[go: up one dir, main page]

WO2025114760A1 - Tyk2 inhibitors and uses thereof - Google Patents

Tyk2 inhibitors and uses thereof Download PDF

Info

Publication number
WO2025114760A1
WO2025114760A1 PCT/IB2024/000679 IB2024000679W WO2025114760A1 WO 2025114760 A1 WO2025114760 A1 WO 2025114760A1 IB 2024000679 W IB2024000679 W IB 2024000679W WO 2025114760 A1 WO2025114760 A1 WO 2025114760A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
compound
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/000679
Other languages
French (fr)
Inventor
Anjali Pandey
Mahesh THAKKAR
Athisayamani Jeyaraj DURAISWAMY
Naveena MADHYASTHA
Rajeev Goswami
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sudo Biosciences Ltd
Original Assignee
Sudo Biosciences Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sudo Biosciences Ltd filed Critical Sudo Biosciences Ltd
Publication of WO2025114760A1 publication Critical patent/WO2025114760A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases.
  • JAKs Janus kinase
  • the mammalian JAK family consists of four members, TYK2, JAKl, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling.
  • TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding.
  • Cytokines implicated in TYK2 activation include interferons (e.g. IFN-a, IFN- ⁇ , IFN-K, IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN-co, and IFN- ⁇ (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 cytokine, and LIF).
  • interferons e.g. IFN-a, IFN- ⁇ , IFN-K, IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN-co, and IFN- ⁇ (also known as limitin)
  • interleukins e.g.
  • TYK2 goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.
  • Compounds described herein are modulators of the JAK family of kinases. More specifically, the compounds of the present disclosure are inhibitors of TYK2. In some embodiments, compounds are selective for TYK2 over other JAKs. For example, compounds may bind specifically to the pseudokinase domain (JH2) of TYK2 thereby enhancing selectivity over JAK family members. In some embodiments, a compound of the present disclosure may be an allosteric modulator or noncompetitive inhibitor of TYK2.
  • a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders.
  • the compounds of the present disclosure penetrate the blood- brain barrier and are useful for the treatment of certain neurological disorders.
  • R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)- C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl,
  • the compound is a compound of Formula (II): Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (III): Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IV): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (V): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VI): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VII): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (X): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • 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.
  • the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
  • Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof useful in the treatment of TYK2-mediated disorders.
  • Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful in the treatment of an inflammatory or autoimmune disease.
  • the disease or condition is an inflammatory disease or condition.
  • the inflammatory disease or condition is a neuroinflammatory disease or condition.
  • the disease or condition is a neurodegenerative disease or condition.
  • the disease or condition is selected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or a neuromyelitis optica spectrum disorder.
  • the disease or condition is multiple sclerosis.
  • the multiple sclerosis is relapsing or relapsing-remitting.
  • the disease or condition is a neuromyelitis optica spectrum disorder.
  • the disease or condition is neuromyelitis optica.
  • the disease or condition is encephalomyelitis.
  • the disease or condition is acute disseminated encephalomyelitis.
  • the disease or condition is polyneuropathy.
  • the disease or condition is chronic inflammatory demyelinating polyneuropathy.
  • disease or condition is encephalitis.
  • disease or condition is autoimmune encephalitis.
  • the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
  • the effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
  • the compound is administered on a continuous dosing schedule.
  • the compound is administered on a continuous daily dosing schedule.
  • the mammal is a human.
  • compounds provided herein are orally administered to a human.
  • Articles of manufacture which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating TYK2, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating TYK2, are provided. [0021] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description.
  • TYK2 activation has been linked to many diseases and disorders, including inflammatory diseases and disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer.
  • IL-23 activation of TYK2 is associated with inflammatory diseases such as inflammatory bowel disease (IBD), Crohn’s disease, celiac disease, and ulcerative colitis.
  • TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Bechet’s disease.
  • Tyk 2 has also been associated with diseases and conditions of the skin, such as psoriasis, vitiligo, atopic dermatitis, scleroderma; or diseases and conditions 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.
  • COPD chronic obstructive pulmonary disease
  • GCH Goblet cell hyperplasia
  • mucous hypersecretion is mediated by IL-13-induced activation of the TYK2/STAT6 pathway.
  • TYK2 is also associated with autoimmune diseases and conditions, such as multiple sclerosis (MS), lupus, and systemic lupus erythematosus (SLE). Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.
  • Various type I IFN signaling pathways dependent on TYK2 signaling have implicated TYK2 in SLE and other autoimmune diseases and conditions.
  • TYK2 is associated with arthritis, including psoriatic arthritis and rheumatoid arthritis. Decreased TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. [0027] TYK2 has also been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. These effects are largely due to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection.
  • NK natural killer
  • cytotoxic T lymphocytes suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection.
  • T-ALL T-cell acute lymphoblastic leukemia
  • TYK2 is a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects.
  • T-ALL T-cell acute lymphoblastic leukemia
  • selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and/or BCL2-addicted tumors, such as 70% of adult T- cell leukemia cases.
  • TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid- ⁇ ( ⁇ ) peptide. Decreased TYK2 phosphorylation of STAT3 following ⁇ administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer’s patients. [0029] Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata. [0030] There is a continuing need to provide novel inhibitors having more effective or advantageous pharmaceutically relevant properties.
  • compounds with increased mobility across blood-brain barrier or with increased activity or increased selectivity over other JAK kinases especially JAK2.
  • the present disclosure provides inhibitors of TYK2 that show increased mobility across the blood-brain barrier.
  • the TYK2 inhibitors show selectivity over JAK1, JAK2, and/or JAK3.
  • compounds with this selectivity (particularly over JAK2) deliver a pharmacological response that favorably treats one or more of the diseases or conditions described herein without the side- effects associated with the inhibition of JAK2.
  • compounds with increased activity or increased selectivity over other JAK kinases especially JAK2).
  • the present disclosure relates to compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2) and inhibit certain cytokine signaling, in particular IL-23 and IFN ⁇ 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 in the synthesis of the compounds.
  • the TYK2 inhibitors described herein are used in the treatment of a disease or condition in a mammal.
  • Compounds described herein are inhibitors of TYK2.
  • compounds described herein are selective for TYK2 over other JAKs.
  • compounds described herein bind selectively/specifically to the pseudokinase domain (JH2) of TYK2.
  • a compound described herein binds to an allosteric site of TYK2.
  • a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders.
  • disclosed herein are compounds containing a substituted tricyclic ring.
  • the substituted tricyclic ring demonstrates increased bioavailability over compounds without the substitution on the tricyclic ring.
  • a compound described herein exhibits improved blood–brain barrier penetration relative to previously disclosed TYK2 inhibitors.
  • a compound described herein exhibits improved bioavailability relative to previously disclosed TYK2 inhibitors.
  • a compound described herein exhibits decreased metabolic clearance relative to previously disclosed TYK2 inhibitors.
  • the present disclosure provides compounds of Formula (I): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: X is N or CH; Y is -NH- or -CH2-; Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1- C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substitute
  • the compound of Formula (I) is not N-(5-(propanoyl-3,3,3-d3)- 4-((2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin- 2-yl)cyclopropanecarboxamide, which has the following structure: [0036]
  • the compound of Formula (I) is a compound of Formula (X): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroal
  • substituents are selected from among a subset of the listed alternatives.
  • Y is -NH-. In other embodiments, Y is -CH2-.
  • X is N. In other embodiments, X is CH.
  • Z is carbon or nitrogen. In some embodiments, Z is carbon which can be further substituted by R1 or R2. In some embodiments, Z is carbon and is denoted as CH, which can be substituted by R1 or R2, per the floating attachment points of R1 and R2 in the pictoral representation of Formula (I). In some embodiments, Z is CH. In other embodiments, Z in N.
  • R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl.
  • R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl.
  • R7 is C1-C4 alkyl, C1-C4 deuteroalkyl, or C3-C6 cycloalkyl.
  • R7 is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R7 is C1-C4 alkyl. In some embodiments, R7 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R7 is methyl or ethyl. In some embodiments, R7 is methyl. In some embodiments, R7 is ethyl. In some embodiments, R7 is C1-C4 deuteroalkyl. In some embodiments, R7 is trideuteromethyl or 2,2,2- trideuterioeth-1-yl. In some embodiments, R7 is -CD3.
  • R7 is C3-C4 cycloalkyl. In some embodiments, R7 is cyclopropyl. In some embodiments, R7 is -CH3 or -CD3.
  • R8 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R8 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R8 is hydrogen or C1-C6 alkyl. In some embodiments, R8 is hydrogen or C1-C4 alkyl. In some embodiments, R8 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl.
  • R8 is hydrogen or methyl. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl. [0042] In some embodiments, R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10. In some embodiments, R9 is -C(O)R10. In some embodiments, R9 is -C(O)NR10R11. In some embodiments, R9 is -C(O)OR10.
  • R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl.
  • R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl.
  • R10 is unsubstituted or substituted C1- C6 alkyl, unsubstituted or substituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl. In some embodiments, R10 is unsubstituted or substituted C3-C6 cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R10 is unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R10 is unsubstituted or substituted C3-C4 cycloalkyl.
  • R10 is unsubstituted or substituted cyclopropyl.
  • R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more Rs groups.
  • R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more Rs groups.
  • the one or more Rs groups are each independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, -CN, -OR18, and -N(R18)2.
  • the one or more Rs groups are each independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, - OCHF2, and -OCF3.
  • R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, - OCH3, -OCHF2, and -OCF3.
  • R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, - CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
  • R10 is unsubstituted or substituted C3-C6 cycloalkyl or unsubstituted or substituted 3- or 6-membered heterocycloalkyl; wherein the substituted cycloalkyl or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), - N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
  • R10 is unsubstituted or substituted C3-C4 cycloalkyl or unsubstituted or substituted 3- or 4- membered heterocycloalkyl; wherein the substituted cycloalkyl or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, - OCH3, -OCHF2, and -OCF3.
  • R10 is unsubstituted or substituted C3-C6 cycloalkyl; wherein the substituted cycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
  • R10 is unsubstituted or substituted C3-C4 cycloalkyl; wherein the substituted cycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, - CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
  • R10 is unsubstituted or substituted cyclopropyl; wherein the substituted cycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, - OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
  • R10 is substituted cyclopropyl; wherein the substituted cyclopropyl is substituted with one or more -F.
  • R10 is cyclopropyl.
  • R10 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl, .
  • R is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl,
  • R10 is [0048]
  • R11 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl.
  • R11 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R11 is hydrogen or C1-C6 alkyl. In some embodiments, R11 is hydrogen or C1-C4 alkyl. In some embodiments, R11 is hydrogen or methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R11 is hydrogen or methyl. In some embodiments, R11 is hydrogen. In some embodiments, R11 is methyl.
  • R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl. In some embodiments, R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl. [0050] In some embodiments, R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl.
  • R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycloalkyl. In some embodiments, R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle. In some embodiments, R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- membered monocyclic heterocycloalkyl. [0051] In some embodiments, the compound is a compound of Formula (II) or Formula (III):
  • the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl.
  • R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -
  • R9 is an unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, unsubstituted or substituted bicyclic heterocyclyl, unsubstituted or substituted spirocyclic carbocyclyl, unsubstituted or substituted spirocyclic heterocyclyl, unsubstituted or substituted bridged carbocyclyl, or unsubstituted or substituted bridged heterocyclyl.
  • R9 is an unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R9 is an unsubstituted or substituted monocyclic carbocyclyl. In some embodiments, R9 is an unsubstituted or substituted bicyclic carbocyclyl. In some embodiments, R9 is an unsubstituted or substituted monocyclic heterocyclyl. In some embodiments, R9 is an unsubstituted or substituted bicyclic heterocyclyl.
  • R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl.
  • R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted
  • R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5- membered heteroaryl.
  • R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)
  • R9 is an unsubstituted or substituted monocyclic 6-membered heteroaryl or an unsubstituted or substituted monocyclic 5-membered heteroaryl.
  • R9 is an unsubstituted or substituted monocyclic 6-membered heteroaryl or an unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted or substituted or substituted or substitute
  • R9 is an unsubstituted or substituted monocyclic 5-membered heteroaryl.
  • R9 is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thiophenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, or unsubstituted or substituted tetrazolyl.
  • R9 if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13, -S
  • R9 is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl. In some embodiments, R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl.
  • R9 if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13, -S
  • R9 is an unsubstituted or substituted 6-membered heteroaryl. In some embodiments, R9 is an unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl. In some embodiments, R9 is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl. In some embodiments, R9 is an unsubstituted or substituted pyridinyl.
  • R9 is an unsubstituted or substituted pyrimidinyl. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, - CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR
  • R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13
  • R9 if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1- C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2.
  • R9 if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1- C6 fluoroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -C(O)R12, -C(O)OR12, and -C(O)N(R12)2.
  • R9 if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, - C(O)R12, -C(O)OR12, and -C(O)N(R12)2. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -C(O)R12, -C(O)OR12, and -C(O)N(R12)2.
  • R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, C1- C6 alkyl, and -CN.
  • R9 is 2,6-dimethylpyrimidin-4-yl or 5-fluoropyridin-2-yl.
  • R1 is not hydrogen or fluoro.
  • R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups.
  • R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group.
  • R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl.
  • R1 is -Cl, -CN, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -CHF2, -CH2F, -OCH3, -OCH2CH3, -OCH(CH3)2, - OCF3, -OCH2CF3, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
  • R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, -OCF3, -OCH2CF3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
  • R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy.
  • R1 is chloro or C1-C4 alkyl.
  • R1 is C1-C4 alkyl.
  • R1 is -CH3.
  • n is 1.
  • R2 is halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl.
  • R2 is halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl.
  • R2 is halogen or C1-C4 alkyl.
  • R2 is fluoro, chloro, or C1-C4 alkyl.
  • R2 is fluoro, chloro, or -CH3.
  • n is 0.
  • the compound is a compound of Formula (IV), Formula (V), Formula (VI) or Formula (VII): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group.
  • R1 is chloro, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl.
  • R1 is -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -CHF2, -CH2F, - OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -CH2OCH3, cyclopropyl, or 1-fluoro- cyclopropyl.
  • R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, -OCF3, -OCH2CF3, - OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
  • R1 is chloro or C1-C4 alkyl.
  • R1 is C1-C4 alkyl.
  • R1 is - CH3.
  • X is N. In other embodiments, X is CH.
  • R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl.
  • R3 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl.
  • R3 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R3 is C1- C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl.
  • R3 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some embodiments, R3 is C1-C4 alkyl, C1-C4 deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some embodiments, R3 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl.
  • R3 C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, R3 is C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, R3 is hydrogen or C1-C6 alkyl. In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C1-C4 alkyl. In some embodiments, R3 is methyl or ethyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is C1-C6 deuteroalkyl.
  • R3 is C1-C4 deuteroalkyl. In some embodiments, R3 is trideuteromethyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is methyl, ethyl, trideuteromethyl, or cyclopropyl. In some embodiments, R3 is -CH3 or -CD3. In some embodiments, R3 is -CH3.
  • R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2.
  • R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and -N(R12)2.
  • R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl.
  • R4 and R5 are each independently hydrogen, deuterium, C1-C4 alkyl, or C1-C4 deuteroalkyl.
  • R4 and R5 are each independently hydrogen, deuterium, methyl, ethyl, or trideuteromethyl.
  • R4 and R5 are each independently hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. In some embodiments, R4 is methyl, ethyl, or trideuteromethyl; and R5 is hydrogen, methyl, ethyl, or trideuteromethyl.
  • R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1- C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2.
  • R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and -N(R12)2. In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments, R4 is hydrogen, deuterium, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R4 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl.
  • R4 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl.
  • R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2.
  • R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and - N(R12)2. In some embodiments, R4 is C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments, R4 is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R4 is methyl, ethyl, or trideuteromethyl. In some embodiments, R4 is methyl.
  • R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1- C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2.
  • R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and -N(R12)2.
  • R4 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl.
  • R5 is hydrogen, deuterium, C1-C4 alkyl, or C1-C4 deuteroalkyl.
  • R5 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl.
  • R5 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. In some embodiments, R5 is hydrogen or deuterium. In some embodiments, R5 is hydrogen. [0077] In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1- C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2; and R5 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalky
  • R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; and R5 is hydrogen.
  • R4 and R5 are each independently hydrogen or -CH3. In some embodiments, R4 is methyl; and R5 is hydrogen or methyl. In some embodiments, R4 and R5 are each methyl. In some embodiments, R4 is methyl; and R5 is hydrogen. [0079] In some embodiments, R4 and R5 are each independently hydrogen or deuterium. In some embodiments, R4 and R5 are each hydrogen. In some embodiments, R4 and R5 are each deuterium.
  • R4 and R5 are taken together with the carbon atom to which they are attached to form -C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. [0081] In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form -C(O)-.
  • R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. [0083] In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkylene.
  • R4 and R5 are taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclopropylene or cyclobutylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclopropylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclobutylene.
  • R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered heterocycloalkyl ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 4-membered heterocycloalkyl ring.
  • R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted oxetane ring or azetidine ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted oxetane ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an oxetane ring. [0085] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia):
  • the compound is a compound of Formula (Ia-1) or Formula (Ia- 2): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (Ia-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (Ia-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound of Formula (II) is a compound of Formula (IIa): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IIa-1) or Formula (IIa-2): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound of Formula (III) is a compound of Formula (IIIa): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IIIa-1) or Formula (IIIa-2): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IIIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IIIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound of Formula (IV) is a compound of Formula (IVa): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IVa-1) or Formula or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IVa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (IVa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound of Formula (V) is a compound of Formula (Va): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (Va-1) or Formula (Va-2): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (Va-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (Va-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound of Formula (VI) is a compound of Formula (VIa): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VIa-1) or Formula or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound of Formula (VII) is a compound of Formula (VIIa): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VIIa-1) or Formula (VIIa-2): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VIIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound is a compound of Formula (VIIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2.
  • R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, - CN, -OH, -OR13, and -N(R12)2. In some embodiments, R4 is C1-C6 alkyl or C1-C6 deuteroalkyl. In some embodiments, R4 is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R4 is methyl, ethyl, or trideuteromethyl. In some embodiments, R4 is methyl. [00101] In some embodiments, Ring A is a 5-membered heteroaryl ring.
  • Ring A is a pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, or thiadiazole.
  • Ring A is a triazole, imidazole, pyrazole, thiazole, or oxazole.
  • Ring A is a triazole.
  • Ring A is an imidazole.
  • Ring A is a pyrazole.
  • Ring A is a thiazole.
  • Ring A is an oxazole.
  • Ring A is a 6-membered heteroaryl ring.
  • Ring A is a pyridine, pyridazine, pyrimidine, or pyrazine.
  • Ring A is a pyridine or pyrazine.
  • Ring A is a pyridine.
  • Ring A is a pyrazine.
  • Ring A is a pyrimidine.
  • Ring A is a pyridazine.
  • each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, - CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13
  • each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, - CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, or - S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsub
  • each R6 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, or -S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6- membered heterocycloalkyl, -C(O)
  • each R6 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, or -S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -C(O)OR12, - C(O)N(R12)2, or -S(O)2N(R12)2.
  • each R6 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, or -S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2.
  • each R6 is independently hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, or -N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.
  • each R6 is independently hydrogen, halogen, C1-C6 alkyl, -CN, -OH, -OR13, or -N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen or C1-C6 alkyl.
  • each R6 is independently hydrogen, -F, -Cl, methyl, ethyl, isopropyl, -CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -OH, -C(O)OH, or - C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, ethyl, isopropyl, - CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -C(O)OH, or -C(O)OCH3.
  • each R6 is independently hydrogen, -F, methyl, -OH, -CH2OH, -CD3, cyclopropyl, oxetanyl, or -C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, -CH2OH, -CD3, cyclopropyl, oxetanyl, or -C(O)OCH3.
  • each R6 is independently hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, or -N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.
  • each R6 is independently hydrogen, -F, -Cl, methyl, ethyl, isopropyl, -CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -OH, -C(O)OH, or - C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, ethyl, isopropyl, - CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -C(O)OH, or -C(O)OCH3.
  • each R6 is independently hydrogen, -F, methyl, -OH, -CH2OH, -CD3, oxetanyl, or -C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, -CH2OH, -CD3, oxetanyl, or -C(O)OCH3.
  • m is 1, 2, 3, or 4.
  • m is 1, 2, or 3.
  • m is 1 or 2.
  • m is 1.
  • m is 2.
  • each R6 is independently hydrogen, fluoro, methyl, or cyclopropyl; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, or cyclopropyl; and m is 1 or 2.
  • the compound of Formula (I) is a compound of Formula (X): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups;
  • X is N.
  • X is CH.
  • R7 is C1-C4 alkyl or C1-C4 deuteroalkyl.
  • R8 is hydrogen or C 9 10 1-C4 alkyl
  • R is -C(O)R , - C(O)NR10R11, or -C(O)OR10
  • R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl
  • R11 is hydrogen or C1-C4 alkyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl.
  • R8 is hydrogen; R9 is -C(O)R10; and R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, - OCH3, -OCHF2, and -OCF3.
  • R3 is hydrogen or C 4 5 1-C6 alkyl; and R and R are each independently hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl; or R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene.
  • R3 is C1-C6 alkyl
  • R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2; and R5 is hydrogen.
  • R4 is C1-C6 alkyl or C1-C6 deuteroalkyl.
  • n is 1; and R2 is halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl.
  • n is 0.
  • the compound of Formula (X) is a compound of Formula (XI): or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
  • the compound of Formula (XI) is a compound of Formula (XIa) or Formula (XIb):
  • R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3- C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group.
  • R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl.
  • R1 is -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, - CHF2, -CH2F, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
  • R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, - OCF3, -OCH2CF3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
  • R6 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2.
  • R6 is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl. In some specific embodiments, R6 is hydrogen, methyl, or cyclopropyl.
  • each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl.
  • each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl.
  • each R12 is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a 4- to 6-membered N-containing heterocycloalkyl.
  • each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.
  • each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl.
  • each R13 is independently C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.
  • compounds described herein have the following structure: [00135] In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described herein. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 1 or Table 2. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 1. [00136] In some embodiments, compounds described herein have the following structure:
  • Y, X, R1, R4, R5, R6, m, and Ring A are as described herein. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 1 or Table 2. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 2. [00138] In some embodiments, compounds described herein have the following structure: [00139] In some embodiments, R7, R8, and R9 are as described herein In some embodiments, R7, R8, and R9 are as described in Table 3. [00140] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00141] Exemplary compounds described herein include the compounds described in the following Tables: Table 1:
  • ⁇ single isomer at -C(R4)(R5)- obtained by chiral separation of racemic compound.
  • Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined.
  • Table 3: ⁇ single isomer obtained by chiral separation of racemic compound. Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined.
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with an acid.
  • the compound of Formula (I) i.e. free base form
  • 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-oxoglutaric 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 (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2- disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); glu
  • a compound of Formula (I) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with a base.
  • the compound of Formula (I) is acidic and is reacted with a base. In such situations, an acidic proton of the compound of Formula (I) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N- methylglucamine salt or ammonium salt.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of Formula (I) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, 123I, 124I, 125I, 131I, 32P and 33P.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds of Formula (I) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compound of Formula (I) exists in the R configuration.
  • the compound of Formula (I) exists in the S configuration.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • Z isomers as well as the appropriate mixtures thereof.
  • Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
  • 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 diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
  • resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N- alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H.
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs. [00163] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I) as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds is a prodrug for another derivative or active compound.
  • any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety.
  • the prodrug moiety is as described above.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • heterocyclic rings may exist in tautomeric forms.
  • pyridones could exist in the following tautomeric forms: are encapsulated within the group, “substituted pyridines.”
  • pyrazoles, triazoles, pyrimidines, and the like are known to tautomerize; for the purpose of this disclosure, all tautomeric forms (including charged and zwitterionic tautomers) are considered within the scope of the present disclosure.
  • nucleophilic substitution of one chloro group of intermediate A with the free amino group of B affords intermediate C.
  • this substitution can be carried out with a suitable Lewis acid such as Zn(OAc)2.
  • a suitable base such as LDA.
  • intermediate C may be accessed by a cross-coupling reaction of intermediates A and B.
  • Cross-coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like.
  • intermediate C is converted to the final compound D (e.g., Compound 1) via a cross-coupling reaction.
  • Cross-coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like.
  • compounds are prepared as described in the Examples.
  • C1-Cx includes C1-C2, C1-C3... C1-Cx.
  • a group designated as “C1-C6” indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.
  • An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1- C10alkyl.
  • an alkyl is a C1-C6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • an alkylene is a C1-C6 alkylene. In other embodiments, an alkylene is a C1-C4alkylene.
  • Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.
  • An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein. In some embodiments, the alkoxy group is a C1-C6alkoxy, which refers to a (C1-C6alkyl)-O- group.
  • Typical alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n- propoxy (-OCH2CH2CH3), isopropoxy (-O-iPr; -OCH(CH3)2), n-butoxy(-OCH2CH2CH2CH3), iso-butoxy (-OCH2CH(CH3)2), sec-butoxy (-OCH(CH3)(CH2CH3)), tert-butoxy (-OC(CH3)3), and the like.
  • An “alkoxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by an alkoxy group, as defined herein.
  • an alkoxyalkyl is a (C1-C6alkoxy)-C1- C6alkyl, which can also be considered a (C1-C6alkyl)-O-(C1-C6alkyl)- group.
  • an alkoxyalkyl is a (C1-C4alkoxy)-C1-C4alkyl, which can also be considered a (C1-C4alkyl)-O-(C1-C4alkyl)- group.
  • alkoxyalkyl groups include, but are not limited to, - CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2OCH2CH3, - CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, and the like.
  • alkylamine refers to the –N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • hydroxyalkyl refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl.
  • a hydroxyalkyl is a C1-C4hydroxyalkyl.
  • Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like.
  • aminoalkyl refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a C1-C4aminoalkyl.
  • Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, - CH2CH2CH2CH2NH2, and the like.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH3 - C ⁇ CCH2CH3, -CH2C ⁇ CH.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, - N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C6 heteroalkyl.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl (“aryl,” e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • carbocyclic or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl.
  • an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl.
  • a cycloalkyl is a C3- C6cycloalkyl.
  • a cycloalkyl is a C3-C4cycloalkyl.
  • cycloalkyloxy refers to a cycloalkyl group attached to the parent molecular moiety through an oxy.
  • the cycloalkyloxy is a C3-C6cycloalkyloxy, which refers to a (C3-C6cycloalkyl)-O- group.
  • a “cycloalkylalkyl” refers to an alkyl in which one hydrogen atom is replaced by a cycloalkyl group, as defined herein.
  • a cycloalkylalkyl is a (C3- C6cycloalkyl)-C1-C6alkyl.
  • a cycloalkylalkyl is a (C3-C6cycloalkyl)-C1- C4alkyl.
  • a “cycloalkoxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a cycloalkoxy group, as defined herein.
  • a cycloalkoxyalkyl is a (C3- C6cycloalkoxy)-C1-C6alkyl, which refers to a (C3-C6cycloalkyl)-O-(C1-C6alkyl)- group.
  • a “cycloalkylalkoxy” refers to an alkoxy in which one hydrogen atom is replaced by a cycloalkyl group, as defined herein.
  • a cycloalkylalkoxy is a (C3- C6cycloalkyl)-C1-C6alkoxy, which refers to a (C3-C6cycloalkyl)-(C1-C6alkyl)-O- group.
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C1-C6 fluoroalkyl.
  • a fluoroalkyl is a C1-C4 fluoroalkyl.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • the haloalkoxy is a C1-C6haloalkoxy, which refers to a (C1-C6haloalkyl)-O- group.
  • the haloalkoxy is a C1-C4haloalkoxy, which refers to a (C1-C4haloalkyl)-O- group.
  • the haloalkoxy when the halo is a fluorine, the haloalkoxy is a fluoroalkoxy.
  • fluoroalkoxy refers to an alkoxy in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkoxy is a C1-C6 fluoroalkoxy.
  • a fluoroalkoxy is a C1-C4 fluoroalkoxy.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 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 heterocyclic groups also known as heterocycloalkyls
  • aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-1-yl (N- attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5- yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C1-C9 heteroaryl.
  • monocyclic heteroaryl is a C1-C5heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C6-C9 heteroaryl.
  • a “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2- onyl, or thiazolidin-2-onyl.
  • a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring.
  • a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a 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 two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • the term “moiety” refers to a specific segment or functional group of a molecule.
  • optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
  • substituted groups are substituted with one or two of the preceding groups.
  • the term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
  • the term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • the term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.
  • the term “degrader” as used herein refers to a bifunctional compound that binds to and/or inhibits both a TYK2 kinase and an E3 ubiquitin ligase resulting in the ubiquitination and subsequent degradation of the TYK2 kinase.
  • degraders are bifunctional or proteolysis-targeting chimeric (PROTAC®) protein degrader compounds, which find utility as modulators of targeted ubiquitination of TYK2 proteins, which are then degraded and/or inhibited by the bifunctional compounds.
  • such bifunctional molecules function by recruiting the TYK2 kinase to the E3 ubiquitin ligase for ubiquitination and subsequent degradation of the TYK2 kinase.
  • the degrader comprises a TYK2 binding moiety (e.g., a group comprising a compound described herein) bound to an E3 ubiquitin ligase moiety, optionally through a linker.
  • compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that the active ingredients, e.g.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the term “subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth 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, Seventh Ed.
  • a compound or a pharmaceutical composition of the present disclosure is, in some embodiments, useful for the treatment of a TYK2 mediated disease or disorder.
  • the pharmaceutical composition is effective at treating a disease or disorder wherein TYK2 is overexpressed or hyperactive.
  • the pharmaceutical composition is effective at treating a disease or disorder which would benefit from a reduction in TYK2 activity or expression.
  • the pharmaceutical composition is useful in the treatment of disease or disorder associated with high levels of cytokines driven by TYK2, such as interferons (e.g.
  • the disease or disorder is an inflammatory disease or disorder, an autoimmune disease or disorder, a respiratory disease or disorder, type 1 diabetes, and interferonopathies such as Alcardi-Goutieres syndrome, or combinations thereof.
  • the pharmaceutical composition is useful in the treatment of an inflammatory disease or disorder.
  • the inflammatory disease or disorder is an auto-inflammatory disease or disorder, a host-mediated inflammatory disease or disorder, an injury-related inflammatory disease or disorder, an infection-related inflammatory disease or disorder, a hyperproliferative (e.g., cancer, fibrosis) mediated inflammatory disease or disorder.
  • the inflammatory disease or disorder or infection-related inflammatory disease or disorder is a respiratory disease or disorder.
  • the respiratory disease or disorder is associated with a viral in microbial infection.
  • the respiratory disease or disorder is a problematic immune response to a viral or microbial infection.
  • the respiratory disease or disorder is associated with a coronavirus such as MERS-CoV, SARS-CoV-1, or SARS-CoV-2.
  • the pharmaceutical composition is effective in decreasing symptoms associated with COVID-19, or an immune response associated therewith. [00221] In some embodiments, the pharmaceutical composition is useful in the treatment of an autoimmune disease or disorders.
  • an autoimmune disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
  • an autoimmune disease or disorder is lupus or systemic lupus erythematosus. In some embodiments, an autoimmune disease or disorder is psoriasis. In some embodiments, an autoimmune disease or disorder is irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IBS-D). In some embodiments, an autoimmune disease or disorder is dry eye or uveitis. In some embodiments, an autoimmune disease or disorder is Crohn’s disease. In some embodiments, an autoimmune disease or disorder is atopic dermatitis. [00222] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • compounds described herein can be administered locally to the area in need of treatment, by for example, topical application such as creams or ointments. Additional examples of local administration of the present compounds include eye drops, ocular creams, gels or hydrogels, implants, transdermal patches, or drug depots.
  • a pharmaceutical composition is administered orally (e.g., in a liquid formulation, tablet, capsule, nebulized liquid, aerosolized liquid, dry powder spray).
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example, as an emulsion in an acceptable oil
  • ion exchange resins for example, as an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present disclosure externally to the epidermis or the buccal cavity and the installation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
  • Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations 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 dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding.
  • JAKs Janus kinase
  • Cytokines implicated in TYK2 activation include interferons (e.g. IFN- ⁇ , IFN- ⁇ , IFN-K, IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN-co, and IFN- ⁇ (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 cytokine, and LIF).
  • interferons e.g. IFN- ⁇ , IFN- ⁇ , IFN-K, IFN- ⁇ , IFN- ⁇ , IFN-co, and IFN- ⁇ (also known as limitin)
  • interleukins e.g. IL-6, IL-10, IL-12, IL-23, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF.
  • mice containing the rs3456443 loss of function (LoF) mutation in the pseudokinase domain of TYK2 show a decreased risk of disease in EAE, with evidence showing that this is due to impaired IL-12, IL-23, and Type 1 IFN signaling (See, Dendrou et al, Sci Transl Med (2016)).
  • Cytokine induced pSTAT phosphorylation by the rs3456443 genotype in primary human immune cells confirm a dose response for wild type – heterozygous – homozygous for IFN- ⁇ / ⁇ , IL-23, and IL-12, confirming that this is a TYK2 LoF mutation.
  • This LoF mutation in TYK2 leads to decreased demyelination and increased remyelination of neurons, which supports the role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.
  • increased levels of IL-12 and IL-23 have been found in MS lesions, and IFN- ⁇ 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 widely 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 an IL-23 encoding adenoviral vector induces clinical relapses of EAE. Accordingly, use of a TYK2 inhibitor can 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- ⁇ (A ⁇ ) peptide, which demonstrates its role in potential treatment of Alzheimer’s Disease (AD). Decreased TYK2 phosphorylation of STAT3 following A ⁇ administration leads to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. (See, Wan et al., J. Neurosci. (2010) 30(20):6873-6881). [00235] In some embodiments, certain TYK2 inhibitors described herein penetrate the blood- brain barrier.
  • certain TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of more than 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of more than 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean 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.
  • the compounds of this disclosure are useful in neuroinflammatory diseases and conditions.
  • neuroinflammatory diseases and conditions include, but are not limited to, multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or a neuromyelitis optica spectrum disorder.
  • compounds of the instant disclosure are useful in the treatment of multiple sclerosis (MS).
  • the MS is relapsing MS or relapsing-remitting MS (RRMS).
  • RRMS relapsing-remitting MS
  • compounds of the instant disclosure are useful in the treatment of a neuromyelitis optica spectrum disorder, such as neuromyelitis optica.
  • compounds of the instant disclosure are useful in the treatment of encephalomyelitis, including acute disseminated encephalomyelitis.
  • compounds of the instant disclosure are useful in the treatment of polyneuropathy, such as chronic inflammatory demyelinating polyneuropathy.
  • compounds of the instant disclosure are useful in the treatment of encephalitis, including autoimmune encephalitis.
  • the present disclosure provides methods of 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.
  • 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 a neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is multiple sclerosis.
  • the multiple sclerosis is relapsing or relapsing-remitting.
  • the disease or condition is a neuromyelitis optica spectrum disorder.
  • the disease or condition is neuromyelitis optica.
  • the disease or condition is encephalomyelitis.
  • the disease or condition is acute disseminated encephalomyelitis.
  • the disease or condition is polyneuropathy.
  • the disease or condition is chronic inflammatory demyelinating polyneuropathy.
  • the disease or condition is encephalitis.
  • the disease or condition is autoimmune encephalitis.
  • the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
  • the compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of TYK2 activity.
  • Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • 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 of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.”
  • a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a “prophylactically effective amount or dose.”
  • dose a pharmaceutically effective amount or dose.
  • the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • prophylactic treatments include administering to a mammal, who 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, in order to prevent a return of the symptoms of the disease or condition.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout 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.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day.
  • the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg/kg per body weight.
  • the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • 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.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co- administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • Step-2 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylethan-1-amine (I-1c): To a stirred solution of I-1b (17 g, 83.3 mmol) in MeOH (80 mL) was added TEA (23.2 mL, 167 mmol) and methylamine hydrochloride (11.3 g, 167 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. It was then cooled to 0 °C and NaBH4 (6.3 g, 167 mmol) was added to it portion-wise. The reaction mixture was allowed to warm to room temperature over 2 h.
  • Step-3 tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol- 4-yl)ethyl)(methyl)carbamate (I-1d): A solution of (Boc)2O (35.7 mL, 155 mmol) in THF (100 mL) was added to the 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 to it. Extraction was carried out using EtOAc (50 mL x 2).
  • Step-4 tert-butyl (1-(5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-1e): Argon gas was purged through a solution of I-1d (15.0 g, 47 mmol), (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (22.2 g, 117.0 mmol) and CsF (21.4 g, 141 mmol) in THF (75 mL) for 15 min.
  • Step-5 6-chloro-2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-1f): A 4M solution of HCl in 1,4-dioxane (120 mL) was added to a solution of I-1e (9 g, 23.4 mmol) in dichloromethane (50 mL) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and dried (co-evaporation with 1,4-dioxane).
  • Step-6 N-(2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-1g): Argon gas was purged through a stirred suspension of I-1f (2.5 g, 9.48 mmol), cyclopropanecarboxamide (1.21 g, 14.2 mmol) and Cs2CO3 (6.18 g, 19.0 mmol) in 1,4-dioxane (30 mL) for 15 min.
  • Step-7 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-1): To a stirred solution of I-1g (2.1 g, 6.7 mmol) in THF (15 mL) was added an aqueous solution of LiOH.H2O (1.61 g, 67.2 mmol, in 10 mL water) at room temperature. It was then stirred at 80 °C for 16 h. After completion, it was cooled to room temperature and water (20 mL) was added to it.
  • Example 2 Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-2): [00266] Step-1: tert-butyl methyl(1-(2-methyl-5-(tributylstannyl)-2H-1,2,3-triazol-4- yl)ethyl)carbamate (I-2a): Argon gas was purged through a stirred suspension of I-1d (15.0 g, 47 mmol) in hexabutyl ditin ( 24.5 mL, 73.8 mmol) for 15 min, before addition of Pd(OAc)2 (0.15 g, 0.67 mmol) and tricyclohexylphosphine (0.38 g, 1.34 mmol).
  • the reaction mixture was heated at 110 °C for 20 h in a sealed tube. It was then cooled to room temperature, filtered through 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 gradient elution of 0-20% EtOAc in heptane) to afford I-2a (9.2 g) as a pale yellow semi-solid. It was carried forward for the next step.
  • Step-2 tert-butyl (1-(5-(2-chloro-3-fluoro-5-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-2b): Argon gas was purged through a stirred suspension of I-2a (13.6 g, 25.7 mmol), 2-chloro-3-fluoro-4-iodo-5-methylpyridine (13.9 g, 51.4 mmol) and LiCl (2.5 g, 59.1 mmol) in DMF (130.0 mL) for 15 min.
  • Step-3 6-chloro-2,4,5,9-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-2c): TFA (8 mL) was added to a solution of I-2b (2 g, 5.21 mmol) in dichloromethane (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. After completion (as indicated by TLC), volatiles were removed under reduced pressure and dried (co-evaporation with 1,4-dioxane).
  • Step-4 N-(2,4,5,9-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-2d): I-2d (1.33 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-2c (1.7 g, 6.45 mmol) and cyclopropanecarboxamide (0.82 g, 9.67 mmol) as the starting materials. LCMS (ES) m/z; 313.1 [M+H]+.
  • Step-5 2,4,5,9-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-2): I-2 (0.94 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-2d (1.33 g, 4.26 mmol) as the starting material. LCMS (ES) m/z; 245.2 [M+H]+.
  • Racemate I-2 (0.94 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 ⁇ m) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (95:05) Flow rate : 18.0 mL/min] to afford two enantiomers ⁇ I-2A (0.25 g): peak-1; Rt; 12.17 min and I-2B (0.28 g): peak-2; Rt; 15.31 min ⁇ , which were used further without their absolute configuration determination.
  • Example 3 Preparation of 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-3): [00272]
  • Step-1 tert-butyl (1-(5-(2,5-dichloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate
  • I-3a (4.4 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-2a (20 g, 37.8 mmol) as the starting material.
  • Step-2 6,9-dichloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-3b): I-3b (1.2 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-3a (4.4 g, 14.5 mmol) as the starting material. LCMS (ES) m/z; 284.0 [M+H]+.
  • Step-3 N-(9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-3c): I-3c (1.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-3b (1.0 g, 3.52 mmol) as the starting material. LCMS (ES) m/z; 333.1 [M+H]+.
  • Step-4 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-3): I-3 (0.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-3c (1.1 g, 3.31 mmol) as the starting material. LCMS (ES) m/z; 265.1 [M+H]+.
  • Racemate I-3 (0.7 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 ⁇ m) Mobile phase: n-hexane:EtOH with 0.1% DEA (90:10) Flow rate : 18.0 mL/min] to afford two enantiomers ⁇ I-3A (0.25 g): peak-1; Rt; 11.4 min and I-3B (0.25 g): peak-2; Rt; 17.7 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 5-bromo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde (I-4a): To a stirred solution of I-1a (10 g, 41.6 mmol) in THF (100 mL) was added a 2M solution of isopropylmagnesium chloride in THF (22.8 mL, 45.6 mmol) at -30 °C and stirred for 1 h at the same temperature.
  • Step-2 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylmethanamine (I-4b): To a stirred solution of I-4a (15 g, 78.9 mmol) in MeOH (150 mL) was added TEA (22.0 mL, 158 mmol) and methylamine hydrochloride (10.7 g, 158 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature.
  • Step-3 tert-butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-4c): A solution of (Boc)2O (33.6 mL, 146.2 mmol) in THF (60 mL) was added to the aqueous NaHCO3 solution containing I-4b 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 to it. Extraction was carried out using EtOAc (50 mL x 2).
  • Step-4 tert-butyl ((5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)methyl)(methyl)carbamate (I-4d):
  • I-4d (4.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-4c (6.0 g, 19.7 mmol) as the starting material.
  • Step-5 6-chloro-2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-4e): I-4e (2.1g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-4d (4.4 g, 11.9 mmol) as the starting material. LCMS (ES) m/z; 250.1 [M+H]+.
  • Step-6 N-(2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-4f): I-4f (1.9g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-4e (2.1 g, 8.41 mmol) as the starting material. LCMS (ES) m/z; 299.1 [M+H]+.
  • Step-7 2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- amine (I-4): I-4 (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-4f (1.9 g, 6.37 mmol) as the starting material. LCMS (ES) m/z; 231.1 [M+H]+.
  • Example 5 Preparation of 2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-amine (I-5): [00284] Step-1: 5-bromo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde (I-5a): To a stirred solution of I-1a (10 g, 41.6 mmol) in THF (100 mL) was added a 2M solution of isopropylmagnesium chloride in THF (22.8 mL, 45.6 mmol) at -30 °C and stirred for 1 h at the same temperature.
  • Step-2 (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methanol (I-5b): To a stirred solution of I-5a (9.3 g, 48.9 mmol) in MeOH (100 mL) at 0 °C was added sodium borohydride (2.78 g, 73.4 mmol) and the mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was quenched with addition of water (100 mL) and MeOH was concentrated under reduced pressure.
  • Step-3 4-bromo-5-(bromomethyl)-2-methyl-2H-1,2,3-triazole (I-5c): To a stirred solution of I-5b (8.0 g, 41.7 mmol) in DCM (80 mL) was added CBr4 (18.0 g, 54.2 mmol) and PPh3 (14.2 g, 54.2 mmol) at 0 °C and the reaction was stirred for 1 h at room temperature. After completion of the reaction (as indicated by TLC), water (100 mL) was added to it and extracted with DCM (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude product.
  • Step-4 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)acetonitrile (I-5d): To a stirred solution of I-5c (10.2 g, 40.0 mmol) in ACN (100 mL) was added TMSCN (7.51 mL, 60.0 mmol) and tetrabutylammonium fluoride (1.0 M in THF) (60.0 mL, 60.0 mmol) and the reaction mixture was stirred for 1 h at room temperature. After completion of the reaction (as indicated by TLC), the reaction mixture was diluted with EtOAc (200 mL) and was washed with water (100 mL).
  • Step-5 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropane-1-carbonitrile (I- 5e): To a stirred solution of I-5d (7.4 g, 36.8 mmol) in DMF (70 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C and stirred for 30 min before addition of 1,2-dibromoethane (6.37 mL, 73.6 mmol). The reaction was stirred for 2 h at room temperature, while monitoring reaction progress by TLC. After completion of the reaction, it was quenched with addition of ice cold water (100 mL).
  • Step-6 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylic acid (I-5f): A suspension of I-5e (10.5 g, 46.2 mmol) in 10% aqueous NaOH solution (250 mL) was stirred at 100 °C for 16 h, while monitoring reaction progress by TLC. After completion of the reaction, the homogeneous solution was washed with EtOAc (300 mL) and the aqueous layer was then acidified using 6 M aqueous HCl (pH ⁇ 3).
  • Step-7 tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)cyclopropyl)carbamate (I-5g): To a solution of I-5f (12.2 g, 49.6 mmol) in t-butanol (250 mL) was added triethylamine (10.5 mL, 74.4 mmol) and DPPA (11.3 mL, 59.5 mmol). The resulting mixture was heated at 100 °C for 16 h, while monitoring reaction progress by LCMS. After completion, the reaction mixture was cooled to room temperature and volatile were removed under reduced pressure.
  • Step-8 tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)cyclopropyl)(methyl)carbamate (I-5h): To a stirred solution of I-5g (2.7 g, 8.51 mmol) in DMF (30 mL) was added sodium hydride (0.41 g, 10.2 mmol) at 0 °C and was stirred for 20 min at 0 °C. Then iodomethane (0.64 mL, 10.2 mmol) was added and the reaction was stirred at room temperature for 1 h.
  • reaction mixture was quenched with addition of ice cold water (50 mL) and extraction was carried out using EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-20 % EtOAc in n-heptane) to afford I-5h (2.8 g) as colourless thick oil.
  • Step-9 tert-butyl (1-(5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)cyclopropyl)(methyl)carbamate (I-5i):
  • I-5i (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-5h (3.5 g, 10.6 mmol) and (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (4 g, 21.1 mmol) as the starting materials.
  • Step-10 6'-chloro-2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine]
  • I-5j (1.6 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-5i (3.0 g, 7.58 mmol) as the starting material.
  • Step-11 N-(2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)cyclopropanecarboxamide (I-5k): I-5k (1.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-5j (1.6 g, 5.73 mmol) as the starting material. LCMS (ES) m/z; 325.1 [M+H]+.
  • Step-12 2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-amine
  • I-5 (0.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-5k (1.8 g, 5.55 mmol) as the starting material.
  • Step-1 N-(3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-yl)-2- methylpropane-2-sulfinamide (I-6a): To a stirred solution of I-1a (10 g, 41.5 mmol) in anhydrous THF (100 mL) was added a 2M solution of n-BuLi in cyclohexane (18.7 mL, 37.5 mmol) at -30 °C and stirred for 30 min at -78 °C.
  • Step-2 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-amine (I-6b): To a stirred solution of I-6a (9.0 g, 26.7 mmol) in MeOH (100 mL) was added a 4M solution of HCl in 1,4-dioxane (30 mL) at 0 °C and the reaction mixture was stirred for 15 min.
  • Step-3 tert-butyl (3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3- yl)carbamate (I-6c): A solution of (Boc)2O (12.2 mL, 53.2 mmol) in THF (60 mL) was added to an aqueous NaHCO3 solution containing I-6b and the reaction mixture was stirred at room temperature for 16 h. Water (50 mL) was then added to it and extraction was carried out using EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step-4 tert-butyl (3-(5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)oxetan-3-yl)carbamate (I-6d): I-6d (2.9 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-6c (5.0 g, 15 mmol) as the starting material. LCMS (ES) m/z; 398.1 [M+H]+.
  • Step-5 6'-chloro-2',8'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine]
  • I-6e (1.0 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-6d (2.96 g, 7.44 mmol) as the starting material.
  • Step-6 6'-chloro-2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine]
  • I-6f 6'-chloro-2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine]
  • Step-7 N-(2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-yl)cyclopropanecarboxamide (I-6g): I-6g (0.55 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-6f (0.67 g, 2.3 mmol) and cyclopropanecarboxamide (0.67 g, 2.3 mmol) as the starting materials.
  • Step-8 2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-amine (I-6): I-6 (0.27 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-6g (0.39 g, 4.59 mmol) as the starting material. LCMS (ES) m/z; 273.2 [M+H]+.
  • Example 7 Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-7): [00304] Step-1: 1-(3-bromo-1-methyl-1H-pyrazol-4-yl)ethan-1-ol (I-7b): To a stirred solution of I-7a (25 g, 132.3 mmol) in anhydrous THF (250 mL) was added a 1M solution of MeMgBr in Et2O (198.3 mL, 198.4 mmol) at -78 °C and the reaction mixture was allowed to warm to room temperature over 20 min.
  • Step-2 1-(3-bromo-1-methyl-1H-pyrazol-4-yl)ethan-1-one (I-7c): To a stirred solution of I-7b (15 g, 73.2 mmol) in DCM (150.0 mL) was added DMP (40.3 g, 95.1 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature over 1 h. The reaction progress was monitored by LCMS. After completion, it was filtered through Celite bed and washed with DCM (50 mL x 2).
  • Step-3 1-(3-bromo-1-methyl-1H-pyrazol-4-yl)-N-methylethan-1-amine (I-7d): To a stirred solution of I-7c (15.5 g, 76.35 mmol) in THF (150 mL) was added titanium(IV) isopropoxide (45.2 mL, 152.70 mmol) in a sealed tube at 0 °C. To this was then added a 2M solution of MeNH2 in THF (76.3 mL, 152.70 mmol) and the reaction mixture was stirred at 60 °C for 16 h. It was then cooled to room temperature and volatiles were removed under reduced pressure.
  • Step-4 tert-butyl (1-(3-bromo-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)carbamate (I-7e): I-7e (19 g) was synthesized by following procedure as described for the synthesis of I-1 (step-3). LCMS (ES) m/z; 318.0 [M+H]+.
  • Step-5 tert-butyl (1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1-methyl-1H- pyrazol-4-yl)ethyl)(methyl)carbamate (I-7f):
  • I-7f (5.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-7e (5.0 g, 15.7 mmol) and (2- chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (5.95 g, 31.4 mmol) as the starting materials.
  • Step-6 6-chloro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridine (I-7g): I-7g (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-7f (10.0 g, 26.2 mmol) as the starting material. LCMS (ES) m/z; 263.1 [M+H]+.
  • Step-7 N-(2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-7h): I-7h (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-7g (3.0 g, 11.4 mmol) and cyclopropanecarboxamide (1.46 g, 17.1 mmol) as the starting materials. LCMS (ES) m/z; 312.2 [M+H]+.
  • Step-8 2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- amine (I-7): I-7 (2.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-7h (3.2 g, 10.3 mmol) as the starting material. LCMS (ES) m/z; 244.1 [M+H]+.
  • Example 8 Preparation of 3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-8): [00312]
  • Step-1 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (I-8b): I-8b (13.0 g) was synthesized by following procedure as described for the synthesis of I-5 (step-1) using I-8a (16.8 g, 69.7 mmol) as the starting material.1H NMR (400 MHz, CDCl3) ⁇ 9.92 (s, 1H); 4.32 (s, 3H).
  • Step-2 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol (I-8c): I-8c (12.0 g) was synthesized by following procedure as described for the synthesis of I-6 (step-1) using I-8b (13.0 g, 68.4 mmol) as the starting material. LCMS (ES) m/z; 206.1 [M+H]+.
  • Step-3 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-one (I-8d):
  • I-8d (8.8 g) was synthesized by following procedure as described for the synthesis of I-6 (step-2) using I-8c (12.0 g, 58.2 mmol) as the starting material.1H NMR (400 MHz, CDCl3) ⁇ 4.26 (s, 3H); 2.71 (s, 3H).
  • Step-4 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylethan-1-amine (I-8e): I-8e was synthesized by following procedure as described for the synthesis of I-6 (step-3) using I-8d (8.8 g, 43.1 mmol) as the starting material. LCMS (ES) m/z; 219.1 [M+H]+.
  • Step-5 tert-butyl (1-(4-bromo-1-methyl-1H-1,2,3-triazol-5- yl)ethyl)(methyl)carbamate (I-8f): I-8f (12.0 g) was synthesized by following procedure as described for the synthesis of I-6 (step-4) using I-8e as the starting material. LCMS (ES) m/z; 319.1 [M+H]+.
  • Step-6 tert-butyl (1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1-methyl-1H- 1,2,3-triazol-5-yl)ethyl)(methyl)carbamate (I-8g): I-8g (5.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-8f (9 g, 28.2 mmol) and (2- chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (10.7 g, 56.4 mmol) as the starting material. LCMS (ES) m/z; 384.1 [M+H]+.
  • Step-7 6-chloro-3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-8h): I-8h (0.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-8g (5.4 g, 14.1 mmol) as the starting material. LCMS (ES) m/z; 264.1 [M+H]+.
  • Step-8 N-(3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-8i): I-8i (2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-8h (2 g, 7.58 mmol) and cyclopropanecarboxamide (1.29 g, 15.2 mmol) as the starting materials. LCMS (ES) m/z; 313.2 [M+H]+.
  • Step-9 3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-8): I-8 (1.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-8i (2 g, 6.4 mmol) as the starting material. LCMS (ES) m/z; 245.1 [M+H]+.
  • Step-1 4-bromo-1,2-dimethyl-1H-imidazole-5-carbaldehyde (I-9b): To a stirred solution of I-9a (10.0 g, 39.4 mmol) in anhydrous THF (100.0 mL) was added n-BuLi (2.5M solution in hexane) (15.76 mL, 39.4 mmol) at -78 °C and stirred for 30 min at the same temperature.
  • n-BuLi 2.5M solution in hexane
  • Step-2 1-(4-bromo-1,2-dimethyl-1H-imidazol-5-yl)ethan-1-ol (I-9c): I-9c (5.5 g) was synthesized by following procedure as described for the synthesis of I-7 (step-1) using I-9b (9.0 g, 44.35 mmol) as the starting material. LCMS (ES) m/z; 219.0 [M+H]+.
  • Step-3 1-(4-bromo-1,2-dimethyl-1H-imidazol-5-yl)ethan-1-one (I-9d): I-9d (3.0 g) was synthesized by following procedure as described for the synthesis of I-7 (step-2) using I-9c (6.0 g, 27.4 mmol) as the starting material. LCMS (ES) m/z; 216.9 [M+H]+.
  • Step-4 1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1,2-dimethyl-1H-imidazol-5- yl)ethan-1-one (I-9e): I-9e (5.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-9d (9.0 g, 28.2 mmol) and (2-chloro-3-fluoro-6-methylpyridin- 4-yl)boronic acid (10.7 g, 56.4 mmol) as the starting materials. LCMS (ES) m/z; 282.1 [M+H]+.
  • Step-5 1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1,2-dimethyl-1H-imidazol-5- yl)-N-methylethan-1-amine (I-9f): I-9f (5.7 g) was synthesized by following procedure as described for the synthesis of I-6 (step-3) using I-9e (5.7 g, 20.2 mmol) as the starting material. LCMS (ES) m/z; 297.1 [M+H]+.
  • Step-6 6-chloro-2,3,4,5,8-pentamethyl-4,5-dihydro-3H-imidazo[4,5- c][1,7]naphthyridine (I-9g): To a stirred solution of I-9f (5.5 g, 18.5 mmol) in NMP (50.0 mL) was added DIPEA (16.1 mL, 92.7 mmol) at 0 °C and the reaction mixture was heated at 140 °C for 2 h, while monitoring reaction progress by LCMS. After completion, the reaction mixture was cooled to room temperature and water (50 mL) was added to it.
  • Step-7 N-(2,3,4,5,8-pentamethyl-4,5-dihydro-3H-imidazo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-9h): I-9h (0.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-9g (1.0 g, 3.61 mmol) and cyclopropanecarboxamide (0.46 g, 5.42 mmol) as the starting materials. LCMS (ES) m/z; 326.2 [M+H]+.
  • Step-8 2,3,4,5,8-pentamethyl-4,5-dihydro-3H-imidazo[4,5-c][1,7]naphthyridin-6- amine (I-9): I-9 (0.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-9h (1.1 g, 3.38 mmol) as the starting material. LCMS (ES) m/z; 258.2 [M+H]+.
  • Racemate I-9 (2.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 ⁇ m); Mobile phase: n-hexane:IPA with 0.1% DEA (50:50); Flow rate: 40 mL/min)] to afford two enantiomers ⁇ I-9A (0.15 g): peak-1; Rt; 9.75 min and I-9B (0.15 g): peak-2; Rt; 12.44 min ⁇ , which were used further without their absolute configuration determination.
  • Example 10 Preparation of 5,6,9-trimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin- 7-amine (I-10): [00330]
  • Step-1 1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)pyrazin-2-yl)ethan-1-one (I- 10b): I-1-10b (4.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-10a (6.0 g, 38.3 mmol) as the starting material.
  • Step-2 1-(3-(2-chloro-3-fluoropyridin-4-yl)pyrazin-2-yl)ethan-1-one (I-10c): I-10c (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-2) using I-10b (4.1 g, 15.4 mmol) as the starting material. LCMS (ES) m/z; 261.1 [M+H]+.
  • Step-3 7-chloro-5,6-dimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridine (I- 10d): I-10d (1.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-10c (2.0 g, 7.67 mmol) as the starting material. LCMS (ES) m/z; 310.2 [M+H]+.
  • Step-4 N-(5,6-dimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7- yl)cyclopropanecarboxamide (I-10): I-10 (1.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-10d (1.6 g, 5.17 mmol) as the starting material. LCMS (ES) m/z; 242.2 [M+H]+.
  • Racemate I-10 (2.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 ⁇ m); Mobile phase: n-hexane:IPA with 0.1% DEA (95:05); Flow rate: 18 mL/min)] to afford two enantiomers ⁇ I-10A (0.35 g): peak-1; Rt; 12.14 min and I-10B (0.0.35 g): peak-2; Rt; 15.42 min ⁇ , which were used further without their absolute configuration determination.
  • Example 11 Preparation of 2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-11): [00335] Step-1: 2,4-dibromothiazole-5-carboxylic acid (I-11b): To a stirred solution of I-11a (30 g, 123 mmol) in tetrahydrofuran (200 mL) at - 78 ° C was added LDA (123 mL, 247 mmol, 2M in THF) and allowed the reaction mixture to stir at -78 °C for 45 min.
  • LDA 123 mL, 247 mmol, 2M in THF
  • Step-2 2,4-dibromo-N-methoxy-N-methylthiazole-5-carboxamide (I-11c): To a stirred solution of I-11b (40 g, 139 mmol) in DCM (400 mL) was added DIPEA (71.5 mL, 418 mmol), methoxy(methyl)amine hydrochloride (27.2 g, 279 mmol), HATU (79.5 g, 209 mmol) and the reaction was allowed to stir at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS.
  • Step-3 4-bromo-N-methoxy-N,2-dimethylthiazole-5-carboxamide (I-11d): To a solution of I-11c (36.6 g, 111 mmol) in THF (400 mL) in a sealed tube was added methylboronic acid (7.97 g, 133 mmol), potassium phosphate (58.8 g, 277 mmol), [5- (diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (6.42 g, 11.1 mmol) and the reaction mixture was purged with argon for 15 min.
  • methylboronic acid 7.97 g, 133 mmol
  • potassium phosphate 58.8 g, 277 mmol
  • [5- (diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (6.42 g, 1
  • Step-4 1-(4-bromo-2-methylthiazol-5-yl)ethan-1-one (I-11e): To a solution of I-11d (5.8 g, 21.9 mmol) in THF (60 mL) was added methyl magnesium bromide (3.0M in diethyl ether) (21.9 mL, 65.6 mmol) at 0 °C and the reaction was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS.
  • Step-5 1-(4-bromo-2-methylthiazol-5-yl)-N-methylethan-1-amine (I-11f): I-11f (4.4 g) was synthesized by following procedure as described for the synthesis of I-7 (step-3) using I-11e (4.1 g, 18.6 mmol) as the starting material. LCMS (ES) m/z; 237.0 [M+2H]+.
  • Step-6 tert-butyl (1-(4-bromo-2-methylthiazol-5-yl)ethyl)(methyl)carbamate (I- 11g): I-11g (5.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-3) using I-11f (4.4 g, 18.7 mmol) as the starting material.1H NMR (400 MHz, CDCl3) ⁇ 5.56 - 5.47 (m, 1H), 2.72 (s, 3H), 2.67 (s, 3H), 1.52 - 1.50 (m, 3H), 1.48 (s, 9H). LCMS (ES) m/z; 335.1 [M+H]+.
  • Step-7 tert-butyl (1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methylthiazol-5- yl)ethyl)(methyl)carbamate (I-11h): I-11h (8.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-11g (12.9 g, 38.5 mmol) and (2-chloro-3- fluoro-6-methylpyridin-4-yl)boronic acid (10.9 g, 57.7 mmol) as the starting material. LCMS (ES) m/z; 400.1 [M+H]+.
  • Step-9 N-(2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4-c][1,7]naphthyridin-6- yl)cyclopropanecarboxamide (I-11j): I-11j (4.46 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-11i (2.9 g, 10.4 mmol) and cyclopropanecarboxamide (1.76 g, 20.7 mmol) as the starting materials. LCMS (ES) m/z; 329.1 [M+H]+.
  • Step-10 2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4-c][1,7]naphthyridin-6-amine (I-11): I-11 (2.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-11j (4.46 g, 10.9 mmol) as the starting material. LCMS (ES) m/z; 261.1 [M+H]+.
  • Example 12 Preparation of 2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-12): [00345] Step-1: tert-butyl (1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1,5-dimethyl-1H- pyrazol-4-yl)ethyl)(methyl)carbamate (I-12a): I-12a (14.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-5g (13.6 g, 40.9 mmol) as the starting material.
  • Step-2 6-chloro-2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridine (I-12b): I-12b (3.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-12a (10.8 g, 36.4 mmol) as the starting material. LCMS (ES) m/z; 277.1 [M+H]+.
  • Step-3 N-(2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-12c): I-12c (2.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-12b (2.4 g, 8.67 mmol) and cyclopropanecarboxamide (0.840 g, 9.87 mmol) as the starting materials. LCMS (ES) m/z; 326.2 [M+H]+.
  • Step-4 2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- amine (I-12): I-12 (1.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-12c (2.7 g, 8.3 mmol) as the starting material. LCMS (ES) m/z; 258.2 [M+H]+.
  • Example 13 Preparation of 2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-13): [00349] Step-1: tert-butyl ⁇ 1-[3-(2-chloro-3-fluoro-5-methyl-4-pyridyl)-1-methyl-4- pyrazolyl]ethyl ⁇ (methyl)carbamate (I-13a) : I-13a (4.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-6e (6 g, 18.9 mmol) as the starting material.
  • Step-2 6-chloro-2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridine (I-13b): I-13b (2.7 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-13a (8.6 g, 22.5 mmol) as the starting material. LCMS (ES) m/z; 263.1 [M+H]+.
  • Step-3 N-(2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-13c): I-13c (3.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-13b (2.7 g, 10.3 mmol) and cyclopropanecarboxamide (1.75 g, 20.6 mmol) as the starting materials. LCMS (ES) m/z; 312.1 [M+H]+.
  • Step-4 2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- amine (I-13): I-13 (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-13c (3.6 g, 11.6 mmol) as the starting material. LCMS (ES) m/z; 244.2 [M+H]+.
  • Racemate I-13 (1.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK AD-H (250 mm x 30 mm x 5 ⁇ m) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (85:15) Flow rate : 40.0 mL/min] to afford two enantiomers ⁇ I-13A (0.6 g): peak-1; Rt; 11.93 min and I-13B (0.55 g): peak-2; Rt; 14.24 min ⁇ , which were used further without their absolute configuration determination.
  • Example 14 Preparation of 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-14): [00354] Step-1: 2,5-dichloro-3-fluoro-4-iodopyridine (I-14b): To a stirred solution of I-14a (10 g, 60.2 mmol) in anhydrous THF (100 mL) was added a 2M solution of LDA in THF (60.2 mL, 120 mmol) at -78 °C and stirred for 2 h at -78 °C.
  • Step-2 tert-butyl (1-(5-(2,5-dichloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-14c): I-14c (3.2 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-14b (8.27 g, 28.3 mmol) and I-2a (10 g, 18.9 mmol) as the starting materials. LCMS (ES) m/z; 405.1 [M+H]+.
  • Step-3 6,9-dichloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-14d): I-14b (1.4 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-14c (4.4 g, 14.5 mmol) as the starting material. LCMS (ES) m/z; 284.0 [M+H]+.
  • Step-4 N-(9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-14e): I-14e (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-14d (1.4 g, 4.93 mmol) and cyclopropanecarboxamide (0.63 g, 7.39 mmol) as the starting materials. LCMS (ES) m/z; 333.1 [M+H]+.
  • Step-5 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-14): I-14 (0.85 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-14e (1.3 g, 3.91 mmol) as the starting material. LCMS (ES) m/z; 244.2 [M+H]+.
  • Racemate I-14 (1.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 ⁇ m) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (85:15) Flow rate : 18.0 mL/min] and afforded two enantiomers ⁇ I-14A (0.4 g): peak-1; Rt; 8.78 min and I-14B (0.38 g): peak-2; Rt; 12.28 min ⁇ , which were used further without their absolute configuration determination.
  • Example 15 Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidin-6-amine (I-15): [00360] Step-1: tert-butyl (1-(5-(2,5-dichloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-15a): I-15a (10.9 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-2a (15 g, 28.3 mmol) as the starting material.
  • Step-2 6-chloro-2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidine (I-15b): I-15b (1.0 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-15a (11 g, 28.6 mmol) as the starting material. LCMS (ES) m/z; 265.1 [M+H]+.
  • Step-3 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4',5':4,5]pyrido[3,2- d]pyrimidin-6-amine (I-15):
  • the stirred solution of I-15b (1 g, 3.78 mmol) in ammonium hydroxide (40 mL) in a steel bomb was heated at 100 oC for 16 h. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-2% MeOH in dichloromethane) to afford I-15 (0.7 g) as an off-white solid.
  • Step-1 Synthesis of (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (I-16b): To a stirred solution of I-16a (20 g, 137 mmol) in tetrahydrofuran (250 mL) at -78 °C was added LDA (137 mL, 274 mmol, 2M in THF) dropwise and the reaction mixture was stirred for 2 hours at -78 °C then triisopropylborate (60.2 mL, 261 mmol) was added at -78 °C and stirred for 2 hours at same temperature and at room temperature for 16 h.
  • LDA 137 mL, 274 mmol, 2M in THF
  • Step-2 Synthesis of 1-(2'-chloro-3'-fluoro-6'-methyl-[2,4'-bipyridin]-3-yl)ethan-1- one (I-16c): I-16c (10.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-16b (24.3 g, 129 mmol) and 1-(2-chloropyridin-3-yl)ethan-1- one (10 g, 64.3 mmol) as the starting materials. LCMS (ES) m/z; 265.0 [M+H]+.
  • Step-3 Synthesis of 7-chloro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-16d): To a stirred solution of I-16c (10.5 g, 39.7 mmol) in MeOH (220 mL) was added acetic acid (11.3 mL, 198 mmol) and methylamine (199 mL, 397 mmol, 2M in THF) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. It was then cooled to 0 °C and NaBH3CN (4.99 g, 79.3 mmol) was added to it portion-wise.
  • I-16d 7-chloro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine
  • Step-4 Synthesis of N-(5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-16e): I-16e (4.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-16d (4.8 g, 24.3 mmol) and cyclopropanecarboxamide (3.13 g, 48.5 mmol) as the starting materials. LCMS (ES) m/z; 309.2 [M+H]+.
  • Step-5 Synthesis of 5,6,9-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- amine (I-16): I-16 (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-16e (4.2 g, 19.8 mmol) as the starting material. LCMS (ES) m/z; 241.2 [M+H]+.
  • Racemate I-16 (3.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK AD-H (250 mm x 30 mm x 5 ⁇ m) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (85:15) Flow rate : 38.0 mL/min] to afford two enantiomers ⁇ I-16A (1.1 g): peak-1; Rt; 7.68 min and I-16B (0.9 g): peak-2; Rt; 10.54 min ⁇ , which were used further without their absolute configuration determination.
  • Example 17 Preparation of 6-amino-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine-9-carbonitrile (I-17): [00370]
  • Step-1 Synthesis of 6-chloro-5-fluoro-4-iodonicotinonitrile (I-17b): To a stirred solution of I-17a (15 g, 95.8 mmol) and iodine (42.6 g, 335 mmol) in THF (150 mL) at -78 °C was added LDA (144 mL, 287 mmol, 2M in THF) over a period of 15 minutes and stirred at same temperature for 2 h.
  • LDA 144 mL, 287 mmol, 2M in THF
  • Step-2 Synthesis of tert-butyl (1-(5-(2-chloro-5-cyano-3-fluoropyridin-4-yl)-2- methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-17c): I-17c (5.9 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-18c (14.7 g, 52.1 mmol) and I-2a (23 g, 43.4 mmol) as the starting materials. LCMS (ES) m/z; 339.1 [M+H-56]+.
  • Step-3 Synthesis of 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine-9-carbonitrile (I-17d): I-17d (1.8 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-17c (6.5 g, 16.5 mmol) as the starting material. LCMS (ES) m/z; 275.1 [M+H]+.
  • Step-4 Synthesis of N-(9-cyano-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-17e): I-17e (1.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 17d (2.8 g, 10.2 mmol) and cyclopropanecarboxamide (1.73 g, 20.4 mmol) as the starting materials. LCMS (ES) m/z; 324.2 [M+H]+.
  • Step-5 Synthesis of 6-amino-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine-9-carbonitrile (I-17): I-17 (0.87 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-17e (1.4 g, 4.33 mmol) as the starting material. LCMS (ES) m/z; 256.2 [M+H]+.
  • Racemate I-17 (0.94 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 ⁇ m) Mobile phase: n-Hexane:IPA with 0.1% DEA (55:45) Flow rate : 38.0 mL/min] to afford two enantiomers ⁇ I-17A (0.27 g): peak-1; Rt; 7.81 min and I-17B (0.37 g): peak-2; Rt; 11.45 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 Synthesis of 2-chloro-3-fluoro-5-methoxypyridine (I-18b): To a solution of I-18a (12 g, 81.3 mmol) in acetone (100 mL) was added MeI (8.44 mL, 136 mmol) and potassium carbonate (18.74 g, 136 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC.
  • Step-2 Synthesis of 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (I-18c): To a solution of I-18b (9.8 g, 60.7 mmol) in tetrahydrofuran (20 mL) was added n-butyl lithium (29.1 mL, 72.8 mmol, 2.5 M in hexane) dropwise at -78 °C and the reaction mixture was stirred at -78 °C for 30 min. Then iodine (10.02 g, 78.9 mmol) was added to the above reaction mixture and was stirred at -78 °C for 2 h.
  • n-butyl lithium 29.1 mL, 72.8 mmol, 2.5 M in hexane
  • the reaction mixture was quenched by the addition of saturated sodium thiosulfate solution (50 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure.
  • the crude product was purified by Combi-Flash (using gradient elution 0-20% EtOAc in heptane) to afford I-18c (10.0 g).
  • Step-3 Synthesis of tert-butyl (1-(5-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-2- methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-18d): I-18d (2.8 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-18c (5.86 g, 20.4 mmol) and I-2a (9 g, 17 mmol) as the starting materials. LCMS (ES) m/z; 344.1 [M+H-56]+.
  • Step-4 Synthesis of 6-chloro-9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-18e): I-18e (1.5 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-18d (2.5 g, 6.25 mmol) as the starting material. LCMS (ES) m/z; 280.1 [M+H]+.
  • Step-5 Synthesis of N-(9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-18f): I-18f (1.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 18e (1.4 g, 5.0 mmol) and cyclopropanecarboxamide (0.85 g, 10.0 mmol) as the starting materials. LCMS (ES) m/z; 329.1 [M+H]+.
  • Step-6 Synthesis of 9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-18): I-18 (0.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-18f (1.5 g, 4.57 mmol) as the starting material. LCMS (ES) m/z; 261.2 [M+H]+.
  • Racemate I-18 (0.8 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 ⁇ m) Mobile phase: n-Hexane:IPA with 0.1% DEA (50:50) Flow rate : 38.0 mL/min] to afford two enantiomers ⁇ I-18A (0.25 g): peak-1; Rt; 6.69 min and I-18B (0.3 g): peak-2; Rt; 9.83 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 Synthesis of (2-chloro-3-fluoro-5-methylpyridin-4-yl)boronic acid (I-19b): To a stirred solution of I-19a (20 g, 137 mmol) in THF (200 mL) at -78 °C was added LDA (137 mL, 137 mmol, 1M in THF) over a period of 15 minutes and stirred for 2 hours at -78 °C then triisopropyl borate (60.2 mL, 261 mmol) was added and stirred at -78 °C for 2 h and then the reaction mixture was stirred at room temperature for 16 h.
  • LDA 137 mL, 137 mmol, 1M in THF
  • Step-2 Synthesis of tert-butyl (1-(4-(2-chloro-3-fluoro-5-methylpyridin-4-yl)-2- methylthiazol-5-yl)ethyl)(methyl)carbamate (I-19c): I-19c (6.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-11g (8.5 g, 25.4 mmol) and (2-chloro-3-fluoro-5-methylpyridin-4-yl)boronic acid (I-19b) (9.6 g, 50.7 mmol) as the starting material. LCMS (ES) m/z; 400.1 [M+H]+.
  • Step-3 Synthesis of 6-chloro-2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridine (I-19d): I-19d (1.18 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-19c (6.2 g, 15.5 mmol) as the starting material.
  • Step-4 Synthesis of N-(2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-19e): I-19e (1.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-19d (1.18 g, 4.22 mmol) and cyclopropanecarboxamide (0.72 g, 8.43 mmol) as the starting materials. LCMS (ES) m/z; 329.1 [M+H]+.
  • Step-5 Synthesis of 2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-19): I-19 (0.75 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-19e (1.5 g, 4.57 mmol) as the starting material. LCMS (ES) m/z; 261.1 [M+H]+.
  • Racemate I-19 (0.8 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 ⁇ m) Mobile phase: n-Hexane:IPA with 0.1% DEA (90:10) Flow rate : 38.0 mL/min] to afford two enantiomers ⁇ I-19A (0.26 g): peak-1; Rt; 13.25 min and I-19B (0.16 g): peak-2; Rt; 16.5 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 Synthesis of 2-chloro-3-fluoro-4-iodo-5-methylpyridine (I-20b): To a stirred solution of I-20a (10 g, 68.7 mmol) in THF (100 mL, 1) at -78 °C was added LDA (69 mL, 137 mmol, 2M in THF) was added over a period of 15 minutes and stirred at same temperature for 2 h.
  • Step-2 Synthesis of 2-chloro-3-fluoro-5-methyl-4-(trimethylstannyl)pyridine (I- 20c): To a stirred solution of I-20b (16 g, 58.9 mmol) in 1,4-dioxane (200 mL) was added hexamethylditin (13.4 mL, 64.8 mmol) and the reaction mixture was purged with nitrogen for 15 minutes, added Pd(PPh3)2Cl2 (1.24 g, 1.77 mmol) and the reaction mixture was heated at 100 °C for 48 h in a sealed tube.
  • Step-3 Synthesis of 1-(3-(2-chloro-3-fluoro-5-methylpyridin-4-yl)pyrazin-2- yl)ethan-1-one (I-20d): To a stirred solution of I-20c (17.8 g, 57.7 mmol), 1-(3-chloro-2- pyrazinyl)-1-ethanone (13.6 g, 86.6 mmol) in 1,4-dioxane (95 mL) in a sealed tube was added lithium chloride (7.34 g, 173 mmol), copper iodide (1.1 g, 5.77 mmol) and the reaction mixture was purged with nitrogen for 10 minutes.
  • Step-4 Synthesis of 7-chloro-5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridine (I-20e): I-20e (2.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-20d (7.0 g, 26.3 mmol) as the starting material. LCMS (ES) m/z; 261.0 [M+H]+.
  • Step-5 Synthesis of N-(5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide (I-20f): I-20f (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-20e (2.8 g, 10.7 mmol) and cyclopropanecarboxamide (1.37 g, 16.1 mmol) as the starting materials. LCMS (ES) m/z; 310.2 [M+H]+.
  • Step-6 Synthesis of 5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-20): I-20 (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-20f (3.2 g, 10.3 mmol) as the starting material. LCMS (ES) m/z; 242.1 [M+H]+.
  • Racemate I-20 (2.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 20 mm x 5 ⁇ m) Mobile phase: n-Hexane:IPA with 0.1% DEA (85:15) Flow rate : 18.0 mL/min] to afford two enantiomers ⁇ I-20A (0.8 g): peak-1; Rt; 9.01 min and I-20B (0.75 g): peak-2; Rt; 11.85 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 Synthesis of tert-butyl (1-(3-bromo-5-fluoro-1-methyl-1H-pyrazol-4- yl)ethyl)(methyl)carbamate (I-21a): To a stirred solution of I-7e (10 g, 31.4 mmol) in tetrahydrofuran (100 mL) was added LDA (18.9 mL, 37.7 mmol, 2M in THF) at -78 °C and the reaction mixture was stirred at -78 °C for 1 h.
  • Step-2 Synthesis of tert-butyl (1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-5- fluoro-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)carbamate (I-21b):
  • I-21b (7.35 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-21a (13.0 g, 38.7 mmol) and (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (I-16b) (11.0 g, 58 mmol) as the starting material.
  • Step-3 Synthesis of 6-chloro-3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H- pyrazolo[4,3-c][1,7]naphthyridine (I-21c): I-21c (3.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-21b (6.5 g, 16.2 mmol) as the starting material. LCMS (ES) m/z; 281.0 [M+H]+.
  • Step-4 Synthesis of N-(3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-21d):
  • I-21d (4.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-21c (4.0 g, 14.2 mmol) and cyclopropanecarboxamide (1.82 g, 21.4 mmol) as the starting materials.
  • Step-5 Synthesis of 3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-21): I-21 (1.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-21d (4.2 g, 12.8 mmol) as the starting material. LCMS (ES) m/z; 262.0 [M+H]+.
  • Example 22 Preparation of 2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-22): [00401]
  • Step-1 Synthesis of 2-chloro-N-methoxy-N,6-dimethylnicotinamide (I-22b): I-22b (12.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-22a (12 g, 69.9 mmol) as the starting material.
  • Step-2 Synthesis of 1-(2-chloro-6-methylpyridin-3-yl)ethan-1-one (I-22c): I-22c (10 g) was synthesized by following procedure as described for the synthesis of I-11 (step-4) using I-22b (12.0 g, 55.9 mmol) as the starting material. LCMS (ES) m/z; 170.1 [M+H]+.
  • Step-3 Synthesis of 1-(2'-chloro-3'-fluoro-6,6'-dimethyl-[2,4'-bipyridin]-3- yl)ethan-1-one (I-22d):
  • I-22d (11 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-22c (10.0 g, 59 mmol) and (2-chloro-3-fluoro-6- methylpyridin-4-yl)boronic acid (I-16b) (22.3 g, 118 mmol) as the starting material.
  • Step-4 Synthesis of 7-chloro-2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-22e): I-22e (3.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-22d (11.0 g, 39.5 mmol) as the starting material. LCMS (ES) m/z; 274.1 [M+H]+.
  • Step-5 Synthesis of N-(2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-22f): I-22f (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-22e (3.88 g, 14.2 mmol) and cyclopropanecarboxamide (1.81 g, 21.3 mmol) as the starting materials. LCMS (ES) m/z; 323.1 [M+H]+.
  • Step-6 Synthesis of 2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-22): I-22 (1.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-22f (3.0 g, 9.3 mmol) as the starting material. LCMS (ES) m/z; 255.1 [M+H]+.
  • Racemate I-22 (1.5 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 21 mm x 5 ⁇ m) Mobile phase: n-Hexane:IPA with 0.1% DEA (95:05) Flow rate : 18.0 mL/min] to afford two enantiomers ⁇ I-22A (0.45 g): peak-1; Rt; 16.44 min and I-22B (0.35 g): peak-2; Rt; 18.02 min ⁇ , which were used further without their absolute configuration determination.
  • Example 23 Preparation of 2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-23):
  • Step-1 Synthesis of 4-bromo-2-cyclopropylthiazole (I-23a): To a stirred solution of I-11a (30 g, 123 mmol) in THF (300 mL) in a sealed tube was added cyclopropylboronic acid (11.7 g, 136 mmol), potassium phosphate (78.5 g, 370 mmol) and the reaction mixture was purged with argon for 15 min. Then palladium acetate (2.77 g, 12.3 mmol) was added and the reaction mixture was heated at 60 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS.
  • Step-2 Synthesis of 4-bromo-2-cyclopropylthiazole-5-carboxylic acid (I-23b): I- 23b (30.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-1) using I-23a (16.9 g, 82.8 mmol) as the starting material. LCMS (ES) m/z; 248.0 [M+H]+.
  • Step-3 Synthesis of 4-bromo-2-cyclopropyl-N-methoxy-N-methylthiazole-5- carboxamide (I-23c):
  • I-23c (10.1 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-23b (30 g, 90.7 mmol) as the starting material.
  • LCMS (ES) m/z; 291.0 [M+H]+.1H NMR (400 MHz, CDCl3) ⁇ 3.68 (s, 3H); 3.34 (s, 3H); 2.30-2.23 (m, 1H); 1.21-1.15 (m, 4H).
  • Step-4 Synthesis of 1-(4-bromo-2-cyclopropylthiazol-5-yl)ethan-1-one (I-23d): I- 23d (7.8 g) was synthesized by following procedure as described for the synthesis of I-11 (step- 4) using I-23c (10.1 g, 34.7 mmol) as the starting material.1H NMR (400 MHz, CDCl3) ⁇ 2.67 (s, 3H); 2.31-2.25 (m, 1H); 1.27-1.14 (m, 4H). LCMS (ES) m/z; 245.9 [M+H]+.
  • Step-5 Synthesis of 1-(4-bromo-2-cyclopropylthiazol-5-yl)-N-methylethan-1- amine (I-23e): I-23e (8.3 g) was synthesized by following procedure as described for the synthesis of I-11 (step-5) using I-23d (7.8 g, 31.7 mmol) as the starting material. LCMS (ES) m/z; 261.0 [M+H]+.
  • Step-6 Synthesis of tert-butyl (1-(4-bromo-2-cyclopropylthiazol-5- yl)ethyl)(methyl)carbamate (I-23f): I-23f (11.2 g) was synthesized by following procedure as described for the synthesis of I-11 (step-6) using I-23e (8.3 g, 31.8 mmol) as the starting material. LCMS (ES) m/z; 361.0 [M+H]+.
  • Step-7 Synthesis of tert-butyl (1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2- cyclopropylthiazol-5-yl)ethyl)(methyl)carbamate (I-23g): I-23g (9.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-23f (11.2 g, 31 mmol) and (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (I-16b) (14.7 g, 77.5 mmol) as the starting material. LCMS (ES) m/z; 426.2 [M+H]+.
  • Step-8 Synthesis of 6-chloro-2-cyclopropyl-4,5,8-trimethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridine (I-23h): I-23h (6.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-23g (9.4 g, 7.58 mmol) as the starting material. LCMS (ES) m/z; 306.1 [M+H]+.
  • Step-9 Synthesis of N-(2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-23i): I-23i (4.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-23h (6.0 g, 13.7 mmol) and cyclopropanecarboxamide (2.34 g, 27.5 mmol) as the starting materials. LCMS (ES) m/z; 355.2 [M+H]+.
  • Step-10 Synthesis of 2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-23): I-23 (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-23i (4.5 g, 12.7 mmol) as the starting material. LCMS (ES) m/z; 287.0 [M+H]+.
  • Racemate I-23 (3.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 21 mm x 5 ⁇ m) Mobile phase: 100% MeOH; Flow rate : 12.0 mL/min] to afford two enantiomers ⁇ I-23A (1.1 g): peak-1; Rt; 10.19 min and I-23B (0.91 g): peak-2; Rt; 11.51 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 Synthesis of 2-chloro-3-fluoro-5-methoxy-4-(trimethylstannyl)pyridine (I- 24a): To a stirred solution of I-18c (15 g, 52.2 mmol) in 1,4-dioxane (30 mL) was added hexamethylditin (11.9 mL, 57.4 mmol) and the reaction mixture was purged with argon for 15 min.
  • Step-2 Synthesis of 1-(3-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)pyrazin-2- yl)ethan-1-one (I-24b): I-24b (10.0 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-24a (26.0 g, 80.2 mmol) and I-10a (12.5 g, 80.2 mmol) as the starting materials. LCMS (ES) m/z; 282.0 [M+H]+.
  • Step-3 Synthesis of 7-chloro-10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridine (I-24c): I-24c (3.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-24b (16.5 g, 58.6 mmol) as the starting material. LCMS (ES) m/z; 277.1 [M+H]+.
  • Step-4 Synthesis of N-(10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide (I-24d): I-24d (8.5 g ) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-24c (6.0 g, 21.7 mmol) as the starting material. LCMS (ES) m/z; 326.0 [M+H]+.
  • Step-5 Synthesis of 10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-24): I-24 (3.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-24d (8.5 g, 26.1 mmol) as the starting material. LCMS (ES) m/z; 258.1 [M+H]+.
  • Racemate I-24 (3.1 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 ⁇ m); Mobile phase: n-Hexane : Ethanol with 0.1% DEA (55:45); Flow rate: 38 mL/min)] to afford two enantiomers ⁇ I-24A (1.0 g): peak-1; Rt; 14.48 min and I-24B (1.1 g): peak-2; Rt; 18.05 min ⁇ , which were used further without their absolute configuration determination.
  • Example 25 Preparation of 3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-25): [00425]
  • Step-1 Synthesis of methyl 3-chloro-6-methylpyrazine-2-carboxylate (I-25b): To a stirred solution of I-25a (15 g, 57.9 mmol) in 1,4-dioxane (150 mL) was added methyl boronic acid (4.16 g, 69.4 mmol), potassium carbonate (16 g, 116 mmol) and the reaction mixture was purged with nitrogen for 10 min.
  • Step-2 Synthesis of 3-chloro-6-methylpyrazine-2-carboxylic acid (I-25c): A stirred solution of I-25b (10.6 g, 54 mmol) in conc HCl (100 mL, 540 mmol) was heated at 80 °C for 5 h. Progress of the reaction was monitored by LCMS and TLC. After the completion, the reaction mixture was cooled and concentrated under reduced pressure. The residue was triturated with mixture of diethyl ether, pentane (100 mL, 1:1) to afford I-25c (8.3 g) as brown solid .LCMS (ES) m/z; 173.0 [M+H]+.
  • Step-3 Synthesis of 3-chloro-N-methoxy-N,6-dimethylpyrazine-2-carboxamide (I- 25d): I-25d (6.2 g) was synthesized by following procedure as described for the synthesis of I- 11 (step-2) using I-25c (8.2 g, 35.3 mmol) as the starting material. LCMS (ES) m/z; 216.0 [M+H]+.
  • Step-4 Synthesis of 1-(3-chloro-6-methylpyrazin-2-yl)ethan-1-one (I-25e): I-25e (2.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-4) using I-25d (4.2 g, 17.5 mmol) as the starting material. LCMS (ES) m/z; 171.0 [M+H]+.
  • Step-5 Synthesis of 1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-6- methylpyrazin-2-yl)ethan-1-one (I-25f):
  • I-25f (4.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-25e (3.0 g, 13.2 mmol) and (2-chloro-3- fluoro-6-methylpyridin-4-yl)boronic acid (I-16b) (6.2 g, 33 mmol) as the starting material.
  • Step-6 Synthesis of 7-chloro-3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridine (I-25g): I-25g (3.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-25f (4.2 g, 14.3 mmol) as the starting material. LCMS (ES) m/z; 275.0 [M+H]+.
  • Step-7 Synthesis of N-(3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide (I-25h): I-25h (5.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-25g (5.0 g, 17.3 mmol) and cyclopropanecarboxamide (2.94 g, 34.6 mmol) as the starting materials. LCMS (ES) m/z; 324.0 [M+H]+.
  • Step-8 Synthesis of 3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-25): I-25 (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-25h (5.0 g, 15.5 mmol) as the starting material. LCMS (ES) m/z; 256.1 [M+H]+.
  • Racemate I-25 (1.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 ⁇ m) Mobile phase: : n-Hexane:IPA with 0.1% DEA (90:10); Flow rate : 35.0 mL/min] to afford two enantiomers ⁇ I-25A (0.285 g): peak-1; Rt; 11.094 min and I-25B (0.285 g): peak-2; Rt; 13.02 min ⁇ , which were used further without their absolute configuration determination.
  • Example 26 Preparation of 5,6,10-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- amine (I [00434]
  • Step-1 Synthesis of 1-(2'-chloro-3'-fluoro-5'-methyl-[2,4'-bipyridin]-3-yl)ethan-1- one (I-26a):
  • I-26a (9.0 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-20c (24 g, 77.8 mmol) and 1-(2-chloro-3-pyridyl)-1-ethanone (13.3 g, 85.6 mmol) as the starting materials.
  • Step-2 Synthesis of 7-chloro-5,6,10-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-26b): I-26b (5.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-26a (9.0 g, 34 mmol) as the starting material. LCMS (ES) m/z; 260.0 [M+H]+.
  • Step-3 Synthesis of N-(5,6,10-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-26c): I-26c (4.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-26b (5.0 g, 19.3 mmol) and cyclopropanecarboxamide (2.46 g, 28.9 mmol) as the starting materials. LCMS (ES) m/z; 309.1 [M+H]+.
  • Step-4 Synthesis of 5,6,10-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin- 7-amine (I-26): I-26 (2.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-26c (4.0 g, 13.0 mmol) as the starting material. LCMS (ES) m/z; 241.2 [M+H]+.
  • Racemate I-26 (2.5 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 ⁇ m) Mobile phase: : n-Hexane: EtOH with 0.1% DEA (55:45); Flow rate : 38.0 mL/min] to afford two enantiomers ⁇ I-26A (1.0 g): peak-1; Rt; 12.45 min and I-26B (1.0 g): peak-2; Rt; 14.43 min ⁇ , which were used further without their absolute configuration determination.
  • Example 27 Preparation of 3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-27): [00439]
  • Step-1 Synthesis of 2-chloro-5-fluoro-N-methoxy-N-methylnicotinamide (I-27b): I-27b (21 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-27a (20.0 g, 114 mmol) as the starting material.
  • Step-2 Synthesis of 1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-one (I-27c): I-27c (18.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-4) using I-27b (24.0 g, 110 mmol) as the starting material. LCMS (ES) m/z; 174.0 [M+H]+.
  • Step-3 Synthesis of 1-(2'-chloro-3',5-difluoro-6'-methyl-[2,4'-bipyridin]-3- yl)ethan-1-one (I-27d): To a stirred solution of I-27c (14 g, 80.7 mmol) in 1,4-dioxane (280 mL) was added (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (30.6 g, 161 mmol), cesium carbonate (78.8 g, 242 mmol) the reaction mixture was purged with nitrogen for 15 min.
  • Step-4 Synthesis of 7-chloro-3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-27e): I-27e (3.6 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-27d (4.0 g, 14.16 mmol) as the starting material. LCMS (ES) m/z; 278.1 [M+H]+.
  • Step-5 Synthesis of N-(3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-27f): I-27f (3.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-27e (3.0 g, 10.8 mmol) and cyclopropanecarboxamide (1.37 g, 16.2 mmol) as the starting materials. LCMS (ES) m/z; 327.1 [M+H]+.
  • Step-6 Synthesis of 3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-27): I-27 (2.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-27f (4.8 g, 13.14 mmol) as the starting material. LCMS (ES) m/z; 259.1 [M+H]+.
  • Example 28 Preparation of 10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-28): [00445]
  • Step-1 Synthesis of 1-(2'-chloro-3'-fluoro-5'-methoxy-[2,4'-bipyridin]-3-yl)ethan- 1-one (I-28a): I-28a (6.5 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-24a (15 g, 46.2 mmol) and 1-(2-chloro-3-pyridyl)-1-ethanone (7.91 g, 50.9 mmol) as the starting materials.
  • Step-2 Synthesis of 7-chloro-10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-28b): I-28b (8.2 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-28a (10.0 g, 35.6 mmol) as the starting material. LCMS (ES) m/z; 276.0 [M+H]+.
  • Step-3 Synthesis of N-(10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-28c):
  • I-28c (8.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-28b (8.0 g, 29.0 mmol) and cyclopropanecarboxamide (6.17 g, 72.5 mmol) as the starting materials.
  • Step-4 Synthesis of 10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-28): I-28 (1.9 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-28c (8.0 g, 24.7 mmol) as the starting material. LCMS (ES) m/z; 257.2 [M+H]+.
  • Racemate I-28 (3.7 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IK (250 mm x 21 mm x 5 ⁇ m) Mobile phase: : n-Hexane: EtOH (70:30); Flow rate : 19.0 mL/min] to afford two enantiomers ⁇ I-28A (1.5 g): peak-1; Rt; 8.62 min and I-28B (1.5 g): peak-2; Rt; 15.37 min ⁇ , which were used further without their absolute configuration determination.
  • Example 29 Preparation of 9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-amine (I-29): [00450]
  • Step-1 Synthesis of 4-bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-3- carboxamide (I-29b): I-29b (28 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-29a (20.0 g, 97.6 mmol) as the starting material.
  • Step-2 Synthesis of 1-(4-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-one (I-29c): I- 29c (20.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step- 4) using I-29b (28.0 g, 113 mmol) as the starting material. LCMS (ES) m/z; 203.0 [M+H]+.
  • Step-3 Synthesis of 1-(1-methyl-4-(tributylstannyl)-1H-pyrazol-3-yl)ethan-1-one (I-29d): To a stirred suspension of I-29c (20.0 g, 49.3 mmol) in hexabutylditin ( 36 mL, 49.3mmol) argon was purged for 5 min, added Pd(OAc)2 (0.22 g, 49.3 mmol), tricyclohexylphosphine (0.552 g, 1.34 mmol) and the reaction mixture was heated at 110 °C for 20 h in a sealed tube. Progress of the reaction was monitored by TLC.
  • Step-4 Synthesis of 1-(4-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1-methyl-1H- pyrazol-3-yl)ethan-1-one (I-29e):
  • I-29e (5.0 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-29d (15 g, 40.4 mmol) and 2-chloro-3-fluoro- 4-iodo-5-methoxypyridine (17.4 g, 60.6 mmol) as the starting materials.
  • Step-5 Synthesis of 6-chloro-9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- pyrazolo[3,4-c][1,7]naphthyridine (I-29f): To a stirred solution of I-29e (5 g, 17.6 mmol) in THF (50 mL) at 0 °C was added titanium tetraisopropoxide (10.4 mL, 32.5 mmol), methylamine in THF (8.8 mL, 17.6 mmol, 2M solution) and the reaction mixture was heated at 60 °C in a sealed tube for 16 h. Then the reaction mixture was cooled to room temperature and evaporated under reduced pressure.
  • Step-6 Synthesis of N-(9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-29g): I-29g (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-29f (4.0 g, 14.4 mmol) and cyclopropanecarboxamide (2.44 g, 28.7 mmol) as the starting materials. LCMS (ES) m/z; 328.0 [M+H]+.
  • Step-7 Synthesis of 9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-amine (I-29): I-29 (1.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-29g (2.0 g, 6.11 mmol) as the starting material. LCMS (ES) m/z; 260.0 [M+H]+.
  • Racemate I-29 (1.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 ⁇ m) Mobile phase: : n-Hexane: IPA with 0.1% DEA (80:20); Flow rate : 18.0 mL/min] to afford two enantiomers ⁇ I-29A (0.5 g): peak-1; Rt; 25.59 min and I-29B (0.3 g): peak-2; Rt; 35.52 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 Synthesis of 2-chloro-5-cyclopropyl-3-fluoropyridine (I-30b): To a stirred solution of I-30a (25.0 g, 119 mmol) in 1,4-dioxane (250 mL) was added cyclopropylboronic acid (15.3 g, 178 mmol), potassium phosphate tribasic (75.7 g, 356 mmol), the reaction mixture was purged with nitrogen for 15 min.
  • Step-2 Synthesis of 2-chloro-5-cyclopropyl-3-fluoro-4-iodopyridine (I-30c): To a stirred solution of I-30b (10 g, 58.3 mmol) in THF (100 mL, 1) at -78 °C was added LDA (43.7 mL, 87.4 mmol, 2M in THF) was added over a period of 15 minutes and stirred at same temperature for 1 h.
  • LDA 43.7 mL, 87.4 mmol, 2M in THF
  • Step-3 Synthesis of tert-butyl (1-(5-(2-chloro-5-cyclopropyl-3-fluoropyridin-4-yl)- 2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-30d):
  • I-30d (2.5 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-30c (5 g, 9.45 mmol) and tert-butyl methyl(1-(2-methyl-5-(tributylstannyl)-2H-1,2,3-triazol-4- yl)ethyl)carbamate (2.81 g, 9.45 mmol) as the starting materials.
  • Step-4 Synthesis of 6-chloro-9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-30e): I-30e (8.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-30d (21.0 g, 51.2 mmol) as the starting material. LCMS (ES) m/z; 290.0 [M+H]+.
  • Step-5 Synthesis of N-(9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-30f): I-30f (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 30e (4.0 g, 8.86 mmol) and cyclopropanecarboxamide (1.76 g, 20.7 mmol) as the starting materials. LCMS (ES) m/z; 339.2 [M+H]+.
  • Step-6 Synthesis of 9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-30): I-30 (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-30f (4.5 g, 13.3 mmol) as the starting material. LCMS (ES) m/z; 271.1 [M+H]+.
  • Racemate I-30 (3.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IK (250 mm x 20 mm x 5 ⁇ m) Mobile phase: : n-Hexane: IPA with 0.1% DEA (80:20); Flow rate : 18.0 mL/min] to afford two enantiomers ⁇ I-30A (1.3 g): peak-1; Rt; 7.36 min and I-30B (1.3 g): peak-2; Rt; 8.78 min ⁇ , which were used further without their absolute configuration determination.
  • Step-1 Synthesis of 6-chloro-5-fluoronicotinaldehyde (I-31a): To a stirred solution of I-30a (10.0 g, 47.5 mmol) in diethyl ether (100.0 mL) was added n-BuLi (23.8 mL, 71.3 mmol, 3.0M in hexane) at -78 °C and the reaction mixture was stirred at the same temperature for 15 min.
  • Step-2 Synthesis of (6-chloro-5-fluoropyridin-3-yl)methanol (I-31b): To a stirred solution of I-31a (9.0 g, 56.4 mmol) in MeOH (100 mL) at 0 °C was added sodium borohydride (4.27 g, 113 mmol) and the reaction mixture was stirred at room temperature for 1.5 h.
  • Step-3 Synthesis of 2-chloro-3-fluoro-5-(methoxymethyl)pyridine (I-31c): To a stirred solution of I-31b (6.0 g, 37.1 mmol) in THF (60 mL) was added sodium hydride (2.97 g, 74.3 mmol, 60% in mineral oil) at 0 °C and the reaction mixture was stirred for 15 min at 0 °C. Then iodomethane (4.62 mL, 74.3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLS and LCMS.
  • Step-4 Synthesis of 2-chloro-3-fluoro-4-iodo-5-(methoxymethyl)pyridine (I-31d): I-31d (9.9 g) was synthesized by following procedure as described for the synthesis of I-20 (step-1) using I-31c (7.0 g, 39.9 mmol) as the starting material. LCMS (ES) m/z; 301.9 [M+H]+.
  • Step-5 Synthesis of tert-butyl (1-(5-(2-chloro-3-fluoro-5-(methoxymethyl)pyridin- 4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-31e): I-31e (6.1 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-31d (5.7 g, 18.9 mmol) and I-2a (10.0 g, 18.9 mmol) as the starting materials. LCMS (ES) m/z; 358.1 [M+H-56]+.
  • Step-6 Synthesis of 6-chloro-9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-31f): I-31f (9.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-31e (15.5 g, 37.5 mmol) as the starting material. LCMS (ES) m/z; 294.0 [M+H]+.
  • Step-7 Synthesis of N-(9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-31g): I-31g (7.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-31f (9.0 g, 30.6 mmol) and cyclopropanecarboxamide (3.91 g, 46.0 mmol) as the starting materials. LCMS (ES) m/z; 343.2 [M+H]+.
  • Step-8 Synthesis of 9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-31): I-31 (5.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-31g (7.0 g, 20.4 mmol) as the starting material. LCMS (ES) m/z; 275.1 [M+H]+.
  • Racemate I-31 (4.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 20 mm x 5 ⁇ m) Mobile phase: : n-Hexane: EtOH with 0.1% DEA (85:15); Flow rate : 20.0 mL/min] to afford two enantiomers ⁇ I-31A (1.8 g): peak-1; Rt; 18.63 min and I-31B (1.8 g): peak-2; Rt; 24.15 min ⁇ , which were used further without their absolute configuration determination.
  • Example 32 Preparation of 9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-32): [00474] Step-1: Synthesis of 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-9-ol (I-32a): To a stirred solution of I-18e (5 g, 17.8 mmol) in THF (100 mL) was added borontribromide (10.0 mL, 89.3 mmol) drop wise at -78 °C and the reaction mixture was stirred at same temperature for 2 h.
  • reaction mixture was warmed to room temperature and stirred for 16 h. Progress of the reaction was monitored by TLC. After completion, reaction mixture was quenched with cold saturated ammonium chloride solution (100 mL) and was extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution 0-50% EtOAc in heptane) to afford 1-32a (5 g, crude) as a pale yellow solid. LCMS (ES) m/z; 266.0 [M+H]+.
  • Step-2 Synthesis of 6-chloro-9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-32b): To a stirred solution of I-32a (5 g, 18.8 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (6.5 g, 47 mmol) and 2-bromopropane (7.08 mL, 75.3 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 2 h. Progress of the reaction was monitored by TLC.
  • Step-3 Synthesis of N-(9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-32c): I-32c (7.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 32b (5.5 g, 17.9 mmol) and cyclopropanecarboxamide (6.08 g, 71.5 mmol) as the starting materials. LCMS (ES) m/z; 357.2 [M+H]+.
  • Step-4 Synthesis of 9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-32): I-32 (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-32c (4.0 g, 11.2 mmol) as the starting material. LCMS (ES) m/z; 289.1 [M+H]+.
  • Racemate I-32 (1.3 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 20 mm x 5 ⁇ m) Mobile phase: : n-Hexane: IPA with 0.1% DEA (50:50); Flow rate : 20.0 mL/min] to afford two enantiomers ⁇ I-32A (0.49 g): peak-1; Rt; 7.86 min and I-32B (0.35 g): peak-2; Rt; 8.95 min ⁇ , which were used further without their absolute configuration determination.
  • Example 33 Preparation of 2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-33): [00479] Step-1: Synthesis of 6-chloro-2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-33a): To a stirred solution of I-32a (4 g, 15.1 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (5.2 g, 37.6 mmol) and 1,1,1-trifluoro-2-iodoethane (9.48 g, 45.2 mmol) at room temperature.
  • reaction mixture was stirred at 110 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in heptane) to afford I-33a (3.5 g) as yellow solid. LCMS (ES) m/z; 348.1 [M+H]+.
  • Step-2 Synthesis of N-(2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-33b): I-33b (3.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-33a (3.4 g, 9.78 mmol) and cyclopropanecarboxamide (3.33 g, 39.1 mmol) as the starting materials. LCMS (ES) m/z; 397.1 [M+H]+.
  • Step-3 Synthesis of 2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-33): I-33 (2.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-33b (3.4 g, 8.58 mmol) as the starting material. LCMS (ES) m/z; 329.1 [M+H]+.
  • Example 34 Preparation of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (A-1): [00482] To a stirred solution of A-1a (5.0 g, 25.1 mmol) in anhydrous DCM (40 mL) was added catalytic amount of DMF (2 to 3 drops) and oxalyl chloride (4.6 mL, 50.3 mmol) drop wise at 0 °C. The reaction mixture was then allowed to warm to room temperature over 2 h. After completion, volatiles were removed under reduced pressure and the residue was dried.
  • Example 35 Preparation of 4-bromo-6-chloro-N-(methyl-d3)nicotinamide (A-2): [00483] To a stirred solution of A-2a (4.75 g, 20.1 mmol), methan-d3-amine hydrochloride (1.7 g, 24.1 mmol) and DIPEA (10.4 mL, 60.3 mmol) in DCM (15 mL) was added HATU (11.5 g, 30.1 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature for 3 h. After completion, water (50 mL) was added to it and extracted with DCM (75 mL x 2).
  • Example 36 Preparation of N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2- yl)cyclopropanecarboxamide (A-3): [00484] Step 1: 4,6-dichloro-N-methoxy-N-methylnicotinamide (A-3b): To a stirred solution of A-3a (20.0 g, 104.0 mmol) in DCM (50.0 mL) were added TEA (43.6 mL, 313.0 mmol) and HATU (39.6 g, 104 mmol) at 0 °C.
  • Step-2 1-(4,6-dichloropyridin-3-yl)ethan-1-one (A-3c): To a stirred solution of A- 3b (15 g, 63.8 mmol) in anhydrous THF (50.0 mL) was added a 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 starting material, it was quenched with addition of saturated NH4Cl solution (100 mL) and extraction was carried out using EtOAc (100 mL x 2).
  • Step-3 methyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropanoate (A-3d): To a stirred solution of A-3c (10 g, 52.6 mmol) in dimethyl carbonate (150 mL) was added NaH (60% suspension) (6.31 g, 158 mmol) in portion-wise at 0 °C. The reaction mixture was the stirred at room temperature for 3 h. After complete consumption of starting material, it was quenched with addition of 2N aqueous HCl solution (20 mL) and extraction was carried out using EtOAc (100 mL x 2).
  • Step-4 methyl 2-(6-chloro-4-methoxynicotinoyl)propanoate-3,3,3-d3 (A-3e): To a stirred solution of A-3d (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. To this was then added iodomethane-d3 (2.45 mL, 38.8 mmol) drop wise at 0 °C and the reaction mixture was stirred at room temperature for 6 h.
  • Step-5 1-(6-chloro-4-hydroxypyridin-3-yl)propan-1-one-3,3,3-d3 (A-3f): To a solution of A-3e (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 extraction was carried out using EtOAc (100 x 2 mL). The combined organic extracts were washed brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step-6 1-(4,6-dichloropyridin-3-yl)propan-1-one-3,3,3-d3 (A-3g): To a solution of A-3f (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.
  • Step-7 N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (A-3): Argon gas was purged through a stirred suspension of A-3g (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. To this was then added rac-BINAP (0.9 g, 1.45 mmol) and Pd2(dba)3- CHCl3 (1.5 g, 1.45 mmol).
  • reaction mixture was then heated at 110 °C for 2 h in a sealed tube. After completion, it was cooled to room temperature and filtered through Celite bed. It is washed with EtOAc (50 mL x 2) and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-25% EtOAc in heptane) to afford A-3 (1.8 g) as a yellow solid.
  • Example 37 Preparation of 4,6-dichloro-N-(2,2-difluoroethyl)pyridazine-3-carboxamide (A-4): [00491] A-4 (1.1 g) was synthesized by following procedure as described for the synthesis of A-1 (step-1) using A-1a (1.0 g, 5.03 mmol) as the starting material. LCMS (ES) m/z; 256.0 [M+H]+.
  • Example 38 Preparation of 1-cyclopropylimidazolidin-2-one (A-5) [00492] To a stirred solution of cyclopropylamine (0.27 g, 4.74 mmol) in tetrahydrofuran (10 mL) was added 1-chloro-2-isocyanatoethane A-5a (0.5 g, 4.74 mmol) and the reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was cooled to 0 °C, added sodium hydride (0.38 g, 9.48 mmol, 60 % w/w) and the reaction mixture was stirred at room temperature for 2 h.
  • Example 41 Preparation of 1-(2,2,2-trifluoroethyl)imidazolidin-2-one (A-8): [00495]
  • Example 42 Preparation of 1-((1s,3s)-3-fluorocyclobutyl)imidazolidin-2-one (A-9): [00496] A-9 (0.2 g) was synthesized by following procedure as described for the synthesis of A-5 (step-1) using A-5a (0.25 g, 2.39 mmol) as the starting material. LCMS (ES) m/z; 159.1 [M+H]+.
  • Example 43 Preparation of 1-ethylimidazolidin-2-one (A-10): [00497] A-10 (0.8 g) was synthesized by following procedure as described for the synthesis of A-5 (step-1) using A-5a (4.7 g, 44.4 mmol) as the starting material.
  • Example 45 6-chloro-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide
  • 5a [00499] 6-chloro-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide
  • Racemate 5a (0.3 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 ⁇ m) Mobile phase: n-hexane:IPA with 0.1% DEA (70:30) Flow rate : 40.0 mL/min] to afford two enantiomers ⁇ 5A (0.1 g): peak-1; Rt; 13.15 min and 5B (0.1 g): peak-2; Rt; 14.69 min ⁇ , which were used further without their absolute configuration determination.
  • Example 46 6-chloro-N-(methyl-d3)-4-((2,5,8-trimethyl-4,5-dihydro-2H- [1,2,3 [00501] 6-chloro-N-(methyl-d3)-4-((2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)nicotinamide (9a) (Procedure M1-B): Argon gas was purged through a stirred suspension of I-4 (0.2 g, 0.87 mmol), A-2 (0.22 g, 0.87 mmol) and NaOBu-t (0.17 g, 1.74 mmol) in toluene (20 mL) for 15 min, before addition of [5-(diphenylphosphanyl)- 9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.05 g, 0.087
  • Example 47 6-chloro-N-(methyl-d3)-4-((3,4,5,8-tetramethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide (11a): [00502] 11a (0.3 g) was synthesized by following procedure as described for the synthesis of 5a (M1-A, step-1) using I-8 (0.3 g, 1.23 mmol) as the starting material. LCMS (ES) m/z; 417.2 [M+H]+.
  • Racemate 11a (0.3 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 ⁇ m) Mobile phase: n-hexane:IPA with 0.1% DEA (50:50) Flow rate : 40.0 mL/min] to afford two enantiomers ⁇ 11A (0.13 g): peak-1; Rt; 16.29 min and 11B (0.12 g): peak-2; Rt; 19.78 min ⁇ , which were used further without their absolute configuration determination.
  • Example 48 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide
  • Compound 2 [00504]
  • Step-1 6-chloro-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide
  • I-10A 0.2 g, 0.83 mmol
  • THF a 1M solution of LiHMDS (in THF)
  • Step-2 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide
  • Compound 2 (Procedure M2): Argon gas was purged through a stirred suspension of 1a (0.16 g, 0.39 mmol), cyclopropanecarboxamide (0.05 g, 0.58 mmol) and Cs2CO3 (0.25 g, 0.77 mmol) in 1,4-dioxane (5 mL) for 15 min, before addition of [5-(diphenylphosphanyl)-9,9- dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.022 g, 0.039 mmol) and Pd2(dba)3 (0.035 g
  • reaction mixture was then stirred at 130 °C for 3 h in a sealed tube, while monitoring reaction progress by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature and water (25 mL) was added to it. Extraction was carried out using EtOAc (50 mL x 2); the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-100% EtOAc in heptane). It was further purified by preparative HPLC to afford Compound 2 (0.04 g) as a yellow solid.
  • ⁇ single isomer at obtained by chiral separation of racemic final compound, or racemic intermediate.
  • Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined.
  • Example 49 Preparation of N-(5-(propanoyl-3,3,3-d3)-4-((2',5',8'-trimethyl-2',5'- dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)amino)pyridin-2- yl)cyclopropanecarboxamide (Compound 17) (Procedure M3): [00507] Argon gas was purged through a stirred suspension of I-6 (0.125 g, 0.46 mmol), A-3 (0.14 g, 0.55 mmol) and Cs2CO3 (0.3 g, 0.92 mmol) in 1,4-dioxane (3.0 mL) for 15 min, before addition of rac-BINAP (0.029 g, 0.046 mmol) and Pd2(dba)3-CHCl3 (0.0
  • reaction mixture was then stirred at 110 °C for 5 h in a sealed tube. After completion, the reaction mixture was cooled to room temperature and diluted with 10% MeOH in DCM (50 mL). The organic layer was washed with saturated bicarbonate solution (20 mL), water (20 mL), brine (20 mL), dried over anhydrous sulfate and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-90% EtOAc in heptane). The solid thus obtained was triturated in MeOH (10 mL x 3), filtered and dried to afford Compound 17 (0.018 g) as an off-white solid.
  • Example A-1 Oral Solution [00509] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s),optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution.
  • Example A-2 Oral Tablet [00510] A tablet is prepared by mixing 20-50% by weight of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
  • Example A-3 Oral Capsule [00511] To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend.
  • an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
  • 10-500 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed. II.
  • HEK-BlueTM IL-23 and IFN ⁇ / ⁇ Reporter Assays for Profiling TYK2 Pseudokinase (JH2) Inhibition [00513] HEK-BlueTM IL-23 and IFN ⁇ / ⁇ cells with a stably-integrated cytokine receptor and STAT3 or STAT1 express STAT-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene upon cytokine stimulation. These cells are plated in DMEM (Gibco) containing 10% heat-inactivated FBS (Gibco) and 100 U/mL PenStrep (Gibco) at 37 °C under 5% CO2 conditions for 20-22 hours.
  • SEAP STAT-inducible secreted embryonic alkaline phosphatase
  • the cells are then pretreated with serially diluted test compounds for 60 min prior to stimulation with either 10 ng/mL human recombinant IL-23 (Miltenyl Biotech) or 1ng/mL human recombinant IFN ⁇ (InvivoGen) for 22-24 hours for IL-23 or 16-18 h for IFN ⁇ .
  • SEAP induction is measured using the QUANTI BlueTM Solution (InvivoGen) according to the manufacturer's instructions.
  • Inhibition data are calculated by comparison to no inhibitor control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves are generated to determine the concentration required to inhibit 50% of cellular response (IC50) as derived by non-linear regression analysis.
  • Table B-1 provides TYK2 inhibitory activity of illustrative compounds, where A means IC50 ⁇ 30 nM; B means IC50 is between 30 and 300 nM; C means IC50 is between 300 and 1000 nM; D means IC50 > 1000 nM; n/a means no observed activity at 1000 nM; and n.d. means not determined.
  • Table B-1 Representative TYK2 Inhibitory Activity
  • Example B-2 HEK-BlueTM IL-2 and IFN ⁇ Reporter Assays for determining selectivity
  • HEK-BlueTM IL-2 and IFN ⁇ reporter cells with a stably-integrated cytokine receptor and STAT5 or STAT1 express STAT-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene upon cytokine stimulation.
  • SEAP STAT-inducible secreted embryonic alkaline phosphatase
  • SEAP embryonic alkaline phosphatase
  • the cells were then pretreated with serially diluted test compounds for 60 min prior to stimulation with either 4 ng/mL human recombinant IL-2 (Miltenyl Biotech) or 50 ng/mL human recombinant IFN ⁇ (InvivoGen) for 24 hours. SEAP induction was measured using the QUANTI-BlueTM Solution (InvivoGen) according to the manufacturer's instructions. Inhibition data were calculated by comparison to no inhibitor control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves were generated to determine the concentration required to inhibit 50% of cellular response (IC50) as derived by non-linear regression analysis.
  • IC50 cellular response
  • Table B-2 provides selectivity data (SEAP) of illustrative compounds for IL-2 and IFN- ⁇ , where A means IC50 ⁇ 30 nM; B means IC50 is between 30 and 300 nM; C means IC50 is between 300 and 1000 nM; D means IC50 > 1000 nM; n/a means no observed activity at 1000 nM; and n.d. means not determined.
  • SEAP selectivity data
  • Example B-3 Pharmacokinetic Studies
  • Test compounds were dosed IV at 1mg/kg, the formulation was prepared in DMSO:PEG-400:Tween80: Normal Saline (10:10:10:70). Blood was collected by retro orbital plexus in centrifuge tube containing K2EDTA, and plasma obtained by centrifugation at 1000 rpm for 5 min at 4 °C and stored at ⁇ 80 °C. Blood collection schedule post dose 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h.
  • Test compound was administered/dosed at 10 mg/kg via oral route.
  • Tables B-3 and B-4 provide summary of the in vivo PK data for selected compounds.
  • Table B-3 Summary of in vivo Rat PK for Selected Compounds Dosed at 1 mg/kg IV
  • Reference compound A is Compound 94 in WO 2022175747 and has the following structure:
  • Reference compound B has the following structure:
  • Reference compound C is Compound 73 in WO 2023/227946 and has the following structure: .
  • Each reference compound is a single enantiomer.
  • Example B-4 Brain Exposure Steady-State Study in Rats
  • the experiments were performed on male Sprague-Dawley rats (Vivo biotech, Hyderabad, collaboration with Taconic USA) weighing 220 to 240 g. All animals were acclimatized for at least 5 days after arrival and were group housed at 18 °C to 22 °C under a 12- h light-dark cycle with food and water ad libitum at all times before the experiments.
  • Test compound was administered/dosed at 10 mg/kg orally BID (2nd dose post 8 h of 1st dose) for 3 days and QD for 4th day.
  • the formulation was prepared in Ethanol+TPGS (1:1):PEG-300 (10:90) vehicle.
  • Blood, brain and CSF sample were collected post 6 h of dose on 4th days.
  • Blood was collected from the retro-orbital plexus in a centrifuge tube containing K2EDTA, and plasma was obtained by centrifugation at 10000 rpm for 5 min at 4 °C and stored at -80 °C.
  • the cerebrospinal fluid was collected by cisterna magna puncture with the help of a sterilised needle and stored at -80 °C.
  • the whole brain was quickly removed from the skull and rinsed in ice-cold saline, immediately flash-frozen, and stored at -80 °C.
  • brains were carefully weighed and transferred into a sample collection tube, and then 5 time of brain weight phosphate buffer saline (PBS) was added to this, and the samples were homogenized using probe homogenizer.
  • PBS brain weight phosphate buffer saline
  • Artificial cerebrospinal fluid was prepared and used to plot the calibration curve and quality control samples.
  • Blood, CSF and homogenized brain sample were precipitated with 400 ⁇ L of acetonitrile containing internal standard. Precipitated samples were centrifuged at 14000 rpm for 5 min at 4 °C, and the supernatants were used for LC-MS/MS analysis.
  • the mean brain to plasma exposure ratio was calculated for selected compounds and is provided in Table B-5.
  • Reference compound D has the following structure:
  • Reference compound E has the following structure:
  • Reference compound F has the following structure:
  • Each reference compound is a single enantiomer.
  • the examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of US Provisional Application No.63/604,078, filed on November 29, 2023, US Provisional Application No.63/659,710, filed on June 13, 2024, and US Provisional Application No.63/677,846, filed on July 31, 2024, each of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [0002] The present disclosure relates to compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2). Compounds of the present disclosure may inhibit certain cytokine signaling, for example IL-12, IL-23, and IFNα signaling. Additional aspects of the disclosure include pharmaceutical compositions comprising the compounds described herein, methods of using the compounds to treat certain diseases, and intermediates and processes useful in the synthesis of the compounds. [0003] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAKl, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-a, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, 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 cytokine, and LIF). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6. SUMMARY OF THE INVENTION [0004] Compounds described herein are modulators of the JAK family of kinases. More specifically, the compounds of the present disclosure are inhibitors of TYK2. In some embodiments, compounds are selective for TYK2 over other JAKs. For example, compounds may bind specifically to the pseudokinase domain (JH2) of TYK2 thereby enhancing selectivity over JAK family members. In some embodiments, a compound of the present disclosure may be an allosteric modulator or noncompetitive inhibitor of TYK2. In additional embodiments, a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders. In some embodiments, the compounds of the present disclosure penetrate the blood- brain barrier and are useful for the treatment of certain neurological disorders. [0005] In one aspect, described herein is a compound of Formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: X is N or CH; Y is -NH- or -CH2-; Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)- C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups; R2 is halogen, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy; R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1- C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, - S(O)2R13, or -S(O)2N(R13)2; or R4 and R5 are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Ring A is a 5-membered heteroaryl ring or a 6-membered heteroaryl ring; each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -CN, - OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; wherein any R6 attached to a nitrogen atom is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, - S(O)R13, -S(O)2R13, or -S(O)2N(R12)2; R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10; R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2- C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R11 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; or R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2; each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; m is 1, 2, or 3; and n is 0 or 1; wherein the compound is not N-(5-(propanoyl-3,3,3-d3)-4-((2,5,8-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2- yl)cyclopropanecarboxamide. [0006] In some embodiments, the compound is a compound of Formula (II):
Figure imgf000005_0001
Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0007] In some embodiments, the compound is a compound of Formula (III):
Figure imgf000005_0002
Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
Figure imgf000005_0003
[0008] In some embodiments, the compound is a compound of Formula (IV):
Figure imgf000006_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0009] In some embodiments, the compound is a compound of Formula (V):
Figure imgf000006_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0010] In some embodiments, the compound is a compound of Formula (VI):
Figure imgf000006_0003
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
Figure imgf000006_0004
[0011] In some embodiments, the compound is a compound of Formula (VII):
Figure imgf000007_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0012] In some embodiments, the compound is a compound of Formula (X):
Figure imgf000007_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0013] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [0014] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient. 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 ophthalmic 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. [0015] Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof useful in the treatment of TYK2-mediated disorders. Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful in the treatment of an inflammatory or autoimmune disease. 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 a neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is multiple sclerosis. In some embodiments, the 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 disseminated encephalomyelitis. In some embodiments, the disease or condition is polyneuropathy. In some embodiments, the disease or condition is chronic inflammatory demyelinating polyneuropathy. In some embodiments, 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, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. [0016] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal. [0017] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one 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. [0018] In any of the embodiments disclosed herein, the mammal is a human. [0019] In some embodiments, compounds provided herein are orally administered to a human. [0020] Articles of manufacture, which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating TYK2, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating TYK2, are provided. [0021] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION [0022] TYK2 activation has been linked to many diseases and disorders, including inflammatory diseases and disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer. [0023] In particular, IL-23 activation of TYK2 is associated with inflammatory diseases such as inflammatory bowel disease (IBD), Crohn’s disease, celiac disease, and ulcerative colitis. As the downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Bechet’s disease. Tyk 2 has also been associated with diseases and conditions of the skin, such as psoriasis, vitiligo, atopic dermatitis, scleroderma; or diseases and conditions of the eye, such as Sjögren’s syndrome, uveitis, and dry eye. [0024] 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 mucous hypersecretion is mediated by IL-13-induced activation of the TYK2/STAT6 pathway. [0025] TYK2 is also associated with autoimmune diseases and conditions, such as multiple sclerosis (MS), lupus, and systemic lupus erythematosus (SLE). Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders. Various type I IFN signaling pathways dependent on TYK2 signaling have implicated TYK2 in SLE and other autoimmune diseases and conditions. [0026] TYK2 is associated with arthritis, including psoriatic arthritis and rheumatoid arthritis. Decreased TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. [0027] TYK2 has also been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. These effects are largely due to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 is a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects. However, studies in 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 through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Thus, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and/or BCL2-addicted tumors, such as 70% of adult T- cell leukemia cases. [0028] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Αβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Αβ administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer’s patients. [0029] Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata. [0030] There is a continuing need to provide novel inhibitors having more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased mobility across blood-brain barrier or with increased activity or increased selectivity over other JAK kinases (especially JAK2). In some embodiments, the present disclosure provides inhibitors of TYK2 that show increased mobility across the blood-brain barrier. In some embodiments, the TYK2 inhibitors show selectivity over JAK1, JAK2, and/or JAK3. In some embodiments, compounds with this selectivity (particularly over JAK2) deliver a pharmacological response that favorably treats one or more of the diseases or conditions described herein without the side- effects associated with the inhibition of JAK2. For example, compounds with increased activity or increased selectivity over other JAK kinases (especially JAK2). The present disclosure relates to compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2) and inhibit certain cytokine signaling, in particular 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 in the synthesis of the compounds. [0031] In some embodiments, the TYK2 inhibitors described herein are used in the treatment of a disease or condition in a mammal. Compounds of the Present Disclosure [0032] Compounds described herein, including pharmaceutically acceptable salts, tautomers, and solvates thereof, are inhibitors of TYK2. In some embodiments, compounds described herein are selective for TYK2 over other JAKs. In some embodiments, compounds described herein bind selectively/specifically to the pseudokinase domain (JH2) of TYK2. In some embodiments, a compound described herein binds to an allosteric site of TYK2. In additional embodiments, a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders. [0033] In specific embodiments, disclosed herein are compounds containing a substituted tricyclic ring. In some such embodiments, the substituted tricyclic ring demonstrates increased bioavailability over compounds without the substitution on the tricyclic ring. In some embodiments, a compound described herein exhibits improved blood–brain barrier penetration relative to previously disclosed TYK2 inhibitors. In some embodiments, a compound described herein exhibits improved bioavailability relative to previously disclosed TYK2 inhibitors. In some embodiments, a compound described herein exhibits decreased metabolic clearance relative to previously disclosed TYK2 inhibitors. [0034] In one aspect, the present disclosure provides compounds of Formula (I):
Figure imgf000011_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: X is N or CH; Y is -NH- or -CH2-; Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1- C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups; R2 is halogen, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy; R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6- membered heterocycloalkyl; R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2; or R4 and R5 are taken together with the carbon atom to which they are attached to form -C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Ring A is a 5-membered heteroaryl ring or a 6-membered heteroaryl ring; each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3- C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -CN, -OH, - OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, - S(O)2R13, or -S(O)2N(R13)2; wherein any R6 attached to a nitrogen atom is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -S(O)R13, -S(O)2R13, or -S(O)2N(R12)2; R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10; R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R11 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; or R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; m is 1, 2, or 3; and n is 0 or 1. [0035] In some embodiments, the compound of Formula (I) is not N-(5-(propanoyl-3,3,3-d3)- 4-((2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin- 2-yl)cyclopropanecarboxamide, which has the following structure:
Figure imgf000014_0002
[0036] In certain embodiments disclosed herein, the compound of Formula (I) is a compound of Formula (X):
Figure imgf000014_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups; R2 is halogen, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy; R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, - OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; or R4 and R5 are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; R6 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1- C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -S(O)R13, -S(O)2R13, or -S(O)2N(R12)2; R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10; R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R11 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; or R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, - S(O)2R13, or -S(O)2N(R13)2; each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; m is 1, 2, or 3; and n is 0 or 1. [0037] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, Y is -NH-. In other embodiments, Y is -CH2-. [0038] In some embodiments, X is N. In other embodiments, X is CH. [0039] In some embodiments, Z is carbon or nitrogen. In some embodiments, Z is carbon which can be further substituted by R1 or R2. In some embodiments, Z is carbon and is denoted as CH, which can be substituted by R1 or R2, per the floating attachment points of R1 and R2 in the pictoral representation of Formula (I). In some embodiments, Z is CH. In other embodiments, Z in N. [0040] In some embodiments, R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl. In some embodiments, R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R7 is C1-C4 alkyl, C1-C4 deuteroalkyl, or C3-C6 cycloalkyl. In some embodiments, R7 is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R7 is C1-C4 alkyl. In some embodiments, R7 is methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R7 is methyl or ethyl. In some embodiments, R7 is methyl. In some embodiments, R7 is ethyl. In some embodiments, R7 is C1-C4 deuteroalkyl. In some embodiments, R7 is trideuteromethyl or 2,2,2- trideuterioeth-1-yl. In some embodiments, R7 is -CD3. In some embodiments, R7 is C3-C4 cycloalkyl. In some embodiments, R7 is cyclopropyl. In some embodiments, R7 is -CH3 or -CD3. [0041] In some embodiments, R8 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R8 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R8 is hydrogen or C1-C6 alkyl. In some embodiments, R8 is hydrogen or C1-C4 alkyl. In some embodiments, R8 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R8 is hydrogen or methyl. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl. [0042] In some embodiments, R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10. In some embodiments, R9 is -C(O)R10. In some embodiments, R9 is -C(O)NR10R11. In some embodiments, R9 is -C(O)OR10. [0043] In some embodiments, R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R10 is unsubstituted or substituted C1- C6 alkyl, unsubstituted or substituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl. In some embodiments, R10 is unsubstituted or substituted C3-C6 cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R10 is unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R10 is unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R10 is unsubstituted or substituted cyclopropyl. [0044] In some embodiments, R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more Rs groups. In some embodiments, R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more Rs groups. In some embodiments, the one or more Rs groups are each independently selected from the group consisting of deuterium, halogen, C1-C6 alkyl, -CN, -OR18, and -N(R18)2. In some embodiments, the one or more Rs groups are each independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, - OCHF2, and -OCF3. [0045] In some embodiments, R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, - OCH3, -OCHF2, and -OCF3. In some embodiments, R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, - CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. [0046] In some embodiments, R10 is unsubstituted or substituted C3-C6 cycloalkyl or unsubstituted or substituted 3- or 6-membered heterocycloalkyl; wherein the substituted cycloalkyl or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), - N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, R10 is unsubstituted or substituted C3-C4 cycloalkyl or unsubstituted or substituted 3- or 4- membered heterocycloalkyl; wherein the substituted cycloalkyl or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, - OCH3, -OCHF2, and -OCF3. In some embodiments, R10 is unsubstituted or substituted C3-C6 cycloalkyl; wherein the substituted cycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, R10 is unsubstituted or substituted C3-C4 cycloalkyl; wherein the substituted cycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, - CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, R10 is unsubstituted or substituted cyclopropyl; wherein the substituted cycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, - OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, R10 is substituted cyclopropyl; wherein the substituted cyclopropyl is substituted with one or more -F. In some embodiments, R10 is cyclopropyl. [0047] In some embodiments, R10 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl, . In some e 10
Figure imgf000019_0001
mbodiments, R is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl,
Figure imgf000019_0002
In some embodiments, R10 is
Figure imgf000019_0003
Figure imgf000019_0004
[0048] In some embodiments, R11 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R11 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R11 is hydrogen or C1-C6 alkyl. In some embodiments, R11 is hydrogen or C1-C4 alkyl. In some embodiments, R11 is hydrogen or methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R11 is hydrogen or methyl. In some embodiments, R11 is hydrogen. In some embodiments, R11 is methyl. [0049] In some embodiments, R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl. In some embodiments, R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl. [0050] In some embodiments, R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl. In some embodiments, R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycloalkyl. In some embodiments, R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle. In some embodiments, R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- membered monocyclic heterocycloalkyl. [0051] In some embodiments, the compound is a compound of Formula (II) or Formula (III):
Figure imgf000020_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0052] In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0053] In some embodiments, R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl. In some embodiments, R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2. [0054] In some embodiments, R9 is an unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, unsubstituted or substituted bicyclic heterocyclyl, unsubstituted or substituted spirocyclic carbocyclyl, unsubstituted or substituted spirocyclic heterocyclyl, unsubstituted or substituted bridged carbocyclyl, or unsubstituted or substituted bridged heterocyclyl. [0055] In some embodiments, R9 is an unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R9 is an unsubstituted or substituted monocyclic carbocyclyl. In some embodiments, R9 is an unsubstituted or substituted bicyclic carbocyclyl. In some embodiments, R9 is an unsubstituted or substituted monocyclic heterocyclyl. In some embodiments, R9 is an unsubstituted or substituted bicyclic heterocyclyl. [0056] In some embodiments, R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl. In some embodiments, R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. [0057] In some embodiments, R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5- membered heteroaryl. In some embodiments, R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. [0058] In some embodiments, R9 is an unsubstituted or substituted monocyclic 6-membered heteroaryl or an unsubstituted or substituted monocyclic 5-membered heteroaryl. In some embodiments, R9 is an unsubstituted or substituted monocyclic 6-membered heteroaryl or an unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2. [0059] In some embodiments, R9 is an unsubstituted or substituted monocyclic 5-membered heteroaryl. In some embodiments, R9 is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thiophenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, or unsubstituted or substituted tetrazolyl. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. [0060] In some embodiments, R9 is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl. In some embodiments, R9 is an unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. [0061] In some embodiments, R9 is an unsubstituted or substituted 6-membered heteroaryl. In some embodiments, R9 is an unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl. In some embodiments, R9 is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl. In some embodiments, R9 is an unsubstituted or substituted pyridinyl. In some embodiments, R9 is an unsubstituted or substituted pyrimidinyl. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, - CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. [0062] In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. In some embodiments, In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1- C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1- C6 fluoroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -C(O)R12, -C(O)OR12, and -C(O)N(R12)2. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, - C(O)R12, -C(O)OR12, and -C(O)N(R12)2. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -C(O)R12, -C(O)OR12, and -C(O)N(R12)2. In some embodiments, if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, C1- C6 alkyl, and -CN. [0063] In some embodiments, R9 is 2,6-dimethylpyrimidin-4-yl or 5-fluoropyridin-2-yl. [0064] In all embodiments disclosed herein, R1 is not hydrogen or fluoro. In some embodiments, compounds containing an R1 substituent as described herein have increased lipophilicity (for example, a higher log P value) compared to compounds without an R1 substituent as described herein (e.g., with no R1 substituent or with R1 = F). In some embodiments, compounds containing an R1 substituent as described herein have increased bioavailability compared to compounds without an R1 substituent as described herein (e.g., with no R1 substituent or with R1 = F). In some embodiments, compounds containing an R1 substituent as described herein have increased blood–brain barrier penetration, or brain exposure, compared to compounds without an R1 substituent as described herein (e.g., with no R1 substituent or with R1 = F). In some embodiments, compounds containing an R1 substituent as described herein have decreased metabolic clearance compared to compounds without an R1 substituent as described herein (e.g., with no R1 substituent or with R1 = F). [0065] In some embodiments of the compounds disclosed herein, R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups. In some embodiments, R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group. In some embodiments, R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R1 is -Cl, -CN, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -CHF2, -CH2F, -OCH3, -OCH2CH3, -OCH(CH3)2, - OCF3, -OCH2CF3, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl. In some embodiments, R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, -OCF3, -OCH2CF3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl. [0066] In some embodiments of the compounds disclosed herein, R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy. In some embodiments, chloro, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R1 is chloro or C1-C4 alkyl. In some embodiments, R1 is C1-C4 alkyl. In some embodiments, R1 is -CH3. [0067] In some embodiments, n is 1. In some such embodiments, R2 is halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. In some such embodiments, R2 is halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some such embodiments, R2 is halogen or C1-C4 alkyl. In some such embodiments, R2 is fluoro, chloro, or C1-C4 alkyl. In some such embodiments, R2 is fluoro, chloro, or -CH3. [0068] In some embodiments, n is 0. [0069] In some embodiments, the compound is a compound of Formula (IV), Formula (V), Formula (VI) or Formula (VII):
Figure imgf000025_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0070] In some embodiments, R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group. In some embodiments, R1 is chloro, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R1 is -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -CHF2, -CH2F, - OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -CH2OCH3, cyclopropyl, or 1-fluoro- cyclopropyl. In some embodiments, R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, -OCF3, -OCH2CF3, - OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl. In some embodiments, R1 is chloro or C1-C4 alkyl. In some embodiments, R1 is C1-C4 alkyl. In some embodiments, R1 is - CH3. [0071] In some embodiments, X is N. In other embodiments, X is CH. [0072] In some embodiments, R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl. In some embodiments, R3 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl. In some embodiments, R3 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R3 is C1- C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R3 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some embodiments, R3 is C1-C4 alkyl, C1-C4 deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some embodiments, R3 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, R3 C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, R3 is C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, R3 is hydrogen or C1-C6 alkyl. In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C1-C4 alkyl. In some embodiments, R3 is methyl or ethyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is C1-C6 deuteroalkyl. In some embodiments, R3 is C1-C4 deuteroalkyl. In some embodiments, R3 is trideuteromethyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is methyl, ethyl, trideuteromethyl, or cyclopropyl. In some embodiments, R3 is -CH3 or -CD3. In some embodiments, R3 is -CH3. [0073] In some embodiments, R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. In some embodiments, R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and -N(R12)2. In some embodiments, R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments, R4 and R5 are each independently hydrogen, deuterium, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R4 and R5 are each independently hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. In some embodiments, R4 and R5 are each independently hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. In some embodiments, R4 is methyl, ethyl, or trideuteromethyl; and R5 is hydrogen, methyl, ethyl, or trideuteromethyl. [0074] In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1- C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2. In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and -N(R12)2. In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments, R4 is hydrogen, deuterium, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R4 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. In some embodiments, R4 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. [0075] In some embodiments, R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2. In some embodiments, R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and - N(R12)2. In some embodiments, R4 is C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments, R4 is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R4 is methyl, ethyl, or trideuteromethyl. In some embodiments, R4 is methyl. [0076] In some embodiments, R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1- C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2. In some embodiments, R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, and -N(R12)2. In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments, R5 is hydrogen, deuterium, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R5 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. In some embodiments, R5 is hydrogen, deuterium, methyl, ethyl, or trideuteromethyl. In some embodiments, R5 is hydrogen or deuterium. In some embodiments, R5 is hydrogen. [0077] In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1- C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2; and R5 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments, R4 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; and R5 is hydrogen. [0078] In some embodiments, R4 and R5 are each independently hydrogen or -CH3. In some embodiments, R4 is methyl; and R5 is hydrogen or methyl. In some embodiments, R4 and R5 are each methyl. In some embodiments, R4 is methyl; and R5 is hydrogen. [0079] In some embodiments, R4 and R5 are each independently hydrogen or deuterium. In some embodiments, R4 and R5 are each hydrogen. In some embodiments, R4 and R5 are each deuterium. [0080] In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form -C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. [0081] In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form -C(O)-. [0082] In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. [0083] In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclopropylene or cyclobutylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclopropylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclobutylene. [0084] In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered heterocycloalkyl ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 4-membered heterocycloalkyl ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted oxetane ring or azetidine ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted oxetane ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an oxetane ring. [0085] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia):
Figure imgf000029_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0086] In some embodiments, the compound is a compound of Formula (Ia-1) or Formula (Ia- 2):
Figure imgf000029_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (Ia-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (Ia-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0087] In some embodiments, the compound of Formula (II) is a compound of Formula (IIa):
Figure imgf000030_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0088] In some embodiments, the compound is a compound of Formula (IIa-1) or Formula (IIa-2):
Figure imgf000030_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (IIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (IIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0089] In some embodiments, the compound of Formula (III) is a compound of Formula (IIIa):
Figure imgf000031_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0090] In some embodiments, the compound is a compound of Formula (IIIa-1) or Formula (IIIa-2):
Figure imgf000031_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (IIIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (IIIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0091] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVa):
Figure imgf000032_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0092] In some embodiments, the compound is a compound of Formula (IVa-1) or Formula
Figure imgf000032_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (IVa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (IVa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0093] In some embodiments, the compound of Formula (V) is a compound of Formula (Va):
Figure imgf000033_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0094] In some embodiments, the compound is a compound of Formula (Va-1) or Formula (Va-2):
Figure imgf000033_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (Va-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (Va-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0095] In some embodiments, the compound of Formula (VI) is a compound of Formula (VIa):
Figure imgf000034_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0096] In some embodiments, the compound is a compound of Formula (VIa-1) or Formula
Figure imgf000034_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (VIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (VIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0097] In some embodiments, the compound of Formula (VII) is a compound of Formula (VIIa):
Figure imgf000035_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0098] In some embodiments, the compound is a compound of Formula (VIIa-1) or Formula (VIIa-2):
Figure imgf000035_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (VIIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (VIIa-2), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0099] For each of Formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), and their subformulas, the substituent groups are as defined herein. [00100] For example, in some embodiments, R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2. In some embodiments, R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, - CN, -OH, -OR13, and -N(R12)2. In some embodiments, R4 is C1-C6 alkyl or C1-C6 deuteroalkyl. In some embodiments, R4 is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R4 is methyl, ethyl, or trideuteromethyl. In some embodiments, R4 is methyl. [00101] In some embodiments, Ring A is a 5-membered heteroaryl ring. [00102] In some embodiments, Ring A is a pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, or thiadiazole. In some embodiments, Ring A is a triazole, imidazole, pyrazole, thiazole, or oxazole. In some embodiments, Ring A is a triazole. In some embodiments, Ring A is an imidazole. In some embodiments, Ring A is a pyrazole. In some embodiments, Ring A is a thiazole. In some embodiments, Ring A is an oxazole. [00103] In some embodiments,
Figure imgf000036_0001
Figure imgf000036_0002
where * represents the attachment point to -C(R4)(R5)-.
Figure imgf000036_0003
Figure imgf000037_0001
[00106] In some embodiments, Ring A is a 6-membered heteroaryl ring. [00107] In some embodiments, Ring A is a pyridine, pyridazine, pyrimidine, or pyrazine. In some embodiments, Ring A is a pyridine or pyrazine. In some embodiments, Ring A is a pyridine. In some embodiments, Ring A is a pyrazine. In some embodiments, Ring A is a pyrimidine. In some embodiments, Ring A is a pyridazine.
Figure imgf000038_0001
[00110] In some embodiments,
Figure imgf000039_0001
where * represents the attachment point to -C(R4)(R5)-. In some embodiments,
Figure imgf000039_0002
Figure imgf000039_0004
In some embodiments,
Figure imgf000039_0003
[00111] In some embodiments, each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, - CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; wherein any R6 attached to a nitrogen atom is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -S(O)R13, -S(O)2R13, or -S(O)2N(R12)2. [00112] In some embodiments, each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, - CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, or - S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2. [00113] In some embodiments, each R6 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, or -S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6- membered heterocycloalkyl, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2. [00114] In some embodiments, each R6 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, or -S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -C(O)OR12, - C(O)N(R12)2, or -S(O)2N(R12)2. In some embodiments, each R6 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR13, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, or -S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2. [00115] In some embodiments, each R6 is independently hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, or -N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R6 is independently hydrogen, halogen, C1-C6 alkyl, -CN, -OH, -OR13, or -N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen or C1-C6 alkyl. [00116] In some embodiments, each R6 is independently hydrogen, -F, -Cl, methyl, ethyl, isopropyl, -CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -OH, -C(O)OH, or - C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, ethyl, isopropyl, - CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -C(O)OH, or -C(O)OCH3. In some embodiments, each R6 is independently hydrogen, -F, methyl, -OH, -CH2OH, -CD3, cyclopropyl, oxetanyl, or -C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, -CH2OH, -CD3, cyclopropyl, oxetanyl, or -C(O)OCH3. In some embodiments, each R6 is independently hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, or -N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl. [00117] In some embodiments, each R6 is independently hydrogen, -F, -Cl, methyl, ethyl, isopropyl, -CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -OH, -C(O)OH, or - C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, ethyl, isopropyl, - CH2OH, -CD3, -CF3, cyclopropyl, oxetanyl, azetidinyl, -C(O)OH, or -C(O)OCH3. In some embodiments, each R6 is independently hydrogen, -F, methyl, -OH, -CH2OH, -CD3, oxetanyl, or -C(O)OCH3; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, -CH2OH, -CD3, oxetanyl, or -C(O)OCH3. [00118] In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. [00119] In some embodiments, each R6 is independently hydrogen, fluoro, methyl, or cyclopropyl; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, or cyclopropyl; and m is 1 or 2.
Figure imgf000041_0001
[00121] In some embodiments, the compound of Formula (I) is a compound of Formula (X):
Figure imgf000041_0002
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups; R2 is halogen, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy; R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, - OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; or R4 and R5 are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; R6 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1- C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -S(O)R13, -S(O)2R13, or -S(O)2N(R12)2; R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10; R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R11 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; or R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, - S(O)2R13, or -S(O)2N(R13)2; each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; m is 1, 2, or 3; and n is 0 or 1. [00122] Any of the paragraphs and definitions above that relate to any substituent groups present in Formula (X) are applicable to Formula (X). For example, in some embodiments, X is N. In other embodiments, X is CH. [00123] In some specific embodiments, R7 is C1-C4 alkyl or C1-C4 deuteroalkyl. [00124] In some specific embodiments, R8 is hydrogen or C 9 10 1-C4 alkyl; R is -C(O)R , - C(O)NR10R11, or -C(O)OR10; R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl; and R11 is hydrogen or C1-C4 alkyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl. In some specific embodiments, R8 is hydrogen; R9 is -C(O)R10; and R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, - OCH3, -OCHF2, and -OCF3. [00125] In some specific embodiments, R3 is hydrogen or C 4 5 1-C6 alkyl; and R and R are each independently hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl; or R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. [00126] In some specific embodiments, R3 is C1-C6 alkyl; R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or - S(O)2N(R13)2; and R5 is hydrogen. In some specific embodiments, R4 is C1-C6 alkyl or C1-C6 deuteroalkyl. [00127] In some specific embodiments, n is 1; and R2 is halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. In some specific embodiments, n is 0. [00128] In some embodiments, the compound of Formula (X) is a compound of Formula (XI):
Figure imgf000044_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [00129] In some embodiments, the compound of Formula (XI) is a compound of Formula (XIa) or Formula (XIb):
Figure imgf000045_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [00130] In some specific embodiments, R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3- C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group. In some specific embodiments, R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl. In some specific embodiments, R1 is -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, - CHF2, -CH2F, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl. In some specific embodiments, R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, - OCF3, -OCH2CF3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl. [00131] In some specific embodiments, R6 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2. In some specific embodiments, R6 is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl. In some specific embodiments, R6 is hydrogen, methyl, or cyclopropyl. [00132] In some embodiments, each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl. In some embodiments, each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, each R12 is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a 4- to 6-membered N-containing heterocycloalkyl. [00133] In some embodiments, each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. In some embodiments, each R13 is independently C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl. [00134] In some embodiments, compounds described herein have the following structure:
Figure imgf000046_0001
[00135] In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described herein. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 1 or Table 2. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 1. [00136] In some embodiments, compounds described herein have the following structure:
Figure imgf000047_0001
[00137] In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described herein. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 1 or Table 2. In some embodiments, Y, X, R1, R4, R5, R6, m, and Ring A are as described in Table 2. [00138] In some embodiments, compounds described herein have the following structure:
Figure imgf000047_0002
[00139] In some embodiments, R7, R8, and R9 are as described herein In some embodiments, R7, R8, and R9 are as described in Table 3. [00140] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00141] Exemplary compounds described herein include the compounds described in the following Tables: Table 1:
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
†
Figure imgf000063_0001
= single isomer at -C(R4)(R5)- obtained by chiral separation of racemic compound. Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined. * = attachment point to -C(R4)(R5)- [00142] Compounds in Table 1 are named: 1: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 2: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 3: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 4: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 5: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 6: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 7: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,4,5,8-pentamethyl-4,5- dihydro-3H-imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 8: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,4,5,8-pentamethyl-4,5- dihydro-3H-imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 9: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 10: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide 11: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5,8-tetramethyl-4,5-dihydro- 3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 12: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5,8-tetramethyl-4,5-dihydro- 3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 13: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 14: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 15: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,5,8-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 16: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,5,8-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 17: N-(5-(propanoyl-3,3,3-d3)-4-((2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 18: N-(5-(propanoyl-3,3,3-d3)-4-((2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 19: (S)-N-(4-((9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 20: (R)-N-(4-((9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 21: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,9-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 22: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,9-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 23: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 24: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 25: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 26: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 27: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 28: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 29: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 30: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 31: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 32: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 33: (S)-N-(4-((2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 34: (R)-N-(4-((2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 35: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,4,5,8-pentamethyl-4,5- dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 36: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,4,5,8-pentamethyl-4,5- dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 37: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 38: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 39: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 40: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 41: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 42: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 43: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 44: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 45: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2',5',8'-trimethyl-2',5'- dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)amino)pyridazine-3- carboxamide; 46: (S)-4-((9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 47: (R)-4-((9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 52: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 53: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 54: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 55: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydro- 2H-pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 56: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 57: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 58: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 59: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 60: (R)-N-(4-((9-cyano-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 61: (S)-N-(4-((9-cyano-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 62: (R)-N-(4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 63: (S)-N-(4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 64: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)nicotinamide; 65: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)nicotinamide; 66: (R)-6-(cyclopropanecarboxamido)-4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 67: (S)-6-(cyclopropanecarboxamido)-4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 68: (R)-4-((9-cyano-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 69: (S)-4-((9-cyano-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 70: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 71: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,9-tetramethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 72: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 73: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 74: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide; 75: (R)-6-(cyclopropanecarboxamido)-4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide; 76: (S)-6-(cyclopropanecarboxamido)-4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide; 77: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 78: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 79: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,10-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 80: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,10-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 81: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,10-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide; 82: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,10-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide; 83: (R)-6-(cyclopropanecarboxamido)-4-((3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H- pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 84: (S)-6-(cyclopropanecarboxamido)-4-((3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H- pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 85: (R)-N-(4-((3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 86: (S)-N-(4-((3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 87: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,5,6,9-tetramethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 88: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,5,6,9-tetramethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 89: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 90: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 91: (S)-N-(4-((2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4-c][1,7]naphthyridin- 6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 92: (R)-N-(4-((2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4-c][1,7]naphthyridin- 6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 93: (S)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-4,5,8-trimethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 94: (R)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-4,5,8-trimethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 95: (S)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-4,5,8-trimethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide; 96: (R)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-4,5,8-trimethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide; 97: (S)-6-(cyclopropanecarboxamido)-4-((3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H- pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide; 98: (R)-6-(cyclopropanecarboxamido)-4-((3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H- pyrazolo[4,3-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide; 99: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,5,6,9-tetramethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)nicotinamide; 100: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,5,6,9-tetramethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)nicotinamide; 101: (R)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 102: (S)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 103: (R)-N-(4-((10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 104: (S)-N-(4-((10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 105: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 106: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 107: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,10-trimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 108: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,10-trimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 109: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,10-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 110: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((5,6,10-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; 111: (R)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide; 112: (S)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide; 113: (S)-6-(cyclopropanecarboxamido)-4-((3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 114: (R)-6-(cyclopropanecarboxamido)-4-((3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 115: (R)-N-(4-((3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 116: (S)-N-(4-((3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 117: (R)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 118: (S)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 119: (R)-N-(4-((10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 120: (S)-N-(4-((10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 121: (R)-N-(4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 122: (S)-N-(4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 123: (R)-6-(cyclopropanecarboxamido)-4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- pyrazolo[3,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 124: (S)-6-(cyclopropanecarboxamido)-4-((9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- pyrazolo[3,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 125: (R)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl-5,6- dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide; 126: SUJB-0001272 (S)-6-(cyclopropanecarboxamido)-4-((10-methoxy-5,6-dimethyl- 5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide; 127: (R)-6-(cyclopropanecarboxamido)-4-((9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 128: (S)-6-(cyclopropanecarboxamido)-4-((9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 129: (R)-N-(4-((9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 130: (S)-N-(4-((9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 131: (R)-N-(4-((9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 132: (S)-N-(4-((9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 133: (S)-N-(4-((9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 134: (R)-N-(4-((9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 135: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,5,6,9-tetramethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 136: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,5,6,9-tetramethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; 137: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,5,6,9-tetramethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide; 138: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,5,6,9-tetramethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide; 139: (R)-6-(cyclopropanecarboxamido)-4-((9-(methoxymethyl)-2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 140: (S)-6-(cyclopropanecarboxamido)-4-((9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 141: (S)-6-(cyclopropanecarboxamido)-4-((9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 142: (R)-6-(cyclopropanecarboxamido)-4-((9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 143: (S)-6-(cyclopropanecarboxamido)-4-((9-(difluoromethyl)-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 144: (R)-6-(cyclopropanecarboxamido)-4-((9-(difluoromethyl)-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 145: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-9- (trifluoromethoxy)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- yl)amino)pyridazine-3-carboxamide; 146: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-9- (trifluoromethoxy)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- yl)amino)pyridazine-3-carboxamide; 147: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-9-(2,2,2- trifluoroethoxy)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine- 3-carboxamide; 148: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-9-(2,2,2- trifluoroethoxy)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine- 3-carboxamide; 149: (S)-6-(cyclopropanecarboxamido)-4-((9-cyclopropoxy-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 150: (R)-6-(cyclopropanecarboxamido)-4-((9-cyclopropoxy-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 151: (S)-6-(cyclopropanecarboxamido)-4-((9-(1-fluorocyclopropyl)-2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 152: (R)-6-(cyclopropanecarboxamido)-4-((9-(1-fluorocyclopropyl)-2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 153: (S)-6-(cyclopropanecarboxamido)-4-((1-fluoro-9-methoxy-2,4,5-trimethyl-4,5- dihydro-2H-pyrazolo[3,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 154: (R)-6-(cyclopropanecarboxamido)-4-((1-fluoro-9-methoxy-2,4,5-trimethyl-4,5- dihydro-2H-pyrazolo[3,4-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3- carboxamide; 155: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2- yl)cyclopropanecarboxamide; and 156: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2- yl)cyclopropanecarboxamide. [00143] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 1. Table 2:
Figure imgf000073_0001
Figure imgf000073_0002
†
Figure imgf000074_0002
= single isomer at -C(R4)(R5)- obtained by chiral separation of racemic compound. Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined. * = attachment point to -C(R4)(R5)- [00144] Compounds in Table 2 are named: 48: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidin-6-yl)amino)pyridin-2- yl)cyclopropanecarboxamide; 49: (R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidin-6-yl)amino)pyridin-2- yl)cyclopropanecarboxamide 50: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidin-6-yl)amino)pyridazine-3-carboxamide; and 51: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidin-6-yl)amino)pyridazine-3-carboxamide. [00145] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 2. Table 3:
Figure imgf000074_0001
Figure imgf000075_0001
†
Figure imgf000076_0001
= single isomer obtained by chiral separation of racemic compound. Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined. [00146] Compounds in Table 3 are named: 157: (S)-6-(3-isopropyl-2-oxoimidazolidin-1-yl)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 158: (S)-6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl- 4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 159: (S)-6-(3-cyclobutyl-2-oxoimidazolidin-1-yl)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl- 4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 160: (S)-6-(3-isopropyl-2-oxotetrahydropyrimidin-1(2H)-yl)-N-(methyl-d3)-4-((2,4,5,8- tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3- carboxamide; 161: N-(methyl-d3)-6-(((R)-tetrahydrofuran-3-yl)amino)-4-(((S)-2,4,5,8-tetramethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 162: N-(methyl-d3)-6-(((S)-tetrahydrofuran-3-yl)amino)-4-(((S)-2,4,5,8-tetramethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 163: (S)-N-(methyl-d3)-6-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-((2,4,5,8- tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3- carboxamide; 164: (S)-N-(methyl-d3)-6-(3-methyl-2-oxoimidazolidin-1-yl)-4-((2,4,5,8-tetramethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 165: (S)-N-(methyl-d3)-6-(2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl)-4-((2,4,5,8- tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3- carboxamide; 166: 6-(3-((1s,3R)-3-fluorocyclobutyl)-2-oxoimidazolidin-1-yl)-N-(methyl-d3)-4-(((S)- 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- yl)amino)pyridazine-3-carboxamide; 167: (S)-6-(3-ethyl-2-oxoimidazolidin-1-yl)-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 168: 6-(3-((1r,3S)-3-fluorocyclobutyl)-2-oxoimidazolidin-1-yl)-N-(methyl-d3)-4-(((S)- 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- yl)amino)pyridazine-3-carboxamide; and 169: (S)-6-(cyclopropanecarboxamido)-N-(2,2-difluoroethyl)-4-((2,4,5,8-tetramethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide. [00147] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 3. [00148] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [00149] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. [00150] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, 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. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted. [00151] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with an acid. In some embodiments, the compound of Formula (I) (i.e. free base form) is basic and is reacted 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-oxoglutaric 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 (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2- disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. [00152] In some embodiments, a compound of Formula (I) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt. [00153] 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 is reacted with a base. In such situations, an acidic proton of the compound of Formula (I) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, 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 a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N- methylglucamine salt or ammonium salt. [00154] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. [00155] The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity. [00156] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of Formula (I) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group. [00157] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00158] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, 123I, 124I, 125I, 131I, 32P and 33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. [00159] In some embodiments, the compounds of Formula (I) possess one or more stereocenters and each stereocenter exists independently in either 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 diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. [00160] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture 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 diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation 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. [00161] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. [00162] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N- alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1- 38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs. [00163] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I) as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. [00164] In some embodiments, any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above. [00165] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. [00166] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. [00167] In some instances, heterocyclic rings may exist in tautomeric forms. In such situations, it is understood that the structures of said compounds are illustrated or named in one tautomeric form but could be illustrated or named in the alternative tautomeric form. The alternative tautomeric forms are expressly included in this disclosure, such as, for example, the structures illustrated below. For example, pyridones could exist in the following tautomeric forms:
Figure imgf000082_0001
are encapsulated within the group, “substituted pyridines.” Similarly, pyrazoles, triazoles, pyrimidines, and the like are known to tautomerize; for the purpose of this disclosure, all tautomeric forms (including charged and zwitterionic tautomers) are considered within the scope of the present disclosure. General Synthesis of the Compounds of the Present Disclosure [00168] 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. [00169] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed. [00170] 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 variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. [00171] In some embodiments, compounds described herein are prepared as described in Scheme A.
Figure imgf000082_0002
Variables are as defined in Formula (I). [00172] In some embodiments, nucleophilic substitution of one chloro group of intermediate A with the free amino group of B affords intermediate C. In some embodiments, for example when intermediate A is a pyridazine compound (X = N), this substitution can be carried out with a suitable Lewis acid such as Zn(OAc)2. In other embodiments, for example when intermediate B is a pyridine compound (X = CH), this substitution is carried out by deprotonation of the amino group with a suitable base, such as LDA. In still other embodiments, intermediate C may be accessed by a cross-coupling reaction of intermediates A and B. Cross-coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like. Finally, in some embodiments, intermediate C is converted to the final compound D (e.g., Compound 1) via a cross-coupling reaction. Cross-coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like. [00173] In some embodiments, compounds are prepared as described in the Examples. Certain Terminology [00174] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [00175] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C6” indicates that there are one to six carbon atoms in the moiety, i.e. groups 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 among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl. [00176] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1- C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6 alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. [00177] An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6 alkylene. In other embodiments, an alkylene is a C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-. [00178] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein. In some embodiments, the alkoxy group is a C1-C6alkoxy, which refers to a (C1-C6alkyl)-O- group. Typical alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n- propoxy (-OCH2CH2CH3), isopropoxy (-O-iPr; -OCH(CH3)2), n-butoxy(-OCH2CH2CH2CH3), iso-butoxy (-OCH2CH(CH3)2), sec-butoxy (-OCH(CH3)(CH2CH3)), tert-butoxy (-OC(CH3)3), and the like. [00179] An “alkoxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by an alkoxy group, as defined herein. In some embodiments, an alkoxyalkyl is a (C1-C6alkoxy)-C1- C6alkyl, which can also be considered a (C1-C6alkyl)-O-(C1-C6alkyl)- group. In some embodiments, an alkoxyalkyl is a (C1-C4alkoxy)-C1-C4alkyl, which can also be considered a (C1-C4alkyl)-O-(C1-C4alkyl)- group. Typical alkoxyalkyl groups include, but are not limited to, - CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2OCH2CH3, - CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2CH2OCH2CH3, and the like. [00180] The term “alkylamine” refers to the –N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0. [00181] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl is a C1-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like. [00182] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a C1-C4aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, - CH2CH2CH2CH2NH2, and the like. [00183] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non- limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, - C(CH3)=CHCH3, and –CH2CH=CH2. [00184] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3 - C≡CCH2CH3, -CH2C≡CH. [00185] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl. [00186] The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl,” e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. [00187] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is 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 aryls and cycloalkyls. [00188] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group). [00189] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3- C6cycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl. [00190] The term “cycloalkyloxy” refers to a cycloalkyl group attached to the parent molecular moiety through an oxy. In some embodiments, the cycloalkyloxy is a C3-C6cycloalkyloxy, which refers to a (C3-C6cycloalkyl)-O- group. [00191] A “cycloalkylalkyl” refers to an alkyl in which one hydrogen atom is replaced by a cycloalkyl group, as defined herein. In some embodiments, a cycloalkylalkyl is a (C3- C6cycloalkyl)-C1-C6alkyl. In some embodiments, a cycloalkylalkyl is a (C3-C6cycloalkyl)-C1- C4alkyl. [00192] A “cycloalkoxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a cycloalkoxy group, as defined herein. In some embodiments, a cycloalkoxyalkyl is a (C3- C6cycloalkoxy)-C1-C6alkyl, which refers to a (C3-C6cycloalkyl)-O-(C1-C6alkyl)- group. [00193] A “cycloalkylalkoxy” refers to an alkoxy in which one hydrogen atom is replaced by a cycloalkyl group, as defined herein. In some embodiments, a cycloalkylalkoxy is a (C3- C6cycloalkyl)-C1-C6alkoxy, which refers to a (C3-C6cycloalkyl)-(C1-C6alkyl)-O- group. [00194] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo. [00195] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6 fluoroalkyl. In one aspect, a fluoroalkyl is a C1-C4 fluoroalkyl. [00196] The term “haloalkoxy” refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. In one aspect, the haloalkoxy is a C1-C6haloalkoxy, which refers to a (C1-C6haloalkyl)-O- group. In another aspect, the haloalkoxy is a C1-C4haloalkoxy, which refers to a (C1-C4haloalkyl)-O- group. In some embodiments, when the halo is a fluorine, the haloalkoxy is a fluoroalkoxy. [00197] The term “fluoroalkoxy” refers to an alkoxy in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkoxy is a C1-C6 fluoroalkoxy. In one aspect, a fluoroalkoxy is a C1-C4 fluoroalkoxy. [00198] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 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 heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1- onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)- onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N- attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5- yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2- one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. [00199] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9 heteroaryl. [00200] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2- onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. [00201] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups. [00202] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [00203] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from 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, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, - NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), - C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1- C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). [00204] In some embodiments, each substituted alkyl, substituted fluoroalkyl, 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, -OR18, -CO2R18, -C(=O)N(R18)2, - N(R18)2, -NR18C(=O)R19, -SR18, -S(=O)R19, -SO2R19, or -SO2N(R18)2; each R18 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2- C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R18 groups are taken together with the N atom to which they are attached to form a N-containing heterocycle; each R19 is independently selected from C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl. [00205] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. [00206] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. [00207] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor. [00208] The term “degrader” as used herein, refers to a bifunctional compound that binds to and/or inhibits both a TYK2 kinase and an E3 ubiquitin ligase resulting in the ubiquitination and subsequent degradation of the TYK2 kinase. In particular, in some instances, degraders are bifunctional or proteolysis-targeting chimeric (PROTAC®) protein degrader compounds, which find utility as modulators of targeted ubiquitination of TYK2 proteins, which are then degraded and/or inhibited by the bifunctional compounds. In some instances, such bifunctional molecules function by recruiting the TYK2 kinase to the E3 ubiquitin ligase for ubiquitination and subsequent degradation of the TYK2 kinase. The degrader comprises a TYK2 binding moiety (e.g., a group comprising a compound described herein) bound to an E3 ubiquitin ligase moiety, optionally through a linker. [00209] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These 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 of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. [00210] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [00211] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study. [00212] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system. [00213] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients. [00214] The terms “article of manufacture” and “kit” are used as synonyms. [00215] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; 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. [00216] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. Pharmaceutical Compositions [00217] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth 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, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [00218] A compound or a pharmaceutical composition of the present disclosure is, in some embodiments, useful for the treatment of a TYK2 mediated disease or disorder. In some embodiments, the pharmaceutical composition is effective at treating a disease or disorder wherein TYK2 is overexpressed or hyperactive. In some embodiments, the pharmaceutical composition is effective at treating a disease or disorder which would benefit from a reduction in TYK2 activity or expression. [00219] In some embodiments, the pharmaceutical composition is useful in the treatment of disease or disorder associated with high levels of cytokines driven by TYK2, such as interferons (e.g. IFN-a, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, 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 cytokine, 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 interferonopathies such as Alcardi-Goutieres syndrome, or combinations thereof. [00220] In some embodiments, the pharmaceutical composition is useful in the treatment of an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is an auto-inflammatory disease or disorder, a host-mediated inflammatory disease or disorder, an injury-related inflammatory disease or disorder, an infection-related inflammatory disease or disorder, a hyperproliferative (e.g., cancer, fibrosis) mediated inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder or infection-related inflammatory disease or disorder is a respiratory disease or disorder. In some embodiments, the respiratory disease or disorder is associated with a viral in microbial infection. In some embodiments, the respiratory disease or disorder is a problematic immune response to a viral or microbial infection. In some embodiments, the respiratory disease or disorder 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 decreasing symptoms associated with COVID-19, or an immune response associated therewith. [00221] In some embodiments, the pharmaceutical composition is useful in the treatment of an autoimmune disease or disorders. In some embodiments, an autoimmune disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, an autoimmune disease or disorder is lupus or systemic lupus erythematosus. In some embodiments, an autoimmune disease or disorder is psoriasis. In some embodiments, an autoimmune disease or disorder is irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IBS-D). In some embodiments, an autoimmune disease or disorder is dry eye or uveitis. In some embodiments, an autoimmune disease or disorder is Crohn’s disease. In some embodiments, an autoimmune disease or disorder is atopic dermatitis. [00222] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, topical application such as creams or ointments. Additional examples of local administration of the present compounds include eye drops, ocular creams, gels or hydrogels, implants, transdermal patches, or drug depots. In some embodiments, a pharmaceutical composition is administered orally (e.g., in a liquid formulation, tablet, capsule, nebulized liquid, aerosolized liquid, dry powder spray). [00223] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste. [00224] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses. [00225] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [00226] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [00227] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present disclosure externally to the epidermis or the buccal cavity and the installation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. [00228] Pharmaceutical compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. [00229] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise 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 to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations 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 dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. [00230] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional 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 [00231] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-α, IFN- β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, 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 cytokine, and LIF). [00232] Mice containing the rs3456443 loss of function (LoF) mutation in the pseudokinase domain of TYK2 show a decreased risk of disease in EAE, with evidence showing that this is due to impaired IL-12, IL-23, and Type 1 IFN signaling (See, Dendrou et al, Sci Transl Med (2016)). Cytokine induced pSTAT phosphorylation by the rs3456443 genotype in primary human immune cells confirm a dose response for wild type – heterozygous – homozygous for IFN-α/β, IL-23, and IL-12, confirming that this is a TYK2 LoF mutation. This LoF mutation in TYK2 leads to decreased demyelination and increased remyelination of neurons, which supports the role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders. [00233] Additionally, 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 widely 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 an IL-23 encoding adenoviral vector induces clinical relapses of EAE. Accordingly, use of a TYK2 inhibitor can interrupt this important pathology in MS and other CNS disorders. [00234] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide, which demonstrates its role in potential treatment of Alzheimer’s Disease (AD). Decreased TYK2 phosphorylation of STAT3 following Aβ administration leads to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. (See, Wan et al., J. Neurosci. (2010) 30(20):6873-6881). [00235] In some embodiments, certain TYK2 inhibitors described herein penetrate the blood- brain barrier. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of more than 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of more than 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean 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. [00236] In some embodiments, the compounds of this disclosure are useful in 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 a neuromyelitis optica spectrum disorder. In some embodiments, compounds of the instant disclosure are useful in the treatment of multiple sclerosis (MS). In some embodiments, the MS is relapsing MS or relapsing-remitting MS (RRMS). In some embodiments, compounds of the instant disclosure are useful in the treatment of a neuromyelitis optica spectrum disorder, such as neuromyelitis optica. In some embodiments, compounds of the instant disclosure are useful in the treatment of encephalomyelitis, including acute disseminated encephalomyelitis. In some embodiments, compounds of the instant disclosure are useful in the treatment of polyneuropathy, such as chronic inflammatory demyelinating polyneuropathy. In some embodiments, compounds of the instant disclosure are useful in the treatment of encephalitis, including autoimmune encephalitis. [00237] In one aspect, the present disclosure provides methods of 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 a neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is multiple sclerosis. In some embodiments, the 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 disseminated encephalomyelitis. In some embodiments, the disease or condition is polyneuropathy. In some embodiments, the disease or condition is chronic inflammatory demyelinating 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, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. Methods of Dosing and Treatment Regimens [00238] In one embodiment, the compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of TYK2 activity. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal. [00239] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. 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 of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [00240] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who 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, in order to prevent a return of the symptoms of the disease or condition. [00241] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout 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. [00242] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms. [00243] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. [00244] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day. [00245] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [00246] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized. [00247] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal. [00248] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day. [00249] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Combination Treatments [00250] In certain instances, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents. [00251] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [00252] In one 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. [00253] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit. [00254] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co- administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially. [00255] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). [00256] The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. EXAMPLES [00257] As used above, and throughout the description of the disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: Abbreviations: ACN acetonitrile Aq. aqueous Boc tert-butyloxycarbonyl BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Cy cyclohexyl DCM dichloromethane DIPEA N,N-diisopropylethylamine DMA dimethylacetamide DMF N,N-dimethylformamide DMP Dess–Martin periodinane DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc ethyl acetate FBS fetal bovine serum h, hr(s) hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate HEK human embryonic kidney HMDS bis(trimethylsilyl)amide HPLC high pressure liquid chromatography IC50 half maximal inhibitory concentration IFN interferon IL interleukin IPA isopropyl alcohol JAK Janus kinase LCMS liquid chromatography-mass spectrometry M molar MeOH methanol min(s) minute(s) mg; g milligram; gram mL milliliter mmol; mol millimole; mole NMR nuclear magnetic resonance Pd(OAc)2 palladium (II) acetate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Ph phenyl rac racemic rt room temperature Rt; tR retention time SEAP secreted embryonic alkaline phosphatase STAT signal transducer and activator of transcription TBAF tetra-n-butylammonium fluoride t-Bu tert-butyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Ti(OiPr)4 titanium(IV) isopropoxide TLC thin-layer chromatography TMSCN trimethylsilyl cyanide TYK non-receptor tyrosine-protein kinase Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) [00258] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. I. Synthesis of Compounds Example 1: Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-1):
Figure imgf000103_0001
[00259] Step-1: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethan-1-one (I-1b): To a stirred solution of I-1a (40 g, 166 mmol) in THF (300 mL) was added 2M solution of isopropylmagnesium chloride in THF (91.3 mL, 183 mmol) at -30 °C and stirred for 1 h at the same temperature. To this was then added DMA (77 mL, 830 mmol) at -30 °C. The reaction mixture was slowly allowed to warm to room temperature over 1 h. After completion, it was quenched with addition of saturated NH4Cl solution (100 mL) and extraction was carried out using EtOAc (75 mL x 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 resulting crude was purified by Combi-Flash (using gradient elution 0-10% EtOAc in heptane) to afford I-1b (19 g) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 4.23 (s, 3H); 2.59 (s, 3H). [00260] Step-2: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylethan-1-amine (I-1c): To a stirred solution of I-1b (17 g, 83.3 mmol) in MeOH (80 mL) was added TEA (23.2 mL, 167 mmol) and methylamine hydrochloride (11.3 g, 167 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. It was then cooled to 0 °C and NaBH4 (6.3 g, 167 mmol) was added to it portion-wise. The reaction mixture was allowed to warm to room temperature over 2 h. After completion (as indicated by LCMS), saturated NaHCO3 solution (30 mL) was added to it and washed with EtOAc (20 mL x 2). The aqueous NaHCO3 solution containing I-1c was used for the next step without further purification. LCMS (ES) m/z; 219.0 [M+H]+. [00261] Step-3: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol- 4-yl)ethyl)(methyl)carbamate (I-1d): A solution of (Boc)2O (35.7 mL, 155 mmol) in THF (100 mL) was added to the 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 to it. Extraction was carried out using EtOAc (50 mL x 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 gradient elution of 0-50% EtOAc in hexane) to afford I-1d (16.0 g) as a colorless thick oil. LCMS (ES) m/z; 220.1 [(M-100)+H]+. [00262] Step-4: tert-butyl (1-(5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-1e): Argon gas was purged through a solution of I-1d (15.0 g, 47 mmol), (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (22.2 g, 117.0 mmol) and CsF (21.4 g, 141 mmol) in THF (75 mL) for 15 min. To this was added tri-tert- butylphosphonium tetrafluoroborate (0.82 g, 2.82 mmol) and Pd2(dba)3 (2.15 g, 2.35 mmol). The reaction mixture was then stirred at 70 °C for 16 h in a sealed tube. After completion, the reaction mixture was cooled to room temperature and saturated NaHCO3 solution was added to it. Extraction was carried out using EtOAc (100 mL x 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 gradient elution of 0-30% EtOAc in heptane) to afford I-1e (9 g) as a pale yellow thick oil. LCMS (ES) m/z; 384.2 [M+H]+. [00263] Step-5: 6-chloro-2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-1f): A 4M solution of HCl in 1,4-dioxane (120 mL) was added to a solution of I-1e (9 g, 23.4 mmol) in dichloromethane (50 mL) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and dried (co-evaporation with 1,4-dioxane). To this was added 1,4-dioxane (100 mL) and DIPEA (20.4 mL, 117.0 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 16 h. After completion (as indicated by LCMS), volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-35% EtOAc in hexane) to afford I-1f (2.5 g) as brown liquid. LCMS (ES) m/z; 264.0 [M+H]+. [00264] Step-6: N-(2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-1g): Argon gas was purged through a stirred suspension of I-1f (2.5 g, 9.48 mmol), cyclopropanecarboxamide (1.21 g, 14.2 mmol) and Cs2CO3 (6.18 g, 19.0 mmol) in 1,4-dioxane (30 mL) for 15 min. To this was then added [5- (diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.55 g, 0.95 mmol) and Pd2(dba)3 (0.87 g, 0.95 mmol). The reaction mixture was then stirred at 130 °C for 16 h in a sealed tube. It was then cooled to room temperature, filtered through celite bed and washed with EtOAc (50 mL x 2). The filtrate was concentrated under reduced pressure to afford crude I-1g (2.5 g) as a brown solid. LCMS (ES) m/z; 313.2 [M+H]+. [00265] Step-7: 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-1): To a stirred solution of I-1g (2.1 g, 6.7 mmol) in THF (15 mL) was added an aqueous solution of LiOH.H2O (1.61 g, 67.2 mmol, in 10 mL water) at room temperature. It was then stirred at 80 °C for 16 h. After completion, it was cooled to room temperature and water (20 mL) was added to it. Extraction was carried out using 10% MeOH in DCM (50 mL x 2); the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% MeOH in DCM) to afford I-1 (0.88 g) as an off- white solid. LCMS (ES) m/z; 245.1 [M+H]+. Example 2: Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-2):
Figure imgf000105_0001
Figure imgf000106_0001
[00266] Step-1: tert-butyl methyl(1-(2-methyl-5-(tributylstannyl)-2H-1,2,3-triazol-4- yl)ethyl)carbamate (I-2a): Argon gas was purged through a stirred suspension of I-1d (15.0 g, 47 mmol) in hexabutyl ditin ( 24.5 mL, 73.8 mmol) for 15 min, before addition of Pd(OAc)2 (0.15 g, 0.67 mmol) and tricyclohexylphosphine (0.38 g, 1.34 mmol). The reaction mixture was heated at 110 °C for 20 h in a sealed tube. It was then cooled to room temperature, filtered through 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 gradient elution of 0-20% EtOAc in heptane) to afford I-2a (9.2 g) as a pale yellow semi-solid. It was carried forward for the next step. [00267] Step-2: tert-butyl (1-(5-(2-chloro-3-fluoro-5-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-2b): Argon gas was purged through a stirred suspension of I-2a (13.6 g, 25.7 mmol), 2-chloro-3-fluoro-4-iodo-5-methylpyridine (13.9 g, 51.4 mmol) and LiCl (2.5 g, 59.1 mmol) in DMF (130.0 mL) for 15 min. To this was then added Pd(PPh3)4 (2.98 g, 2.58 mmol) and CuI (2.45 g, 12.8 mmol). The reaction mixture was then stirred at 90 °C for 16 h in a sealed tube. It was then cooled to room temperature, ice cold water (50 mL) was added to it and extraction was carried out using EtOAc (70 mL x 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 gradient elution of 0-40% EtOAc in heptane) to afford I-2b (6.4 g) as a brown liquid. LCMS (ES) m/z; 384.1 [M+H]+. [00268] Step-3: 6-chloro-2,4,5,9-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-2c): TFA (8 mL) was added to a solution of I-2b (2 g, 5.21 mmol) in dichloromethane (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. After completion (as indicated by TLC), volatiles were removed under reduced pressure and dried (co-evaporation with 1,4-dioxane). To this was added 1,4-dioxane (10 mL) and DIPEA (3.77 mL, 21.1 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 16 h. After completion, volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-35% EtOAc in heptane) to afford I-2c (0.45 g) as a white solid. LCMS (ES) m/z; 264.1 [M+H]+. [00269] Step-4: N-(2,4,5,9-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-2d): I-2d (1.33 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-2c (1.7 g, 6.45 mmol) and cyclopropanecarboxamide (0.82 g, 9.67 mmol) as the starting materials. LCMS (ES) m/z; 313.1 [M+H]+. [00270] Step-5: 2,4,5,9-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-2): I-2 (0.94 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-2d (1.33 g, 4.26 mmol) as the starting material. LCMS (ES) m/z; 245.2 [M+H]+. [00271] Note: Racemate I-2 (0.94 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 µm) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (95:05) Flow rate : 18.0 mL/min] to afford two enantiomers {I-2A (0.25 g): peak-1; Rt; 12.17 min and I-2B (0.28 g): peak-2; Rt; 15.31 min}, which were used further without their absolute configuration determination. Example 3: Preparation of 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-3):
Figure imgf000107_0001
[00272] Step-1: tert-butyl (1-(5-(2,5-dichloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-3a): I-3a (4.4 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-2a (20 g, 37.8 mmol) as the starting material. LCMS (ES) m/z; 348.0 [(M-56)+H]+. [00273] Step-2: 6,9-dichloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-3b): I-3b (1.2 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-3a (4.4 g, 14.5 mmol) as the starting material. LCMS (ES) m/z; 284.0 [M+H]+. [00274] Step-3: N-(9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-3c): I-3c (1.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-3b (1.0 g, 3.52 mmol) as the starting material. LCMS (ES) m/z; 333.1 [M+H]+. [00275] Step-4: 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-3): I-3 (0.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-3c (1.1 g, 3.31 mmol) as the starting material. LCMS (ES) m/z; 265.1 [M+H]+. [00276] Note: Racemate I-3 (0.7 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 µm) Mobile phase: n-hexane:EtOH with 0.1% DEA (90:10) Flow rate : 18.0 mL/min] to afford two enantiomers {I-3A (0.25 g): peak-1; Rt; 11.4 min and I-3B (0.25 g): peak-2; Rt; 17.7 min}, which were used further without their absolute configuration determination. Example 4: Preparation of 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6- amine (I-4):
Figure imgf000108_0001
[00277] Step-1: 5-bromo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde (I-4a): To a stirred solution of I-1a (10 g, 41.6 mmol) in THF (100 mL) was added a 2M solution of isopropylmagnesium chloride in THF (22.8 mL, 45.6 mmol) at -30 °C and stirred for 1 h at the same temperature. To this was then added DMF (16.08 mL, 208 mmol) at -30 °C. The reaction mixture was slowly allowed to warm to room temperature over 1 h. After completion, it was quenched with addition of saturated NH4Cl solution (30 mL) and extraction was carried out using EtOAc (75 mL x 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 product was purified by Combi-Flash (using gradient elution 0-10% EtOAc in heptane) to afford I-4a (6 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H); 4.26 (s, 3H). [00278] Step-2: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylmethanamine (I-4b): To a stirred solution of I-4a (15 g, 78.9 mmol) in MeOH (150 mL) was added TEA (22.0 mL, 158 mmol) and methylamine hydrochloride (10.7 g, 158 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. It was then cooled to 0 °C and NaBH4 (3.58 g, 94.8 mmol) was added to it portion-wise. The reaction mixture was allowed to warm to room temperature over 2 h. After completion (as indicated by LCMS), saturated NaHCO3 solution (30 mL) was added to it and washed with EtOAc (20 mL x 2). The aqueous NaHCO3 solution containing I-4b was used for the next step without further purification. LCMS (ES) m/z; 205.0 [M+H]+. [00279] Step-3: tert-butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-4c): A solution of (Boc)2O (33.6 mL, 146.2 mmol) in THF (60 mL) was added to the aqueous NaHCO3 solution containing I-4b 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 to it. Extraction was carried out using EtOAc (50 mL x 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 gradient elution of 0-50% EtOAc in heptane) to afford I-4c (6.0 g) as a colourless thick oil. LCMS (ES) m/z; 305.1 [M+H]+. [00280] Step-4: tert-butyl ((5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)methyl)(methyl)carbamate (I-4d): I-4d (4.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-4c (6.0 g, 19.7 mmol) as the starting material. LCMS (ES) m/z; 370.2 [M+H]+. [00281] Step-5: 6-chloro-2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-4e): I-4e (2.1g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-4d (4.4 g, 11.9 mmol) as the starting material. LCMS (ES) m/z; 250.1 [M+H]+. [00282] Step-6: N-(2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-4f): I-4f (1.9g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-4e (2.1 g, 8.41 mmol) as the starting material. LCMS (ES) m/z; 299.1 [M+H]+. [00283] Step-7: 2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- amine (I-4): I-4 (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-4f (1.9 g, 6.37 mmol) as the starting material. LCMS (ES) m/z; 231.1 [M+H]+. Example 5: Preparation of 2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-amine (I-5):
Figure imgf000110_0001
Figure imgf000110_0003
Figure imgf000110_0002
Figure imgf000110_0005
Figure imgf000110_0004
Figure imgf000110_0007
Figure imgf000110_0008
Figure imgf000110_0006
[00284] Step-1: 5-bromo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde (I-5a): To a stirred solution of I-1a (10 g, 41.6 mmol) in THF (100 mL) was added a 2M solution of isopropylmagnesium chloride in THF (22.8 mL, 45.6 mmol) at -30 °C and stirred for 1 h at the same temperature. To this was then added DMF (16.08 mL, 208 mmol) at -30 °C. The reaction mixture was slowly allowed to warm to room temperature over 1 h. After completion, it was quenched with addition of saturated NH4Cl solution (30 mL) and extraction was carried out using EtOAc (75 mL x 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 resulting crude was purified by Combi-Flash (using gradient elution 0-10% EtOAc in heptane) to afford I-5a (6 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H); 4.26 (s, 3H). [00285] Step-2: (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methanol (I-5b): To a stirred solution of I-5a (9.3 g, 48.9 mmol) in MeOH (100 mL) at 0 °C was added sodium borohydride (2.78 g, 73.4 mmol) and the mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was quenched with addition of water (100 mL) and MeOH was concentrated under reduced pressure. Extraction was then carried out using EtOAc (2 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30 % EtOAc in n-heptane) to afford I-5b (8.0 g) as colorless thick oil. LCMS (ES) m/z; 192.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 4.63 (s, 2H), 4.10 (s, 3H), 2.22 (bs, 1H). [00286] Step-3: 4-bromo-5-(bromomethyl)-2-methyl-2H-1,2,3-triazole (I-5c): To a stirred solution of I-5b (8.0 g, 41.7 mmol) in DCM (80 mL) was added CBr4 (18.0 g, 54.2 mmol) and PPh3 (14.2 g, 54.2 mmol) at 0 °C and the reaction was stirred for 1 h at room temperature. After completion of the reaction (as indicated by TLC), water (100 mL) was added to it and extracted with DCM (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified by Combi-Flash (using gradient elution of 0-15 % EtOAc in n-heptane) to afford I-5c (10.2 g) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.44 (s, 2H), 4.15 (s, 3H). [00287] Step-4: 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)acetonitrile (I-5d): To a stirred solution of I-5c (10.2 g, 40.0 mmol) in ACN (100 mL) was added TMSCN (7.51 mL, 60.0 mmol) and tetrabutylammonium fluoride (1.0 M in THF) (60.0 mL, 60.0 mmol) and the reaction mixture was stirred for 1 h at room temperature. After completion of the reaction (as indicated by TLC), the reaction mixture was diluted with EtOAc (200 mL) and was washed with water (100 mL). Aqueous layer was again extracted with EtOAc (250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-30 % EtOAc in n- heptane) to afford I-5d (7.4 g) as a white solid.1H NMR (400 MHz, CDCl3) δ 4.18 (s, 3H), 3.74 (s, 2H). [00288] Step-5: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropane-1-carbonitrile (I- 5e): To a stirred solution of I-5d (7.4 g, 36.8 mmol) in DMF (70 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C and stirred for 30 min before addition of 1,2-dibromoethane (6.37 mL, 73.6 mmol). The reaction was stirred for 2 h at room temperature, while monitoring reaction progress by TLC. After completion of the reaction, it was quenched with addition of ice cold water (100 mL). Extraction was carried out using EtOAc (2 x 250 mL); the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-20 % EtOAc in n- heptane) to afford I-5e (7.1 g) as a colourless oil. LCMS (ES) m/z; 227.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 4.13 (s, 3H), 1.77-1.70 (m, 2H), 1.58 -1.51 (m, 2H). [00289] Step-6: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropane-1-carboxylic acid (I-5f): A suspension of I-5e (10.5 g, 46.2 mmol) in 10% aqueous NaOH solution (250 mL) was stirred at 100 °C for 16 h, while monitoring reaction progress by TLC. After completion of the reaction, the homogeneous solution was washed with EtOAc (300 mL) and the aqueous layer was then acidified using 6 M aqueous HCl (pH ~3). Extraction was carried out using 10% MeOH in DCM (2 x 500 mL); the combined organic extracts were dried over anhydrous sodium sulfate, filtered and dried under reduced pressure to afford I-5f (11.3 g) as an off-white solid. LCMS (ES) m/z; 245.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.64 (bs, 1H), 4.09 (s, 3H), 1.52-1.49 (m, 2H), 1.21-1.18 (m, 2H). [00290] Step-7: tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)cyclopropyl)carbamate (I-5g): To a solution of I-5f (12.2 g, 49.6 mmol) in t-butanol (250 mL) was added triethylamine (10.5 mL, 74.4 mmol) and DPPA (11.3 mL, 59.5 mmol). The resulting mixture was heated at 100 °C for 16 h, while monitoring reaction progress by LCMS. After completion, the reaction mixture was cooled to room temperature and volatile were removed under reduced pressure. The residue was dissolved in EtOAc (500 mL) and was washed with 10% citric acid (100 mL) and water (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-25 % EtOAc in n-heptane) to afford I-5g (9.3 g) as an off-white solid. LCMS (ES) m/z; 263.0 [(M-56)+H]+.1H NMR (400 MHz, CDCl3) δ 5.31 (bs, 1H), 4.07 (s, 3H), 1.42 (s, 9H), 1.38-133 (m, 2H), 1.21 (bs, 2H). [00291] Step-8: tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)cyclopropyl)(methyl)carbamate (I-5h): To a stirred solution of I-5g (2.7 g, 8.51 mmol) in DMF (30 mL) was added sodium hydride (0.41 g, 10.2 mmol) at 0 °C and was stirred for 20 min at 0 °C. Then iodomethane (0.64 mL, 10.2 mmol) was added and the reaction was stirred at room temperature for 1 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with addition of ice cold water (50 mL) and extraction was carried out using EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-20 % EtOAc in n-heptane) to afford I-5h (2.8 g) as colourless thick oil. LCMS (ES) m/z; 277.0 [(M-56)+H]+.1H NMR (400 MHz, CDCl3) δ 4.06 (s, 3H), 2.94 (s, 3H), 1.43 (s, 11H), 1.30 (s, 2H). [00292] Step-9: tert-butyl (1-(5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)cyclopropyl)(methyl)carbamate (I-5i): I-5i (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-5h (3.5 g, 10.6 mmol) and (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (4 g, 21.1 mmol) as the starting materials. LCMS (ES) m/z; 396.1 [M+H]+. [00293] Step-10: 6'-chloro-2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine] (I-5j): I-5j (1.6 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-5i (3.0 g, 7.58 mmol) as the starting material. LCMS (ES) m/z; 276.1 [M+H]+. [00294] Step-11: N-(2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)cyclopropanecarboxamide (I-5k): I-5k (1.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-5j (1.6 g, 5.73 mmol) as the starting material. LCMS (ES) m/z; 325.1 [M+H]+. [00295] Step-12: 2',5',8'-trimethyl-2',5'-dihydrospiro[cyclopropane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-amine (I-5): I-5 (0.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-5k (1.8 g, 5.55 mmol) as the starting material. LCMS (ES) m/z; 257.1 [M+H]+. Example 6: Preparation of 2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-amine (I-6):
Figure imgf000114_0001
[00296] Step-1: N-(3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-yl)-2- methylpropane-2-sulfinamide (I-6a): To a stirred solution of I-1a (10 g, 41.5 mmol) in anhydrous THF (100 mL) was added a 2M solution of n-BuLi in cyclohexane (18.7 mL, 37.5 mmol) at -30 °C and stirred for 30 min at -78 °C. To this was then added 2-methyl-N-(oxetan-3- ylidene)propane-2-sulfinamide (7.28 g, 41.5 mmol) at -78 °C. The reaction mixture was stirred at the same temperature for another 30 min. It was quenched with addition of saturated NH4Cl solution (50 mL) and extraction was carried out using EtOAc (75 mL x 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 resulting crude was purified by Combi- Flash (using gradient elution 0-30% EtOAc in heptane) to afford I-6a (9.0 g) as an off-white solid. LCMS (ES) m/z; 337.1 [M+H]+. [00297] Step-2: 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-amine (I-6b): To a stirred solution of I-6a (9.0 g, 26.7 mmol) in MeOH (100 mL) was added a 4M solution of HCl in 1,4-dioxane (30 mL) at 0 °C and the reaction mixture was stirred for 15 min. After complete consumption of starting material, saturated NaHCO3 solution (30 mL) was added to it and washed using EtOAc (20 mL x 3). The aqueous NaHCO3 solution containing I-6b was carried forward for the next step without further purification. LCMS (ES) m/z; 230.9 [M-H]+. [00298] Step-3: tert-butyl (3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3- yl)carbamate (I-6c): A solution of (Boc)2O (12.2 mL, 53.2 mmol) in THF (60 mL) was added to an aqueous NaHCO3 solution containing I-6b and the reaction mixture was stirred at room temperature for 16 h. Water (50 mL) was then added to it and extraction was carried out using EtOAc (50 mL x 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 gradient elution of 0-40% EtOAc in heptane) to afford I-6c (8.0 g) as an off-white solid. LCMS (ES) m/z; 333.1 [M+H]+. [00299] Step-4: tert-butyl (3-(5-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methyl-2H- 1,2,3-triazol-4-yl)oxetan-3-yl)carbamate (I-6d): I-6d (2.9 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-6c (5.0 g, 15 mmol) as the starting material. LCMS (ES) m/z; 398.1 [M+H]+. [00300] Step-5: 6'-chloro-2',8'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine] (I-6e): I-6e (1.0 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-6d (2.96 g, 7.44 mmol) as the starting material. LCMS (ES) m/z; 278.1 [M+H]+. [00301] Step-6: 6'-chloro-2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine] (I-6f): To a stirred solution of I-6e (1.0 g, 3.6 mmol) in DMF (10.0 mL) was added NaH (60% suspension) (0.22 g, 5.4 mmol) at 0 °C and stirred for 30 min. To this was then added iodomethane (0.27 mL, 4.32 mmol) drop wise at 0° C and the reaction mixture was stirred at room temperature for 1 h. After complete consumption of starting material, water (50 mL) was added to it and extraction was carried out using Et2O (3 x 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 gradient elution of 0- 10% EtOAc in heptane) to afford 6'-chloro-2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine] I-6f (0.67 g) as a pale yellow solid. LCMS (ES) m/z; 292.1 [M+H]+. [00302] Step-7: N-(2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-yl)cyclopropanecarboxamide (I-6g): I-6g (0.55 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-6f (0.67 g, 2.3 mmol) and cyclopropanecarboxamide (0.67 g, 2.3 mmol) as the starting materials. LCMS (ES) m/z; 341.2 [M+H]+. [00303] Step-8: 2',5',8'-trimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-amine (I-6): I-6 (0.27 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-6g (0.39 g, 4.59 mmol) as the starting material. LCMS (ES) m/z; 273.2 [M+H]+. Example 7: Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-7):
Figure imgf000116_0003
Figure imgf000116_0001
Figure imgf000116_0004
Figure imgf000116_0005
Figure imgf000116_0002
Figure imgf000116_0006
[00304] Step-1: 1-(3-bromo-1-methyl-1H-pyrazol-4-yl)ethan-1-ol (I-7b): To a stirred solution of I-7a (25 g, 132.3 mmol) in anhydrous THF (250 mL) was added a 1M solution of MeMgBr in Et2O (198.3 mL, 198.4 mmol) at -78 °C and the reaction mixture was allowed to warm to room temperature over 20 min. After complete consumption of starting material, it was quenched with addition of saturated NH4Cl solution (100 mL) and extraction was carried out using EtOAc (70 mL x 3). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford I- 7b (23 g) as a brown semi-solid. LCMS (ES) m/z; 205.0 [M+H]+. [00305] Step-2: 1-(3-bromo-1-methyl-1H-pyrazol-4-yl)ethan-1-one (I-7c): To a stirred solution of I-7b (15 g, 73.2 mmol) in DCM (150.0 mL) was added DMP (40.3 g, 95.1 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature over 1 h. The reaction progress was monitored by LCMS. After completion, it was filtered through Celite bed and washed with DCM (50 mL x 2). The resulting filtrate was washed with saturated NaHCO3 solution (100 mL), water (100 mL), brine (70 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% EtOAc in heptane) to afford I-7c (10.0 g) as a yellow oil. LCMS (ES) m/z; 203.0 [M+H]+. [00306] Step-3: 1-(3-bromo-1-methyl-1H-pyrazol-4-yl)-N-methylethan-1-amine (I-7d): To a stirred solution of I-7c (15.5 g, 76.35 mmol) in THF (150 mL) was added titanium(IV) isopropoxide (45.2 mL, 152.70 mmol) in a sealed tube at 0 °C. To this was then added a 2M solution of MeNH2 in THF (76.3 mL, 152.70 mmol) and the reaction mixture was stirred at 60 °C for 16 h. It was then cooled to room temperature and volatiles were removed under reduced pressure. It was then diluted with MeOH (180 mL) and to this was added NaBH4 (8.66 g, 229.06 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature over 2 h. After completion, saturated NaHCO3 solution (100 mL) was added to it and washed with EtOAc (30 mL x 2). The aqueous NaHCO3 solution containing I-7d was carried forward for the next step. [00307] Step-4: tert-butyl (1-(3-bromo-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)carbamate (I-7e): I-7e (19 g) was synthesized by following procedure as described for the synthesis of I-1 (step-3). LCMS (ES) m/z; 318.0 [M+H]+. [00308] Step-5: tert-butyl (1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1-methyl-1H- pyrazol-4-yl)ethyl)(methyl)carbamate (I-7f): I-7f (5.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-7e (5.0 g, 15.7 mmol) and (2- chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (5.95 g, 31.4 mmol) as the starting materials. LCMS (ES) m/z; 383.1 [M+H]+. [00309] Step-6: 6-chloro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridine (I-7g): I-7g (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-7f (10.0 g, 26.2 mmol) as the starting material. LCMS (ES) m/z; 263.1 [M+H]+. [00310] Step-7: N-(2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-7h): I-7h (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-7g (3.0 g, 11.4 mmol) and cyclopropanecarboxamide (1.46 g, 17.1 mmol) as the starting materials. LCMS (ES) m/z; 312.2 [M+H]+. [00311] Step-8: 2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- amine (I-7): I-7 (2.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-7h (3.2 g, 10.3 mmol) as the starting material. LCMS (ES) m/z; 244.1 [M+H]+. Example 8: Preparation of 3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-8):
Figure imgf000118_0001
[00312] Step-1: 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (I-8b): I-8b (13.0 g) was synthesized by following procedure as described for the synthesis of I-5 (step-1) using I-8a (16.8 g, 69.7 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H); 4.32 (s, 3H). LCMS (ES) m/z; 189.9 [M+H]+. [00313] Step-2: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol (I-8c): I-8c (12.0 g) was synthesized by following procedure as described for the synthesis of I-6 (step-1) using I-8b (13.0 g, 68.4 mmol) as the starting material. LCMS (ES) m/z; 206.1 [M+H]+. [00314] Step-3: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-one (I-8d): I-8d (8.8 g) was synthesized by following procedure as described for the synthesis of I-6 (step-2) using I-8c (12.0 g, 58.2 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 4.26 (s, 3H); 2.71 (s, 3H). LCMS (ES) m/z; 204.0 [M+H]+. [00315] Step-4: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylethan-1-amine (I-8e): I-8e was synthesized by following procedure as described for the synthesis of I-6 (step-3) using I-8d (8.8 g, 43.1 mmol) as the starting material. LCMS (ES) m/z; 219.1 [M+H]+. [00316] Step-5: tert-butyl (1-(4-bromo-1-methyl-1H-1,2,3-triazol-5- yl)ethyl)(methyl)carbamate (I-8f): I-8f (12.0 g) was synthesized by following procedure as described for the synthesis of I-6 (step-4) using I-8e as the starting material. LCMS (ES) m/z; 319.1 [M+H]+. [00317] Step-6: tert-butyl (1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1-methyl-1H- 1,2,3-triazol-5-yl)ethyl)(methyl)carbamate (I-8g): I-8g (5.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-8f (9 g, 28.2 mmol) and (2- chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (10.7 g, 56.4 mmol) as the starting material. LCMS (ES) m/z; 384.1 [M+H]+. [00318] Step-7: 6-chloro-3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-8h): I-8h (0.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-8g (5.4 g, 14.1 mmol) as the starting material. LCMS (ES) m/z; 264.1 [M+H]+. [00319] Step-8: N-(3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-8i): I-8i (2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-8h (2 g, 7.58 mmol) and cyclopropanecarboxamide (1.29 g, 15.2 mmol) as the starting materials. LCMS (ES) m/z; 313.2 [M+H]+. [00320] Step-9: 3,4,5,8-tetramethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-8): I-8 (1.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-8i (2 g, 6.4 mmol) as the starting material. LCMS (ES) m/z; 245.1 [M+H]+. Example 9: Preparation of 2,3,4,5,8-pentamethyl-4,5-dihydro-3H-imidazo[4,5- c][1,7]naphthyridin-6-amine (I-9):
Figure imgf000119_0001
[00321] Step-1: 4-bromo-1,2-dimethyl-1H-imidazole-5-carbaldehyde (I-9b): To a stirred solution of I-9a (10.0 g, 39.4 mmol) in anhydrous THF (100.0 mL) was added n-BuLi (2.5M solution in hexane) (15.76 mL, 39.4 mmol) at -78 °C and stirred for 30 min at the same temperature. To this was then added DMF (3.06 mL, 39.4 mmol) at -78 °C. After stirring at -78 °C for 1 h, the reaction mixture was slowly allowed to warm to room temperature over 1 h. After completion, it was quenched with addition of saturated NH4Cl solution (50 mL) and extraction was carried out using DCM (75 mL x 3). The combined organic extracts were washed with water (70 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0- 40% EtOAc in heptane) to afford desired compound 4-bromo-1,2-dimethyl-1H-imidazole-5- carbaldehyde I-9b (5.0 g) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H); 3.56 (s, 3H); 2.35 (s, 3H). [00322] Step-2: 1-(4-bromo-1,2-dimethyl-1H-imidazol-5-yl)ethan-1-ol (I-9c): I-9c (5.5 g) was synthesized by following procedure as described for the synthesis of I-7 (step-1) using I-9b (9.0 g, 44.35 mmol) as the starting material. LCMS (ES) m/z; 219.0 [M+H]+. [00323] Step-3: 1-(4-bromo-1,2-dimethyl-1H-imidazol-5-yl)ethan-1-one (I-9d): I-9d (3.0 g) was synthesized by following procedure as described for the synthesis of I-7 (step-2) using I-9c (6.0 g, 27.4 mmol) as the starting material. LCMS (ES) m/z; 216.9 [M+H]+. [00324] Step-4: 1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1,2-dimethyl-1H-imidazol-5- yl)ethan-1-one (I-9e): I-9e (5.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-9d (9.0 g, 28.2 mmol) and (2-chloro-3-fluoro-6-methylpyridin- 4-yl)boronic acid (10.7 g, 56.4 mmol) as the starting materials. LCMS (ES) m/z; 282.1 [M+H]+. [00325] Step-5: 1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1,2-dimethyl-1H-imidazol-5- yl)-N-methylethan-1-amine (I-9f): I-9f (5.7 g) was synthesized by following procedure as described for the synthesis of I-6 (step-3) using I-9e (5.7 g, 20.2 mmol) as the starting material. LCMS (ES) m/z; 297.1 [M+H]+. [00326] Step-6: 6-chloro-2,3,4,5,8-pentamethyl-4,5-dihydro-3H-imidazo[4,5- c][1,7]naphthyridine (I-9g): To a stirred solution of I-9f (5.5 g, 18.5 mmol) in NMP (50.0 mL) was added DIPEA (16.1 mL, 92.7 mmol) at 0 °C and the reaction mixture was heated at 140 °C for 2 h, while monitoring reaction progress by LCMS. After completion, the reaction mixture was cooled to room temperature and water (50 mL) was added to it. Extraction was carried out using 10% MeOH in DCM (50 mL x 2); the combined organic extracts were washed with water (100 mL), brine (70 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-100% EtOAc in heptane) to afford desired compound 6-chloro-2,3,4,5,8-pentamethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridine I-9g (2.0 g) as a brown oil. LCMS (ES) m/z; 277.1 [M+H]+. [00327] Step-7: N-(2,3,4,5,8-pentamethyl-4,5-dihydro-3H-imidazo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-9h): I-9h (0.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-9g (1.0 g, 3.61 mmol) and cyclopropanecarboxamide (0.46 g, 5.42 mmol) as the starting materials. LCMS (ES) m/z; 326.2 [M+H]+. [00328] Step-8: 2,3,4,5,8-pentamethyl-4,5-dihydro-3H-imidazo[4,5-c][1,7]naphthyridin-6- amine (I-9): I-9 (0.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-9h (1.1 g, 3.38 mmol) as the starting material. LCMS (ES) m/z; 258.2 [M+H]+. [00329] Note: Racemate I-9 (2.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 μm); Mobile phase: n-hexane:IPA with 0.1% DEA (50:50); Flow rate: 40 mL/min)] to afford two enantiomers {I-9A (0.15 g): peak-1; Rt; 9.75 min and I-9B (0.15 g): peak-2; Rt; 12.44 min}, which were used further without their absolute configuration determination. Example 10: Preparation of 5,6,9-trimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin- 7-amine (I-10):
Figure imgf000121_0001
[00330] Step-1: 1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)pyrazin-2-yl)ethan-1-one (I- 10b): I-1-10b (4.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-10a (6.0 g, 38.3 mmol) as the starting material. LCMS (ES) m/z; 266.1 [M+H]+. [00331] Step-2: 1-(3-(2-chloro-3-fluoropyridin-4-yl)pyrazin-2-yl)ethan-1-one (I-10c): I-10c (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-2) using I-10b (4.1 g, 15.4 mmol) as the starting material. LCMS (ES) m/z; 261.1 [M+H]+. [00332] Step-3: 7-chloro-5,6-dimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridine (I- 10d): I-10d (1.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-10c (2.0 g, 7.67 mmol) as the starting material. LCMS (ES) m/z; 310.2 [M+H]+. [00333] Step-4: N-(5,6-dimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7- yl)cyclopropanecarboxamide (I-10): I-10 (1.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-10d (1.6 g, 5.17 mmol) as the starting material. LCMS (ES) m/z; 242.2 [M+H]+. [00334] Note: Racemate I-10 (2.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 μm); Mobile phase: n-hexane:IPA with 0.1% DEA (95:05); Flow rate: 18 mL/min)] to afford two enantiomers {I-10A (0.35 g): peak-1; Rt; 12.14 min and I-10B (0.0.35 g): peak-2; Rt; 15.42 min}, which were used further without their absolute configuration determination. Example 11: Preparation of 2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-11):
Figure imgf000122_0001
Figure imgf000123_0001
[00335] Step-1: 2,4-dibromothiazole-5-carboxylic acid (I-11b): To a stirred solution of I-11a (30 g, 123 mmol) in tetrahydrofuran (200 mL) at - 78 ° C was added LDA (123 mL, 247 mmol, 2M in THF) and allowed the reaction mixture to stir at -78 °C for 45 min. Then crushed dry ice (45 g) was added to the reaction mixture and stirred for 2 h at -78 °C. The reaction mixture was quenched with saturated NH4Cl solution (150 mL) and was acidified with 1M HCl (pH ~ 3) and was extracted with 10% MeOH in DCM (3 x 500 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 2,4- dibromothiazole-5-carboxylic acid I-11b (40 g) as brown solid. LCMS (ES) m/z; 287.8 [M+H]+ [00336] Step-2: 2,4-dibromo-N-methoxy-N-methylthiazole-5-carboxamide (I-11c): To a stirred solution of I-11b (40 g, 139 mmol) in DCM (400 mL) was added DIPEA (71.5 mL, 418 mmol), methoxy(methyl)amine hydrochloride (27.2 g, 279 mmol), HATU (79.5 g, 209 mmol) and the reaction was allowed to stir at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with ice- cold water (200 mL) and was extracted with DCM (2 x 500 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 17-20% EtOAc in n-heptane) to afford 2,4-dibromo-N-methoxy-N-methylthiazole-5-carboxamide I-11c (36.6 g, 79.5 % yield) as off white solid. LCMS (ES) m/z; 330.9 [M+2H]+. [00337] Step-3: 4-bromo-N-methoxy-N,2-dimethylthiazole-5-carboxamide (I-11d): To a solution of I-11c (36.6 g, 111 mmol) in THF (400 mL) in a sealed tube was added methylboronic acid (7.97 g, 133 mmol), potassium phosphate (58.8 g, 277 mmol), [5- (diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (6.42 g, 11.1 mmol) and the reaction mixture was purged with argon for 15 min. Then palladium acetate (1.25 g, 5.55 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 18 - 20% EtOAc in n-heptane) to afford 4-bromo-N-methoxy-N,2-dimethylthiazole-5-carboxamide I-11d (5.8 g) as yellow gum. LCMS (ES) m/z; 267.0 [M+2H]+.1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H); 3.35 (s, 3H); 2.73 (s, 3H). [00338] Step-4: 1-(4-bromo-2-methylthiazol-5-yl)ethan-1-one (I-11e): To a solution of I-11d (5.8 g, 21.9 mmol) in THF (60 mL) was added methyl magnesium bromide (3.0M in diethyl ether) (21.9 mL, 65.6 mmol) at 0 °C and the reaction was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with water (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 15 - 18% EtOAc in n-heptane) to afford 1-(4-bromo-2-methylthiazol-5-yl)ethan-1-one I-11e (4.1 g) as a yellow gum. LCMS (ES) m/z; 219.9 [M+H]+. [00339] Step-5: 1-(4-bromo-2-methylthiazol-5-yl)-N-methylethan-1-amine (I-11f): I-11f (4.4 g) was synthesized by following procedure as described for the synthesis of I-7 (step-3) using I-11e (4.1 g, 18.6 mmol) as the starting material. LCMS (ES) m/z; 237.0 [M+2H]+. [00340] Step-6: tert-butyl (1-(4-bromo-2-methylthiazol-5-yl)ethyl)(methyl)carbamate (I- 11g): I-11g (5.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-3) using I-11f (4.4 g, 18.7 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 5.56 - 5.47 (m, 1H), 2.72 (s, 3H), 2.67 (s, 3H), 1.52 - 1.50 (m, 3H), 1.48 (s, 9H). LCMS (ES) m/z; 335.1 [M+H]+. [00341] Step-7: tert-butyl (1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2-methylthiazol-5- yl)ethyl)(methyl)carbamate (I-11h): I-11h (8.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-11g (12.9 g, 38.5 mmol) and (2-chloro-3- fluoro-6-methylpyridin-4-yl)boronic acid (10.9 g, 57.7 mmol) as the starting material. LCMS (ES) m/z; 400.1 [M+H]+. [00342] Step-8: 6-chloro-2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4-c][1,7]naphthyridine (I-11i): I-11i (2.9 g) was synthesized by following procedure as described for the synthesis of I- 1 (step-5) using I-11h (8.11 g, 20.3 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 4.41 (q, J = 7.2 Hz, 1H), 2.77 - 2.75 (m, 6H), 2.55 (s, 3H), 1.25 (d, J = 7.2 Hz, 3H). LCMS (ES) m/z; 280.1 [M+H]+. [00343] Step-9: N-(2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4-c][1,7]naphthyridin-6- yl)cyclopropanecarboxamide (I-11j): I-11j (4.46 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-11i (2.9 g, 10.4 mmol) and cyclopropanecarboxamide (1.76 g, 20.7 mmol) as the starting materials. LCMS (ES) m/z; 329.1 [M+H]+. [00344] Step-10: 2,4,5,8-tetramethyl-4,5-dihydrothiazolo[5,4-c][1,7]naphthyridin-6-amine (I-11): I-11 (2.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-11j (4.46 g, 10.9 mmol) as the starting material. LCMS (ES) m/z; 261.1 [M+H]+. Example 12: Preparation of 2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-12):
Figure imgf000125_0001
[00345] Step-1: tert-butyl (1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-1,5-dimethyl-1H- pyrazol-4-yl)ethyl)(methyl)carbamate (I-12a): I-12a (14.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-5g (13.6 g, 40.9 mmol) as the starting material. LCMS (ES) m/z; 397.1 [M+H]+. [00346] Step-2: 6-chloro-2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridine (I-12b): I-12b (3.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-12a (10.8 g, 36.4 mmol) as the starting material. LCMS (ES) m/z; 277.1 [M+H]+. [00347] Step-3: N-(2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-12c): I-12c (2.7 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-12b (2.4 g, 8.67 mmol) and cyclopropanecarboxamide (0.840 g, 9.87 mmol) as the starting materials. LCMS (ES) m/z; 326.2 [M+H]+. [00348] Step-4: 2,3,4,5,8-pentamethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- amine (I-12): I-12 (1.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-12c (2.7 g, 8.3 mmol) as the starting material. LCMS (ES) m/z; 258.2 [M+H]+. Example 13: Preparation of 2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-13):
Figure imgf000126_0001
[00349] Step-1: tert-butyl {1-[3-(2-chloro-3-fluoro-5-methyl-4-pyridyl)-1-methyl-4- pyrazolyl]ethyl}(methyl)carbamate (I-13a) : I-13a (4.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-6e (6 g, 18.9 mmol) as the starting material. LCMS (ES) m/z; 383.1 [M+H]+. [00350] Step-2: 6-chloro-2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridine (I-13b): I-13b (2.7 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-13a (8.6 g, 22.5 mmol) as the starting material. LCMS (ES) m/z; 263.1 [M+H]+. [00351] Step-3: N-(2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-13c): I-13c (3.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-13b (2.7 g, 10.3 mmol) and cyclopropanecarboxamide (1.75 g, 20.6 mmol) as the starting materials. LCMS (ES) m/z; 312.1 [M+H]+. [00352] Step-4: 2,4,5,9-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-6- amine (I-13): I-13 (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-13c (3.6 g, 11.6 mmol) as the starting material. LCMS (ES) m/z; 244.2 [M+H]+. [00353] Note: Racemate I-13 (1.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK AD-H (250 mm x 30 mm x 5 µm) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (85:15) Flow rate : 40.0 mL/min] to afford two enantiomers {I-13A (0.6 g): peak-1; Rt; 11.93 min and I-13B (0.55 g): peak-2; Rt; 14.24 min}, which were used further without their absolute configuration determination. Example 14: Preparation of 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-14):
Figure imgf000127_0001
[00354] Step-1: 2,5-dichloro-3-fluoro-4-iodopyridine (I-14b): To a stirred solution of I-14a (10 g, 60.2 mmol) in anhydrous THF (100 mL) was added a 2M solution of LDA in THF (60.2 mL, 120 mmol) at -78 °C and stirred for 2 h at -78 °C. Iodine (30.6 g, 120 mmol) solution in THF (30 mL) at -78 °C was added and the reaction mixture was warmed to room temperature and stirred for another 16 h. It was quenched with addition of saturated NH4Cl solution (50 mL) and extraction was carried out using EtOAc (75 mL x 3). The combined organic layer was washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2SO4. Organic layer was filtered and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using gradient elution 0-20% EtOAc in heptane) to afford I-14b (17.0 g) as an off-white solid. LCMS (ES) m/z; 291.9 [M+H]+. [00355] Step-2: tert-butyl (1-(5-(2,5-dichloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-14c): I-14c (3.2 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-14b (8.27 g, 28.3 mmol) and I-2a (10 g, 18.9 mmol) as the starting materials. LCMS (ES) m/z; 405.1 [M+H]+. [00356] Step-3: 6,9-dichloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-14d): I-14b (1.4 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-14c (4.4 g, 14.5 mmol) as the starting material. LCMS (ES) m/z; 284.0 [M+H]+. [00357] Step-4: N-(9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-14e): I-14e (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-14d (1.4 g, 4.93 mmol) and cyclopropanecarboxamide (0.63 g, 7.39 mmol) as the starting materials. LCMS (ES) m/z; 333.1 [M+H]+. [00358] Step-5: 9-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-14): I-14 (0.85 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-14e (1.3 g, 3.91 mmol) as the starting material. LCMS (ES) m/z; 244.2 [M+H]+. [00359] Note: Racemate I-14 (1.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IA (250 mm x 20 mm x 5 µm) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (85:15) Flow rate : 18.0 mL/min] and afforded two enantiomers {I-14A (0.4 g): peak-1; Rt; 8.78 min and I-14B (0.38 g): peak-2; Rt; 12.28 min}, which were used further without their absolute configuration determination. Example 15: Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidin-6-amine (I-15):
Figure imgf000128_0001
[00360] Step-1: tert-butyl (1-(5-(2,5-dichloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-15a): I-15a (10.9 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-2a (15 g, 28.3 mmol) as the starting material. LCMS (ES) m/z; 385.2 [M+H]+. [00361] Step-2: 6-chloro-2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4',5':4,5]pyrido[3,2-d]pyrimidine (I-15b): I-15b (1.0 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-15a (11 g, 28.6 mmol) as the starting material. LCMS (ES) m/z; 265.1 [M+H]+. [00362] Step-3: 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4',5':4,5]pyrido[3,2- d]pyrimidin-6-amine (I-15): The stirred solution of I-15b (1 g, 3.78 mmol) in ammonium hydroxide (40 mL) in a steel bomb was heated at 100 oC for 16 h. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-2% MeOH in dichloromethane) to afford I-15 (0.7 g) as an off-white solid. LCMS (ES) m/z; 246.2 [M+H]+. [00363] Note: Racemate I-15 (1.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 µm) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (60:40) Flow rate : 40.0 mL/min] and afforded two enantiomers {I-15A (0.2 g): peak-1; Rt; 5.2 min and I-15B (0.19 g): peak-2; Rt; 7.3 min}, which were used further without their absolute configuration determination. Example 16: Preparation of 5,6,9-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- amine (
Figure imgf000129_0001
Figure imgf000129_0002
[00364] Step-1: Synthesis of (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (I-16b): To a stirred solution of I-16a (20 g, 137 mmol) in tetrahydrofuran (250 mL) at -78 °C was added LDA (137 mL, 274 mmol, 2M in THF) dropwise and the reaction mixture was stirred for 2 hours at -78 °C then triisopropylborate (60.2 mL, 261 mmol) was added at -78 °C and stirred for 2 hours at same temperature and at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (50 mL), neutralized with 2N HCl (pH 5~6) and was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 40% EtOAc in n-heptane) to afford I-16b (21 g) as off white solid. LCMS (ES) m/z: 190.1 [M+H] +. [00365] Step-2: Synthesis of 1-(2'-chloro-3'-fluoro-6'-methyl-[2,4'-bipyridin]-3-yl)ethan-1- one (I-16c): I-16c (10.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-16b (24.3 g, 129 mmol) and 1-(2-chloropyridin-3-yl)ethan-1- one (10 g, 64.3 mmol) as the starting materials. LCMS (ES) m/z; 265.0 [M+H]+. [00366] Step-3: Synthesis of 7-chloro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-16d): To a stirred solution of I-16c (10.5 g, 39.7 mmol) in MeOH (220 mL) was added acetic acid (11.3 mL, 198 mmol) and methylamine (199 mL, 397 mmol, 2M in THF) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. It was then cooled to 0 °C and NaBH3CN (4.99 g, 79.3 mmol) was added to it portion-wise. The reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by LCMS. After completion, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The resulting crude was purified by Combi-Flash (using gradient elution 15-20% EtOAc in heptane) to afford I-16d (4.8 g) as pale yellow solid. LCMS (ES) m/z; 260.1 [M+H]+. [00367] Step-4: Synthesis of N-(5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-16e): I-16e (4.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-16d (4.8 g, 24.3 mmol) and cyclopropanecarboxamide (3.13 g, 48.5 mmol) as the starting materials. LCMS (ES) m/z; 309.2 [M+H]+. [00368] Step-5: Synthesis of 5,6,9-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- amine (I-16): I-16 (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-16e (4.2 g, 19.8 mmol) as the starting material. LCMS (ES) m/z; 241.2 [M+H]+. [00369] Note: Racemate I-16 (3.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK AD-H (250 mm x 30 mm x 5 µm) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (85:15) Flow rate : 38.0 mL/min] to afford two enantiomers {I-16A (1.1 g): peak-1; Rt; 7.68 min and I-16B (0.9 g): peak-2; Rt; 10.54 min}, which were used further without their absolute configuration determination. Example 17: Preparation of 6-amino-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine-9-carbonitrile (I-17):
Figure imgf000131_0001
[00370] Step-1: Synthesis of 6-chloro-5-fluoro-4-iodonicotinonitrile (I-17b): To a stirred solution of I-17a (15 g, 95.8 mmol) and iodine (42.6 g, 335 mmol) in THF (150 mL) at -78 °C was added LDA (144 mL, 287 mmol, 2M in THF) over a period of 15 minutes and stirred at same temperature for 2 h. The reaction mixture was quenched with ammonium chloride solution (100 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution 0-20% EtOAc in Heptane) to afford I-17b (15 g) as pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H). [00371] Step-2: Synthesis of tert-butyl (1-(5-(2-chloro-5-cyano-3-fluoropyridin-4-yl)-2- methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-17c): I-17c (5.9 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-18c (14.7 g, 52.1 mmol) and I-2a (23 g, 43.4 mmol) as the starting materials. LCMS (ES) m/z; 339.1 [M+H-56]+. [00372] Step-3: Synthesis of 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine-9-carbonitrile (I-17d): I-17d (1.8 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-17c (6.5 g, 16.5 mmol) as the starting material. LCMS (ES) m/z; 275.1 [M+H]+. [00373] Step-4: Synthesis of N-(9-cyano-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-17e): I-17e (1.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 17d (2.8 g, 10.2 mmol) and cyclopropanecarboxamide (1.73 g, 20.4 mmol) as the starting materials. LCMS (ES) m/z; 324.2 [M+H]+. [00374] Step-5: Synthesis of 6-amino-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine-9-carbonitrile (I-17): I-17 (0.87 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-17e (1.4 g, 4.33 mmol) as the starting material. LCMS (ES) m/z; 256.2 [M+H]+. [00375] Note: Racemate I-17 (0.94 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 µm) Mobile phase: n-Hexane:IPA with 0.1% DEA (55:45) Flow rate : 38.0 mL/min] to afford two enantiomers {I-17A (0.27 g): peak-1; Rt; 7.81 min and I-17B (0.37 g): peak-2; Rt; 11.45 min}, which were used further without their absolute configuration determination. Example 18: Preparation of 9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-18):
Figure imgf000132_0001
[00376] Step-1: Synthesis of 2-chloro-3-fluoro-5-methoxypyridine (I-18b): To a solution of I-18a (12 g, 81.3 mmol) in acetone (100 mL) was added MeI (8.44 mL, 136 mmol) and potassium carbonate (18.74 g, 136 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution 0-20% EtOAc in heptane) to afford I-18b (11 g) as off white solid. LCMS (ES) m/z; 162.1 [M+H]+. [00377] Step-2: Synthesis of 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (I-18c): To a solution of I-18b (9.8 g, 60.7 mmol) in tetrahydrofuran (20 mL) was added n-butyl lithium (29.1 mL, 72.8 mmol, 2.5 M in hexane) dropwise at -78 °C and the reaction mixture was stirred at -78 °C for 30 min. Then iodine (10.02 g, 78.9 mmol) was added to the above reaction mixture and was stirred at -78 °C for 2 h. The reaction mixture was quenched by the addition of saturated sodium thiosulfate solution (50 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution 0-20% EtOAc in heptane) to afford I-18c (10.0 g). LCMS (ES) m/z; 287.8 [M+H]+ [00378] Step-3: Synthesis of tert-butyl (1-(5-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-2- methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-18d): I-18d (2.8 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-18c (5.86 g, 20.4 mmol) and I-2a (9 g, 17 mmol) as the starting materials. LCMS (ES) m/z; 344.1 [M+H-56]+. [00379] Step-4: Synthesis of 6-chloro-9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-18e): I-18e (1.5 g) was synthesized by following procedure as described for the synthesis of I-2 (step-3) using I-18d (2.5 g, 6.25 mmol) as the starting material. LCMS (ES) m/z; 280.1 [M+H]+. [00380] Step-5: Synthesis of N-(9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-18f): I-18f (1.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 18e (1.4 g, 5.0 mmol) and cyclopropanecarboxamide (0.85 g, 10.0 mmol) as the starting materials. LCMS (ES) m/z; 329.1 [M+H]+. [00381] Step-6: Synthesis of 9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-18): I-18 (0.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-18f (1.5 g, 4.57 mmol) as the starting material. LCMS (ES) m/z; 261.2 [M+H]+. [00382] Note: Racemate I-18 (0.8 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 µm) Mobile phase: n-Hexane:IPA with 0.1% DEA (50:50) Flow rate : 38.0 mL/min] to afford two enantiomers {I-18A (0.25 g): peak-1; Rt; 6.69 min and I-18B (0.3 g): peak-2; Rt; 9.83 min}, which were used further without their absolute configuration determination. Example 19: Preparation of 2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1
Figure imgf000134_0001
Figure imgf000134_0002
[00383] Step-1: Synthesis of (2-chloro-3-fluoro-5-methylpyridin-4-yl)boronic acid (I-19b): To a stirred solution of I-19a (20 g, 137 mmol) in THF (200 mL) at -78 °C was added LDA (137 mL, 137 mmol, 1M in THF) over a period of 15 minutes and stirred for 2 hours at -78 °C then triisopropyl borate (60.2 mL, 261 mmol) was added and stirred at -78 °C for 2 h and then the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was neutralized with 2N aq HCl (pH ~5-6) and the reaction mixture was stirred at room temperature for 30 min. Then it was extracted with 10% MeOH in DCM (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-flash (using gradient elution of 25 - 30% Ethyl acetate in heptane) to afford I-19b (5.7 g) as brown liquid. LCMS (ES) m/z; 190.1 [M+H]+. [00384] Step-2: Synthesis of tert-butyl (1-(4-(2-chloro-3-fluoro-5-methylpyridin-4-yl)-2- methylthiazol-5-yl)ethyl)(methyl)carbamate (I-19c): I-19c (6.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-11g (8.5 g, 25.4 mmol) and (2-chloro-3-fluoro-5-methylpyridin-4-yl)boronic acid (I-19b) (9.6 g, 50.7 mmol) as the starting material. LCMS (ES) m/z; 400.1 [M+H]+. [00385] Step-3: Synthesis of 6-chloro-2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridine (I-19d): I-19d (1.18 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-19c (6.2 g, 15.5 mmol) as the starting material. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 4.40 (q, J = 6.8 Hz, 1H), 2.76 (s, 3H), 2.71 (s, 3H), 2.69 (s, 3H). LCMS (ES) m/z; 280.1 [M+H]+. [00386] Step-4: Synthesis of N-(2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-19e): I-19e (1.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-19d (1.18 g, 4.22 mmol) and cyclopropanecarboxamide (0.72 g, 8.43 mmol) as the starting materials. LCMS (ES) m/z; 329.1 [M+H]+. [00387] Step-5: Synthesis of 2,4,5,9-tetramethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-19): I-19 (0.75 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-19e (1.5 g, 4.57 mmol) as the starting material. LCMS (ES) m/z; 261.1 [M+H]+. [00388] Note: Racemate I-19 (0.8 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 µm) Mobile phase: n-Hexane:IPA with 0.1% DEA (90:10) Flow rate : 38.0 mL/min] to afford two enantiomers {I-19A (0.26 g): peak-1; Rt; 13.25 min and I-19B (0.16 g): peak-2; Rt; 16.5 min}, which were used further without their absolute configuration determination. Example 20: Preparation of 5,6,10-trimethyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin- 7-amine (I-20):
Figure imgf000135_0001
[00389] Step-1: Synthesis of 2-chloro-3-fluoro-4-iodo-5-methylpyridine (I-20b): To a stirred solution of I-20a (10 g, 68.7 mmol) in THF (100 mL, 1) at -78 °C was added LDA (69 mL, 137 mmol, 2M in THF) was added over a period of 15 minutes and stirred at same temperature for 2 h. Then a solution of iodine (34.9 g, 137 mmol) in THF (100 mL) was added at -78 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combi-flash (using gradient elution of 0-10% EtOAc in heptane) to afford I-20b (16 g) as brown solid. LCMS (ES) m/z: 272.8 [M+H]+. [00390] Step-2: Synthesis of 2-chloro-3-fluoro-5-methyl-4-(trimethylstannyl)pyridine (I- 20c): To a stirred solution of I-20b (16 g, 58.9 mmol) in 1,4-dioxane (200 mL) was added hexamethylditin (13.4 mL, 64.8 mmol) and the reaction mixture was purged with nitrogen for 15 minutes, added Pd(PPh3)2Cl2 (1.24 g, 1.77 mmol) and the reaction mixture was heated at 100 °C for 48 h in a sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled and concentrated under reduced pressure. The crude product was purified by Combi-flash (using gradient elution of 0-5% ethyl acetate in heptane) to afford I-20c (12 g) as pale yellow liquid. LCMS (ES) m/z: 310.0 [M+H]+. [00391] Step-3: Synthesis of 1-(3-(2-chloro-3-fluoro-5-methylpyridin-4-yl)pyrazin-2- yl)ethan-1-one (I-20d): To a stirred solution of I-20c (17.8 g, 57.7 mmol), 1-(3-chloro-2- pyrazinyl)-1-ethanone (13.6 g, 86.6 mmol) in 1,4-dioxane (95 mL) in a sealed tube was added lithium chloride (7.34 g, 173 mmol), copper iodide (1.1 g, 5.77 mmol) and the reaction mixture was purged with nitrogen for 10 minutes. Then added Pd(PPh3)4 (6.67 g, 5.77 mmol) and the reaction mixture was heated at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combi-flash (using gradient elution of 0-5% ethyl acetate in heptane) to afford I-20d (7 g) as a brown solid. LCMS (ES) m/z: 266.6 [M+H]+. [00392] Step-4: Synthesis of 7-chloro-5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridine (I-20e): I-20e (2.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-20d (7.0 g, 26.3 mmol) as the starting material. LCMS (ES) m/z; 261.0 [M+H]+. [00393] Step-5: Synthesis of N-(5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide (I-20f): I-20f (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-20e (2.8 g, 10.7 mmol) and cyclopropanecarboxamide (1.37 g, 16.1 mmol) as the starting materials. LCMS (ES) m/z; 310.2 [M+H]+. [00394] Step-6: Synthesis of 5,6,10-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-20): I-20 (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-20f (3.2 g, 10.3 mmol) as the starting material. LCMS (ES) m/z; 242.1 [M+H]+. [00395] Note: Racemate I-20 (2.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 20 mm x 5 µm) Mobile phase: n-Hexane:IPA with 0.1% DEA (85:15) Flow rate : 18.0 mL/min] to afford two enantiomers {I-20A (0.8 g): peak-1; Rt; 9.01 min and I-20B (0.75 g): peak-2; Rt; 11.85 min}, which were used further without their absolute configuration determination. Example 21: Preparation of 3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-21):
Figure imgf000137_0001
[00396] Step-1: Synthesis of tert-butyl (1-(3-bromo-5-fluoro-1-methyl-1H-pyrazol-4- yl)ethyl)(methyl)carbamate (I-21a): To a stirred solution of I-7e (10 g, 31.4 mmol) in tetrahydrofuran (100 mL) was added LDA (18.9 mL, 37.7 mmol, 2M in THF) at -78 °C and the reaction mixture was stirred at -78 °C for 1 h. Then a solution of NFSI (14.9 g, 47.1 mmol) in THF (25 mL) cooled to -78 °C was added to the reaction mixture at -78 °C and the reaction mixture was warmed to room temperature and stirred for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with aqueous ammonium chloride solution (50 mL) and was extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified by Combi Flash (using gradient elution 5 - 10% EtOAc in n-heptane) to afford I-21a (7 g) as yellow liquid. LCMS (ES) m/z; 336.1[M+H]+. [00397] Step-2: Synthesis of tert-butyl (1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-5- fluoro-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)carbamate (I-21b): I-21b (7.35 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-21a (13.0 g, 38.7 mmol) and (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (I-16b) (11.0 g, 58 mmol) as the starting material. LCMS (ES) m/z; 400.1 [M+H]+. [00398] Step-3: Synthesis of 6-chloro-3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H- pyrazolo[4,3-c][1,7]naphthyridine (I-21c): I-21c (3.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-21b (6.5 g, 16.2 mmol) as the starting material. LCMS (ES) m/z; 281.0 [M+H]+. [00399] Step-4: Synthesis of N-(3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-21d): I-21d (4.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-21c (4.0 g, 14.2 mmol) and cyclopropanecarboxamide (1.82 g, 21.4 mmol) as the starting materials. LCMS (ES) m/z; 330.1 [M+H]+. [00400] Step-5: Synthesis of 3-fluoro-2,4,5,8-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][1,7]naphthyridin-6-amine (I-21): I-21 (1.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-21d (4.2 g, 12.8 mmol) as the starting material. LCMS (ES) m/z; 262.0 [M+H]+. Example 22: Preparation of 2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-22):
Figure imgf000138_0001
[00401] Step-1: Synthesis of 2-chloro-N-methoxy-N,6-dimethylnicotinamide (I-22b): I-22b (12.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-22a (12 g, 69.9 mmol) as the starting material. LCMS (ES) m/z; 215.1 [M+H]+. [00402] Step-2: Synthesis of 1-(2-chloro-6-methylpyridin-3-yl)ethan-1-one (I-22c): I-22c (10 g) was synthesized by following procedure as described for the synthesis of I-11 (step-4) using I-22b (12.0 g, 55.9 mmol) as the starting material. LCMS (ES) m/z; 170.1 [M+H]+. [00403] Step-3: Synthesis of 1-(2'-chloro-3'-fluoro-6,6'-dimethyl-[2,4'-bipyridin]-3- yl)ethan-1-one (I-22d): I-22d (11 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-22c (10.0 g, 59 mmol) and (2-chloro-3-fluoro-6- methylpyridin-4-yl)boronic acid (I-16b) (22.3 g, 118 mmol) as the starting material. LCMS (ES) m/z; 279.0 [M+H]+. [00404] Step-4: Synthesis of 7-chloro-2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-22e): I-22e (3.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-22d (11.0 g, 39.5 mmol) as the starting material. LCMS (ES) m/z; 274.1 [M+H]+. [00405] Step-5: Synthesis of N-(2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-22f): I-22f (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-22e (3.88 g, 14.2 mmol) and cyclopropanecarboxamide (1.81 g, 21.3 mmol) as the starting materials. LCMS (ES) m/z; 323.1 [M+H]+. [00406] Step-6: Synthesis of 2,5,6,9-tetramethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-22): I-22 (1.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-22f (3.0 g, 9.3 mmol) as the starting material. LCMS (ES) m/z; 255.1 [M+H]+. [00407] Note: Racemate I-22 (1.5 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 21 mm x 5 µm) Mobile phase: n-Hexane:IPA with 0.1% DEA (95:05) Flow rate : 18.0 mL/min] to afford two enantiomers {I-22A (0.45 g): peak-1; Rt; 16.44 min and I-22B (0.35 g): peak-2; Rt; 18.02 min}, which were used further without their absolute configuration determination. Example 23: Preparation of 2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-23):
Figure imgf000139_0001
Figure imgf000140_0001
[00408] Step-1: Synthesis of 4-bromo-2-cyclopropylthiazole (I-23a): To a stirred solution of I-11a (30 g, 123 mmol) in THF (300 mL) in a sealed tube was added cyclopropylboronic acid (11.7 g, 136 mmol), potassium phosphate (78.5 g, 370 mmol) and the reaction mixture was purged with argon for 15 min. Then palladium acetate (2.77 g, 12.3 mmol) was added and the reaction mixture was heated at 60 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, filtered through celite bed and the filtrate was concentrated under reduced pressure. The crude product was purified by Combi- Flash (using gradient elution of 8 - 10 % EtOAc in n-heptane) to afford I-23a (17.5 g) as yellow gum. LCMS (ES) m/z; 203.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 6.95 (s, 1H), 2.32-2.28 (m, 1H), 1.20-1.07 (s, 4H). [00409] Step-2: Synthesis of 4-bromo-2-cyclopropylthiazole-5-carboxylic acid (I-23b): I- 23b (30.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-1) using I-23a (16.9 g, 82.8 mmol) as the starting material. LCMS (ES) m/z; 248.0 [M+H]+. [00410] Step-3: Synthesis of 4-bromo-2-cyclopropyl-N-methoxy-N-methylthiazole-5- carboxamide (I-23c): I-23c (10.1 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-23b (30 g, 90.7 mmol) as the starting material. LCMS (ES) m/z; 291.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H); 3.34 (s, 3H); 2.30-2.23 (m, 1H); 1.21-1.15 (m, 4H). [00411] Step-4: Synthesis of 1-(4-bromo-2-cyclopropylthiazol-5-yl)ethan-1-one (I-23d): I- 23d (7.8 g) was synthesized by following procedure as described for the synthesis of I-11 (step- 4) using I-23c (10.1 g, 34.7 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 2.67 (s, 3H); 2.31-2.25 (m, 1H); 1.27-1.14 (m, 4H). LCMS (ES) m/z; 245.9 [M+H]+. [00412] Step-5: Synthesis of 1-(4-bromo-2-cyclopropylthiazol-5-yl)-N-methylethan-1- amine (I-23e): I-23e (8.3 g) was synthesized by following procedure as described for the synthesis of I-11 (step-5) using I-23d (7.8 g, 31.7 mmol) as the starting material. LCMS (ES) m/z; 261.0 [M+H]+. [00413] Step-6: Synthesis of tert-butyl (1-(4-bromo-2-cyclopropylthiazol-5- yl)ethyl)(methyl)carbamate (I-23f): I-23f (11.2 g) was synthesized by following procedure as described for the synthesis of I-11 (step-6) using I-23e (8.3 g, 31.8 mmol) as the starting material. LCMS (ES) m/z; 361.0 [M+H]+. [00414] Step-7: Synthesis of tert-butyl (1-(4-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-2- cyclopropylthiazol-5-yl)ethyl)(methyl)carbamate (I-23g): I-23g (9.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-23f (11.2 g, 31 mmol) and (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (I-16b) (14.7 g, 77.5 mmol) as the starting material. LCMS (ES) m/z; 426.2 [M+H]+. [00415] Step-8: Synthesis of 6-chloro-2-cyclopropyl-4,5,8-trimethyl-4,5- dihydrothiazolo[5,4-c][1,7]naphthyridine (I-23h): I-23h (6.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-23g (9.4 g, 7.58 mmol) as the starting material. LCMS (ES) m/z; 306.1 [M+H]+. [00416] Step-9: Synthesis of N-(2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-23i): I-23i (4.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-23h (6.0 g, 13.7 mmol) and cyclopropanecarboxamide (2.34 g, 27.5 mmol) as the starting materials. LCMS (ES) m/z; 355.2 [M+H]+. [00417] Step-10: Synthesis of 2-cyclopropyl-4,5,8-trimethyl-4,5-dihydrothiazolo[5,4- c][1,7]naphthyridin-6-amine (I-23): I-23 (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-23i (4.5 g, 12.7 mmol) as the starting material. LCMS (ES) m/z; 287.0 [M+H]+. [00418] Note: Racemate I-23 (3.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 21 mm x 5 µm) Mobile phase: 100% MeOH; Flow rate : 12.0 mL/min] to afford two enantiomers {I-23A (1.1 g): peak-1; Rt; 10.19 min and I-23B (0.91 g): peak-2; Rt; 11.51 min}, which were used further without their absolute configuration determination. Example 24: Preparation of 10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-24):
Figure imgf000142_0001
[00419] Step-1: Synthesis of 2-chloro-3-fluoro-5-methoxy-4-(trimethylstannyl)pyridine (I- 24a): To a stirred solution of I-18c (15 g, 52.2 mmol) in 1,4-dioxane (30 mL) was added hexamethylditin (11.9 mL, 57.4 mmol) and the reaction mixture was purged with argon for 15 min. Then added bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.57 mmol) and reaction mixture was heated at 100 °C for 16 h. Progress of the reaction monitored by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0 - 20 % EtOAc in n-heptane) to afford I-24a as pale yellow solid (16 g). LCMS (ES) m/z; 325.9 [M+H]+. [00420] Step-2: Synthesis of 1-(3-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)pyrazin-2- yl)ethan-1-one (I-24b): I-24b (10.0 g) was synthesized by following procedure as described for the synthesis of I-2 (step-2) using I-24a (26.0 g, 80.2 mmol) and I-10a (12.5 g, 80.2 mmol) as the starting materials. LCMS (ES) m/z; 282.0 [M+H]+. [00421] Step-3: Synthesis of 7-chloro-10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridine (I-24c): I-24c (3.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-24b (16.5 g, 58.6 mmol) as the starting material. LCMS (ES) m/z; 277.1 [M+H]+. [00422] Step-4: Synthesis of N-(10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide (I-24d): I-24d (8.5 g ) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-24c (6.0 g, 21.7 mmol) as the starting material. LCMS (ES) m/z; 326.0 [M+H]+. [00423] Step-5: Synthesis of 10-methoxy-5,6-dimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-24): I-24 (3.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-24d (8.5 g, 26.1 mmol) as the starting material. LCMS (ES) m/z; 258.1 [M+H]+. [00424] Note: Racemate I-24 (3.1 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane : Ethanol with 0.1% DEA (55:45); Flow rate: 38 mL/min)] to afford two enantiomers {I-24A (1.0 g): peak-1; Rt; 14.48 min and I-24B (1.1 g): peak-2; Rt; 18.05 min}, which were used further without their absolute configuration determination. Example 25: Preparation of 3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-25):
Figure imgf000143_0001
[00425] Step-1: Synthesis of methyl 3-chloro-6-methylpyrazine-2-carboxylate (I-25b): To a stirred solution of I-25a (15 g, 57.9 mmol) in 1,4-dioxane (150 mL) was added methyl boronic acid (4.16 g, 69.4 mmol), potassium carbonate (16 g, 116 mmol) and the reaction mixture was purged with nitrogen for 10 min. Then Pd(dppf)Cl2 (3.39 g, 4.63 mmol) was added and the reaction mixture was heated at 100 °C in a sealed tube for 20 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, filtered through celite bed and filtrate was concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0 - 30 % EtOAc in n-heptane) to afford I-25b (6.5 g) as pale yellow solid. LCMS (ES) m/z; 187.0 [M+H]+. [00426] Step-2: Synthesis of 3-chloro-6-methylpyrazine-2-carboxylic acid (I-25c): A stirred solution of I-25b (10.6 g, 54 mmol) in conc HCl (100 mL, 540 mmol) was heated at 80 °C for 5 h. Progress of the reaction was monitored by LCMS and TLC. After the completion, the reaction mixture was cooled and concentrated under reduced pressure. The residue was triturated with mixture of diethyl ether, pentane (100 mL, 1:1) to afford I-25c (8.3 g) as brown solid .LCMS (ES) m/z; 173.0 [M+H]+. [00427] Step-3: Synthesis of 3-chloro-N-methoxy-N,6-dimethylpyrazine-2-carboxamide (I- 25d): I-25d (6.2 g) was synthesized by following procedure as described for the synthesis of I- 11 (step-2) using I-25c (8.2 g, 35.3 mmol) as the starting material. LCMS (ES) m/z; 216.0 [M+H]+. [00428] Step-4: Synthesis of 1-(3-chloro-6-methylpyrazin-2-yl)ethan-1-one (I-25e): I-25e (2.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-4) using I-25d (4.2 g, 17.5 mmol) as the starting material. LCMS (ES) m/z; 171.0 [M+H]+. [00429] Step-5: Synthesis of 1-(3-(2-chloro-3-fluoro-6-methylpyridin-4-yl)-6- methylpyrazin-2-yl)ethan-1-one (I-25f): I-25f (4.1 g) was synthesized by following procedure as described for the synthesis of I-1 (step-4) using I-25e (3.0 g, 13.2 mmol) and (2-chloro-3- fluoro-6-methylpyridin-4-yl)boronic acid (I-16b) (6.2 g, 33 mmol) as the starting material. LCMS (ES) m/z; 280.0 [M+H]+. [00430] Step-6: Synthesis of 7-chloro-3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridine (I-25g): I-25g (3.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-25f (4.2 g, 14.3 mmol) as the starting material. LCMS (ES) m/z; 275.0 [M+H]+. [00431] Step-7: Synthesis of N-(3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide (I-25h): I-25h (5.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-25g (5.0 g, 17.3 mmol) and cyclopropanecarboxamide (2.94 g, 34.6 mmol) as the starting materials. LCMS (ES) m/z; 324.0 [M+H]+. [00432] Step-8: Synthesis of 3,5,6,9-tetramethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-amine (I-25): I-25 (3.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-25h (5.0 g, 15.5 mmol) as the starting material. LCMS (ES) m/z; 256.1 [M+H]+. [00433] Note: Racemate I-25 (1.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 µm) Mobile phase: : n-Hexane:IPA with 0.1% DEA (90:10); Flow rate : 35.0 mL/min] to afford two enantiomers {I-25A (0.285 g): peak-1; Rt; 11.094 min and I-25B (0.285 g): peak-2; Rt; 13.02 min}, which were used further without their absolute configuration determination. Example 26: Preparation of 5,6,10-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7- amine (I
Figure imgf000145_0001
Figure imgf000145_0002
[00434] Step-1: Synthesis of 1-(2'-chloro-3'-fluoro-5'-methyl-[2,4'-bipyridin]-3-yl)ethan-1- one (I-26a): I-26a (9.0 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-20c (24 g, 77.8 mmol) and 1-(2-chloro-3-pyridyl)-1-ethanone (13.3 g, 85.6 mmol) as the starting materials. LCMS (ES) m/z; 265.1 [M+H]+. [00435] Step-2: Synthesis of 7-chloro-5,6,10-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-26b): I-26b (5.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-26a (9.0 g, 34 mmol) as the starting material. LCMS (ES) m/z; 260.0 [M+H]+. [00436] Step-3: Synthesis of N-(5,6,10-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-26c): I-26c (4.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-26b (5.0 g, 19.3 mmol) and cyclopropanecarboxamide (2.46 g, 28.9 mmol) as the starting materials. LCMS (ES) m/z; 309.1 [M+H]+. [00437] Step-4: Synthesis of 5,6,10-trimethyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin- 7-amine (I-26): I-26 (2.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-26c (4.0 g, 13.0 mmol) as the starting material. LCMS (ES) m/z; 241.2 [M+H]+. [00438] Note: Racemate I-26 (2.5 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 µm) Mobile phase: : n-Hexane: EtOH with 0.1% DEA (55:45); Flow rate : 38.0 mL/min] to afford two enantiomers {I-26A (1.0 g): peak-1; Rt; 12.45 min and I-26B (1.0 g): peak-2; Rt; 14.43 min}, which were used further without their absolute configuration determination. Example 27: Preparation of 3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-27):
Figure imgf000146_0001
[00439] Step-1: Synthesis of 2-chloro-5-fluoro-N-methoxy-N-methylnicotinamide (I-27b): I-27b (21 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-27a (20.0 g, 114 mmol) as the starting material. LCMS (ES) m/z; 218.9 [M+H]+. [00440] Step-2: Synthesis of 1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-one (I-27c): I-27c (18.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step-4) using I-27b (24.0 g, 110 mmol) as the starting material. LCMS (ES) m/z; 174.0 [M+H]+. [00441] Step-3: Synthesis of 1-(2'-chloro-3',5-difluoro-6'-methyl-[2,4'-bipyridin]-3- yl)ethan-1-one (I-27d): To a stirred solution of I-27c (14 g, 80.7 mmol) in 1,4-dioxane (280 mL) was added (2-chloro-3-fluoro-6-methylpyridin-4-yl)boronic acid (30.6 g, 161 mmol), cesium carbonate (78.8 g, 242 mmol) the reaction mixture was purged with nitrogen for 15 min. Then cataCXium A Pd G3 (5.87 g, 8.07 mmol) was added and the reaction mixture was heated at 120 °C in a sealed tube for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0 - 15 % EtOAc in n-heptane) to afford I-27d (7 g) as yellow solid. LCMS (ES) m/z; 282.9 [M+H]+. [00442] Step-4: Synthesis of 7-chloro-3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-27e): I-27e (3.6 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-27d (4.0 g, 14.16 mmol) as the starting material. LCMS (ES) m/z; 278.1 [M+H]+. [00443] Step-5: Synthesis of N-(3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-27f): I-27f (3.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-27e (3.0 g, 10.8 mmol) and cyclopropanecarboxamide (1.37 g, 16.2 mmol) as the starting materials. LCMS (ES) m/z; 327.1 [M+H]+. [00444] Step-6: Synthesis of 3-fluoro-5,6,9-trimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-27): I-27 (2.6 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-27f (4.8 g, 13.14 mmol) as the starting material. LCMS (ES) m/z; 259.1 [M+H]+. Example 28: Preparation of 10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-28):
Figure imgf000147_0001
[00445] Step-1: Synthesis of 1-(2'-chloro-3'-fluoro-5'-methoxy-[2,4'-bipyridin]-3-yl)ethan- 1-one (I-28a): I-28a (6.5 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-24a (15 g, 46.2 mmol) and 1-(2-chloro-3-pyridyl)-1-ethanone (7.91 g, 50.9 mmol) as the starting materials. LCMS (ES) m/z; 281.1 [M+H]+. [00446] Step-2: Synthesis of 7-chloro-10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridine (I-28b): I-28b (8.2 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-28a (10.0 g, 35.6 mmol) as the starting material. LCMS (ES) m/z; 276.0 [M+H]+. [00447] Step-3: Synthesis of N-(10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-28c): I-28c (8.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-28b (8.0 g, 29.0 mmol) and cyclopropanecarboxamide (6.17 g, 72.5 mmol) as the starting materials. LCMS (ES) m/z; 325.0 [M+H]+. [00448] Step-4: Synthesis of 10-methoxy-5,6-dimethyl-5,6-dihydropyrido[3,4- h][1,6]naphthyridin-7-amine (I-28): I-28 (1.9 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-28c (8.0 g, 24.7 mmol) as the starting material. LCMS (ES) m/z; 257.2 [M+H]+. [00449] Note: Racemate I-28 (3.7 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IK (250 mm x 21 mm x 5 µm) Mobile phase: : n-Hexane: EtOH (70:30); Flow rate : 19.0 mL/min] to afford two enantiomers {I-28A (1.5 g): peak-1; Rt; 8.62 min and I-28B (1.5 g): peak-2; Rt; 15.37 min}, which were used further without their absolute configuration determination. Example 29: Preparation of 9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-amine (I-29):
Figure imgf000148_0001
[00450] Step-1: Synthesis of 4-bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-3- carboxamide (I-29b): I-29b (28 g) was synthesized by following procedure as described for the synthesis of I-11 (step-2) using I-29a (20.0 g, 97.6 mmol) as the starting material. LCMS (ES) m/z; 248.0 [M+H]+. [00451] Step-2: Synthesis of 1-(4-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-one (I-29c): I- 29c (20.0 g) was synthesized by following procedure as described for the synthesis of I-11 (step- 4) using I-29b (28.0 g, 113 mmol) as the starting material. LCMS (ES) m/z; 203.0 [M+H]+. [00452] Step-3: Synthesis of 1-(1-methyl-4-(tributylstannyl)-1H-pyrazol-3-yl)ethan-1-one (I-29d): To a stirred suspension of I-29c (20.0 g, 49.3 mmol) in hexabutylditin ( 36 mL, 49.3mmol) argon was purged for 5 min, added Pd(OAc)2 (0.22 g, 49.3 mmol), tricyclohexylphosphine (0.552 g, 1.34 mmol) and the reaction mixture was heated at 110 °C for 20 h in a sealed tube. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled, diluted with ethyl acetate (100 mL) and was filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by Combi- Flash (using gradient elution of 0-10% EtOAc in heptane) to afford I-29d (20 g) as pale yellow liquid.1H NMR (400MHz, CDCl3) δ 7.22 (s, 1H), 3.97 (s, 3H), 2.57 (s, 3H), 1.54-1.47 (m, 6H), 1.33-1.21 (m, 6H), 1.04-1.00 (m, 6H), 0.86 (t, J = 7.2 Hz, 9H). [00453] Step-4: Synthesis of 1-(4-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1-methyl-1H- pyrazol-3-yl)ethan-1-one (I-29e): I-29e (5.0 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-29d (15 g, 40.4 mmol) and 2-chloro-3-fluoro- 4-iodo-5-methoxypyridine (17.4 g, 60.6 mmol) as the starting materials. LCMS (ES) m/z; 284.1 [M+H]+. [00454] Step-5: Synthesis of 6-chloro-9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H- pyrazolo[3,4-c][1,7]naphthyridine (I-29f): To a stirred solution of I-29e (5 g, 17.6 mmol) in THF (50 mL) at 0 °C was added titanium tetraisopropoxide (10.4 mL, 32.5 mmol), methylamine in THF (8.8 mL, 17.6 mmol, 2M solution) and the reaction mixture was heated at 60 °C in a sealed tube for 16 h. Then the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with MeOH (50 mL), added NaBH4 (2.0 g, 52.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with saturated NaHCO3 solution (100 mL) and was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-35% EtOAc in heptane) to afford I-29f (4.0 g) as pale yellow liquid LCMS (ES) m/z; 279.0 [M+H]+. [00455] Step-6: Synthesis of N-(9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-29g): I-29g (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-29f (4.0 g, 14.4 mmol) and cyclopropanecarboxamide (2.44 g, 28.7 mmol) as the starting materials. LCMS (ES) m/z; 328.0 [M+H]+. [00456] Step-7: Synthesis of 9-methoxy-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3,4- c][1,7]naphthyridin-6-amine (I-29): I-29 (1.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-29g (2.0 g, 6.11 mmol) as the starting material. LCMS (ES) m/z; 260.0 [M+H]+. [00457] Note: Racemate I-29 (1.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 µm) Mobile phase: : n-Hexane: IPA with 0.1% DEA (80:20); Flow rate : 18.0 mL/min] to afford two enantiomers {I-29A (0.5 g): peak-1; Rt; 25.59 min and I-29B (0.3 g): peak-2; Rt; 35.52 min}, which were used further without their absolute configuration determination. Example 30: Preparation of 9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [
Figure imgf000150_0001
Figure imgf000150_0002
[00458] Step-1: Synthesis of 2-chloro-5-cyclopropyl-3-fluoropyridine (I-30b): To a stirred solution of I-30a (25.0 g, 119 mmol) in 1,4-dioxane (250 mL) was added cyclopropylboronic acid (15.3 g, 178 mmol), potassium phosphate tribasic (75.7 g, 356 mmol), the reaction mixture was purged with nitrogen for 15 min. Then Pd(dppf)Cl2.DCM (2.17 g, 2.97 mmol) was added and the reaction mixture was heated at 100 °C in a sealed tube for 6 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0 - 30 % EtOAc in n-heptane) to afford I-30b (18 g) as white solid. LCMS (ES) m/z; 172.0 [M+H]+. [00459] Step-2: Synthesis of 2-chloro-5-cyclopropyl-3-fluoro-4-iodopyridine (I-30c): To a stirred solution of I-30b (10 g, 58.3 mmol) in THF (100 mL, 1) at -78 °C was added LDA (43.7 mL, 87.4 mmol, 2M in THF) was added over a period of 15 minutes and stirred at same temperature for 1 h. Then a solution of iodine (22.2 g, 87.4 mmol) in THF (100 mL) was added at -78 °C and the reaction mixture was stirred at same temperature for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combi-flash (using gradient elution of 0-30% ethyl acetate in heptane) to afford I- 30c (17 g) as white solid. LCMS (ES) m/z: 298.1 [M+H]+. [00460] Step-3: Synthesis of tert-butyl (1-(5-(2-chloro-5-cyclopropyl-3-fluoropyridin-4-yl)- 2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-30d): I-30d (2.5 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-30c (5 g, 9.45 mmol) and tert-butyl methyl(1-(2-methyl-5-(tributylstannyl)-2H-1,2,3-triazol-4- yl)ethyl)carbamate (2.81 g, 9.45 mmol) as the starting materials. LCMS (ES) m/z; 354.0 [M+H- 56]+. [00461] Step-4: Synthesis of 6-chloro-9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-30e): I-30e (8.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-30d (21.0 g, 51.2 mmol) as the starting material. LCMS (ES) m/z; 290.0 [M+H]+. [00462] Step-5: Synthesis of N-(9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-30f): I-30f (2.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 30e (4.0 g, 8.86 mmol) and cyclopropanecarboxamide (1.76 g, 20.7 mmol) as the starting materials. LCMS (ES) m/z; 339.2 [M+H]+. [00463] Step-6: Synthesis of 9-cyclopropyl-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-30): I-30 (3.2 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-30f (4.5 g, 13.3 mmol) as the starting material. LCMS (ES) m/z; 271.1 [M+H]+. [00464] Note: Racemate I-30 (3.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IK (250 mm x 20 mm x 5 µm) Mobile phase: : n-Hexane: IPA with 0.1% DEA (80:20); Flow rate : 18.0 mL/min] to afford two enantiomers {I-30A (1.3 g): peak-1; Rt; 7.36 min and I-30B (1.3 g): peak-2; Rt; 8.78 min}, which were used further without their absolute configuration determination. Example 31: Preparation of 9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-31):
Figure imgf000152_0001
[00465] Step-1: Synthesis of 6-chloro-5-fluoronicotinaldehyde (I-31a): To a stirred solution of I-30a (10.0 g, 47.5 mmol) in diethyl ether (100.0 mL) was added n-BuLi (23.8 mL, 71.3 mmol, 3.0M in hexane) at -78 °C and the reaction mixture was stirred at the same temperature for 15 min. Then DMF (18.5 mL, 238 mmol) was added drop wise at same temperature and the reaction mixture was slowly to warmed to room temperature and stirred for 1 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with water (70 mL), brine (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution 0-20% ethyl acetate in n-heptane) to afford I- 31a (4.7 g) as pale yellow solid. LCMS (ES) m/z: 160.0 [M+H]+. [00466] Step-2: Synthesis of (6-chloro-5-fluoropyridin-3-yl)methanol (I-31b): To a stirred solution of I-31a (9.0 g, 56.4 mmol) in MeOH (100 mL) at 0 °C was added sodium borohydride (4.27 g, 113 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (100 mL) and was extracted with ethyl acetate (150 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0- 50 % ethyl acetate in n-heptane) to afford I-31b (6.2 g) as white solid. LCMS (ES) m/z; 162.1 [M+H]+. [00467] Step-3: Synthesis of 2-chloro-3-fluoro-5-(methoxymethyl)pyridine (I-31c): To a stirred solution of I-31b (6.0 g, 37.1 mmol) in THF (60 mL) was added sodium hydride (2.97 g, 74.3 mmol, 60% in mineral oil) at 0 °C and the reaction mixture was stirred for 15 min at 0 °C. Then iodomethane (4.62 mL, 74.3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLS and LCMS. After completion, the reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combi- Flash (using gradient elution of 0-30 % ethyl acetate in n-heptane) to afford I-31c (5.4 g) as colorless liquid. LCMS (ES) m/z; 176.0 [M+H]+. [00468] Step-4: Synthesis of 2-chloro-3-fluoro-4-iodo-5-(methoxymethyl)pyridine (I-31d): I-31d (9.9 g) was synthesized by following procedure as described for the synthesis of I-20 (step-1) using I-31c (7.0 g, 39.9 mmol) as the starting material. LCMS (ES) m/z; 301.9 [M+H]+. [00469] Step-5: Synthesis of tert-butyl (1-(5-(2-chloro-3-fluoro-5-(methoxymethyl)pyridin- 4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-31e): I-31e (6.1 g) was synthesized by following procedure as described for the synthesis of I-20 (step-3) using I-31d (5.7 g, 18.9 mmol) and I-2a (10.0 g, 18.9 mmol) as the starting materials. LCMS (ES) m/z; 358.1 [M+H-56]+. [00470] Step-6: Synthesis of 6-chloro-9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-31f): I-31f (9.5 g) was synthesized by following procedure as described for the synthesis of I-1 (step-5) using I-31e (15.5 g, 37.5 mmol) as the starting material. LCMS (ES) m/z; 294.0 [M+H]+. [00471] Step-7: Synthesis of N-(9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-31g): I-31g (7.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-31f (9.0 g, 30.6 mmol) and cyclopropanecarboxamide (3.91 g, 46.0 mmol) as the starting materials. LCMS (ES) m/z; 343.2 [M+H]+. [00472] Step-8: Synthesis of 9-(methoxymethyl)-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-31): I-31 (5.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-31g (7.0 g, 20.4 mmol) as the starting material. LCMS (ES) m/z; 275.1 [M+H]+. [00473] Note: Racemate I-31 (4.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 20 mm x 5 µm) Mobile phase: : n-Hexane: EtOH with 0.1% DEA (85:15); Flow rate : 20.0 mL/min] to afford two enantiomers {I-31A (1.8 g): peak-1; Rt; 18.63 min and I-31B (1.8 g): peak-2; Rt; 24.15 min}, which were used further without their absolute configuration determination. Example 32: Preparation of 9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-32):
Figure imgf000154_0001
[00474] Step-1: Synthesis of 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-9-ol (I-32a): To a stirred solution of I-18e (5 g, 17.8 mmol) in THF (100 mL) was added borontribromide (10.0 mL, 89.3 mmol) drop wise at -78 °C and the reaction mixture was stirred at same temperature for 2 h. Then the reaction mixture was warmed to room temperature and stirred for 16 h. Progress of the reaction was monitored by TLC. After completion, reaction mixture was quenched with cold saturated ammonium chloride solution (100 mL) and was extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution 0-50% EtOAc in heptane) to afford 1-32a (5 g, crude) as a pale yellow solid. LCMS (ES) m/z; 266.0 [M+H]+. [00475] Step-2: Synthesis of 6-chloro-9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-32b): To a stirred solution of I-32a (5 g, 18.8 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (6.5 g, 47 mmol) and 2-bromopropane (7.08 mL, 75.3 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-35% EtOAc in heptane) to afford I-32b (5.5 g) as a brown gum. LCMS (ES) m/z; 308.0 [M+H]+. [00476] Step-3: Synthesis of N-(9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-32c): I-32c (7.0 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I- 32b (5.5 g, 17.9 mmol) and cyclopropanecarboxamide (6.08 g, 71.5 mmol) as the starting materials. LCMS (ES) m/z; 357.2 [M+H]+. [00477] Step-4: Synthesis of 9-isopropoxy-2,4,5-trimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-32): I-32 (1.3 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-32c (4.0 g, 11.2 mmol) as the starting material. LCMS (ES) m/z; 289.1 [M+H]+. [00478] Note: Racemate I-32 (1.3 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 20 mm x 5 µm) Mobile phase: : n-Hexane: IPA with 0.1% DEA (50:50); Flow rate : 20.0 mL/min] to afford two enantiomers {I-32A (0.49 g): peak-1; Rt; 7.86 min and I-32B (0.35 g): peak-2; Rt; 8.95 min}, which were used further without their absolute configuration determination. Example 33: Preparation of 2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-33):
Figure imgf000155_0001
[00479] Step-1: Synthesis of 6-chloro-2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-33a): To a stirred solution of I-32a (4 g, 15.1 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (5.2 g, 37.6 mmol) and 1,1,1-trifluoro-2-iodoethane (9.48 g, 45.2 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in heptane) to afford I-33a (3.5 g) as yellow solid. LCMS (ES) m/z; 348.1 [M+H]+. [00480] Step-2: Synthesis of N-(2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-33b): I-33b (3.4 g) was synthesized by following procedure as described for the synthesis of I-1 (step-6) using I-33a (3.4 g, 9.78 mmol) and cyclopropanecarboxamide (3.33 g, 39.1 mmol) as the starting materials. LCMS (ES) m/z; 397.1 [M+H]+. [00481] Step-3: Synthesis of 2,4,5-trimethyl-9-(2,2,2-trifluoroethoxy)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-33): I-33 (2.8 g) was synthesized by following procedure as described for the synthesis of I-1 (step-7) using I-33b (3.4 g, 8.58 mmol) as the starting material. LCMS (ES) m/z; 329.1 [M+H]+. Example 34: Preparation of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (A-1):
Figure imgf000156_0001
[00482] To a stirred solution of A-1a (5.0 g, 25.1 mmol) in anhydrous DCM (40 mL) was added catalytic amount of DMF (2 to 3 drops) and oxalyl chloride (4.6 mL, 50.3 mmol) drop wise at 0 °C. The reaction mixture was then allowed to warm to room temperature over 2 h. After completion, volatiles were removed under reduced pressure and the residue was dried. It was then dissolved in anhydrous DCM (25 mL) and added to a stirred solution of methan-d3- amine hydrochloride (2.13, 30.2 mmol) and DIPEA (13.2 mL, 75.4 mmol) in anhydrous DCM (25 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 16 h. Water (50 mL) was then added to it and the organic layer was separated. It was then washed with saturated NaHCO3 solution (30 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using gradient elution of 0-40% EtOAc in heptane) to afford desired compound 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide A-1 (2.6 g) as an off-white solid. LCMS (ES) m/z; 209.0 [M+H]+. Example 35: Preparation of 4-bromo-6-chloro-N-(methyl-d3)nicotinamide (A-2):
Figure imgf000156_0002
[00483] To a stirred solution of A-2a (4.75 g, 20.1 mmol), methan-d3-amine hydrochloride (1.7 g, 24.1 mmol) and DIPEA (10.4 mL, 60.3 mmol) in DCM (15 mL) was added HATU (11.5 g, 30.1 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature for 3 h. After completion, water (50 mL) was added to it and extracted with DCM (75 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using gradient elution 0-20% EtOAc in heptane) to afford desired compound 4-bromo-6-chloro- N-(methyl-d3)nicotinamide A-2 (3.1 g) as an off-white solid. LCMS (ES) m/z; 252.0 [M+H]+. Example 36: Preparation of N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2- yl)cyclopropanecarboxamide (A-3):
Figure imgf000157_0001
[00484] Step 1: 4,6-dichloro-N-methoxy-N-methylnicotinamide (A-3b): To a stirred solution of A-3a (20.0 g, 104.0 mmol) in DCM (50.0 mL) were added TEA (43.6 mL, 313.0 mmol) and HATU (39.6 g, 104 mmol) at 0 °C. To this was then added N,O-dimethylhydroxylamine hydrochloride (15.9 g, 260.0 mmol) and the reaction mixture was allowed to stir at room temperature for 16 h. After complete consumption of starting material, water (100 mL) was added and extraction was carried out using DCM (100 x 2 mL). The combined organic extracts were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of (0-15% EtOAc in Heptane) to afford A-3b (18.0 g) as a colorless liquid. LCMS (ES) m/z; 235.1 [M+H]+. [00485] Step-2: 1-(4,6-dichloropyridin-3-yl)ethan-1-one (A-3c): To a stirred solution of A- 3b (15 g, 63.8 mmol) in anhydrous THF (50.0 mL) was added a 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 starting material, it was quenched with addition of saturated NH4Cl solution (100 mL) and extraction was carried out using EtOAc (100 mL x 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 gradient elution of (0-20% EtOAc in Heptane) to afford A-3c (10.0 g) as a thick yellow liquid. LCMS (ES) m/z; 190.1 [M+H]+. [00486] Step-3: methyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropanoate (A-3d): To a stirred solution of A-3c (10 g, 52.6 mmol) in dimethyl carbonate (150 mL) was added NaH (60% suspension) (6.31 g, 158 mmol) in portion-wise at 0 °C. The reaction mixture was the stirred at room temperature for 3 h. After complete consumption of starting material, it was quenched with addition of 2N aqueous HCl solution (20 mL) and extraction was carried out using EtOAc (100 mL x 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 gradient elution of (0-15% EtOAc in Heptane) to afford A-3d (8.6 g) as a yellow solid. LCMS (ES) m/z; 244.1 [M+H]+. [00487] Step-4: methyl 2-(6-chloro-4-methoxynicotinoyl)propanoate-3,3,3-d3 (A-3e): To a stirred solution of A-3d (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. To this was then added iodomethane-d3 (2.45 mL, 38.8 mmol) drop wise at 0 °C and the reaction mixture was stirred at room temperature for 6 h. After completion, water (80 mL) was added to it and extraction was carried out using EtOAc (3 x 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 gradient elution of 0-8% EtOAc in heptane) to afford A-3e (5.6 g) as on off-white solid. LCMS (ES) m/z; 261.1 [M+H]+. [00488] Step-5: 1-(6-chloro-4-hydroxypyridin-3-yl)propan-1-one-3,3,3-d3 (A-3f): To a solution of A-3e (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 extraction was carried out using EtOAc (100 x 2 mL). The combined organic extracts were washed brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% EtOAc in heptane) to afford A-3f (3.8 g). LCMS (ES) m/z; 189.6 [M+H]+. [00489] Step-6: 1-(4,6-dichloropyridin-3-yl)propan-1-one-3,3,3-d3 (A-3g): To a solution of A-3f (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 starting material, volatiles were removed under reduced pressure and saturated NaHCO3 solution (20 mL) was added to the residue. Extraction was carried out using EtOAc (3 x 30 mL); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% EtOAc in heptane) to afford A-3g (2.6 g). LCMS (ES) m/z; 207.1 [M+H]+. [00490] Step-7: N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (A-3): Argon gas was purged through a stirred suspension of A-3g (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. To this was then added rac-BINAP (0.9 g, 1.45 mmol) and Pd2(dba)3- CHCl3 (1.5 g, 1.45 mmol). The reaction mixture was then heated at 110 °C for 2 h in a sealed tube. After completion, it was cooled to room temperature and filtered through Celite bed. It is washed with EtOAc (50 mL x 2) and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-25% EtOAc in heptane) to afford A-3 (1.8 g) as a yellow solid. LCMS (ES) m/z; 256.6 [M+H]+. Example 37: Preparation of 4,6-dichloro-N-(2,2-difluoroethyl)pyridazine-3-carboxamide (A-4):
Figure imgf000159_0001
[00491] A-4 (1.1 g) was synthesized by following procedure as described for the synthesis of A-1 (step-1) using A-1a (1.0 g, 5.03 mmol) as the starting material. LCMS (ES) m/z; 256.0 [M+H]+. Example 38: Preparation of 1-cyclopropylimidazolidin-2-one (A-5)
Figure imgf000159_0002
[00492] To a stirred solution of cyclopropylamine (0.27 g, 4.74 mmol) in tetrahydrofuran (10 mL) was added 1-chloro-2-isocyanatoethane A-5a (0.5 g, 4.74 mmol) and the reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was cooled to 0 °C, added sodium hydride (0.38 g, 9.48 mmol, 60 % w/w) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with ammonium chloride solution (10 mL) and was extracted with 10% MeOH in DCM (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was washed with pentane and dried to afford A-5 (0.15 g) as off white solid. LCMS (ES) m/z: 127.1 [M+H]+. Example 39: Preparation of 1-cyclobutylimidazolidin-2-one (A-6)
Figure imgf000160_0001
[00493] A-6 (0.5 g) was synthesized by following procedure as described for the synthesis of A-5 (step-1) using A-5a (1.0 g, 5.03 mmol) as the starting material. LCMS (ES) m/z; 141.1 [M+H]+. Example 40: Preparation of 1-isopropyltetrahydropyrimidin-2(1H)-one (A-7):
Figure imgf000160_0002
[00494] To a stirred solution of A-7a (1 g, 8.61 mmol) in dichloromethane (20 mL, 312 mmol) was added CDI (1.4 g, 8.61 mmol) portion wise and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC/ LCMS. After completion, the reaction mixture was diluted with water (10 mL) and was extracted with DCM (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get A-7 (0.62 g) as off white solid.1H NMR (400 MHz, DMSO-d6) δ 4.53- 4.46 (m, 1H), 3.07-3.04 (m, 4H), 1.77-1.71 (m, 2H), 0.99 (d, J = 8.0 Hz, 6H). Example 41: Preparation of 1-(2,2,2-trifluoroethyl)imidazolidin-2-one (A-8):
Figure imgf000161_0001
[00495] A-8 (2.0 g) was synthesized by following procedure as described for the synthesis of A-5 (step-1) using A-5a (2.1 g, 20.2 mmol) as the starting material.1H NMR (400 MHz, DMSO-d6) δ 6.78 (s, 1H), 3.84 (q, J = 8.0 Hz, 2H), 3.46 (t, J = 8.0 Hz, 2H), 3.29 (t, J = 8.0 Hz, 2H). Example 42: Preparation of 1-((1s,3s)-3-fluorocyclobutyl)imidazolidin-2-one (A-9):
Figure imgf000161_0002
[00496] A-9 (0.2 g) was synthesized by following procedure as described for the synthesis of A-5 (step-1) using A-5a (0.25 g, 2.39 mmol) as the starting material. LCMS (ES) m/z; 159.1 [M+H]+. Example 43: Preparation of 1-ethylimidazolidin-2-one (A-10):
Figure imgf000161_0003
[00497] A-10 (0.8 g) was synthesized by following procedure as described for the synthesis of A-5 (step-1) using A-5a (4.7 g, 44.4 mmol) as the starting material. LCMS (ES) m/z; 115.2 [M+H]+. Example 44: Preparation of 1-((1r,3r)-3-fluorocyclobutyl)imidazolidin-2-one (A-11):
Figure imgf000162_0001
[00498] A-11 (0.4 g) was synthesized by following procedure as described for the synthesis of A-5 (step-1) using A-5a (0.33 g, 3.19 mmol) as the starting material. LCMS (ES) m/z; 159.1 [M+H]+. Example 45: 6-chloro-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide (5a):
Figure imgf000162_0002
[00499] 6-chloro-N-(methyl-d3)-4-((2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide (5a) (Procedure M1-A): To a stirred solution of I-1 (0.4 g, 1.64 mmol) in DMF (4.0 mL) was added sodium hydride (60% suspension) (0.32 g, 8.19 mmol) portion-wise at 0 °C and stirred at same temperature for 15 min. To this was then added A-1 (0.41 g, 1.96 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium hydride (60% suspension) (0.012 g, 0.49 mmol) and A-1 (0.1 g, 0.49 mmol) were added to the reaction mixture thrice at the interval of 15 minutes. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with 10% MeOH in DCM (50 mL x 3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by Combi-Flash (using gradient elution 0-40% EtOAc in heptane) to afford 5a (0.25 g) as a white solid. LCMS (ES) m/z; 417.2 [M+H]+. [00500] Note: Racemate 5a (0.3 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 µm) Mobile phase: n-hexane:IPA with 0.1% DEA (70:30) Flow rate : 40.0 mL/min] to afford two enantiomers {5A (0.1 g): peak-1; Rt; 13.15 min and 5B (0.1 g): peak-2; Rt; 14.69 min}, which were used further without their absolute configuration determination. Example 46: 6-chloro-N-(methyl-d3)-4-((2,5,8-trimethyl-4,5-dihydro-2H- [1,2,3
Figure imgf000163_0001
[00501] 6-chloro-N-(methyl-d3)-4-((2,5,8-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)nicotinamide (9a) (Procedure M1-B): Argon gas was purged through a stirred suspension of I-4 (0.2 g, 0.87 mmol), A-2 (0.22 g, 0.87 mmol) and NaOBu-t (0.17 g, 1.74 mmol) in toluene (20 mL) for 15 min, before addition of [5-(diphenylphosphanyl)- 9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.05 g, 0.087 mmol) and Pd2(dba)3 (0.08 g, 0.087 mmol). The reaction mixture was then stirred at 90 °C for 3 h in a sealed tube. It was then cooled to room temperature, filtered through celite bed and washed with EtOAc (50 mL x 2). The filtrate was concentrated under reduced pressure. The crude product was purified by Combi- Flash (using gradient elution 0-80% EtOAc in heptane) to afford 10a (0.09 g) as an off white solid. LCMS (ES) m/z; 417.2 [M+H]+. Example 47: 6-chloro-N-(methyl-d3)-4-((3,4,5,8-tetramethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide (11a):
Figure imgf000163_0002
[00502] 11a (0.3 g) was synthesized by following procedure as described for the synthesis of 5a (M1-A, step-1) using I-8 (0.3 g, 1.23 mmol) as the starting material. LCMS (ES) m/z; 417.2 [M+H]+. [00503] Note: Racemate 11a (0.3 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 µm) Mobile phase: n-hexane:IPA with 0.1% DEA (50:50) Flow rate : 40.0 mL/min] to afford two enantiomers {11A (0.13 g): peak-1; Rt; 16.29 min and 11B (0.12 g): peak-2; Rt; 19.78 min}, which were used further without their absolute configuration determination. Example 48: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide (Compound 2):
Figure imgf000164_0001
[00504] Step-1: 6-chloro-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6-dihydropyrazino[2,3- c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide (1a) (Procedure M1-C): To a stirred solution of I-10A (0.2 g, 0.83 mmol) in anhydrous THF (5.0 mL) was added a 1M solution of LiHMDS (in THF) (5.8 mL, 5.8 mmol) drop wise at 0 °C. It was stirred for 5 minutes before addition of A-1 (0.26 g, 1.24 mmol). The reaction mixture was allowed to stir at the room temperature for 2 h, while monitoring reaction progress by TLC. After completion, it was quenched with addition of cold water (50 mL) and extraction was carried out using DCM (20 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-50% EtOAc in heptane) to afford 1a (0.17 g) as a pale yellow solid. LCMS (ES) m/z; 414.1 [M+H]+. [00505] Step-2: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5,6,9-trimethyl-5,6- dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)pyridazine-3-carboxamide (Compound 2) (Procedure M2): Argon gas was purged through a stirred suspension of 1a (0.16 g, 0.39 mmol), cyclopropanecarboxamide (0.05 g, 0.58 mmol) and Cs2CO3 (0.25 g, 0.77 mmol) in 1,4-dioxane (5 mL) for 15 min, before addition of [5-(diphenylphosphanyl)-9,9- dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.022 g, 0.039 mmol) and Pd2(dba)3 (0.035 g, 0.039 mmol). The reaction mixture was then stirred at 130 °C for 3 h in a sealed tube, while monitoring reaction progress by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature and water (25 mL) was added to it. Extraction was carried out using EtOAc (50 mL x 2); the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-100% EtOAc in heptane). It was further purified by preparative HPLC to afford Compound 2 (0.04 g) as a yellow solid. LCMS (ES) m/z; 463.5 [M+H]+.1H NMR (400 MHZ, DMSO-d6) δ ppm: 12.22 (s, 1H); 11.29 (s, 1H); 10.16 (s, 1H); 9.19 (s, 1H); 8.72-8.70 (m, 2H); 7.59 (s, 1H); 4.43 (q, J = 7.2 Hz, 1H); 2.60 (s, 3H); 2.54 (s, 3H); 2.17-2.11 (m, 1H); 1.19 (d, J = 7.2 Hz, 3H); 0.90-0.82 (m, 4H). Chiral MD: Column: CHIRALPAK IA (100 mm x 4.6 mm x 3 μm); Mobile phase: Hexane:Ethanol with 0.1% DEA (50:50); Flow rate: 1.0 mL/min; peak-1; Rt: 4.86 min. [00506] The below compounds were synthesized by following procedures a described above using appropriate intermediates and reagents.
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
†
Figure imgf000172_0002
= single isomer at obtained by chiral separation of racemic final compound, or racemic intermediate. Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined. Example 49: Preparation of N-(5-(propanoyl-3,3,3-d3)-4-((2',5',8'-trimethyl-2',5'- dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)amino)pyridin-2- yl)cyclopropanecarboxamide (Compound 17) (Procedure M3):
Figure imgf000172_0001
[00507] Argon gas was purged through a stirred suspension of I-6 (0.125 g, 0.46 mmol), A-3 (0.14 g, 0.55 mmol) and Cs2CO3 (0.3 g, 0.92 mmol) in 1,4-dioxane (3.0 mL) for 15 min, before addition of rac-BINAP (0.029 g, 0.046 mmol) and Pd2(dba)3-CHCl3 (0.048 g, 0.046 mmol). The reaction mixture was then stirred at 110 °C for 5 h in a sealed tube. After completion, the reaction mixture was cooled to room temperature and diluted with 10% MeOH in DCM (50 mL). The organic layer was washed with saturated bicarbonate solution (20 mL), water (20 mL), brine (20 mL), dried over anhydrous sulfate and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-90% EtOAc in heptane). The solid thus obtained was triturated in MeOH (10 mL x 3), filtered and dried to afford Compound 17 (0.018 g) as an off-white solid. LCMS (ES) m/z 492.6 [M+H]+.1HNMR (400 MHz, DMSO- d6): δ 12.35 (s, 1H); 10.88 (s, 1H); 9.96 (s, 1H); 8.96 (s, 1H); 7.15 (s, 1H); 4.85 (d, J = 6.4 Hz, 2H); 4.63 (d, J = 6.4 Hz, 2H); 4.31 (s, 3H); 3.15 (s, 2H); 2.50 (s, 3H); 2.32 (s, 3H); 2.12-2.04 (m, 1H); 0.86-0.82 (m, 4H). [00508] The below compounds were synthesized by following procedures a described above using appropriate intermediates and reagents.
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
†
Figure imgf000256_0001
= single isomer at obtained by chiral separation of racemic final compound, or racemic intermediate. Absolute configuration determined by methods known to those in the art, such as enantiomeric synthesis, x-ray crystallography, proton NOE studies, or the like, or by analogy to other compounds for which absolute configuration has been determined. Example A-1: Oral Solution [00509] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s),optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution. Example A-2: Oral Tablet [00510] A tablet is prepared by mixing 20-50% by weight of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg. Example A-3: Oral Capsule [00511] To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration. [00512] In another embodiment, 10-500 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed. II. Biological Evaluation Example B-1: HEK-Blue™ IL-23 and IFNα/β Reporter Assays for Profiling TYK2 Pseudokinase (JH2) Inhibition [00513] HEK-Blue™ IL-23 and IFNα/β cells with a stably-integrated cytokine receptor and STAT3 or STAT1 express STAT-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene upon cytokine stimulation. These cells are plated in DMEM (Gibco) containing 10% heat-inactivated FBS (Gibco) and 100 U/mL PenStrep (Gibco) at 37 °C under 5% CO2 conditions for 20-22 hours. The cells are then pretreated with serially diluted test compounds for 60 min prior to stimulation with either 10 ng/mL human recombinant IL-23 (Miltenyl Biotech) or 1ng/mL human recombinant IFNα (InvivoGen) for 22-24 hours for IL-23 or 16-18 h for IFNα. SEAP induction is measured using the QUANTI Blue™ Solution (InvivoGen) according to the manufacturer's instructions. Inhibition data are calculated by comparison to no inhibitor control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves are generated to determine the concentration required to inhibit 50% of cellular response (IC50) as derived by non-linear regression analysis. [00514] Table B-1 provides TYK2 inhibitory activity of illustrative compounds, where A means IC50 < 30 nM; B means IC50 is between 30 and 300 nM; C means IC50 is between 300 and 1000 nM; D means IC50 > 1000 nM; n/a means no observed activity at 1000 nM; and n.d. means not determined. Table B-1: Representative TYK2 Inhibitory Activity
Figure imgf000258_0001
Figure imgf000258_0002
Figure imgf000258_0003
Figure imgf000259_0003
Figure imgf000259_0001
Figure imgf000259_0002
Example B-2: HEK-Blue™ IL-2 and IFNγ Reporter Assays for determining selectivity [00515] HEK-Blue™ IL-2 and IFNγ reporter cells with a stably-integrated cytokine receptor and STAT5 or STAT1 express STAT-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene upon cytokine stimulation. These cells were plated in DMEM (Gibco) containing 10% heat-inactivated FBS (Gibco) and 100 U/mL PenStrep (Gibco) at 37 °C under 5% CO2 conditions for 20-22 hours. The cells were then pretreated with serially diluted test compounds for 60 min prior to stimulation with either 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 the QUANTI-Blue™ Solution (InvivoGen) according to the manufacturer's instructions. Inhibition data were calculated by comparison to no inhibitor control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves were generated to determine the concentration required to inhibit 50% of cellular response (IC50) as derived by non-linear regression analysis. [00516] Table B-2 provides selectivity data (SEAP) of illustrative compounds for IL-2 and IFN-γ, where A means IC50 < 30 nM; B means IC50 is between 30 and 300 nM; C means IC50 is between 300 and 1000 nM; D means IC50 > 1000 nM; n/a means no observed activity at 1000 nM; and n.d. means not determined. Table B-2: SEAP Selectivity Assay Data at IL-2 and IFN-γ
Figure imgf000259_0004
Figure imgf000259_0005
Figure imgf000259_0006
Figure imgf000260_0003
Figure imgf000260_0001
Figure imgf000260_0002
Example B-3: Pharmacokinetic Studies [00517] The experiments were performed on male Sprague–Dawley rats weighing 220 to 247 g. The total number of 8 animals were used in the study. Test compounds were dosed IV at 1mg/kg, the formulation was prepared in DMSO:PEG-400:Tween80: Normal Saline (10:10:10:70). Blood was collected by retro orbital plexus in centrifuge tube containing K2EDTA, and plasma obtained by centrifugation at 1000 rpm for 5 min at 4 °C and stored at −80 °C. Blood collection schedule post dose 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h. [00518] Test compound was administered/dosed at 10 mg/kg via oral route. Formulation was prepared in Ethanol + TPGS+PEG300+0.5% methylcellulose (5:5:20:70;v/v). Blood collection schedule for oral dosing was 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h. [00519] Tables B-3 and B-4 provide summary of the in vivo PK data for selected compounds. Table B-3: Summary of in vivo Rat PK for Selected Compounds Dosed at 1 mg/kg IV
Figure imgf000260_0004
Figure imgf000261_0001
Table B-4: Summary of in vivo Rat PK for Selected Compounds Dosed at 10 mg/kg PO
Figure imgf000261_0002
Figure imgf000262_0004
[00520] Reference compound A is Compound 94 in WO 2022175747 and has the following structure:
Figure imgf000262_0001
Reference compound B has the following structure: . Reference compound C is Compound 73 in WO 2023/227946 and
Figure imgf000262_0002
has the following structure: . Each reference compound is a single
Figure imgf000262_0003
enantiomer. [00521] Briefly, the compounds disclosed herein generally have higher exposure, lower clearance, and higher bioavailability than reference compounds which do not contain the substitution on the tricyclic ring as required herein (e.g., with no R1 substituent or with R1 = F). Example B-4: Brain Exposure Steady-State Study in Rats [00522] The experiments were performed on male Sprague-Dawley rats (Vivo biotech, Hyderabad, collaboration with Taconic USA) weighing 220 to 240 g. All animals were acclimatized for at least 5 days after arrival and were group housed at 18 °C to 22 °C under a 12- h light-dark cycle with food and water ad libitum at all times before the experiments. [00523] A total of four animals were used for this study. Test compound was administered/dosed at 10 mg/kg orally BID (2nd dose post 8 h of 1st dose) for 3 days and QD for 4th day. The formulation was prepared in Ethanol+TPGS (1:1):PEG-300 (10:90) vehicle. Blood, brain and CSF sample were collected post 6 h of dose on 4th days. Blood was collected from the retro-orbital plexus in a centrifuge tube containing K2EDTA, and plasma was obtained by centrifugation at 10000 rpm for 5 min at 4 °C and stored at -80 °C. The cerebrospinal fluid was collected by cisterna magna puncture with the help of a sterilised needle and stored at -80 °C. The whole brain was quickly removed from the skull and rinsed in ice-cold saline, immediately flash-frozen, and stored at -80 °C. [00524] For analysis, brains were carefully weighed and transferred into a sample collection tube, and then 5 time of brain weight phosphate buffer saline (PBS) was added to this, and the samples were homogenized using probe homogenizer. [00525] Artificial cerebrospinal fluid was prepared and used to plot the calibration curve and quality control samples. [00526] Blood, CSF and homogenized brain sample were precipitated with 400 µL of acetonitrile containing internal standard. Precipitated samples were centrifuged at 14000 rpm for 5 min at 4 °C, and the supernatants were used for LC-MS/MS analysis. [00527] The mean brain to plasma exposure ratio was calculated for selected compounds and is provided in Table B-5. Table B-5: Steady State Brain to Plasma Partitioning Study in Rat by Oral Route
Figure imgf000263_0001
Figure imgf000263_0002
Figure imgf000264_0004
Figure imgf000264_0005
[00528] Reference compound D has the following structure:
Figure imgf000264_0001
Reference compound E has the following structure:
Figure imgf000264_0002
Reference compound F has the following structure: Each reference compound
Figure imgf000264_0003
is a single enantiomer. [00529] Briefly, the compounds disclosed herein generally have higher brain to plasma exposure ratio than reference compounds which do not contain the substitution on the tricyclic ring as required herein (e.g., with no R1 substituent or with R1 = F). [00530] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I):
Figure imgf000265_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: X is N or CH; Y is -NH- or -CH2-; Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups; R2 is halogen, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy; R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, - OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; or R4 and R5 are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Ring A is a 5-membered heteroaryl ring or a 6-membered heteroaryl ring; each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, - NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; wherein any R6 attached to a nitrogen atom is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -S(O)R13, -S(O)2R13, or - S(O)2N(R12)2; R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10; R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R11 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; or R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, - S(O)2R13, or -S(O)2N(R13)2; each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; m is 1, 2, or 3; and n is 0 or 1; wherein the compound is not N-(5-(propanoyl-3,3,3-d3)-4-((2,5,8-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridin-2- yl)cyclopropanecarboxamide.
2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R7 is C1-C4 alkyl or C1-C4 deuteroalkyl.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R7 is -CH3 or -CD3.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R8 is hydrogen or C1-C4 alkyl.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R8 is hydrogen.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R9 is -C(O)R10.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6- membered monocyclic heterocycloalkyl.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, - CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10 is unsubstituted or substituted C3-C4 cycloalkyl.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10 is cyclopropyl.
12. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the compound is a compound of Formula (II) or Formula (III):
Figure imgf000268_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Z is N.
14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Z is CH.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3- C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl.
17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CF3, -CHF2, -CH2F, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, - CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
18. The compound of asny one of claims 1-15, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, -OCF3, - OCH2CF3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein n is 1 and R2 is halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl.
20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein n is 0.
21. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the compound is a compound of Formula (IV), Formula (V), Formula (VI) or Formula (VII):
Figure imgf000269_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X is N.
23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X is CH.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R3 is hydrogen or C1-C6 alkyl.
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R3 is C1-C6 alkyl.
26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl; or R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene.
27. The compound of claim 26, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl.
28. The compound of claim 27, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 and R5 are each independently hydrogen or -CH3.
29. The compound of claim 26, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene.
30. The compound of claim 29, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered heterocycloalkylene.
31. The compound of claim 29 or claim 30, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 and R5 are taken together with the carbon atom to which they are attached to form an oxetane ring.
32. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R5 is hydrogen.
33. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the compound is a compound of Formula (IVa), Formula (Va), Formula (VIa) or Formula (VIIa):
Figure imgf000271_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group.
34. The compound of claim 33, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2.
35. The compound of claim 33 or claim 34, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 is C1-C6 alkyl or C1-C6 deuteroalkyl.
36. The compound of any one of claims 33-35, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 is methyl, ethyl, or trideuteromethyl.
37. The compound of any one of claims 33-36, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4 is methyl.
38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is a 5-membered heteroaryl ring.
39. The compound of claim 38, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is a pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, or thiadiazole.
40. The compound of claim 38, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is a triazole, imidazole, pyrazole, thiazole, or oxazole.
41. The compound of claim 38, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein
Figure imgf000272_0001
where * represents the attachment point to -
Figure imgf000272_0002
C(R4)(R5)-.
42. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is a 6-membered heteroaryl ring.
43. The compound of claim 42, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is a pyridine, pyridazine, pyrimidine, or pyrazine.
44. The compound of claim 42, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is pyridine or pyrazine.
45. The compound of claim 42, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein where * represents
Figure imgf000272_0003
the attachment point to -C(R4)(R5)-.
46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R6 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, - C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, or -S(O)2N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2.
47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R6 is independently hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -CN, -OH, -OR13, or -N(R12)2; wherein any R6 attached to a nitrogen atom is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.
48. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R6 is independently hydrogen, fluoro, methyl, or cyclopropyl; wherein any R6 attached to a nitrogen atom is hydrogen, methyl, or cyclopropyl; and m is 1 or 2.
49. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein
Figure imgf000273_0001
Figure imgf000273_0003
where *
Figure imgf000273_0002
represents the attachment point to -C(R4)(R5)-.
50. A compound of Formula (X):
Figure imgf000273_0004
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is CH or N; R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, (C1-C4 fluoroalkoxy)-C1-C4 alkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, or (C3-C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one, two, or three fluoro groups; R2 is halogen, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, or C1-C4 fluoroalkoxy; R3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, - OR13, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, - S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; or R4 and R5 are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6 cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; R6 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1- C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 4- to 6-membered heterocycloalkyl, -C(O)R12, - C(O)OR12, -C(O)N(R12)2, -S(O)R13, -S(O)2R13, or -S(O)2N(R12)2; R7 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10; R10 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R11 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl; or R10 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocyclyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R9 is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R9 is substituted then it is substituted with 1, 2, or 3 groups independently selected from halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR13, - C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, - S(O)2R13, or -S(O)2N(R13)2; each R12 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R13 is independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; m is 1, 2, or 3; and n is 0 or 1.
51. The compound of claim 50, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R7 is C1-C4 alkyl or C1-C4 deuteroalkyl.
52. The compound of claim 50 or claim 51, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R8 is hydrogen or C1-C4 alkyl; R9 is -C(O)R10, -C(O)NR10R11, or -C(O)OR10; R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl; and R11 is hydrogen or C1-C4 alkyl; or R8 and R11 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl.
53. The compound of any one of claims 50-52, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R8 is hydrogen; R9 is -C(O)R10; and R10 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
54. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R3 is hydrogen or C1-C6 alkyl; and R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl; or R4 and R5 are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene.
55. The compound of any one of claims 50-54, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R3 is C1-C6 alkyl; R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycloalkyl, -CN, -OH, -OR13, -C(O)R12, -C(O)OR12, - C(O)N(R12)2, -N(R12)2, -NR12C(O)R13, -SR12, -S(O)R13, -S(O)2R13, or -S(O)2N(R13)2; and R5 is hydrogen.
56. The compound of claim 55, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R4 is C1-C6 alkyl or C1-C6 deuteroalkyl.
57. The compound of any one of claims 50-56, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 1; and R2 is halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl.
58. The compound of any one of claims 50-56, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0.
59. The compound of claim 50, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the compound is a compound of Formula (XI):
Figure imgf000277_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
60. The compound of any one of claims 50-59, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is chloro, -CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, (C1-C4 alkoxy)-C1-C4 alkyl, or (C3- C6 cycloalkyl)-O-, wherein C3-C6 cycloalkyl is optionally substituted with one fluoro group.
61. The compound of any one of claims 50-60, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is chloro, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl.
62. The compound of any one of claims 50-61, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CF3, -CHF2, -CH2F, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, - CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
63. The compound of any one of claims 50-62, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1 is -Cl, -CN, -CH3, -CHF2, -OCH3, -OCF3, - OCH2CF3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, or 1-fluoro-cyclopropyl.
64. The compound of any one of claims 50-63, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R6 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, -C(O)OR12, -C(O)N(R12)2, or -S(O)2N(R12)2.
65. The compound of any one of claims 50-64, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R6 is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.
66. The compound of any one of claims 50-65, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R6 is hydrogen, methyl, or cyclopropyl.
67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: each R12 is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; or two R12 on the same N atom are taken together with the N atom to which they are attached to form a 4- to 6-membered N-containing heterocycloalkyl; each R13 is independently C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.
68. A compound selected from:
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
pharmaceutically acceptable salt, tautomer, or solvate thereof.
69. A pharmaceutical composition comprising the compound of any one of claims 1-68, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.
70. The pharmaceutical composition of claim 69, wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration.
71. The pharmaceutical composition of claim 69, wherein the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
72. A method of treating a TYK2-mediated 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 1-68, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
73. The method of claim 72, wherein the disease or condition is an inflammatory disease or condition or an autoimmune disease or condition.
74. The method of claim 72 or claim 73, wherein the disease or condition is an inflammatory disease or condition.
75. The method of claim 74, wherein the inflammatory disease or condition is a neuroinflammatory disease or condition.
76. The method of any one of claims 72-75, wherein the disease or condition is a neurodegenerative disease or condition.
77. The method of any one of claims 75-76, wherein the disease or condition is selected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or a neuromyelitis optica spectrum disorder.
78. The method of claim 77, wherein the disease or condition is multiple sclerosis.
79. The method of claim 78, wherein the multiple sclerosis is relapsing or relapsing- remitting.
80. The method of claim 77, wherein the disease or condition is a neuromyelitis optica spectrum disorder.
81. The method of claim 80, wherein the disease or condition is neuromyelitis optica.
82. The method of claim 77, wherein the disease or condition is encephalomyelitis.
83. The method of claim 82, wherein the disease or condition is acute disseminated encephalomyelitis.
84. The method of claim 77, wherein the disease or condition is polyneuropathy.
85. The method of claim 84, wherein the disease or condition is chronic inflammatory demyelinating polyneuropathy.
86. The method of claim 77, wherein the disease or condition is encephalitis.
87. The method of claim 86, wherein the disease or condition is autoimmune encephalitis.
88. The method of any one of claims 72-74, wherein the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
89. The method of any one of claims 72-88, wherein the compound is administered orally.
PCT/IB2024/000679 2023-11-29 2024-11-26 Tyk2 inhibitors and uses thereof Pending WO2025114760A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202363604078P 2023-11-29 2023-11-29
US63/604,078 2023-11-29
US202463659710P 2024-06-13 2024-06-13
US63/659,710 2024-06-13
US202463677846P 2024-07-31 2024-07-31
US63/677,846 2024-07-31

Publications (1)

Publication Number Publication Date
WO2025114760A1 true WO2025114760A1 (en) 2025-06-05

Family

ID=94278204

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/000679 Pending WO2025114760A1 (en) 2023-11-29 2024-11-26 Tyk2 inhibitors and uses thereof

Country Status (2)

Country Link
TW (1) TW202529754A (en)
WO (1) WO2025114760A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022175747A1 (en) 2021-02-19 2022-08-25 Sudo Biosciences Limited Tyk2 inhibitors and uses thereof
WO2023227946A1 (en) 2022-05-27 2023-11-30 Sudo Biosciences Limited Tyk2 inhibitors and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022175747A1 (en) 2021-02-19 2022-08-25 Sudo Biosciences Limited Tyk2 inhibitors and uses thereof
WO2023227946A1 (en) 2022-05-27 2023-11-30 Sudo Biosciences Limited Tyk2 inhibitors and uses thereof

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH/VHCA, article "International Union of Pure and Applied Chemistry"
"Method in Enzymology", vol. 42, 1985, ACADEMIC, pages: 309 - 396
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
"Remington: The Science and Practice of Pharmacy", 1995, JOHN WILEY AND SONS, INC.
BUNDGAARD, H., ADVANCED DRUG DELIVERY REVIEW, vol. 8, 1992, pages 1 - 38
BUNDGAARD, H: "A Textbook of Drug Design and Development", 1991, article "Design and Application of Prodrugs", pages: 113 - 191
DENDROU ET AL., SCI TRANSL MED, 2016
HOOVER, JOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
JEAN JACQUESANDRE COLLETSAMUEL H. WILEN: "Enantiomers, Racemates and Resolutions", 1981, JOHN WILEY AND SONS, INC.
LI ET AL., BRAIN, 2007
S.M. BERGEL.D. BIGHLEYD.C. MONKHOUSE, J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
TZARTOS ET AL., AM J PATH, 2008
WAN ET AL., J. NEUROSCI., vol. 30, no. 20, 2010, pages 6873 - 6881
WINDHAGEN ET AL., J EXP MED, 1996

Also Published As

Publication number Publication date
TW202529754A (en) 2025-08-01

Similar Documents

Publication Publication Date Title
US12084458B2 (en) Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12122785B2 (en) Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
WO2022175745A1 (en) Tyk2 inhibitors and uses thereof
JP2019531280A (en) Compounds and compositions as inhibitors of endosomal Toll-like receptors
AU2022223497A1 (en) Tyk2 inhibitors and uses thereof
WO2022086920A1 (en) Glutaminyl-peptide cyclotransferase like (qpctl) protein inhibitors and uses thereof
EP4532485A1 (en) Tyk2 inhibitors and uses thereof
US20240124440A1 (en) Tyk2 inhibitors and uses thereof
WO2024246599A1 (en) Condensed azines as tyk2 inhibitors and uses thereof
WO2024042361A1 (en) Tyk2 inhibitors and uses thereof
WO2025114760A1 (en) Tyk2 inhibitors and uses thereof
AU2024279507A1 (en) Condensed azines as tyk2 inhibitors and uses thereof
WO2025114761A1 (en) Tyk2 inhibitors and uses thereof
WO2024246602A1 (en) Fused azoled as tyk2 inhibitors and uses thereof
CA3208507A1 (en) Tyk2 inhibitors and uses thereof
CN117120440A (en) TYK2 inhibitors and their uses
TW202515565A (en) Inhibitors of tyk2
CN117242072A (en) TYK2 inhibitors and their uses

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24837103

Country of ref document: EP

Kind code of ref document: A1