5' - dihydrospiro [ oxacyclobutane - 3,4 ' - [ 1,2,3 ] triazolo [ 4,5 - c ] quinoline ] -6' - amine ( I - 3 ) : ​ ​ ​

Step -1 : ( 3- ( 5- ( 2 - fluoro - 3 - nitrophenyl ) -2 - methyl - 2H - 1,2,3 - triazol - 4 - yl ) oxadiazol - 3 - yl ) carbamic acid tributyl ester ( I - 3a ) : I - 3a (4.0 g) was synthesized by following the procedure described for the synthesis of I-1 ( step - 4 ) using I - 4d (7.0 g, 21.0 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (8.4 g, 31.5 mmol) as starting materials. LCMS (ES) m/z ; 394.2 [M+H] ⁺ .

Step - 2 : 2' - Methyl - 6' - nitro - 2 ', 5' - dihydrospiro [ oxacyclobutane - 3,4 '-[ 1,2,3 ] triazolo [ 4,5 - c ] quinoline ] ( I - 3b ) : I - 3b ( 1.65 g ) was synthesized by following the procedure described for the synthesis of I - 3 (step-6) using I - 3a (4.0 g, 10.18 mmol) as the starting material. LCMS (ES ) m/z ; 274.1 [M+H] ⁺ .

Step -3 : 2 ', 5' - dimethyl - 6' - nitro - 2 ', 5' - dihydrospiro [ oxacyclobutane - 3,4 '-[ 1,2,3]triazolo[4,5-c]quinoline] (I-3c): I-3c ( 2.7 g ) was synthesized by following the procedure described for the synthesis of I - 4 ( step - 6 ) using I - 3b ( 2.8 g , 10.2 mmol) as the starting material. LCMS (ES) m/z ; 288.1 [M+H] ⁺ .

Step -4 : 2 ', 5' - dimethyl - 2 ' , 5' - dihydrospiro [ oxacyclobutane - 3,4 ' -[ 1,2,3 ] triazolo [ 4,5 - c ] quinoline ] -6' - amine ( I - 3 ) : I - 3 ( 0.8 g) was synthesized by following the procedure described for the synthesis of I - 1 (Step- 6 ) using I - 3c (3.3 g, 11.4 mmol) as the starting material. LCMS ( ES) m/z ; 258.1 [M+H] ⁺ . Example 9 : Preparation of 2,3,5 - trimethyl - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ] quinolin - 4,3' - oxacyclobutane ] -6 - amine ( I - 7 ) : ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

Step -1 : ( 3- ( 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,2 - dimethyl - 1H - imidazol - 5 - yl ) oxadiazol - 3 - yl ) carbamic acid tributyl ester ( I - 7a ) : I - 7a (2.7 g) was synthesized by following the procedure described for the synthesis of I - 1 (step-4) using I - 5d (3.5 g, 10.1 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (5.94 g, 22.2 mmol) as starting materials. LCMS (ES) m/z ; 407.2 [M+H] ⁺ .

Step -2 : 2,3 - Dimethyl - 6 - nitro - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ] quinoline - 4,3' - oxacyclobutane ] ( I - 7b ) : I - 7b (1.4 g) was synthesized by following the procedure described for the synthesis of I - 3 ( step-6 ) using I - 7a ( 5.3 g , 13.0 mmol) as the starting material. LCMS (ES) m/z ; 287.0 [M+H] ⁺ .

Step -3 : 2,3,5 - trimethyl - 6 - nitro - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ] quinoline - 4,3' - oxacyclobutane ] ( I - 7c ) : I - 7c ( 1.2 g ) was synthesized by following the procedure described for the synthesis of I - 1 (step- 6 ) using I - 7b ( 1.2 g, 4.19 mmol) as the starting material. LCMS (ES) m/z ; 301.1 [M+H] ⁺ .

Step -4 : 2,3,5 - trimethyl - 3,5 - dihydrospiro [ imidazo [ 4,5 - c ] quinolin - 4,3' - oxacyclobutane ] -6 - amine ( I - 7 ) : I - 7 (0.8 g ) was synthesized by following the procedure described for the synthesis of I- 1 ( Step -6) using I - 7c ( 1.2 g , 4.0 mmol ) as the starting material. LCMS (ES) m/z ; 271.0 [M+H] ⁺ .

The following compounds were synthesized following the procedures described above using appropriate intermediates and starting materials. Compound No. Structure Intermediate Analyze data 1 A-1 and I-4 LCMS (ES) m/z ; 478.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.38 (s, 1H); 10.88 (s, 1H); 9.65 (s, 1H); 8.97 (s, 1H); 8.21 (d, J = 5.2 Hz, 1H); 7.27 (d, J = 5.2 Hz, 1H); 4.89 (d, J = 6.4 Hz, 2H); 4.65 (d, J = 6.0 Hz, 2H); 4.32 (s, 3H); 3.15 (s, 2H); 2.36 (s, 3H); 2.10-2.04 (m, 1H); 0.86-0.82 (m, 4H). 2 A-1 and I-5 LCMS (ES) m/z ; 491.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.22 (s, 1H); 10.82 (s, 1H); 9.60 (s, 1H); 8.93 (s, 1H); 8.04 (d, J = 5.2 Hz, 1H); 7.11 (d, J = 5.2 Hz, 1H); 4.95 (d, J = 6.8 Hz, 2H); 4.72 (d, J = 6.8 Hz, 2H); 3.91 (s, 3H); 3.13 (s, 2H); 2.39 (s, 3H); 2.33 (s, 3H); 2.08-2.04 (m, 1H); 0.85-0.80 (m, 4H). 3 A-2 and I-5 LCMS (ES) m/z ; 488.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.23 (s, 1H); 10.85 (s, 1H); 9.61 (s, 1H); 8.94 (s, 1H); 8.05 (d, J = 4.8 Hz, 1H); 7.11 (d, J = 5.2 Hz, 1H); 4.95 (d, J = 6.8 Hz, 2H); 4.72 (d, J = 6.8 Hz, 2H); 3.91 (s, 3H); 3.17 (q, J = 7.2 Hz, 2H); 2.44 (s, 3H); 2.33 (s, 3H); 2.08-2.02 (m, 1H); 1.19 (t, J = 7.2 Hz, 3H); 0.85-0.79 (m, 4H). 4 A-1 and I-6 LCMS (ES) m/z ; 477.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.28 (s, 1H); 10.90 (s, 1H); 8.90 (s, 1H); 8.16 (s, 1H); 7.48 (d, J = 8.0 Hz, 1H); 7.45 (d, J = 7.6 Hz, 1H); 7.30 (d, J = 8.0 Hz, 1H); 4.83 (d, J = 6.0 Hz, 2H); 4.61 (d, J = 6.4 Hz, 2H); 4.28 (s, 3H); 3.12 (s, 2H); 2.26 (s, 3H); 2.04-2.00 (m, 1H); 0.82-0.78 (m, 4H). 5 A-1 and I-7 LCMS (ES) m/z ; 490.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.23 (s, 1H); 10.90 (s, 1H); 8.88 (s, 1H); 8.14 (s, 1H); 7.30 (dd, J ₁ = 1.2 Hz, J ₂ = 7.2 Hz, 1H); 7.22 (d, J = 6.8 Hz, 1H); 7.15 (d, J = 8.0 Hz, 1H); 4.89 (d, J = 6.8 Hz, 2H); 4.66 (d, J = 6.8 Hz, 2H); 3.87 (s, 3H); 3.12 (s, 2H); 2.42 (s, 3H); 2.29 (s, 3H); 2.03-1.98 (m, 1H); 0.70-0.76 (m, 4H). 6 A-2 and I-4 LCMS (ES) m/z ; 475.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.39 (s, 1H); 10.90 (s, 1H); 9.66 (s, 1H); 8.97 (s, 1H); 8.20 (d, J = 4.8 Hz, 1H); 8.26 (d, J = 4.8 Hz, 1H); 4.89-4.87 (m, 2H); 4.65-4.64 (m, 2H); 4.32 (s, 3H); 3.17 (q, J = 7.2 Hz, 2H); 2.35 (s, 3H); 2.06-2.05 (m, 1H); 1.18 (t, J = 7.2 Hz, 3H); 0.85-0.82 (m, 4H). II. Biological Evaluation Example B-1 : HEK - Blue™ IL - 23 and IFNα / β reporter assay for analysis of TYK2 pseudokinase ( JH2 ) inhibition

HEK-Blue™ IL-23 and IFNα/β cells with stably integrated interleukin receptors and STAT3 or STAT1 express a STAT-induced secreted embryonic alkaline phosphatase (SEAP) reporter gene after interleukin stimulation. These cells were plated in DMEM (Gibco) containing 10% heated inactivated FBS (Gibco) and 100 U/mL PenStrep (Gibco) at 37°C in 5% CO2 for 20-22 hours. Cells were then pretreated with serial dilutions of test compounds for 60 min and subsequently stimulated with 10 ng/mL human recombinant IL-23 (Miltenyl Biotech) or 1 ng/mL human recombinant IFNα (InvivoGen) for 22-24 h for IL-23 or 16-18 h for IFNα. SEAP induction was measured using QUANTI Blue™ solution (InvivoGen) according to the manufacturer's instructions. Inhibition data were calculated by comparing uninhibited control wells with 0% inhibition and non-stimulated control wells with 100% inhibition. Dose-response curves were generated to determine the concentration required to inhibit 50% of the cell response (IC ₅₀ ) as derived by nonlinear regression analysis.

Table B-1 provides the TYK2 inhibitory activity of illustrative compounds, where A means IC ₅₀ < 30 nM; B means IC ₅₀ between 30 and 300 nM; C means IC ₅₀ between 300 and 1000 nM; D means IC ₅₀ > 1000 nM; n/a means no activity was observed at 1000 nM; and nd means not determined. Table B-1 : Representative TYK2 Inhibitory Activity Compound No. IL23 IFNα 1 A B 2 B B 3 A B 4 A B 5 A A 6 A B Example B-2 : HEK - Blue™ IL - 2 and IFNγ reporter assay for determining selectivity

HEK-Blue™ IL-2 and IFNγ reporter cells with stably integrated interleukin receptors and STAT5 or STAT1 express a STAT-induced secretory embryonic alkaline phosphatase (SEAP) reporter gene upon interleukin stimulation. These cells were plated in DMEM (Gibco) containing 10% heated inactivated FBS (Gibco) and 100 U/mL PenStrep (Gibco) at 37°C with 5% CO2 for 20-22 hours. Cells were then pretreated with serial dilutions of test compounds for 60 min and subsequently stimulated with 4 ng/mL human recombinant IL-2 (Miltenyl Biotech) or 50 ng/mL human recombinant IFNγ (InvivoGen) for 24 hours. SEAP induction was measured using QUANTI-Blue™ solution (InvivoGen) according to the manufacturer's instructions. Inhibition data were calculated by comparing the non-inhibitor control wells with 0% inhibition and the non-stimulated control wells with 100% inhibition. Dose-response curves were generated to determine the concentration required to inhibit 50% of the cellular response ( _IC50 ), as derived by nonlinear regression analysis.

Table B-2 provides selectivity data (SEAP) of illustrative compounds for IL-2 and IFN-γ, where A means IC ₅₀ < 30 nM; B means IC ₅₀ between 30 and 300 nM; C means IC ₅₀ between 300 and 1000 nM; D means IC ₅₀ > 1000 nM; n/a means no activity was observed at 1000 nM; and nd means not determined. Table B-2 : SEAP selectivity analysis data for IL - 2 and IFNγ Compound No. IL-2 IFN-γ 1 D D 2 D D 3 D D 4 D D 5 D C 6 D D

Examples B- 3 : Brain exposure study in rats via oral route

Test compounds were administered/dosed at 20 mg/kg via the oral route. Formulations were prepared in ethanol + TPGS (1:1): PEG-300 (10:90). Blood samples were collected at 1.0 h and 4.0 h (end of study), while brain samples were collected at 4.0 h (end of study). Blood was collected via the posterior ocular vascular plexus in centrifuge tubes containing K2EDTA, and plasma was obtained by centrifugation at 1000 rpm for 5 min at 4°C and stored at -80°C. Whole brains were quickly removed from the skull and rinsed in ice-cold saline, immediately snap-frozen and stored at -80°C.

For analysis, the brain was carefully weighed and transferred to a sample collection tube, and then 5 times the weight of the brain in phosphate-buffered saline (PBS) was added thereto, and then the sample was homogenized using a probe homogenizer.

Blood and homogenized brain samples were precipitated with 400 µL of acetonitrile containing internal standard. The precipitated samples were centrifuged at 14000 rpm for 5 min at 4°C and the supernatant was used for LCMS/MS analysis. Table B-3 : Brain and plasma partitioning studies in rats by oral ( PO ) administration Compound No. Dosage Time point ( h ) Brain Plasma Average brain : plasma Average concentration (ng/g) (n = 3) SD CV% Mean concentration (ng/mL) (n = 3) SD CV% 1 20 mg/kg PO 4 549 186 34 426 87 20 1.27

The examples and embodiments described herein are for illustrative purposes only and various modifications or variations proposed by persons skilled in the art are intended to be included within the spirit and scope of this application and the scope of the accompanying patent applications.

Claims (75)

A compound of formula (I): Formula (I), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5-membered or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted by p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted C1 _{-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl , unsubstituted} or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 _{-C 6} deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(=O)R ¹⁶ , -CO ₂ R 16 , -C(=O)N(R ¹⁶ ) ² , -S(=O)R ¹⁷ , -SO ₂ R ₁₇ or -SO ₂ N(R ¹⁶ ) ₂ ; or two ^{R 8s} attached to the same carbon atom are combined to form =O, =S or =NH; Z is -NR ¹⁰ -, -O-, -S-, -S(=O)- or -SO ₂ -; R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heterocyclic ring ^X1 , ^X2 and ^X3 are each independently ^CR11 or N; each ^R11 is independently hydrogen, halogen, unsubstituted or substituted C1- _C6 alkyl, unsubstituted or substituted _C2 -C6 _{alkenyl, unsubstituted or substituted C2-C6 alkynyl ,} unsubstituted or substituted _{C1 -C6 fluoroalkyl} , unsubstituted or substituted _{C1 - C6 heteroalkyl} , unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, ^-OR17 , -C(=O) ^R16 , _-CO2R16 , -C(=O)N( ^R16 ) ² , -N( ^R16 ) _{2 ,} -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; B ¹ is N or CR ^12a ; B ² is N or CR ^12b ; R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; R ¹ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; R ² is ring B, which is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if ring B is substituted, ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C _{or two R 16 on adjacent} ^{atoms of Ring} _{B ;} ^​ _​ ^​ _​ ^{​ ​ ​ ​} _​ ^​ _​ ^​ _​ or R ¹³ is combined with the intervening atoms to which it is attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; or R ² is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C R ¹⁵ is hydrogen, C 1 -C ₆ alkyl or C 1 -C 6 fluoroalkyl; or R 14 and R 15 are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted ₄ -membered _{to 6 -} membered monocyclic heterocyclic ring; or ^{R 1} and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; R ⁴ is hydrogen, C ₁ -C ⁶ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ or R ⁴ and R ^12a are combined with the _intervening atoms to which they are attached to form a substituted or unsubstituted C ₅ -C ₆ cycloalkyl group; R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C _{3 -C 6} cycloalkyl or _a monocyclic heterocyclic ring; each R ⁶ and R ⁷ is independently hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C _{1 -C 6 deuterium alkyl, C 1 -C 6} fluoroalkyl, C _{3 -C 6} cycloalkyl, a monocyclic heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(═O)R ¹⁷ , -SR ¹⁶ , -S(═O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; or one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form C═O, unsubstituted or substituted C ₃ -C ₆ cycloalkane or unsubstituted or substituted 3- to 6-membered heterocycloalkyl, wherein when the C ₃ -C ₆ cycloalkane or 3- to 6-membered heterocycloalkyl is substituted, the C ₃ -C ₆ cycloalkane or 3- to 6-membered heterocycloalkyl is substituted with m instances of R ³ , wherein: m is 0, 1, 2, 3, 4, 5 or 6; and each R wherein ^{R 3} is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) 2 , -N(R ¹⁶ ) 2 , -NR 16 C(=O)R 17 , -SR ₁₆ , -S(=O)R ₁₇ , -SO ² R ¹⁷ or -SO ² N(R ¹⁶ ) ₂ ; wherein if R ³ is attached to a nitrogen atom, then R ³ is hydrogen, deuterium, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C ₆ deuterioalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR 17 , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C( ^=O )N(R 16 ) 2 , -N(R 16 ) _{2 , -NR 16 C(=O)R 17} , -SR 16 , -S(=O)R ₁₇ , -SO 2 R 17 or -SO 2 N(R ₁₆ ) 2 _-C6 fluoroalkyl, unsubstituted or substituted C1- _C6 heteroalkyl, -C(=O) _R16 ^, _-CO2R16 , -C(=O)N( ^R16 ) ² , -S(=O) ^R17 , _-SO2R17 or ^-SO2N ( ^R16 ) _{2 ;} provided that at least one ^R6 and _one ^R7 attached to the same carbon atom are combined with the carbon atom to which they are attached to form a substituted cyclopropyl, an unsubstituted or substituted _C4 - _C6 cycloalkane or an unsubstituted or substituted 3-membered to 6-membered heterocycloalkyl; each ^R16 is independently hydrogen, substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted _C1 - _C6 fluoroalkyl, substituted or unsubstituted _C1 -C _{R 16} is a substituted or unsubstituted C ₁ -C ₆ heteroalkyl, a substituted or unsubstituted C 3 -C 7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heteroalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently a substituted or unsubstituted C ₁ -C ₆ alkyl, a substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, a substituted or unsubstituted C ₁ -C ₆ heteroalkyl, a substituted or unsubstituted C ₃ -C wherein each of the _substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle and substituted heterocycle is substituted with one or more R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH _{2 CN, -OR 18 , -CH 2} OR 18 , -CO 2 R ¹⁸ , -CH ₂ CO ₂ R ^{18 , -C} (═O) ^N ( _R ¹⁸ _{) 2 , -CH2C} (=O) ^N ( ^R18 ) ₂ , -N(R18 _{) 2} , ^-CH2N ( ^R18 ) ₂ , -NR18C(=O)R18, _-CH2NR18C (= ^O ) ^R18 , _-NR18SO2R19 , -CH2NR18SO2R19, -SR18 ^{, -CH2SR18} , ^-S (=O) _R19 , _-CH2S (=O) _R19 , _-SO2R19 , ^-CH2SO2R19 , _{-SO2N (} ^R18 ₎₂ ^{, or -CH2SO2N} _{( R18)2 ; each} ^{R18 is independently selected from} hydrogen, _C1 - ^C or two R 18 groups are combined with the N atom to which they are attached to form a N-containing ^heterocyclic ring; _each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C _{1 -C 6} heteroalkyl, C ₃ -C ₆ cycloalkyl, C _{2 -C 6} heterocycloalkyl, phenyl, benzyl, _{5 -} membered heteroaryl and 6-membered heteroaryl; n is 1, ₂ or _{3; p is 1, 2, 3 or 4} ; and q is 0, 1, 2, 3 or 4. The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein at least one R ⁶ and one R ⁷ connected to the same carbon atom are combined with the carbon atom to which they are connected to form an unsubstituted or substituted 3- to 6-membered heterocycloalkyl group. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein n is 1 or 2. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein n is 1. The compound of any one of claims 1 to 4, further defined by formula (IA): Formula (IA), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: m is 0, 1, 2, 3, 4, 5 or 6; r and t are each independently 0, 1 or 2, with the proviso that the sum of t and r is at least 2; ^V1 is ^-NR3- , -O-, -S-, -S(=O)- or _-SO2- ; Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5- or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted with p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C _{1 -C 6} heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ₁₆ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) ² , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ₁₇ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ² _R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to ^the nitrogen atom, then R ^{R 8} is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -S(=O)R ¹⁷ , -SO ₂ ^{R 17 or} -SO ₂ N(R ¹⁶ ) ₂ ; or two R ^8s attached to the same carbon atom are combined to form =O, =S or =NH; Z is -NR R ^{10 is} hydrogen, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C 1 -C _{6 fluoroalkyl, C 3 -C 6 cycloalkyl or a} monocyclic heterocyclic ring; X ¹ , X ^{2 and X 3} _are each independently ^{CR 11} _or N; each R ¹¹ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C _{6 6} heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; B ¹ is N or CR ^12a ; B ² is N or CR ^12b ; R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C _-6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted _C1 - _C6 fluoroalkyl, unsubstituted or substituted _C1 - _C6 heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, ^-OR17 , -C(=O)R16, _-CO2R16 , -C(=O)N( ^R16 ) ² , -N( ^R16 ) ² , ^-NR16C (=O) _R17 , ^-SR16 , -S( ₌ O) ^R17 _{, -SO2R17 or -SO2N(R16)2 ; R1} ^{is hydrogen ,} _C1 ^- _C6 alkyl or _C1 - _C6 fluoroalkyl; R ² is Ring B, and Ring B is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if Ring B is substituted, Ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ or R ² _is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R 14 is hydrogen, _{unsubstituted} or substituted C 1 -C ^{6 alkyl, unsubstituted} or substituted C 2 -C ₆ alkyl, or -C(=O)R ¹⁴ ; or R ¹⁴ is hydrogen, unsubstituted or substituted C 1 -C ₆ alkyl, or -C(=O)R 14 ; or R 14 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, or -C(=O)R ¹⁴ ; or R ¹⁴ is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, or -C(=O)R 14 ; or R ¹⁴ is hydrogen, unsubstituted or substituted C ^{1 -C 6} alkyl, or -C(=O)R ¹⁴ ; or R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, or _-C (=O) R ₁₅ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; or R 14 and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 4-membered to _{6 - membered monocyclic} heterocyclic ring; or R ¹ and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; ^{each R} wherein ^{R 3} is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R 16 ) 2 , -N(R ¹⁶ ) 2 , -NR 16 C(=O)R 17 , -SR ₁₆ , -S(=O)R ₁₇ , -SO ² R ¹⁷ or -SO ² N(R ¹⁶ ) ₂ ; wherein if R ³ is attached to a nitrogen atom, then R ³ is hydrogen, deuterium, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C ₆ deuterioalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR 17 , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C( ^=O )N(R 16 ) 2 , -N(R 16 ) _{2 , -NR 16 C(=O)R 17} , -SR 16 , -S(=O)R ₁₇ , -SO 2 R 17 or -SO 2 N(R ₁₆ ) 2 _R4 ^is hydrogen _{, C1} -C6 alkyl, ^C1 -C6 _heteroalkyl , C1- _C6 deuterated alkyl, C1- ^C6 _fluoroalkyl or ^C3 _-C6 ^cycloalkyl ; ^or R4 and _R12a are combined ^with the intervening ^atoms _to which they are _attached to form _a substituted or unsubstituted _{C5 -C6 cycloalkyl} ^{; R5} is hydrogen, _{C1 - C6 alkyl} , _{C1 - C6} fluoroalkyl _{, C3 - C6} each R ¹⁶ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic ₃ -membered to ₈ -membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3-membered to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ₂ CN, -OR ¹⁸ , -CH ₂ OR ¹⁸ , -CO ₂ R ¹⁸ , -CH ₂ CO ₂ ^{R 18} , -C(=O)N(R ¹⁸ ) ₂ , -CH ₂ C(=O)N(R ¹⁸ ) ₂ , -N(R ¹⁸ ) ₂ , -CH ₂ N(R ¹⁸ ) ₂ , -NR ¹⁸ C(=O)R ¹⁸ , -CH ₂ NR ¹⁸ C(=O)R ¹⁸ , -NR ¹⁸ SO ₂ R ¹⁹ , -CH ₂ NR ¹⁸ SO ₂ R ¹⁹ , -SR ¹⁸ , -CH ₂ SR ¹⁸ , -S(=O)R ¹⁹ , -CH ₂ S(=O)R ¹⁹ , -SO ₂ R ¹⁹ , -CH ₂ SO ₂ R ¹⁹ , -SO ₂ N(R ¹⁸ ) ₂ or -CH ₂ SO ₂ N(R ¹⁸ ) ₂ ; Each R ^{R 18} is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁸ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; n is 1, 2 or 3; p is 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4. The compound of claim 5 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein ^V1 is -O-. The compound of claim 5 or claim 6, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein r is 1. The compound of any one of claims 5 to 7, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein t is 1. The compound of any one of claims 5 to 8, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein m is 0. The compound of any one of claims 1 to 9, further defined by formula (IB): Formula (IB), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5- or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted with p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted C1- _{C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl ,} unsubstituted or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 _{-C 6} deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(=O)R ¹⁶ , -CO ₂ R 16 , -C(=O)N(R ¹⁶ ) ² , -S(=O)R ¹⁷ , -SO ₂ R ₁₇ or -SO ₂ N(R ¹⁶ ) ₂ ; or two ^{R 8s} attached to the same carbon atom are combined to form =O, =S or =NH; Z is -NR ¹⁰ -, -O-, -S-, -S(=O)- or -SO ₂ -; R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heterocyclic ring ^X1 , ^X2 and ^X3 are each independently ^CR11 or N; each ^R11 is independently hydrogen, halogen, unsubstituted or substituted C1- _C6 alkyl, unsubstituted or substituted _C2 -C6 _{alkenyl, unsubstituted or substituted C2-C6 alkynyl ,} unsubstituted or substituted _{C1 -C6 fluoroalkyl} , unsubstituted or substituted _{C1 - C6 heteroalkyl} , unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, ^-OR17 , -C(=O) ^R16 , _-CO2R16 , -C(=O)N( ^R16 ) ² , -N( ^R16 ) _{2 ,} -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; B ¹ is N or CR ^12a ; B ² is N or CR ^12b ; R ^12a and R ^12b are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; R ¹ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl; R ² is ring B, which is an unsubstituted or substituted heterocyclic ring or an unsubstituted or substituted carbocyclic ring, wherein if ring B is substituted, ring B is substituted by q instances of R ¹³ ; each R ¹³ is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C _{or two R 16 on adjacent} ^{atoms of Ring} _{B ;} ^​ _​ ^​ _​ ^{​ ​ ​ ​} _​ ^​ _​ ^​ _​ or R ¹³ is combined with the intervening atoms to which it is attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; or R ² is -C(=O)R ¹⁴ , -C(=O)NR ¹⁴ R ¹⁵ or -C(=O)OR ¹⁴ ; R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C R ¹⁵ is hydrogen, C 1 -C ₆ alkyl or C 1 -C 6 fluoroalkyl; or R 14 and R 15 are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted ₄ -membered _{to 6 -} membered monocyclic heterocyclic ring; or ^{R 1} and R ¹⁵ are combined with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring; R ⁴ is hydrogen, C ₁ -C ⁶ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ or R ⁴ and R ^12a are combined with the _intervening atoms to which they are attached to form a substituted or unsubstituted C ₅ -C ₆ cycloalkyl group; R ⁵ is hydrogen _{, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl , C 3 -C 6 cycloalkyl} or a monocyclic heterocyclic ring; each R ¹⁶ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3-membered to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₁ -C ₆ fluoroalkyl group, a substituted or unsubstituted C ₁ -C ₆ heteroalkyl group, a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted monocyclic heteroaryl group; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more ^R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ₂ CN, -OR ¹⁸ , -CH 2 OR 18 , -CO 2 R 18 , -CH ₂ CO ₂ R ¹⁸ , -C(═O) _N (R 18 ^{) 2} , -CH ₂ C(═O ₎ N(R ¹⁸ ) ₂ , -N(R ¹⁸ ) ₂ , -CH ₂ ^{N(R 18 )} _{2 ,} -NR ¹⁸ C(=O)R ¹⁸ , -CH ₂ NR ¹⁸ C(=O)R ¹⁸ , -NR ¹⁸ SO ₂ R ¹⁹ , -CH ₂ NR ¹⁸ SO ₂ R ¹⁹ , -SR ¹⁸ , -CH ₂ SR ¹⁸ , -S(=O)R ¹⁹ , -CH ₂ S(=O)R ¹⁹ , -SO ₂ R ¹⁹ , -CH ₂ SO ₂ R ¹⁹ , -SO ₂ N(R ¹⁸ ) ₂ or -CH ₂ SO ₂ N(R ¹⁸ ) ₂ ; each R ¹⁸ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C 6 _6- membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁸ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; p is 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein Z is -NR ¹⁰ -, -O- or -S-. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein Z is -NR ¹⁰ -. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁰ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ fluoroalkyl or C ₃ -C ₆ cycloalkyl. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl or C ₃ -C ₆ cycloalkyl. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁰ is C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁰ is methyl. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein ^X1 and ^X2 are each independently selected from ^CR11 . The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein X ¹ is CH. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein X ² is CH. The compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein B ¹ is CR ^12a . The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ^12a is hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ^12a is hydrogen. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein B ² is CR ^12b . The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ^12b is hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ^12b is hydrogen. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹ is hydrogen or C ₁ -C ₄ alkyl. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹ is hydrogen. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ² is -C(=O)R ¹⁴ . The compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁴ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted monocyclic carbocyclic ring. The compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁴ is an unsubstituted or substituted monocyclic carbon ring. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁴ is unsubstituted or substituted C ₃ -C ₈ cycloalkyl. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ¹⁴ is cyclopropyl. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ⁵ is hydrogen or C ₁ -C ₄ alkyl. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ⁵ is hydrogen. The compound of any one of claims 1 to 34, further defined by formula (IC): Formula (IC), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: Ring A is an unsubstituted or substituted carbocyclic ring, wherein ^A1 and ^A2 are both C; or an unsubstituted or substituted 5-membered or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, wherein if Ring A is substituted, Ring A is substituted by p instances of ^R8 ; each ^R8 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted C1 _{-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl , unsubstituted} or substituted _C1 -C6 ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R ¹⁶ , -CO ₂ R ¹⁶ , -C(=O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ R ¹⁷ or -SO ₂ N(R ¹⁶ ) ₂ ; wherein if R ⁸ is attached to the nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C 6 or two R 8 attached to the same carbon atom are combined to form =O, =S or =NH; X ₃ is CR 11 or N, wherein: R ^{11 is} independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C 2 -C ₆ carbocyclic ring, unsubstituted or substituted heterocyclic ring _, -C(=O)R ¹⁶ , -CO 2 R ¹⁶ , -C(=O)N(R ¹⁶ ) 2 , -S(=O)R ¹⁷ , -SO ₂ R 17 or -SO ₂ N(R ¹⁶ ) ₂ ; or two R ⁸ attached to the same carbon atom are combined to form =O, =S or =NH; X ³ is CR ¹¹ or N, wherein: R ¹¹ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR ¹⁷ , -C(=O)R 16 , -CO ₂ R ¹⁶ , -C(=O)N(R ^{16 ) 2 , -N(R 16 ) 2} _, -NR ¹⁶ C(=O)R ₁₇ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO ₂ ^{R 17 or} -SO ₂ N(R ¹⁶ ) ₂ ; R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C 6 each R ¹⁶ is independently hydrogen, substituted or unsubstituted C _{1 -C 6} alkyl, substituted or unsubstituted C ₁ -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic _3- to _{8 -} membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ₁₆ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C 6 heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to ^8- membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R groups independently selected from the group consisting of deuterium, halogen, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ₂ CN, -OR ¹⁸ , -CH ₂ OR ¹⁸ , -CO ₂ R ¹⁸ , -CH ₂ CO ₂ ^{R 18} , -C(=O)N(R ¹⁸ ) ₂ , -CH ₂ C(=O)N(R ¹⁸ ) ₂ , -N(R ¹⁸ ) ₂ , -CH ₂ N(R ¹⁸ ) ₂ , -NR ¹⁸ C(=O)R ¹⁸ , -CH ₂ NR ¹⁸ C(=O)R ¹⁸ , -NR ¹⁸ SO ₂ R ¹⁹ , -CH ₂ NR ¹⁸ SO ₂ R ¹⁹ , -SR ¹⁸ , -CH ₂ SR ¹⁸ , -S(=O)R ¹⁹ , -CH ₂ S(=O)R ¹⁹ , -SO ₂ R ¹⁹ , -CH ₂ SO ₂ R ¹⁹ , -SO ₂ N(R ¹⁸ ) ₂ or -CH ₂ SO ₂ N(R ¹⁸ ) ₂ ; Each R ^{R 18} is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁸ groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; each R ¹⁹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; and p is 1, 2, 3 or 4. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein Ring A is an unsubstituted or substituted 5-membered or 6-membered heterocyclic ring, wherein ^A1 and ^A2 are independently N or C, and if Ring A is substituted, Ring A is substituted with p instances of ^R8 . The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein Ring A is unsubstituted or substituted pyrrole, unsubstituted or substituted furan, unsubstituted or substituted thiophene, unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted oxazole, unsubstituted or substituted isoxazole, unsubstituted or substituted thiazole, unsubstituted or substituted substituted isothiazole, unsubstituted or substituted triazole, unsubstituted or substituted oxadiazole, unsubstituted or substituted thiadiazole, unsubstituted or substituted tetrazole, unsubstituted or substituted triazolone, unsubstituted or substituted pyridine, unsubstituted or substituted pyrrolidone, unsubstituted or substituted pyrrolidone, unsubstituted or substituted pyrimidine, wherein if ring A is substituted, ring A is substituted with p instances of R ⁸ . The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein Ring A is unsubstituted or substituted imidazole or unsubstituted or substituted triazole, wherein if Ring A is substituted, Ring A is substituted with p instances of R ⁸ . The compound of any one of claims 1 to 38, further defined by formula (ID): Formula (ID), or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: ^A1 and ^A2 are each independently N or C; ^A3 is S, O, N, ^NR8 , ^CR8 or C=O; ^A4 and ^A5 are each independently S, O, N, ^NR8 or ^CR8 ; wherein at least one of ^A1 and ^A2 is C, or at least one of ^A3 , ^A4 and ^A5 is ^CR8 ; ^X3 is ^CR11 or N, wherein: ^R11 is independently hydrogen, halogen, unsubstituted or substituted _C1 - _C6 alkyl, unsubstituted or substituted _C2 - _C6 alkenyl, unsubstituted or substituted _C2 - _C6 alkynyl, unsubstituted or substituted _C1 - _C6 fluoroalkyl, unsubstituted or substituted C _R ^{4 is hydrogen} , _{C 1 -C 6} alkyl, C ¹ _{-C 6 heteroalkyl} , C ¹ _-C ^{6 deuterated} _{alkyl , C} ¹ _{-C 6} ^fluoroalkyl _or ^C _{3 -C} ⁶ _{cycloalkyl ;} ^{each R R 16} is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ₁₆ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ₁₇ is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C ₆ heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; or two R ¹⁶ on the same N atom are combined with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and each R ¹⁷ is independently substituted or unsubstituted C 1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C _{3 -C7} cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuterated alkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more ^Rs groups independently selected from the group consisting of deuterium, halogen, _C1 - _C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, _-CH2CN , ^-OR18 , _-CH2OR18 , ^-CO2R18 , ^-CH2CO2R18 , _-C (=O ₎ ^N ( ^R18 _{) 2 , -CH2C} (=O) ^N ( ^R18 ) ₂ , -N(R18 _{) 2} , ^-CH2N ( ^R18 ) ₂ , -NR18C(=O)R18, _-CH2NR18C (= ^O ) ^R18 , _-NR18SO2R19 , -CH2NR18SO2R19, -SR18 ^{, -CH2SR18} , ^-S (=O) _R19 , _-CH2S (=O) _R19 , _-SO2R19 , ^-CH2SO2R19 , _{-SO2N (} ^R18 ₎₂ ^{, or -CH2SO2N} _{( R18)2 ; each} ^{R18 is independently selected from} hydrogen, _C1 - ^C or two R 18 groups are combined with the N atom to which they are attached to form a N-containing heterocyclic ring; _each ^{R 19 is} _{independently} selected from C ₁ -C ₆ alkyl, C _{1 -C 6 heteroalkyl} , C _{3 -C 6} cycloalkyl, C _{2 -C 6} heterocycloalkyl, phenyl, _benzyl , 5 _- membered heteroaryl and 6 _- membered heteroaryl. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein X ³ is N. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein X ³ is CR ¹¹ . The compound of any one of claims 1 to 39 or 41, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein X ³ is CH. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ deuterated alkyl. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein R ⁴ is ethyl or 2,2,2-trideuteroethyl-1-yl. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein ^A1 is C; ^A2 is N or C; ^A3 is N, ^CR8 or C=O; ^A4 is N, ^NR8 , S or ^CR8 ; and ^A5 is N, ^NR8 , S or ^CR8 . The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein ^A1 is C; ^A2 is C; ^A3 is N; ^A4 is ^NR8 or ^CR8 ; and ^A5 is N or ^NR8 . A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: ^A1 is C; ^A2 is C; A3 is N; ^A4 is NR8, O or S; and ^A5 is ^CR8 ; or A1 is C; A2 is C; A3 is N; ^A4 is ^NR8 , O or S; and A5 is N; or ^A1 is C; ^A2 is C; ^A3 is ^NR8 , O or S; A4 is N; and ^A5 is N; or A1 is C; ^A2 is C; ^A3 is NR8, O or S; ^A4 is N; and A5 is N; or A1 is C; A2 is C; ^A3 is ^NR8 , O or S; ^A4 is N; and ^A5 is CR8; or A1 is N; ^A2 is C; ^A3 is N; A4 is N; and ^A5 is ^CR8 ; or A1 is N; A2 is C; ^A3 is N; A4 is N; and ^A5 is ^CR8 ; or ^A1 is N; A2 is C; A3 is N; ^A4 is N; and A5 is CR8; or A1 is N; ^A2 is C; ^A3 is N; ^{A4 is N; and A5} is ^CR8 ; ^A1 is C; ^A2 is C; ^A3 is N; ^A4 is N; and ^A5 is NR ⁸ ; or ^A1 is C; ^A2 is N; A3 is N; ^A4 is CR ⁸ ; and ^A5 is N; or ^A1 is C; ^A2 is N; ^A3 is N; ^A4 is N; and ^A5 is N; or ^A1 is N; ^A2 is C; ^A3 is N; ^A4 is N; and ^A5 is N; or ^A1 is C; ^A2 is N; ^A3 is N; ^A4 is CR ⁸ ; and ^A5 is CR ^{8 ;} or ^A1 is C; A2 is N; ^A3 is N; ^A4 is N; and ^A5 is CR ⁸ ; or ^A1 is C; ^A2 is ^N ; ^{A3 is} N; ^A4 is N; and ^A5 is CR 8 ⁸ ; or ^A1 is C; ^A2 is N; ^A3 is CR ⁸ ; ^A4 is CR ⁸ ; and ^A5 is N; or ^A1 is N; ^A2 is C; A3 is N; ^A4 is CR ⁸ ; and ^A5 is CR ⁸ ; or ^A1 is C; ^A2 is C; ^A3 is N; ^A4 is CR ⁸ ; and ^A5 is NR ^{8 ,} O or S; or ^A1 is C; ^A2 is C; ^A3 is NR ⁸ , O or S; ^A4 is CR ⁸ ; and ^A5 is N; or ^A1 is C; ^A2 is N; ^A3 is C=O; ^A4 is NR ⁸ ; and ^A5 is N; or ^A1 is C; ^A2 is C; ^A3 is N or CR ⁸ ; ^A4 is NR ⁸ ; and A5 is ^A5 is N; or ^A1 is C; ^A2 is N; ^A3 is ^CR8 ; ^A4 is N; and ^A5 is N. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: ^A1 is C; ^A2 is C; ^A3 is N; ^A4 is ^CR8 ; and ^A5 is ^NR8 , O or S; or ^A1 is C; A2 is C; ^A3 is N or ^CR8 ; ^{A4 is NR8} ; and ^A5 is N. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein each R ⁸ is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted carbocyclic ring or unsubstituted or substituted heterocyclic ring; wherein if R ⁸ is attached to a nitrogen atom, R ⁸ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C 1 -C 6 deuterated alkyl, unsubstituted or substituted C ₁ -C _{6 fluoroalkyl, unsubstituted or substituted carbocyclic ring or unsubstituted or substituted heterocyclic ring; or two R 8 attached to the same carbon atom are independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6} alkyl, unsubstituted or substituted C ₁ -C ₆ deuterated alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted carbocyclic ring or unsubstituted or substituted heterocyclic ring; ⁸ combine together to form =O. The compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein each R ⁸ is independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein each R ⁸ is hydrogen or methyl. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein p is 1, 2 or 3. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein p is 1 or 2. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein p is 1. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein p is 2. The compound of any one of claims 1 to 55, wherein the compound is selected from: 1 : N- (4-((2',5'-dimethyl-2',5'-dihydrospiro[cyclohexanobutane-3,4'-[1,2,3]triazolo[4,5-c][1,7]oxadiazine]-6'-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 2 : N -(5-(propanoyl-3,3,3-d3)-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c][1,7]oxadiazine-4,3'-oxadiazine]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 3 : N -(5-propanoyl-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c][1,7]oxadiazine-4,3'-oxadiazine]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 4 : N -(4-((2',5'-dimethyl-2',5'-dihydrospiro[oxacyclobutane-3,4'-[1,2,3]triazolo[4,5-c]quinoline]-6'-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 5 : N -(5-(propionyl-3,3,3-d3)-4-((2,3,5-trimethyl-3,5-dihydrospiro[imidazo[4,5-c]quinoline-4,3'-oxacyclobutane]-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 6 : N -(4-((2',5'-dimethyl-2',5'-dihydrospiro[oxacyclobutane-3,4'-[1,2,3]triazolo[4,5-c][1,7]oxadiazine]-6'-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide; or a pharmaceutically acceptable salt, tautomer or solvent thereof. A pharmaceutical composition comprising the compound of any one of claims 1 to 56 or a pharmaceutically acceptable salt, tautomer or solvate thereof, and a pharmaceutically acceptable excipient. A method for treating a disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 56 or a pharmaceutically acceptable salt, tautomer or solvate thereof, or a pharmaceutical composition of claim 57. The method of claim 58, wherein the disease or condition is a TYK2-mediated disease or condition. The method of claim 58 or claim 59, wherein the disease or condition is an inflammatory disease or condition or an autoimmune disease or condition. The method of claim 60, wherein the disease or condition is an inflammatory disease or condition. The method of claim 61, wherein the inflammatory disease or condition is a neuroinflammatory disease or condition. The method of any one of claims 58 to 62, wherein the disease or condition is a neurodegenerative disease or condition. The method of any one of claims 58 to 63, wherein the disease or condition is selected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or a neuromyelitis optica spectrum disorder. The method of claim 64, wherein the disease or condition is multiple sclerosis. The method of claim 65, wherein the multiple sclerosis is relapsing or relapsing-remitting. The method of claim 64, wherein the disease or condition is a neuromyelitis optica spectrum disorder. The method of claim 67, wherein the disease or condition is neuromyelitis optica. The method of claim 64, wherein the disease or condition is encephalomyelitis. The method of claim 69, wherein the disease or condition is acute disseminated encephalomyelitis. The method of claim 64, wherein the disease or condition is polyneuropathy. The method of claim 71, wherein the disease or condition is chronic inflammatory demyelinating polyneuropathy. The method of claim 64, wherein the disease or condition is encephalitis. The method of claim 73, wherein the disease or condition is autoimmune encephalitis. The method of any one of claims 58 to 61, wherein the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriasis arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eyes, intestinal disease, Crohn's disease, ulcerative colitis, chylous diarrhea, Bechet's disease, type 1 diabetes, systemic sclerosis and idiopathic pulmonary fibrosis.