1h-pyrrolo[2,3-b]pyridine derivatives as mrgprx2 antagonists for the treatment of inflammatory diseases

Abstract

The present disclosure relates to compounds represented by structural formula (I*): such as 1H-pyrrolo[2,3-b]pyridine derivatives, or a pharmaceutically acceptable salt thereof. Further disclosed are pharmaceutical compositions comprising the compounds, and the compounds for use in methods of treating MRGPRX2-mediated diseases or disorders, such as inflammatory diseases, e.g. chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis.

Description

[0001] TITLE MRGPRX2 ANTAGONISTS, PHARMACEUTICAL COMPOSITION INCLUDING MRGPRX2 ANTAGONIST, AND METHOD OF TREATING MRGPRX2-MEDIATED DISEASE OR DISORDER CROSS-REFERENCE TO RELATED APPLICATIONS The present application is based upon and claims the benefit of priority to U.S. Application No.63 / 636,536, filed April 19, 2024, the entire contents of which are incorporated herein by reference. BACKGROUND Technical Field The present invention relates to MRGPRX2 antagonists, a pharmaceutical composition including a MRGPRX2 antagonist, and a method of treating an MRGPRX2- mediated disease or disorder. Description of Background Art Mast cells are involved in a variety of inflammatory diseases, and antigen- dependent activation of tissue mast cells with IgE bound to their surface is a major event in acute allergic reactions. In addition to the case where mast cells are activated by the combination of IgE-allergen, there is the case where the ligand directly stimulates and activates the Mas-related G protein-coupled receptor (MRGPR) on the mast cells. In particular, many new studies on MRGPRX2-mediated IgE-independent mast cell activation have been reported in recent years. International Publication No. WO 2021 / 092264 describes compounds as an MRGPRX2 antagonist. The entire contents of this publication are incorporated herein by reference. BRIEF SUMMARY In some embodiments, the present disclosure relates to a compound represented by structural formula (I*): or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; Rb is selected from H, C1-C6alkyl, and C(=O)O( C1-C6alkyl), wherein each C1-C6alkyl is optionally substituted with one or more substituents independently selected from group Q; CyA is selected from one of the following moieties: , CyB is selected from 5- to 12-membered heteroaryl and C6-C12aryl, wherein the 5- to 12- membered heteroaryl or C6-C12aryl is optionally substituted with one or more substituents independently selected from group Q; Ra is selected from H, deuterium, F, Cl, Br, CN, NO2, C1-C6alkyl, and C1-C6alkoxy, wherein each C1-C6alkyl or C1-C6alkoxy is optionally substituted with one or more substituents independently selected from group Q; R5and R6are each independently selected from deuterium, F, Cl, Br, OH, CN, NO2, NR10aR10b, C(=O)NR11aR11b, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12- membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2- C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from group Q, or R5and R6together with the atoms to which they are attached form C4-C12carbocyclyl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein the C4-C12carbocyclyl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from group Q; n is 0, 1, 2, 3, or 4; R7and R8together with the atoms to which they are attached form 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl is optionally substituted with one or more substituents independently selected from group Q; R7is selected from H, deuterium, F, Cl, Br, OH, CN, NO2, NR10cR10d, C(=O)NR11cR11d, C1- C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; R8is selected from H and C1-6alkyl optionally substituted with one or more substituents independently selected from a group Q; R9is selected from C1-C6alkyl, F, Cl, Br, OH, CN, NO2, NR10eR10f, C(=O)NR11eR11f, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12- membered heteroaryl, and 4- to 12-membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; and R10a, R10b, R10c, R10d, R10e, R10f, R11a, R11b, R11c, R11d, R11e, and R11fare each independently selected from H and C1-C6alkyl optionally substituted with one or more substituents independently selected from a group Q, or one or more of the pairs of variables selected from R10aand R10b, R10cand R10d, R10eand R10f, R11aand R11b, R11cand R11d, and R11eand R11f, together with the nitrogen to which they are attached, form 5- to 12-membered heteroaryl or 4- to 12-membered heterocyclyl, wherein each 5- to 12-membered heteroaryl or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; wherein each of the one or more substituents of group Q is independently selected from deuterium, F, Cl, Br, OH, NH2, NH(C=O)(C1-C6alkyl), NH(C=O)(C3-C8cycloalkyl), NH(C=O)(O-C1-C6alkyl), C1-C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy- carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl- N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, C1-C6alkylsulfinyl- C1-C6alkyl, C1-C6alkylsulfonyl- C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl- C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl- C1-C3alkyl, phenyl-C1-C6alkoxy, N-methylamino-carbonyl-C1-C6alkyl, N,N- dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound represented by structural formula (I*), (Ia*) to (Ik*), (Ia) to (Ie), or (IIa) to (IIe) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound represented by structural formula (I*), (Ia*) to (Ik*), (Ia) to (Ie), or (IIa) to (IIe) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated for the treatment of MRGPRX2-mediated disease or disorder. In some embodiments, the present disclosure relates to a method of treating an MRGPRX2-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the disclosure (e.g., a compound represented by structural formula (I*), (Ia*) to (Ik*), (Ia) to (Ie), or (IIa) to (IIe) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition of the disclosure. In some embodiments, the present disclosure relates to a compound of the disclosure (e.g., a compound represented by structural formula (I*), (Ia*) to (Ik*), (Ia) to (Ie), or (IIa) to (IIe) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition of the disclosure for use in the treatment of an MRGPRX2-mediated disease or disorder. In some embodiments, the present disclosure relates to use of a compound of the disclosure (e.g., a compound represented by structural formula (I*), (Ia*) to (Ik*), (Ia) to (Ie), or (IIa) to (IIe) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition of the disclosure in the manufacture of a medicament for use in the treatment of an MRGPRX2-mediated disease or disorder. [1] According to one aspect of the present disclosure, a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof. In Formula (Ia), X is S, -CRd=CRe-, - CRd=N-, or -N=CRd-; Rd and Re are independently hydrogen, deuterium, halo, CN, C1- C6alkyl, C1-C6haloalkyl or C1-C6alkoxy; Ra is hydrogen, halo, C1-C6alkyl or C1-C6alkoxy; Rb is hydrogen, C1-C6alkyl, hydroxy-C1-C6alkyl, C1-C6alkoxy- C1-C6alkyl, C1- C6alkyl-carbonyl or C1-C6alkoxy-carbonyl; CyA and CyB are independently C6-C10aryl optionally having at least one substituent selected from a group Q, heteroaryl optionally having at least one substituent selected from the group Q, C3-C8cycloalkyl optionally having at least one substituent selected from the group Q, C3-C8cycloalkenyl optionally having at least one substituent selected from the group Q, heterocyclyl optionally having at least one substituent selected from the group Q, fused heterocyclic ring consisting of 9 or 10 atoms optionally having at least one substituent selected from the group Q, where the group Q is deuterium, halo, C1-C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, NO2, CN, CONH2, ,aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy- carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N- methylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, N- methylamino-carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring; and n is 0 or 1. [2] The compound or a pharmaceutically acceptable salt thereof according to [1], wherein the Formula (Ia) is selected from the group consisting of Formulas (Ib), (Ic), (Id) and (Ie), ）

[0002] [3] The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein CyA is fused non-aromatic heterocyclyl-aryl optionally having at least one substituent selected from the group Q, fused non-aromatic heterocyclyl-heteroaryl optionally having at least one substituent selected from the group Q, fused arylheteroaryl optionally having at least one substituent selected from the group Q, or fused heteroarylheteroaryl optionally having at least one substituent selected from the group Q, wherein the group Q is C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl- carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1- C6alkoxy-carbonyl-N-methylamino, C3-C8cyloalkyl, C3-C8cyloalkyl-C1-C3alkoxy, C1- C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl- C1-C3alkyl, phenyl-C1-C6alkoxy, C1-C3alkoxy-carbonyl-C1-C3alkyl, N-methylamino- carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring. [4] The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein CyA is selected from the group consisting of

[0003] wherein each Rf is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1- C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, oxo, C1-C6alkyl- carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3- alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, or phenyl-C1-C6alkoxy or two Rf are taken together with the carbon atom to which they are attached to form a spiro ring; Rg is hydrogen, C1-C6alkyl, C1-C6haloalkyl, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, carboxy-C1-C6alkyl, N-methylamino-carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl- C1-C6alkyl, heterocyclyl or heterocyclyl-C1-C3alkyl; m is an integer of 0 to 5; and asterisks denote the points of attachment. [5] The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein CyB is C6-C10aryl optionally having at least one substituent selected from the group Q, or heteroaryl optionally having at least one substituent selected from the group Q, and the group Q is halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, or C3-C8cycloalkyl. [6] The compound or a pharmaceutically acceptable salt thereof according to [1], 2] or [4], wherein CyB is selected from the group consisting of

[0004] , wherein each Rh is independently halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfonyl, or C3-C8cycloalkyl; Rj is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; p is an integer of 0 to 5; and asterisks denote the points of attachment. [7] The compound or a pharmaceutically acceptable salt thereof according to [1] or [6], wherein the Formula (Ia) is Formula (Ib) ）.[8] The compound or a pharmaceutically acceptable salt thereof according to [7], wherein Ra, Rb, Rd and Re are hydrogens; and n is 0. [9] The compound or a pharmaceutically acceptable salt thereof according to [8], wherein CyB is phenyl optionally having at least one substituent selected from the group Q.

[0010] The compound or a pharmacologically acceptable salt thereof according to [1], wherein the compound has a structure selected from the group consisting of structures,

[0005]

[0011] A pharmaceutical composition, comprising: the compound or pharmaceutically acceptable salt thereof according to any one of [1] -

[0010] ; and a pharmaceutically acceptable excipient.

[0012] A method of treating an MRGPRX2-mediated disease or disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of [1] -

[0010] .

[0013] The method according to

[0012] , wherein the MRGPRX2-mediated disease or disorder is a pseudo-allergic reaction, an itch-associated condition, a pain-associated condition, or an inflammatory or autoimmune disorder.

[0014] The method according to claim

[0012] , wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic urticaria, (e.g. chronic spontaneous urticaria or chronic inducible urticaria, e.g. cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria or contact urticaria), mastocytosis, atopic dermatitis, rosacea, e.g. papulopustular rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, e.g. chronic pruritus of unknown origin, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis.

[0015] The compound or pharmaceutically acceptable salt thereof according to any one of [1] -

[0010] for use in the treatment of an MRGPRX2-mediated disease or disorder.

[0016] The compound or pharmaceutically acceptable salt for use according to

[0015] , wherein the disease or disorder is selected from the group consisting of chronic urticaria, (e.g. chronic spontaneous urticaria or chronic inducible urticaria, e.g. cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria or contact urticaria), mastocytosis, atopic dermatitis, rosacea, e.g. papulopustar rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, e.g. chronic pruritus of unknown origin, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis.

[0017] Use of the compound or pharmaceutically acceptable salt thereof according to any one of [1] -

[0010] , in the manufacture of a medicament for use in the treatment of an MRGPRX2-mediated disease or disorder.

[0018] The use according to

[0017] , wherein said disease or disorder is chronic urticaria, (e.g. chronic spontaneous urticaria or chronic inducible urticaria, e.g. cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria or contact urticaria), mastocytosis, atopic dermatitis, rosacea, e.g. papulopustular rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug- induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, e.g. chronic pruritus of unknown origin, acute pruritus, prurigo nodularis, osteoarthritis, or pseudo anaphylaxis.

[0019] A compound of Formula (IIa), or a pharmaceutically acceptable salt thereof, wherein X is S, -CRd=CRe-, -CRd=N-, or - N=CRd-; Rd and Re are independently hydrogen, deuterium, halo, CN, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy; Ra is hydrogen, halo, C1-C6alkyl or C1-C6alkoxy; Rb is hydrogen, C1-C6alkyl, hydroxy-C1-C6alkyl, C1-C6alkoxy- C1-C6alkyl, C1-C6alkyl- carbonyl or C1-C6alkoxy-carbonyl; CyC and CyD are independently C6-C10aryl optionally having at least one substituent selected from a group W, heteroaryl optionally having at least one substituent selected from the group W, C3-C8cycloalkyl optionally having at least one substituent selected from the group W, C3-C8cycloalkenyl optionally having at least one substituent selected from the group W, heterocyclyl optionally having at least one substituent selected from the group W, fused heterocyclic ring consisting of 8 to 10 atoms optionally having at least one substituent selected from the group W, where the group W is deuterium, halo, C1-C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl or hydroxy-C1-C3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1- C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, aminocarbonyloxy substituted with at least one C1-C6alkyl , C1-C6alkyl-carbonylamino, hydroxy-C1-C6alkyl- carbonylamino, hydroxy-C1-C6alkyl- carbony-N-methylamino, hydroxy-C1-C6alkyl- N- methylamino-carbonylamino, C3-C8cycloalkyl-carbonylamino, C1-C6alkoxy- carbonylamino, heterocycloxy-carbonylamino, hydroxy heterocyclo-carbonylamino, heteroaryl-carbonylamino, C1-C6alkyl-heteroaryl-carbonylamino, C1-C6alkyl-carbonyl- N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C1-C6alkyl-sulfonylamino, hydroxy-C1-C6alkyl-sulfonylamino, C3-C8cycloalkyl-sulfonylamino, C1-C6alkyl- C3-C8cycloalkyl-sulfonylamino, N,N-dimethylaminosulfonyl amino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, C1-C6alkylsulfinyl- C1-C6alkyl, C1-C6alkylsulfonyl- C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy- carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, C1-C6alkoxy-carbonyl-C1-C6alkoxy, amino- carbonyl-C1-C6alkoxy, C1-C6alkoxy-C1-C6alkoxy, C1-C6alkylsulfonylamino-C1-C6alkoxy, C1-C6alkyl-carbonylamino-C1-C6alkoxy, N,N-dimethylamino-C1-C6alkoxy, N- methylamino-carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl optionally substituted with one or more oxo group, heterocyclyl-C1-C3alkyl, ureido, or a spiro ring, where C3-C8cycloalkyl of C3-C8cycloalky-carbonylamino may be substituted by one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, a C1-C6alkyl, and an aminocarboxyl group, where C1-C6alkoxy of C1-C6alkoxy-carbonylamino may be substituted by one or more substituents selected from a hydroxy group, an amino group, a N-methylamino group, an amino-carbonyl group, a N- methylamino-carbonyl group, and oxo group, where ureido may be substituted by one or more substituents selected from a C1-C6alkyl and a hydroxy-C1-C6alkyl group; and n is 0 or 1. DETAILED DESCRIPTION OF THE EMBODIMENTS The present embodiments are described in more detail below. The terms used herein are described below. Halo The term “halo” as used herein means fluorine, chlorine, bromine or iodine. C1-C6alkyl In a preferred embodiment, the term "C1-C6alkyl" as used herein means a straight-or branched-chain alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1 -methylbutyl, 2 -methylbutyl, 1, 2 -dimethylpropyl, hexyl, and isohexyl. In other embodiments, the term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C1-10alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-7alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-6alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6alkyl"). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (such as unsubstituted C1-6alkyl, e.g., -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6alkyl, e.g., -CF3, Bn). C1-C6haloalkyl In a preferred embodiment, the term “C1-C6haloalkyl” as used herein means a C1-C6alkyl group substituted with 1 to 5 same or different halogen atoms. Examples of the C1-C6haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2,2-difluoroethyl group, a 1,1-difluoroethyl group, a 1,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 1,1,2,2,2-pentafluoroethyl group, a 2,2,2-trichloroethyl group, a 3-fluoropropyl group, a 2- fluoropropyl group, a 1-fluoropropyl group, a 3,3-difluoropropyl group, a 2,2- difluoropropyl group, a 1,1-difluoropropyl group, a 4-fluorobutyl group, a 5-fluoropentyl group and a 6-fluorohexyl group. In a other embodiments, the term "haloalkyl" refers to a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C1-8haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C1-6haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C1-4haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C1-3haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C1-2haloalkyl"). Examples of haloalkyl groups include -CHF2, -CH2F, - CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like. C1-C6alkoxy In a preferred embodiment, the term “C1-C6alkoxy” as used herein means a straight-or branched-chain alkoxy group having 1 to 6 carbon atoms; that is, a C1-C6alkyl -O- group. Examples include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. In other embodiments, the term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C1-8alkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C1-6alkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4alkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C1-3alkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C1-2alkoxy"). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy. Hydroxy C1-C6alkyl In a preferred embodiment, the term “hydroxy- C1-C6alkyl” as used herein means a C1-C6alkyl group substituted with a hydroxyl group. Examples of the C1-C6hydroxyalkyl group include a 2-hydroxyethyl group, a 1-hydroxyethyl group, a 3- hydroxypropyl group, a 2-hydroxypropyl group, a 1-hydroxypropyl group, a 4- hydroxybutyl group, a 3-hydroxybutyl group, a 2-hydroxybutyl group, a 1-hydroxybutyl group, a 5-hydroxypentyl group and a 6-hydroxyhexyl group. In other embodiments, the term "hydroxyalkyl" refers to a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a hydroxyl. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms ("C1-8hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms ("C1-6hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms ("C1-4hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms ("C1-3hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms ("C1-2hydroxyalkyl"). C1-C6alkoxy-C1-C6alkyl The term “C1-C6alkoxy-C1-C6alkyl” as used herein means a straight-or branched-chain alkyl group having 1 to 6 carbon atoms substituted with a straight-or branched-chain alkoxy group having 1 to 6 carbon atoms. C1-C6alkyl-carbonyl The term “C1-C6alkyl-carbonyl” as used herein means a straight- or branched- chain alkylcarbonyl group derived from an aliphatic carboxylic acid having 1 to 6 carbon atoms; that is, a C1-C6alkyl-C(=O)- group. Examples of the C1-C6alkylcarbonyl include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butyl carbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 1- methylbutylcarbonyl, 2 -methylbutylcarbonyl, 1,2-dimethylpropylcarbonyl, hexylcarbonyl, and isohexylcarbonyl . C1-C6alkoxy-carbonyl The term “C1-C6alkoxy-carbonyl” as used herein means a straight- or branched- chain alkoxycarbonyl group having 1 to 6 carbon atoms; that is, a C1-C6alkyl-O-C (=O) - group. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. C1-C6alkylaminosulfonyl The term “C1-C6alkylaminosulfonyl” as used herein means an amino- substituted sulfonyl group containing a straight-or branched- chain alkyl group having 1 to 6 carbon atoms; that is, a C1-C6alkyl-NHSO2- group. Examples include methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylaminosulfonyl, sec-butylaminosulfonyl, and tert-butylaminosulfonyl. Carbocyclyl The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3-14carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C3-10carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C3-7carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C4-6carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C5-6carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10carbocyclyl"). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl. In some preferred embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3-14cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3-10cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-6cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10cycloalkyl"). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl. C3-C8cycloalkyl The term “C3-C8cycloalkyl” as used herein means a monocyclic, saturated cycloalkyl group having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. C6-C10aryl In a preferred embodiment, the term “C6-C10aryl” as used herein means a phenyl group or naphthyl group. In a other embodiments, the term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14aryl"; e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl. Heteroaryl In a preferred embodiment, the term “heteroaryl” as used herein means a 5- membered heteroaromatic ring or 6-membered heteroaromatic ring. The term “5- membered heteroaromatic ring” as used herein means a 5-membered heteroaromatic ring containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. The nitrogen atom(s) in the aromatic ring may be N-oxide. Examples of the 5-membered heteroaromatic ring include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, and thiadiazolyl. The term “6-membered heteroaromatic ring” as used herein means a 6-membered heteroaromatic ring containing 1 to 4 nitrogen atoms. The nitrogen atom(s) in the aromatic ring may be N-oxide. Examples of the 6-membered heteroaromatic ring include pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In other embodiments, the term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments, a heteroaryl group is a 5-12 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-12 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1- 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. Heterocyclyl In a preferred embodiment, the term “heterocyclyl” as used herein means a 5-to 7- membered non-aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom and optionally containing 1 to 3 carbonyls. Examples include unsaturated heterocyclic rings such as pyrrolinyl, imidazolinyl, pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, and dihydropyridyl; and saturated heterocyclic rings such as morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, oxathiolanyl, oxazinanyl, oxooxathiolanyl, dioxooxathiolanyl, oxothiazolidinyl, dioxothiazolidinyl, dithiepanyl, oxathiepanyl, and thiazepanyl. In other embodiments, the term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- 14 membered heterocyclyl. In some embodiments, a heterocyclyl group is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 4-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1- 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofurany1, tetrahydrothiopheny1, dihydrothiopheny1, pyrrolidiny1, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6- dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H- furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7 -tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-1,6- naphthyridinyl, and the like. Fused heterocyclic ring consisting of 9 or 10 atoms The term “fused heterocyclic ring consisting of 9 or 10 atoms” as used herein means a fused aromatic or non-aromatic ring constituted with 9 or 10 atoms of which 1 to 5 are heteroatoms containing 1 to 4 heteroatoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom and optionally containing 1 to 4 double bonds and 1 to 3 carbonyls. Examples of the fused heterocyclic ring consisting of 9 or 10 atoms include 2,3-dihydropyrazolo[5,1-b]oxazolyl, pyrazolo[1,5-a]pyrimidinyl, 1H-imidazo[1,2- b]pyrazolyl, 2H-pyrazolo[4,3-b]pyridinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 1,2,5,6,7,7a-hexahydropyrano[3,2- c]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepinyl, pyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidinyl, 2,4-dihydro-1H-pyrazolo[4,3-b]pyridinyl, and 4,7-dihydropyrazolo[1,5- a]pyrimidinyl. Preferable examples of the fused heterocyclic ring consisting of 9 or 10 atoms include 2,3-dihydropyrazolo[5,1-b]oxazole-7-yl, 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine- 3-yl, and pyrazolo[1,5-a]pyrimidine- 3-yl. Fused heterocyclic ring consisting of 8 to 10 atoms The terms “fused heterocyclic ring consisting of 8 to 10 atoms” as used herein means a fused aromatic or non-aromatic heterocyclic rings constituted with 8 to 10 atoms including from 1 to 5 heteroatoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom and optionally containing 1 to 4 double bonds and / or 1 to 3 carbonyls. The heteroatoms may be shared by the fused rings. Examples of the fused heterocyclic ring consisting of 8-10 atoms include, but are not limited to, 2,3-dihydropyrazolo[5,1- b]oxazolyl, pyrazolo[1,5-a]pyrimidinyl, 1H-imidazo[1,2-b]pyrazolyl, 2H-pyrazolo[4,3- b]pyridinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, 6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazinyl, 1,2,5,6,7,7a-hexahydropyrano[3,2-c]pyrazolyl, 4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepinyl, pyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, 2,4-dihydro-1H- pyrazolo[4,3-b]pyridinyl, and 4,7-dihydropyrazolo[1,5-a]pyrimidinyl. Preferable examples of the fused heterocyclic ring consisting of 8 to 10 atoms include 2,3- dihydropyrazolo[5,1-b]oxazole-7-yl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-yl, and pyrazolo[1,5-a]pyrimidine- 3-yl. C1-C6haloalkoxy In a preferred embodiment, the term “C1-C6haloalkoxy” as used herein means a C 1-C6alkoxy group substituted with 1 to 5 same or different halogen atoms. Examples of the halo C1-C6alkoxy group include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2,2- difluoroethoxy group, a 1,1-difluoroethoxy group, a 1,2-difluoroethoxy group, a 2,2,2- trifluoroethoxy group, a 1,1,2,2,2-pentafluoroethoxy group, a 2,2,2-trichloroethoxy group, a 3-fluoropropoxy group, a 2-fluoropropoxy group, a 1-fluoropropoxy group, a 3,3- difluoropropoxy group, a 2,2-difluoropropoxy group, a 1,1-difluoropropoxy group, a 4- fluorobutoxy group, a 5-fluoropentoxy group and a 6-fluorohexyloxy group. In other embodiments, the term "haloalkoxy" refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C1-8haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C1-6haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C1-3haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C1-2haloalkoxy"). Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy. C2-C6alkenyl In a preferred embodiment, the term "C2-C6alkenyl" as used herein means a straight-or branched-chain alkenyl group having 2 to 6 carbon atoms. Examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, pentenyl, isopentenyl, 1 - methylbutenyl, 2 -methylbutenyl, 1, 2 -dimethylpropenyl, hexenyl, and isohexenyl. In other embodiments, the term "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon- carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-7alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3or ) may be an (E)- or (Z)- double bond. Hydroxy C1-C6alkoxy The terms “hydroxy C1-C6alkoxyl” or “C1-C6hydroxyalkoxy” can be used interchangeably and, as used herein, mean a C1-C6alkoxy group substituted with a hydroxyl group. Examples of the C1-C 6 hydroxyalkoxy group a 2- hydroxyethoxy group, a 1-hydroxyethoxy group, a 3-hydroxypropoxy group, a 2- hydroxypropoxy group, a 1-hydroxypropoxy group, a 4-hydroxybutoxy group, a 3- hydroxybutoxy group, a 2-hydroxybutoxy group, a 1-hydroxybutoxy group, a 5- hydroxypentoxygroup, a 6-hydroxyhexoxy group, 2-hydroxy-2-methylpropoxy group, (3- hydroxybutan-2-yl)oxy group, (1-hydroxy-2-methylpropan-2-yl)oxy group, 1-hydroxy-2- methylpropoxy group, (2-hydroxybutan-2-yl)oxy group, (2-hydroxypropan-2-yl)oxy group, and (1-hydroxypropan-2-yl)oxy group. N,N-dimethylamino-C1-C6 alkoxy The term “N,N-dimethylamino-C1- C6alkoxy” means an alkoxy group having a straight-or branched-carbon chain of from 1-6 carbon atoms substituted with a dimethylamino group. The dimethylamino group may be bonded to a chain carbon or bonded to a terminal carbon. Examples of N,N-dimethylamino-C1- C6alkoxy include, but are not limited to, a dimethylaminomethoxy group, a 2-(dimethylamino)ethoxy group, a 3-(dimethylamino)propoxy group, a 2-(dimethylamino)propoxy group, a 4- (dimethylamino)butoxy group, a 3-(dimethylamino)butoxy group, a 5- (dimethylamino)pentoxy group, a 4-(dimethylamino)pentoxy group, a 3- (dimethylamino)pentoxy group, a 6-(dimethylamino)hexoxy group, a 5- (dimethylamino)hexoxy group, a 5-(dimethylamino)hexoxy group, a 4- (dimethylamino)hexoxy group and a 3-(dimethylamino)hexoxy group. Heterocycloxy The term “heterocycloxy” means an alkoxy group derived from a heterocyclic alcohol. Examples of the heterocyclic ring structure include 5-to 7-membered non- aromatic heterocyclic rings containing 1 to 4 heteroatoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. Examples include but are not limited to oxy heterocycles derived from unsaturated heterocyclic rings such as pyrrolinyl, imidazolinyl, pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, and dihydropyridyl; and saturated heterocyclic rings such as morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, oxathiolanyl, oxazinanyl, oxooxathiolanyl, dioxooxathiolanyl, oxothiazolidinyl, dioxothiazolidinyl, dithiepanyl, oxathiepanyl, and thiazepanyl. Heterocyclo-carbonylamino The term “heterocyclo-carbonylamino” means an amido group substituent bonded through the amido N and having a hetercyclic group bonded to the amidocarbonyl carbon. Examples of the heterocyclic ring structure include 5-to 7-membered non-aromatic heterocyclic rings containing 1 to 4 heteroatoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. Examples include but are not limited to aminocarbonyl heterocycles derived from unsaturated heterocyclic rings such as pyrrolinyl, imidazolinyl, pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, and dihydropyridyl; and saturated heterocyclic rings such as morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, oxathiolanyl, oxazinanyl, oxooxathiolanyl, dioxooxathiolanyl, oxothiazolidinyl, dioxothiazolidinyl, dithiepanyl, oxathiepanyl, and thiazepanyl. C1-C6alkylsulfanyl The term “C1-C6alkylsulfanyl” as used herein means a straight- or branched- chain alkylsulfanyl group having 1 to 6 carbon atoms; that is, a C1-C6alkyl-S- group. Examples include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, and tert-butylsulfanyl C1-C6alkylsulfinyl The term “C1-C6alkylsulfinyl” as used herein means a straight- or branched-chain alkylsulfinyl group having 1 to 6 carbon atoms; that is, a C1-C6alkyl-SO- group. Examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, and tert-butylsulfinyl. C1-C6alkylsulfonyl The term “C1-C6alkylsulfonyl” as used herein means a straight- or branched- chain alkylsulfonyl group having 1 to 6 carbon atoms; that is, a C1-C6alkyl-SO2- group. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. The term “C1-C6alkyl-carbonylamino” as used herein means amino substituted with C1-C6alkyl-carbonyl group. The term “C1-C6alkoxy-carbonylamino” as used herein means amino substituted with C1-C6alkoxy-carbonyl group. The term “C1-C6alkyl-carbonyl-N-methylamino” as used herein means amino substituted with C1-C6alkyl-carbonyl group and methyl. The term “C1-C6alkoxy-carbonyl-N-methylamino” as used herein means amino substituted with C1-C6alkoxy-carbonyl group and methyl. The term “C3-C8cycloalkyl-C1-C3alkoxy” as used herein means a C1-C3alkoxy group substituted with a C3-C8cycloalkyl group. The term “C1-C3alkoxy-C1-C3alkyl” as used herein means a C1- C3alkyl group substituted with a C1-C3alkoxy group. The term “C1-C3alkoxy- C1-C3alkoxy-C1-C3alkyl” as used herein means a C1-C3 alkoxy-C1-C3alkyl group substituted with a C1-C3alkoxy group. The term “C1-C3alkoxy-carbonyl-C1-C3alkyl” as used herein means a C1- C3alkyl group substituted with a C1-C3alkoxy-carbonyl group. The term “phenyl-C1-C3alkoxy” as used herein means a C1- C3alkoxy group substituted with phenyl. The term “heterocyclyl-C1-C3alkyl” as used herein means a C1-C3alkyl substituted with a heterocyclyl. Spiro ring In a preferred embodiment, the term “spiro ring “as used herein means a monocyclic, saturated cyclic group having 3 to 8 atoms optionally containing an oxygen atom and / or nitrogen atom. In other embodiments, a spirocyclic carbocyclyl (e.g., cycloalkyl) or heterocyclyl refers to a bicyclic or polycyclic ring system where two or more rings are connected through a single atom. Pharmacologically acceptable salt The term “pharmacologically acceptable salt” means a salt of a compound with a pharmaceutically acceptable non-toxic base or acid (e.g., with an inorganic or organic base or an inorganic or organic acid). Examples of salts derived from a pharmaceutically acceptable non-toxic base include those with an inorganic base such as sodium salts, potassium salts, calcium salts and magnesium salts and those with an organic base such as piperidine, morpholine, pyrrolidine, arginine, and lysine. Examples of salts derived from a pharmaceutically acceptable non-toxic acid includes acid salts of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid and salts formed by the combination of a compound with an organic acid such as formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid. MRGPRX2 antagonist “MRGPRX2 antagonist” used in the present embodiment has a function of inhibiting the degranulation of human mast cells (MCs) induced by basic secretagogues and pseudoallergic drug. MRGPRX2 antagonists are expected as therapeutic agents for inflammatory diseases including IgE-independent allergic reactions. Compound According to one aspect of the present disclosure, a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof. In Formula (Ia), X is S, -CRd=CRe-, -CRd=N-, or -N=CRd-; Rd and Re are independently hydrogen, deuterium, halo, CN, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy; Ra is hydrogen, halo, C1-C6alkyl or C1-C6alkoxy; Rb is hydrogen, C1-C6alkyl, hydroxy-C1-C6alkyl, C1-C6alkoxy- C1-C6alkyl, C1-C6alkyl- carbonyl or C1-C6alkoxy-carbonyl; CyA and CyB are independently C6-C10aryl optionally having at least one substituent selected from a group Q, heteroaryl optionally having at least one substituent selected from the group Q, C3-C8cycloalkyl optionally having at least one substituent selected from the group Q, C3-C8cycloalkenyl optionally having at least one substituent selected from the group Q, heterocyclyl optionally having at least one substituent selected from the group Q, fused heterocyclic ring consisting of 9 or 10 atoms optionally having at least one substituent selected from the group Q, where the group Q is deuterium, halo, C1-C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, NO2, CN, CONH2, ,aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, N-methylamino-carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring; and n is 0 or 1. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is S. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CRd=CRe-. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CRd=N-. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -N=CRd-. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CH=CH-. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is deuterium. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is halo. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is CN. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is C1-C6alkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is C1-C6haloalkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is C1-C6alkoxy. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Re is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Re is deuterium. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Re is halo. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Re is CN. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Re is C1-C6alkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Re is C1-C6haloalkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Re is C1-C6alkoxy. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is hydrogen; and Re is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Ra is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Ra is halo. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Ra is C1-C6alkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Ra is C1-C6alkoxy. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rb is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rb is C1-C6alkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rb is hydroxy-C1-C6alkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rb is C1-C6alkoxy- C1-C6alkyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rb is C1-C6alkyl-carbonyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rb is C1-C6alkoxy-carbonyl. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Ra is hydrogen; and Rb is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, Rd is hydrogen; Re is hydrogen; Ra is hydrogen; and Rb is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CH=CH-; Ra is hydrogen; and Rb is hydrogen. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CH=CH-; Ra is hydrogen; Rb is hydrogen; and n is 0. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is heteroaryl optionally having at least one substituent selected from the group Q, or fused heterocyclic ring consisting of 9 or 10 atoms optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is heteroaryl optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is selected from the group consisting of

[0006] wherein each Rf is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6 alkyl, amino optionally having at least one C1-3 alkyl, NO2, CN, CONH2, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy- carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N- methylamino, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, or phenyl-C1-C6alkoxy or two Rf are taken together with the carbon atom to which they are attached to form a spiro ring; Rg is hydrogen, C1-C6alkyl, C1-C6haloalkyl, carboxy-C1- C6alkyl, amino optionally having at least one C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, C1- C3alkoxy-carbonyl-C1- C3alkyl, carboxy-C1- C6alkyl, N-methylamino-carbonyl-C1- C6alkyl, N,N-dimethylaminocarbonyl-C1- C6alkyl, heterocyclyl or heterocyclyl-C1- C3alkyl; m is an integer of 0 to 5; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is selected from the group consisting of wherein each Rf is independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, hydroxyl, amino optionally having at least one C1- 3 alkyl, or C1- C6alkyl-carbonylamino; Rg is hydrogen or C1- C6alky; m is an integer of 0 to 5; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rf is independently hydrogen, C1- C6alkyl or C1- C6haloalkyl; Rg is C1- C6alky; m is an integer of 0 to 2; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rf is C1- C6haloalkyl; Rg is methyl; m is 1; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is fused heterocyclic ring consisting of 9 or 10 atoms optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is fused non-aromatic heterocyclyl-aryl optionally having at least one substituent selected from the group Q, fused non-aromatic heterocyclyl-heteroaryl optionally having at least one substituent selected from the group Q, fused arylheteroaryl optionally having at least one substituent selected from the group Q, or fused heteroarylheteroaryl optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is fused non-aromatic heterocyclyl-heteroaryl optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is selected from the group consisting of

[0007] wherein each Rf is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6 alkyl, amino optionally having at least one C1-3 alkyl, NO2, CN, CONH2, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy- carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N- methylamino, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, or phenyl-C1-C6alkoxy or two Rf are taken together with the carbon atom to which they are attached to form a spiro ring; Rg is hydrogen, C1-C6alkyl, C1-C6haloalkyl, carboxy-C1- C6alkyl, amino optionally having at least one C1- C3alkyl, C1- C3alkoxy-C1- C3alkyl, C1- C3alkoxy-carbonyl-C1- C3alkyl, carboxy-C1- C6alkyl, N-methylamino-carbonyl-C1- C6alkyl, N,N-dimethylaminocarbonyl-C1- C6alkyl, heterocyclyl or heterocyclyl-C1- C3alkyl; m is an integer of 0 to 5; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rf is independently hydrogen, C1- C6alkyl, C1- C6haloalkyl, hydroxyl, amino optionally having at least one C1- 3 alkyl, or C1- C6alkyl-carbonylamino; m is an integer of 0 to 3; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rf is independently hydrogen, C1- C6alkyl, C1- C6haloalkyl, hydroxyl, amino optionally having at least one C1- 3 alkyl, or C1- C6alkyl-carbonylamino; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rl is C1- C6alkyl or C1- C6haloalkyl; Rk is hydrogen, hydroxyl, amino or C1- C6alkyl-carbonylamino; and asterisks denote the points of attachment.In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is C6-C10 aryl optionally having at least one substituent selected from a group Q or heteroaryl optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is C6-C10 aryl optionally having at least one substituent selected from a group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is phenyl optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is wherein each Rh is independently halo, C1- C6alkyl, C1- C6haloalkyl, C1- C6alkoxy, C1- C6haloalkoxy, or CN; p is an integer of 0 to 2; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is wherein Rn is CN; Rm is C1- C6alkoxy; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is heteroaryl optionally having at least one substituent selected from the group Q. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is wherein each Rh is independently halo, C1- C6alkyl, C1- C6haloalkyl, C1- C6alkoxy, C1- C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1- C6hydroxyalkyl, amino optionally having at least one C1- C3alkyl, CN, oxo, C1- C6alkylsulfonyl, or C3-C8cycloalkyl; Rj is hydrogen or C1- C6alkyl; p is an integer of 0 to 2; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is wherein each Rh is independently C1- C6haloalkoxy or CN; Rj is hydrogen or C1- C6alkyl; p is an integer of 0 to 1; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyB is wherein Rh is C1- C6haloalkoxy; Rj is hydrogen or methyl; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rf is C1- C6haloalkyl; Rg is methyl; m is 1; CyB is wherein each Rh is independently halo, C1- C6alkyl, C1- C6haloalkyl, C1- C6alkoxy, C1- C6haloalkoxy or CN; p is an integer of 0 to 2:and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rf is C1- C6haloalkyl; Rg is methyl; m is 1; CyB is wherein Rn is CN; Rm is C1- C6alkoxy: and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CH=CH-; Ra is hydrogen; Rb is hydrogen; n is 0; CyA is wherein each Rf is C1- C6haloalkyl; Rg is methyl; m is 1; CyB is wherein Rn is CN; Rm is C1- C6alkoxy; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein each Rl is C1- C6alkyl or C1- C6haloalkyl; Rk is hydrogen, hydroxyl, amino or C1- C6alkyl-carbonylamino; CyB is wherein Rn is CN; Rm is C1- C6alkoxy: and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CH=CH-; Ra is hydrogen; Rb is hydrogen; n is 0; CyA is wherein each Rl is C1- C6alkyl or C1- C6haloalkyl; Rk is hydrogen, hydroxyl, amino or C1- C6alkyl-carbonylamino; CyB is wherein Rn is CN; Rm is C1- C6alkoxy: and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, CyA is wherein Rl is C1- C6alkyl or C1- C6haloalkyl; Rk is hydrogen, hydroxyl, amino or C1- C6alkyl-carbonylamino; CyB is wherein Rj is hydrogen or C1- C6alkyl; Rh is independently halo, C1- C6alkyl, C1- C6haloalkyl, C1- C6alkoxy, C1- C6haloalkoxy or CN: p is an integer of 0 to 2; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CH=CH-; Ra is hydrogen; Rb is hydrogen; n is 0; CyA is wherein Rl is C1- C6alkyl or C1- C6haloalkyl; Rk is hydrogen, hydroxyl, amino or C1- C6alkyl-carbonylamino; CyB is wherein Rj is hydrogen or C1- C6alkyl; Rh is independently C1- C6haloalkoxy or CN; p is an integer of 0 to 2; and asterisks denote the points of attachment. In an embodiment of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, X is -CH=CH-; Ra is hydrogen; Rb is hydrogen; n is 0; CyA is wherein Rl is C1- C6alkyl or C1- C6haloalkyl; Rk is hydrogen, hydroxyl, amino or C1- C6alkyl-carbonylamino; CyB is wherein Rj is hydrogen or mehyl; Rh is C1- C6haloalkoxy; and asterisks denote the points of attachment. In some aspects, the present disclosure relates to one of the following embodiments: Embodiment 1. A compound represented by structural formula (I*): or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; Rb is selected from H, C1-C6alkyl, and C(=O)O(C1-C6alkyl), wherein each C1-C6alkyl is optionally substituted with one or more substituents independently selected from group Q; CyA is selected from one of the following moieties: , CyB is selected from 5- to 12-membered heteroaryl and C6-C12aryl, wherein the 5- to 12- membered heteroaryl or C6-C12aryl is optionally substituted with one or more substituents independently selected from group Q; Ra is selected from H, deuterium, F, Cl, Br, CN, NO2, C1-C6alkyl, and C1-C6alkoxy, wherein each C1-C6alkyl or C1-C6alkoxy is optionally substituted with one or more substituents independently selected from group Q; R5and R6are each independently selected from deuterium, F, Cl, Br, OH, CN, NO2, NR10aR10b, C(=O)NR11aR11b, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12- membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2- C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from group Q, or R5and R6together with the atoms to which they are attached form C4-C12carbocyclyl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein the C4-C12carbocyclyl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from group Q; n is 0, 1, 2, 3, or 4; R7and R8together with the atoms to which they are attached form 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl is optionally substituted with one or more substituents independently selected from group Q; R7is selected from H, deuterium, F, Cl, Br, OH, CN, NO2, NR10cR10d, C(=O)NR11cR11d, C1- C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; R8is selected from H and C1-6alkyl optionally substituted with one or more substituents independently selected from a group Q; R9is selected from C1-C6alkyl, F, Cl, Br, OH, CN, NO2, NR10eR10f, C(=O)NR11eR11f, C1-C6 alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12- membered heteroaryl, and 4- to 12-membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; and R10a, R10b, R10c, R10d, R10e, R10f, R11a, R11b, R11c, R11d, R11e, and R11fare each independently selected from H and C1-C6alkyl optionally substituted with one or more substituents independently selected from a group Q, or one or more of the pairs of variables selected from R10aand R10b, R10cand R10d, R10eand R10f, R11aand R11b, R11cand R11d, and R11eand R11f, together with the nitrogen to which they are attached, form 5- to 12-membered heteroaryl or 4- to 12-membered heterocyclyl, wherein each 5- to 12-membered heteroaryl or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; wherein each of the one or more substituents of group Q is independently selected from deuterium, F, Cl, Br, OH, NH2, NH(C=O)(C1-C6alkyl), NH(C=O)(C3-C8cycloalkyl), NH(C=O)(O-C1-C6alkyl), C1-C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1- C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy- carbonyl-N-methylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, C1-C6alkylsulfinyl- C1-C6alkyl, C1-C6alkylsulfonyl- C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl- C1-C3alkyl, phenyl-C1-C6alkoxy, N-methylamino-carbonyl-C1-C6alkyl, N,N- dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring. Embodiment 2. The compound of embodiment 1, wherein Ra is selected from H, F, Cl, Br, CN, and NO2. Embodiment 3. The compound of embodiment 1, wherein Ra is C1-C6alkyl. Embodiment 4. The compound of embodiment 1, wherein Ra is C1-C6alkoxy. Embodiment 5. The compound of embodiment 1, wherein the compound is represented by structural formula (Ia*): or a pharmaceutically acceptable salt thereof. Embodiment 6. The compound of any one of embodiments 1-5, wherein Rb is C1-C3alkyl. Embodiment 7. The compound of embodiment 1, wherein the compound is represented by structural formula (Ib*): or a pharmaceutically acceptable salt thereof. Embodiment 8. The compound of any one of embodiments 1-7, wherein CyB is C6-C12aryl. Embodiment 9. The compound of embodiment 8, wherein CyB is phenyl optionally substituted with one or more substituents independently selected from group Q. Embodiment 10. The compound of any one of embodiments 1-7, wherein CyB is , wherein V is CH or N; Rv1is selected from CN, F, Cl, Br, C1-C3haloalkyl, and C1-C3haloalkoxy; and Rv2is selected from H, F, Cl, Br, NH2, C1-C3alkyl, C1-C3alkoxy, and C1-C3deteuroalkoxy. Embodiment 11. The compound of embodiment 10, wherein V is CH. Embodiment 12. The compound of embodiment 10, wherein V is N. Embodiment 13. The compound of any one of embodiments 10-12, wherein Rv1is selected from CN, F, and OCHF2. Embodiment 14. The compound of embodiment 13, wherein Rv1is OCHF2. Embodiment 15. The compound of embodiment 13, wherein Rv1is CN. Embodiment 16. The compound of any one of embodiments 10-15, wherein Rv2is H. Embodiment 17. The compound of any one of embodiments 10-15, wherein Rv2is OCH3. Embodiment 18. The compound of any one of embodiments 10-15, wherein Rv2is OCD3. Embodiment 19. The compound of any one of embodiments 1-7, wherein CyB is 5- to 12- membered heteroaryl. Embodiment 20. The compound of embodiment 19, wherein CyB is 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from group Q. Embodiment 21. The compound of embodiment 20, wherein CyB is 5-membered heteroaryl. Embodiment 22. The compound of embodiment 20, wherein CyB is selected from the following moieties: , , ,and ,wherein each of the listed moieties, as valence permits, is optionally substituted with one or more substituents independently selected from group Q.Embodiment 23. The compound of embodiment 22, wherein .wherein RN1is selected from H and C1-C3alkyl; and RN2is selected from CN and C1-C3haloalkoxy. Embodiment 24. The compound of embodiment 23, wherein the compound is represented by structural formula (Ic*): or a pharmaceutically acceptable salt thereof. Embodiment 25. The compound of embodiment 23 or 24, wherein RN1is C1-C3alkyl. Embodiment 26. The compound of embodiment 25, wherein RN1is methyl. Embodiment 27. The compound of any one of embodiments 23-26, wherein RN2is CN. Embodiment 28. The compound of any one of embodiments 23-26, wherein RN2is C1-C3haloalkoxy. Embodiment 29. The compound of embodiment 28, wherein RN2is OCHF2. Embodiment 30. The compound of embodiment 1, wherein the compound is represented by structural formula (Id*): or a pharmaceutically acceptable salt thereof. Embodiment 31. The compound of any one of embodiments 1- 30, wherein the compound is represented by structural formula (Ie*): or a pharmaceutically acceptable salt thereof. Embodiment 32. The compound of embodiment 31, wherein the compound is represented by structural formula (If*): or a pharmaceutically acceptable salt thereof. Embodiment 33. The compound of any one of embodiments 1- 30, wherein CyA is selected .Embodiment 34. The compound of any one of embodiments 31- 33, wherein R5is selected from F, OH, C1-C3alkoxy, and C1-C3haloalkyl, wherein the C1-C3alkyl and C1-C3haloalkyl optionally substituted with one or more substituents independently selected from group Q. Embodiment 35. The compound of any one of embodiments 31- 34, wherein R5is selected from F, deuterium, C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl. Embodiment 36. The compound of any one of embodiments 31- 35, wherein R6is selected from deuterium and F. Embodiment 37. The compound of embodiment 31 or 32, wherein R5and R6together with the atoms to which they are attached form 5- to 6-membered heteroaryl. Embodiment 38. The compound of any one of embodiments 31- 35, wherein n is 0. Embodiment 39. The compound of any one of embodiments 1- 30, wherein CyA is selected Embodiment 40. The compound of any one of embodiments 1- 30, wherein the compound is represented by structural formula (Ig*): or a pharmaceutically acceptable salt thereof. Embodiment 41. The compound of embodiment 1, wherein the compound is represented by structural formula (Ih*): (Ih*), or a pharmaceutically acceptable salt thereof. Embodiment 42. The compound of any one of embodiments 39-41, wherein R9is selected from F, Cl, Br, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy. Embodiment 43. The compound of embodiment 42, wherein R9is selected from C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl. Embodiment 44. The compound of embodiment 43, wherein R9is C1-C3haloalkyl. Embodiment 45. The compound of embodiment 44, wherein R9is selected from CH2F, CHF2, and CF3. Embodiment 46. The compound of embodiment 45, wherein R9is CHF2. Embodiment 47. The compound of embodiment 43, wherein R9is C1-C3alkyl. Embodiment 48. The compound of embodiment 47, wherein R9is ethyl. Embodiment 49. The compound of any one of embodiments 39-48, wherein R8is H. Embodiment 50. The compound of any one of embodiments 39-48, wherein R8is C1-C3alkyl. Embodiment 51. The compound of any one of embodiments 39-50, wherein R7is selected from H, F, Cl, Br, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C6haloalkoxy. Embodiment 52. The compound of any one of embodiments 39-50, wherein R7is H. Embodiment 53. The compound of any one of embodiments 39-50, wherein R7is selected from C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl. Embodiment 54. The compound of any one of embodiments 39-48, wherein R7and R8together with the atoms to which they are attached form 5- to 12-membered heteroaryl. Embodiment 55. The compound of embodiment 54, wherein R7and R8together with the atoms to which they are attached form 5- to 6-membered heteroaryl optionally substituted, as valence permits, with one or more substituents independently selected from group Q. Embodiment 56. The compound of any one of embodiments 39-48, wherein R7and R8together with the atoms to which they are attached form 4- to 12-membered heterocyclyl. Embodiment 57. The compound of any one of embodiments 38-44, wherein R7and R8together with the atoms to which they are attached form 5- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from group Q. Embodiment 58. The compound of any one of embodiments 1- 30, wherein the compound is represented by structural formula (Ii*): or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3; and Ro1and Ro2are each independently selected from H, OH, F, Cl, Br, C1-C3alkyl, C1-C3alkoxy, NRx1Rx2, NRx3C(=O)Rx5, and NRx6C(=O)ORx7, wherein Rx1, Rx2, Rx3, Rx5, Rx6, and Rx7is each independently selected from H, C1-3alkyl, and C3-C6cycloalkyl, and wherein each C1-C3alkyl, C1-C3alkoxy, or C3-C6cycloalkyl is substituted with one or more substituents independently selected from group Q. Embodiment 59. The compound of embodiment 58, wherein the compound is represented by structural formula (Ij*): or a pharmaceutically acceptable salt thereof, wherein k is 1 or 2; R9is selected from C1-C3alkyl and C1-C3haloalkyl. RN2is selected from OCHF2and CN; and Ro1and Ro2are each independently selected from H, OH, F, Cl, Br, C1-C3alkyl, C1-C3alkoxy, NRx1Rx2, NRx3C(=O)Rx5, and NRx6C(=O)ORx7, wherein Rx1, Rx2, Rx3, Rx5, Rx6, and Rx7is each independently selected from H, C1-C3alkyl, and C3- C6cycloalkyl, and wherein each C1-C3alkyl, C1-C3alkoxy, or C3-C6cycloalkyl is substituted with one or more substituents independently selected from group Q. Embodiment 60. The compound of embodiment 59, wherein the compound is represented by structural formula (Ik*): or a pharmaceutically acceptable salt thereof, wherein Ro1is selected from H and C1-C2alkyl; and Ro2is selected from OH, F, NHC(=O)O(C1-C2alkyl), NHC(=O)O(C3-C6cycloalkyl), C1-C3alkoxy, and -O(C1-C3hydroxyalkyl). Embodiment 61. The compound of embodiment 59 or 60, wherein RN2is OCHF2. Embodiment 62. The compound of embodiment 69 or 60, wherein RN2is CN. Embodiment 63. The compound of any one of embodiments 59-62, wherein Ro1is H. Embodiment 64. The compound of any one of embodiments 59-62, wherein Ro1is methyl. Embodiment 65. The compound of any one of embodiments 59-63, wherein Ro1and Ro2are each H. Embodiment 66. The compound of embodiment any one of embodiments 54-57, wherein Ro2is OH. Embodiment 67. The compound of any one of embodiments 59-64, wherein Ro2is F. Embodiment 68. The compound of any one of embodiments 59-64, wherein Ro2is methoxy. Embodiment 69. The compound of any one of embodiments 59-64, wherein Ro2is - OCH2CH2OH. Embodiment 70. The compound of any one of embodiments 59-64, wherein Ro2is - OCH2C(Me)2OH. Embodiment 71. The compound of any one of embodiments 59-64, wherein Ro2is NHC(=O)OCH3. Embodiment 72. The compound of any one of embodiments 59-64, wherein Ro2is NHC(=O)O(C3cycloalkyl). Embodiment 73. The compound of any one of embodiments 58-72, wherein R9is CHF2. Embodiment 74. The compound of any one of embodiments 58-72, wherein R9is ethyl. Embodiment 75. The compound of embodiment 1, wherein the compound is selected from

[0008] Embodiment 76. The compound of embodiment 1, wherein the compound is Embodiment 77. The compound of embodiment 1, wherein the compound is pharmaceutically acceptable salt thereof. Embodiment 78. The compound of embodiment 1, wherein the compound is or a pharmaceutically acceptable salt thereof. Embodiment 79. The compound of embodiment 1, wherein the compound is pharmaceutically acceptable salt thereof. Embodiment 80. The compound of embodiment 1, wherein the compound is Embodiment 81. The compound of embodiment 1, wherein the compound is pharmaceutically acceptable salt thereof. Embodiment 82. The compound of embodiment 1, wherein the compound is or a pharmaceutically acceptable salt thereof. Embodiment 83. The compound of embodiment 1, wherein the compound is Embodiment 84. The compound of embodiment 1, wherein the compound is Embodiment 85. The compound of embodiment 1, wherein the compound is pharmaceutically acceptable salt thereof. Embodiment 86. The compound of embodiment 1, wherein the compound is pharmaceutically acceptable salt thereof. Embodiment 87. The compound of embodiment 1, wherein the compound is pharmaceutically acceptable salt thereof. Embodiment 88. The compound of embodiment 1, wherein the compound is pharmaceutically acceptable salt thereof. Embodiment 89. The compound of embodiment 1, wherein the compound is , or a pharmaceutically acceptable salt thereof. Embodiment 90. A pharmaceutical composition, comprising a compound of any one of embodiments 1-89 and a pharmaceutically acceptable carrier. Embodiment 91. The pharmaceutical composition of embodiment 90, wherein the pharmaceutical composition is formulated for the treatment of MRGPRX2-mediated disease or disorder. Embodiment 92. The pharmaceutical composition of embodiment 91, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis. Embodiment 93. The pharmaceutical composition of embodiment 92, wherein the MRGPRX2-mediated disease or disorder is chronic spontaneous urticaria or chronic inducible urticaria. Embodiment 94. The pharmaceutical composition of embodiment 93, wherein the chronic inducible urticaria is cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria. Embodiment 95. The pharmaceutical composition of embodiment 92, wherein the chronic pruritus is chronic pruritus of unknown origin. Embodiment 96. The pharmaceutical composition of embodiment 92, wherein the rosacea is papulopustular rosacea. Embodiment 97. A method of treating an MRGPRX2-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-89 or a pharmaceutically acceptable composition of embodiment 90. Embodiment 98. The method of embodiment 96, wherein the MRGPRX2- mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis. Embodiment 99. The method of embodiment 98, wherein the MRGPRX2- mediated disease or disorder is chronic spontaneous urticaria or chronic inducible urticaria. Embodiment 100. The method of embodiment 99, wherein the chronic inducible urticaria is cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria. Embodiment 101. The method of embodiment 98, wherein the chronic pruritus is chronic pruritus of unknown origin. Embodiment 102. The method of embodiment 98, wherein the rosacea is papulopustular rosacea. Embodiment 103. A compound of any one of embodiments 1-89 or a pharmaceutical composition of embodiment 90 for use in the treatment of an MRGPRX2- mediated disease or disorder. Embodiment 104. The compound of embodiment 103, wherein the MRGPRX2- mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis. Embodiment 105. The compound of embodiment 104, wherein the MRGPRX2- mediated disease or disorder is chronic spontaneous urticaria or chronic inducible urticaria. Embodiment 106. The compound of embodiment 105, wherein the chronic inducible urticaria is cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria. Embodiment 107. The compound of embodiment 104, wherein the chronic pruritus is chronic pruritus of unknown origin. Embodiment 108. The compound of embodiment 104, wherein the rosacea is papulopustular rosacea. Embodiment 109. Use of a compound of any one of embodiments 1-89 or a pharmaceutical composition of embodiment 90 in the manufacture of a medicament for use in the treatment of an MRGPRX2-mediated disease or disorder. Embodiment 110. The use of embodiment 109, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis. Embodiment 111. The use of embodiment 110, wherein the MRGPRX2-mediated disease or disorder is chronic spontaneous urticaria or chronic inducible urticaria. Embodiment 112. The use of embodiment 111, wherein the chronic inducible urticaria is cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria. Embodiment 113. The use of embodiment 110, wherein the chronic pruritus is chronic pruritus of unknown origin. Embodiment 114. The compound of embodiment 110, wherein the rosacea is papulopustular rosacea. Embodiment 115. A compound of Formula (IIa), or a pharmaceutically acceptable salt thereof, wherein X is S, -CRd=CRe-, -CRd=N-, or -N=CRd-; Rd and Re are independently hydrogen, deuterium, halo, CN, C1-C6alkyl, C1-C6haloalkyl or C1-C6 alkoxy; Ra is hydrogen, halo, C1-C6alkyl or C1-C6alkoxy; Rb is hydrogen, C1-C6alkyl, hydroxy-C1-C6alkyl, C1-C6alkoxy- C1-C6alkyl, C1-C6alkyl-carbonyl or C1-C6alkoxy- carbonyl; CyC and CyD are independently C6-C10aryl optionally having at least one substituent selected from a group W, heteroaryl optionally having at least one substituent selected from the group W, C3-C8cycloalkyl optionally having at least one substituent selected from the group W, C3-C8cycloalkenyl optionally having at least one substituent selected from the group W, heterocyclyl optionally having at least one substituent selected from the group W, fused heterocyclic ring consisting of 8 to 10 atoms optionally having at least one substituent selected from the group W, where the group W is deuterium, halo, C1- C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl or hydroxy-C1-C3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, aminocarbonyloxy substituted with at least one C1-C6alkyl , C1-C6alkyl-carbonylamino, hydroxy-C1-C6alkyl-carbonylamino, hydroxy-C1-C6alkyl- carbony- N-methylamino, hydroxy-C1-C6alkyl- N-methylamino-carbonylamino, C3-C8cycloalkyl- carbonylamino, C1-C6alkoxy-carbonylamino, heterocycloxy-carbonylamino, hydroxy heterocyclo-carbonylamino, heteroaryl-carbonylamino, C1-C6alkyl-heteroaryl- carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N- methylamino, C1-C6alkyl-sulfonylamino, hydroxy-C1-C6alkyl-sulfonylamino, C3-C8cycloalkyl-sulfonylamino, C1-C6alkyl- C3-C8cycloalkyl-sulfonylamino, N,N- dimethylaminosulfonyl amino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, C1-C6alkylsulfinyl- C1-C6alkyl, C1-C6alkylsulfonyl- C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3 alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, C1-C6alkoxy-carbonyl-C1-C6alkoxy, amino-carbonyl-C1-C6alkoxy, C1-C6alkoxy-C1-C6alkoxy, C1-C6alkylsulfonylamino-C1-C6alkoxy, C1-C6alkyl- carbonylamino-C1-C6alkoxy, N,N-dimethylamino-C1-C6alkoxy, N-methylamino- carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl optionally substituted with one or more oxo group, heterocyclyl-C1-C3alkyl, ureido, or a spiro ring, where C3-C8cycloalkyl of C3-C8cycloalky-carbonylamino may be substituted by one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, a C1-C6alkyl, and an aminocarboxyl group, where C1-C6alkoxy of C1-C6alkoxy-carbonylamino may be substituted by one or more substituents selected from a hydroxy group, an amino group, a N-methylamino group, an amino-carbonyl group, a N-methylamino-carbonyl group, and oxo group, where ureido may be substituted by one or more substituents selected from a C1-C6alkyl and a hydroxy-C1-C6alkyl group; and n is 0 or 1. Embodiment 116. . The compound or a pharmaceutically acceptable salt thereof according to embodiment 115, wherein the Formula (IIa) is selected from the group consisting of Formulas (IIb), (IIc), (IId) and (IIe), ） ）

[0009] Embodiment 117. The compound or a pharmaceutically acceptable salt thereof according to embodiment 115 or 116, wherein CyC is fused non-aromatic heterocyclyl- aryl optionally having at least one substituent selected from the group W, fused non- aromatic heterocyclyl-heteroaryl optionally having at least one substituent selected from the group W, fused arylheteroaryl optionally having at least one substituent selected from the group W, or fused heteroarylheteroaryl optionally having at least one substituent selected from the group W, wherein the group W is halo, C3-C8cycloalkyl-carbonylamino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N- methylamino, C3-C8cyloalkyl, C3-C8cyloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, C1-C3alkoxy-carbonyl-C1-C3alkyl, N-methylamino-carbonyl-C1-C6alkyl, N,N- dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring. Embodiment 118. The compound or a pharmaceutically acceptable salt thereof according to embodiment 115 or 116, wherein CyC is selected from the group consisting

[0010] wherein each Rf is independently hydrogen, halo, C3-C8cycloalkyl-carbonylamino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1- C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl- carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, or phenyl-C1-C6alkoxy or two Rf are taken together with the carbon atom to which they are attached to form a spiro ring; Rg is hydrogen, C1-C6alkyl, C1-C6haloalkyl, carboxy- C1-C6alkyl, amino optionally having at least one C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, C1- C3alkoxy-carbonyl-C1-C3alkyl, carboxy-C1-C6alkyl, N-methylamino-carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl or heterocyclyl-C1-C3alkyl; m is an integer of 0 to 5; and asterisks denote the points of attachment. Embodiment 119. The compound or a pharmaceutically acceptable salt thereof according to embodiment 115 or 116, wherein CyD is C6-C10aryl optionally having at least one substituent selected from the group W, or heteroaryl optionally having at least one substituent selected from the group W, and the group W is halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkoxy-carbonylamino, C1-C6hydroxyalkoxy, C3-C8cycloalkyl-carbonylamino,or C3-C8cycloalkyl. Embodiment 120. The compound or a pharmaceutically acceptable salt thereof according to embodiment 115, 116 or 118, wherein CyD is selected from the group consisting of

[0011] , wherein each Rh is independently halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfonyl, or C3-C8cycloalkyl; Rj is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; p is an integer of 0 to 5; and asterisks denote the points of attachment. Embodiment 121. The compound or a pharmaceutically acceptable salt thereof according to embodiment 115 or 120, wherein the Formula (IIa) is Formula (IIb) ）. Embodiment 122. The compound or a pharmaceutically acceptable salt thereof according to embodiment 121, wherein Ra, Rb, Rd and Re are hydrogens; and n is 0. Embodiment 123. The compound or a pharmaceutically acceptable salt thereof according to embodiment 122, wherein CyD is phenyl optionally having at least one substituent selected from the group W, pyridyl optionally having at least one substituent selected from the group W, or pyrazolyl optionally having at least one substituent selected from the group W. (1) General Procedure 1 Step 1-1 This step is a step of protecting 1H-N of the 7-azaindole compound (1) to produce the compound (2) by the reaction with an amine protecting agent in a solvent in the presence of a base. The amine protecting reagents used may include di-tert-butyl dicarbonate (Boc2O), 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl), fluorenlmethyloxycarbonyl chloride (Fmoc-Cl), benzyl chloroformate (Cbz-Cl), benzyl chloride (BnCl) and the like. The base used may include triethylamine (TEA), N,N- diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), sodium hydride (NaH) and the like. The amount of the amine protecting agent used is about 1.1 to 1.5 molar equivalents with respect to 1 mole of the compound (1). The amount of the base used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (1). The reaction can be usually performed at room temperature in the solvent such as DMF, THF and the like. The reaction time varies depending on the starting materials, the amine protecting agent, the base and the solvent used. Step 1-2 This step is a step of reacting the compound (2) with a pinacol boronic ester as compound (3) or a boronic acid as compound (4) to produce the compound (5) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II)-DCM adduct (Pd(dppf)Cl2-DCM), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) with 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (XPhos), tetrakis(triphenylphosphine) palladium (0) (Pd(PPh3)4) and the like. Examples of base may include cesium carbonate (Cs2CO3), potassium carbonate (K2CO3) and the like. The amount of compound (3) or (4) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (2). The reaction can be usually performed at 70 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 1- 3 This step is a step of bromination at 2-position of 7-azaindole (5) to produce the compound (6) using a brominating agent such as N-bromosuccinimide (NBS) and / or bromine (Br2). The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of the brominating agent used is usually about 1 to 5 molar equivalents with respect to 1 mole of the compound (5). The reaction time varies depending on the starting materials, the brominating agent and the solvent used. Step 1-4 This step is a step of reacting the compound (6) with a pinacol boronic ester as compound (3’) or a boronic acid as compound (4’) to produce the compound (7) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3’) or (4’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (6). The reaction can be usually performed at 70 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 1-5 This step is a step of deprotecting amine of the compound (7) to produce the final compound by the reaction with an amine deprotecting agent. The amine deprotecting agent can be acid with or without base such as trifluoroacetic acid (TFA), hydrochloric acid (HCl) with or without ethylene diamine, ammonium hydroxide (NH4OH), ammonia (NH3) and the like depending on the protecting groups. The reaction can be usually performed at room temperature to 50 ºC with or without a solvent such as MeOH, 1,4- dioxane and water. The reaction time varies depending on the substrate, acid / base and reaction temperature. (2) General Procedure 2 Step 2-1 This step is a step of reacting the compound (9) with an aryl halide or a heteroaryl halide compound (10) to produce the compound (5’) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (10) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (9). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. (3) General Procedure 3 Step 3-1 This step is a step of reacting the compound (9) with an aryl halide or heteroaryl halide compound (10) to produce the compound (11) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II)- DCM adduct (Pd(dppf)Cl2-DCM), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), tetrakis(triphenylphosphine) palladium (0) (Pd(PPh3)4) and the like. Examples of base may include cesium carbonate (Cs2CO3), potassium carbonate (K2CO3) and the like. The amount of compound (10) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (9). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 3-2 This step is a step of bromination at 2-position of 7-azaindole (11) to produce the compound (12) using a brominating agent such as N-bromosuccinimide (NBS) and / or bromine (Br2). The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of the brominating agent used is usually about 1 to 5 molar equivalents with respect to 1 mole of the compound (11). The reaction time varies depending on the starting materials, the brominating agent and the solvent used. Step 3- 3 This step is a step of reacting the compound (12) with a pinacol boronic ester as compound (3’) or a boronic acid as compound (4’) to produce the final compound using a palladium catalyst in the presence of a base in mixed solvents such as 1, 4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3) with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3’) or (4’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (12). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. (4) General Procedure 4 Step 4-1 This step is a step of reacting the compound (6’) with a pinacol boronic ester as compound (3’) or a boronic acid as compound (4’) to produce the final compound using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3’) or (4’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (6’). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. (5) General Procedure 5 Step 5-1 This step is a step of deprotecting amine of the compound (6) to produce the compound (12’) by the reaction with an amine deprotecting agent. The amine deprotecting agent can be acid with or without base such as TFA, HCl with or without ethylene diamine, NH4OH, NH3 and the like depending on the protecting groups. The reaction can be usually performed at room temperature to 50 ºC with or without a solvent such as MeOH, 1,4-dioxane, and water. The reaction time varies depending on the substrate, acid / base and reaction temperature. Step 5-2 This step is a step of reacting the compound (12’) with bis(pinacolato)diboron in a solvent to produce the compound (13) using a palladium catalyst in the presence of a base such as potassium acetate (KOAc). Examples of palladium catalyst used may include Pd(dppf)Cl2and the like. Examples of solvent used may include 1,4-dioxane, toluene and the like. The amount of bis(pinacolato)diboron used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (12’). The reaction can be usually performed at 90 ºC to the reflux temperature of the solvent. The reaction time varies depending on the starting material, the catalyst system, the base, the solvent, and the reaction temperature used. Step 5- 3 This step is a step of reacting the compound (13) with an aryl halide or a heteroaryl halide compound (10’) to produce the final compound. The final compound can be produced by reacting the boronic acid compound (13) with the aryl halide or heteroaryl halide compound(10’) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (10’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (13). The reaction can be usually performed at 60 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. (6) General Procedure 6

[0012] Step 6-1 This step is a step of reacting the boronic acid compound (17) with the aryl halide or heteroaryl halide compound (10’) to produce the compound (18). The compound (18) can be produced by reacting the boronic acid compound (17) with aryl halide or heteroaryl halide compound (10’) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (10’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (17). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 6-2 This step is a step of bromination at 3-position of the compound (18) to produce the compound (19) using a brominating agent such as NBS and / or Br2. The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of the brominating agent used is usually about 1 to 5 molar equivalents with respect to 1 mole of the compound (18). The reaction time varies depending on the starting materials, the brominating agent and the solvent used. Step 6- 3 This step is a step of reacting the compound (19) with a pinacol boronic ester as compound (3) or a boronic acid as compound (4) to produce the compound (20) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3) or (4) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (19). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 6-4 This step is a step of deprotecting amine of the compound (20) to produce the final compound by the reaction with an amine deprotecting agent. The amine deprotecting agent can be acid with or without base such as TFA, HCl with or without ethylene diamine, NH4OH, NH3and the like depending on the protecting groups. The reaction can be usually performed at room temperature to 50 ºC with or without a solvent such as MeOH, 1, 4-dioxane and water. The reaction time varies depending on the substrate, acid / base and reaction temperature. (7) General Procedure 7 Step 7-1 This step is a step of reacting the boronic acid compound (17’) with the compound (10’) to produce the compound (21). The compound (21) can be produced by reacting the boronic acid compound (17’) with aryl halide or heteroaryl halide compound (10’) using a palladium catalyst in the presence of a base in mixed solvents such as 1, 4- dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (10’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (17’). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 7-2 This step is a step of bromination at 3-position of the compound (21) to produce the compound (22) using a brominating agent such as NBS and / or Br2. The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of the brominating agent used is usually about 1 to 5 molar equivalents with respect to 1 mole of the compound (21). The reaction time varies depending on the starting materials, the brominating agent and the solvent used. Step 7- 3 This step is a step of protecting 1H-N of the 7-azaindole compound (22) to produce the compound (19’) by the reaction with an amine protecting agent such as SEM- Cl in a solvent in the presence of a base such as NaH. The amount of SEM-Cl used is about 1.1 to 1.5 molar equivalents with respect to 1 mole of the compound (22). The amount of NaH is about 1 to 2 molar equivalents with respect to 1 mole of the compound (22). The reaction can be usually performed at room temperature in the solvent such as DMF and the like. The reaction usually goes to completion in 1-2 hours. Step 7-4 This step is a step of reacting the compound (19’) with a pinacol boronic ester as compound (3) or a boronic acid as compound (4) to produce the compound (20’) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3) or (4) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (19’). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 7-5 This step is a step of deprotecting amine of the compound (20’) to produce the final compound by the reaction with an amine deprotecting agent. The amine deprotecting agent can be an acid such as TFA, HCl followed by treating with a base such as ethylene diamine, NH4OH, NH3 and the like. The reaction can be usually performed at room temperature to 50 ºC with or without a solvent such as MeOH, 1,4-dioxane and water. The reaction time varies depending on the substrate, acid / base and reaction temperature. (8) General Procedure 8 Step 8-1 This step is a step of protecting 1H-amine of 2-bromo-7-azaindole (23) to produce the compound (24) by the reaction with an amine protecting agent in a solvent in the presence of a base. The amine protecting agents used may include Boc2O, SEM-Cl, Fmoc-Cl, Cbz-Cl, BnCl and the like. The base used may include TEA, DIPEA, DMAP, NaH and the like. The amount of the amine protecting agent used is about 1.1 to 1.5 molar equivalents with respect to 1 mole of the compound (23). The amount of the base used is about 1.1 to 2.0 molar equivalents with respect to 1 mole of the compound (23). The reaction can be usually performed at room temperature in solvents such as DMF, THF and the like. The reaction time varies depending on the starting materials, the amine protecting agent, the base and the solvent used. Step 8-2 This step is a step of reacting the compound (24) with a pinacol boronic ester as compound (3’) or a boronic acid as compound (4’) to produce the compound (18’) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3’) or (4’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (24). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. (9) General Procedure 9 Step 9-1 This step is a step of converting the bromo group of the compound (28a) to the cyano group to produce the compound (18c). The compound (18c) can be produced by the reaction of the compound (28a) with zinc cyanide (Zn(CN)2) in the presence of Zn and Pd catalysts in a solvent such as DMF and the like. The amount Zn(CN)2 used is usually 3 molar equivalents with respect to 1 mole of the compound (28a). The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd(PPh3)4and the like. The reaction can be usually performed at 90 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. (10) General Procedure 10 Step 10-1 This step is a step of N-alkylation or N-acetylation of the compound (37) to produce the final compound by the reaction with an alkylating agent in the presence of a base. Examples of the alkylating agents may include methyl iodide, MOM-Cl and the like, base may include NaH, K2CO3, NaOtBu and the like. Examples of the solvent may include DMF, THF and the like. The amount of the alkylating agent used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (37). The reaction can be performed at room temperature, and usually goes to completion in 1-2 hours. (11) General Procedure 11 Step 11-1 This step is a step of O-demethylation of the compound (37a) to produce the final compound by the reaction of the compound (37a) with BBr3in a solvent. Examples of the solvent may include DCM, 1,4-dioxane and the like. The amount of BBr3used is usually about 1 to 20 molar equivalents with respect to 1 mole of the compound (37a). The reaction can be performed at room temperature to the reflux temperature of the solvent. The reaction time and temperature vary depending on the starting materials and the solvent used. (12) General Procedure 12

[0013] Step 12-1 This step is a step of O-trideuteriomethylation of the compound (7e or 7g) to produce the compound (7f or 7h) by the reaction with CD3I in the presence of a base. Examples of the base may include NaH, K2CO3, NaOtBu and the like. Examples of the solvent may include DMF, THF and the like. The amount of CD3I used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (7e or 7g). The reaction can be performed at room temperature, and usually goes to completion in 1-2 hours. Step 12-2 This step is a step of deprotecting amine of the compound (7f or 7h) by the removal of SEM group to produce the final compound. The compound (7f or 7h) can be treated with an acid such as TFA, HCl and the like followed by a base such as ethylene diamine, NH4OH, NH3and the like in a solvent such as MeOH, 1,4-dioxane and water. The reaction time varies depending on the substrate, acid / base and reaction temperature. (13) General Procedure 13 Step 13-1 This step is a step of oxidizing pyridine-N of the 7-azaindole compound (37) to produce N-oxide derivative by the reaction with an oxidizing agent such as meta- chloroperoxybenzoic acid (mCPBA) in a solvent. Examples of the solvent used may include dimethoxyethane (DME), DCM and the like. The reaction can be usually performed at room temperature. The reaction time varies depending on the starting material, the oxidizing agent, the solvent, and the reaction temperature used. (14) General Procedure 14 Step 14-1 This step is a step of reducing the ketone moiety of the compound (38) to produce compound (39) according to general procedure 6. The reduced compound can be produced by the reaction with a reducing agent such as sodium borohydride (NaBH4), lithium borohydride (LiBH4), and the like in a solvent. Examples of the solvent may include MeOH and the like. The reaction can be usually performed at 0 ºC to room temperature The reaction time varies depending on the starting materials, the reducing agent, the solvent, and the reaction temperature used. Step 14-2 This step is a step of O-alkylation of the compound (39) to produce the compound (40) by the reaction with an alkylating agent in the presence of a base. Examples of the base may include NaH, K2CO3, NaOtBu and the like. Examples of alkylating agent may include iodomethane (MeI), Iodoethane (EtI) and the like. Examples of the solvent may include DMF, THF and the like. The amount of the alkylating agent used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (39). The reaction can be performed at room temperature, and usually goes to completion in 1-2 hours. Step 14- 3 This step is a step of deprotecting amine of the compound (40) by the removal of SEM group to produce the final compound. The compound (40) can be treated with an acid such as TFA, HCl and the like followed by a base such as ethylene diamine, NH4OH, NH3 and the like in a solvent such as MeOH, 1,4-dioxane and water. The reaction time varies depending on the substrate, acid / base and at 0 ºC to room temperature. (15) General Procedure 15 Step 15-1 This step is a step of bromination of the compound (41) to produce the compound (42) using a brominating agent such as Br2. The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of the brominating agent used is usually about 1.0 to 1.5 molar equivalents with respect to 1 mole of the compound (41). The reaction time varies depending on the starting materials and the brominating agent. Step 15-2 This step is a step of reacting the compound (42) with bis(pinacolato)diboron in a solvent to produce the compound (3b) or (3c) using a palladium catalyst in the presence of a base such as KOAc. Examples of palladium catalysts used may include Pd(ppf)Cl2and the like. Examples of solvents used may include 1,4-dioxane, toluene, and the like. The amount of bis(pinacolato)diboron used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (42). The reaction can be usually performed at 90 ºC to the reflux temperature of the solvent. The reaction time varies depending on the starting material, the catalyst system, the base, the solvent, and the reaction temperature used. (16) General Procedure 16 Step 16-1 This step is a step of alkylating the hydroxyl group of 2-bromo-4-fluorophenol (10n) to produce the ether compounds (10d-g). The ether compounds can be produced by reacting the compound (10n) with heterocyclic methyl bromide (43) in the presence of base in a solvent such as DMF. Examples of base may include K2CO3, potassium t- butoxide (KOtBu) and the like. The amount of heterocyclic methyl bromide (43) used is about 1.1 to 1.5 molar equivalents with respect to 1 mole of the compound (10n). The reaction can be usually performed at 60 ºC to the reflux temperature of the solvent. The reaction time varies depending on the heterocyclic methyl bromide compound (43), the base and the solvent used. (17) General Procedure 17 Step 17-1 This step is a step of converting the compound (44) to the chloride derivative (45). The compound (45) can be produced by reacting the compound (44) with phosphoryl chloride. The reaction is usually performed under heated conditions (90 ºC to 100 ºC) overnight. Step 17-2 This step is a step of iodination of the compound (45) to produce the compound (46) using N-iodosuccinimide (NIS). The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of NIS used is 1.05 molar equivalents with respect to 1 mole of the compound (45). The reaction usually goes to completion in 1 hour. Step 17- 3 This step is a step of converting the chloro pyrazole compound (46) to produce the alkoxy pyrazole compound (10u) or (10v). The compound (10u) or (10v) can be produced by reacting the compound (46) with an alcohol in the presence of base. Examples of base may include KOtBu, K2CO3and the like. The amount of alcohol used is about 2 molar equivalents with respect to 1 mole of the compound (46) or excess amount as a solvent. Examples of other solvents may include 1,4-dioxane, THF and the like. The reaction can be usually performed at reflux temperature of the solvent. The reaction time varies depending on the alcohol, the base and the solvent used. (18) General Procedure 18 Step 18-1 This step is a step of N-methylation of the compound (47) to produce the compound (48) by the reaction with MeI in the presence of a base. Examples of the base may include NaH, K2CO3, NaOtBu and the like. Examples of the solvent may include DMF, THF and the like. The amount of MeI used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (47). The reaction can be performed at room temperature, and usually goes to completion in 1-2 hours. Step 18-2 This step is a step of reacting the compound (48) with bis(pinacolato)diboron in a solvent to produce the compound (3a) using a palladium catalyst in the presence of a base such as KOAc. Examples of palladium catalyst used may include Pd(dppf)Cl2and the like. Examples of solvent used may include 1,4-dioxane, toluene and the like. The amount of bis(pinacolato)diboron used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (48). The reaction can be usually performed at 90 ºC to the reflux temperature of the solvent. The reaction time varies depending on the catalyst system, the base, the solvent, and the reaction temperature used. (19) General Procedure 19 Step 19-1 This step is a step where the carbonyl of (49) is protected as a spiro-dithiane. The compound (50) can be produced by reacting the compound (49) with 1, 2- ethanedithiol, in the presence of a Lewis acid such as boron trifluoride acetic acid complex, Dibutylboron trifluoromethanesulfonate and the likes. The amount of 1, 2- ethanedithiol used is usually about 1 to 1.5 molar equivalents with respect to 1 mole of the compound (49). The reaction can be usually performed at room temperature overnight or longer and in solvents such as DCM, DCE and the like. Step 19-2 This step is a step where compound (50) is converted to (10w) in the presence of halogenating agent and HF.pyridine. Examples of halogenating agent used may include NBS, NIS and the like. The reaction can be usually performed at -78 °C in a solvent such as DCM, DCE and the like. (20) General Procedure 20 Step 20-1 This step is a step of halogenation of compound (51) to produce compound (10x) using a halogenating agent such as N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) and / or Br. The reaction can be usually performed at room temperature in a solvent such as DMF, DCM, DCE and the like. The amount of the halogenating agent used is usually about 1 equivalent with respect to 1 mole of the compound (51). Step 20-2a This step is a step of protecting pyrazole-NH of compound (10x) to produce compound (10y) by the reaction of a protecting agent and a base. The protecting agents used may include Boc2O, SEM-Cl and the like. Examples of the base may include NaH, K2CO3, NaOtBu and the like. Examples of the solvent may include DMF, THF and the like. The amount of the Boc2O used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (10x). The reaction is usually performed at 0 °C. Step 20-2b This step is a step of reacting compound (10x) with bis(pinacolato)diboron in a solvent to produce compound (4k) using a palladium catalyst in the presence of a base such as KOAc. Examples of palladium catalyst used may include Pd(dppf)Cl2and the like. Examples of solvent used may include 1,4-dioxane, toluene and the like. The amount of bis(pinacolato)diboron used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (10x). The reaction can be usually performed at 90 ºC to the reflux temperature of the solvent. The reaction time varies depending on the starting material, the catalyst system, the base, the solvent, and the reaction temperature used. Step 20- 3a This step is a step of reacting compound (10y) with bis(pinacolato)diboron in a solvent to produce compound (4l) using a palladium catalyst in the presence of a base such as KOAc. Examples of palladium catalyst used may include Pd(dppf)Cl2and the like. Examples of solvent used may include 1,4-dioxane, toluene and the like. The amount of bis(pinacolato)diboron used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (10y). The reaction can be usually performed at 90 ºC to the reflux temperature of the solvent. The reaction time varies depending on the starting material, the catalyst system, the base, the solvent, and the reaction temperature used. Step 20- 3b This step is a step of protecting pyrazole-NH of compound (4k) to produce the compound (4l) by the reaction of a protecting agent and a base. The protecting agents used may include Boc2O, SEM-Cl and the like. Examples of the base may include NaH, K2CO3, NaOtBu and the like. Examples of the solvent may include DMF, THF and the like. The amount of the Boc2O used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (4k). The reaction is usually performed at 0 °C. (21) General Procedure 21 Step 21-1 This step is a step that converts 3,3,3-trifluoropropanoyl halide (52) into compound (53) using 1,2-bis(trimethylsilyl)ethyne in the presence of Lewis acid such as AlCl3and solvents such as DCM, DCE and the like. The reaction is performed at 0 °C for 1- 3 h. Step 21-2 This step is a step that converts compound (53) to the corresponding pyrazole (51g) by the reaction with hydrazine in the presence of solvents such as ethanol, CH3CN and the like. The reaction is performed at room temperature and reaction goes to completion in 1-2 h. (22) General Procedure 22 Step 22-1 This step is a step of N-alkylation of the compound (10rr) to produce the compound (10ss) by the reaction with alkylating agent in the presence of a base. Examples of the base may include and the like. The alkylating agent used may include iodomethane (MeI), Iodoethane (EtI) and the like. The reaction can be usually performed at room temperature to 50 ºC in a solvent such as DMSO, THF and the like. The reaction time varies depending on the starting materials, the alkylating agent, the base, the solvent used, and the reaction temperature. Step 22-2 This step is a step of reacting the compound (10ss) with bis(pinacolato)diboron in a solvent to produce the compound (3q) using a palladium catalyst in the presence of a base such as KOAc. Examples of palladium catalyst used may include Pd(dppf)Cl2and the like. Examples of solvent used may include 1, 4-dioxane, toluene and the like. The amount of bis(pinacolato)diboron used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (10ss). The reaction can be usually performed at 90 ºC to the reflux temperature of the solvent. The reaction time varies depending on the starting material, the catalyst system, the base, the solvent, and the reaction temperature used. (23) General Procedure 23 Step 23-1 This step is a step that converts compound (54) to compound (55) using hydrazine in Ethanol. The reaction is usually heated at 110 ºC to 115°C for 2-16 h. Step 23-2 This step is a step where compound (56) is converted to compound (57) via mesylation in the presence of a base and in a solvent such as DCM, THF and the like. Examples of the base may include Et3N, pyridine and the like. Alternatively, compound (57) can also be generated from compound (56) via Appel reaction where Y = Br or Cl (Angew. Chem. Int. Engl. 1975, 14, 801 – 811). Step 23- 3 This step is a step where compounds (55) and (57) are heated together in a solvent such as DMF and in the presence of a base to form bicyclic compound (58). Examples of base may include K2CO3, Cs2CO3and the likes. The reaction can be usually performed at 110 to 120 ºC. The reaction time varies depending on the substrates and reaction temperature. Step 23-4 This step is a step of halogenating compound (58) to produce the compound (10jjj) using a halogenating agent such as NIS or NBS and / or Br2. The reaction can be usually performed at room temperature in a solvent such as CH3CN, DCM, DCE and the like. The amount of the halogenating agent used is usually about 1-1.5 equivalent with respect to 1 mole of the compound (58) (24) General Procedure 24 Step 24-1 This step is a step of cyclization of compound (10zzz) to compound (10aaaa) in the presence of a base and at temperature between 60 °C to 100 °C. Examples of the base may include Cs2CO3and the like. The solvent used may include DMF, DMSO and the like. The reaction time varies depending on the substrate and reaction temperature. (25) General Procedure 25 Step 25-1 This step is a step where compound (10ffff) is converted to compound (59) in the presence of a hydroxide and at temperature between 60 ºC to 70 ºC. Examples of hydroxide my include potassium hydroxide (KOH), sodium hydroxide and the like. The solvent used may include DMF and the like. The reaction time varies depending on the starting material and the solvent used. Step 25-2 This step is a step of protecting the alcohol moiety of compound (59) to produce compound (60) in the presence of a base. The alcohol protecting reagents used may include tert-butyldimethylsilane (TBDMS), SEM-Cl and the likes. The base used may include imidazole, diisopropylethylamine, pyridine and the like. Examples of the solvent may include DMF, DCM and the like. The reaction time varies depending on the starting material, reaction temperature and the protecting reagent used. (26) General Procedure 26 Step 26-1 This step is a step where compound (61) is reacted with compound (62) in the presence of an acid at 100 ºC to obtain cyclized product (10iiii). Examples of the acid may include AcOH, p-Toluenesulfonic acid and the like. (27) General Procedure 27 Step 27-1 This step is a step that converts compound (63) to compound (3s) in the presence of a Ir-catalyst and solvent. The Ir-catalyst may be [Ir(OMe)(cod)]2 and the like. Examples of solvent used may include p-xylene, THF and the like. (J. Am. Chem. Soc.2005, 127, 10539–10544) (28) General Procedure 28 The reaction conditions of Step 28-1 and 28-2 are carried out by utilizing of the method described in Example 25 of WO2018 / 136890. Step 28-1 This step is a step of N-acetylation of compound (55) to produce compound (65) by the reaction with an acylating agent in the presence of a base. Examples of the base may include pyridine, triethyl amine and the like. Examples of the solvent may include DCM, MeCN and the like. Examples of the acetylating agent may include acetyl chloride, acetic anhydride and the like. The amount of the acylating agent used is usually about 1 to 1.05 molar equivalents with respect to 1 mole of the compound (55). The reaction can be performed at 0 ºC to 95 ºC. The reaction time varies depending on the starting materials, the acylating agent, the base and the solvent used. Step 28-2 This step is a step where compound (65) is reacted with compound (66) under Mitsunobu conditions at room temperature to obtain compound (67) in the presence of a solvent. The reagents used may include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and the like in the presence of triphenylphosphine (TPP). Examples of the solvent may include THF, DCM and the like. The reaction time varies depending on the starting materials. Step 28- 3 This step is a step where deprotection of Boc and acetonide groups of compounds (67) was achieved by the reaction of p-toluenesulfonic acid (pTSA) at room temperature in a solvent. Examples of the solvent may include MeOH and the like. After complete deprotection of acetyl and Boc groups, protection of the amine with a Boc group was achieved by reaction with Boc2O in the presence of base and solvent at room temperature. Examples of the base may include Et3N, and the like. Examples of the solvent may include THF and the like. Step 28-4 This step is a step where the alcohol of compound (68) is converted to a mesyl group in the presence of MesylCl and a base to generate compound (69) at room temperature. Examples of the base may include Et3N, pyridine and the like. Examples of the solvent may include THF, DCM and the like. The reaction time varies depending on the starting material. Step 28-5 This step is a step where compound (69) is converted to compound (58k) in the presence of base and solvent. Examples of the base may include K2CO3, and the like. Examples of the solvent may include DMF and the like. The reaction time varies depending on the starting material and temperature of the reaction (80 ºC ~ 100 ºC). (29) General Procedure 29 Step 29-1 This step is a deprotection step of compound (70) to produce compound (71) at room temperature. The deprotecting agent can be an acid such as TFA, HCl in a solvent such as DCM, THF and the like. The reaction time varies depending on the starting material and the acid used. Step 29-2 This step is a step where compound (71) is converted to compound (72) in the presence of acetyl chloride, base and solvent at room temperature. Examples of base include Et3N, DIPEA and the like. Examples of solvent include THF, DCM, and the like. Step 29- 3 This step is a step of compound (70) to produce compound (73) by the reaction with an alkylating agent in the presence of a base. Examples of the base may include sodium hydride (NaH), K2CO3, NaOtBu and the like. Examples of the solvent may include DMF, THF and the like. The alkylating agent used may include MeI, EtI and the like. The amount of the alkylating agent used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (70). The reaction can be performed at room temperature, and usually goes to completion in 1-2 hours. Step 29-4 This step is a step where compound (73) is converted to compound (74) in the presence of TFA, HCl and the like at room temperature. Examples of solvent include DCM, THF and the like. (30) General Procedure 30 Step 30-1 This step is a step of fluorinating compound (10nnnn) to produce compound (10pppp) using a fluorinating reagent such as diethylaminosulfur trifluoride (DAST) and the like. The reaction can be usually performed at -78 ºC to room temperature in a solvent such as DCM, DCE and the like. The amount of the fluorinating agent used is usually about 2 to 3 molar equivalents with respect to 1 mole of the compound (10nnnn). The reaction time varies depending on the starting material and reaction temperature. (31) General Procedure 31 Step 31-1 amine deprotecting reagent X = Halogen Ar1=aryl optionally substituted, P with or without heteroaryl optionally substituted, solvent and heat etc P = THP, Boc, SEM Step 31-1 This step is a step of deprotecting amine moiety of compound (75) to produce compound (76) by the reaction with an amine deprotecting agent. The amine deprotecting agent can be acid with or without base such as TFA, HCl with or without ethylene diamine, NH4OH, NH3and the like depending on the protecting groups. The reaction can be usually performed at room temperature to 50 ºC with or without a solvent such as MeOH, 1, 4-dioxane and water. The reaction time varies depending on the substrate, acid / base and reaction temperature. (32) General Procedure 32 Step 32-1 This step is a step of converting compound (10aaaaa) to compound (10bbbbb) under Horner-Wadsworth-Emmons (HWE) conditions. The HWE reagent and base used are triethylphosphonoacetate and sodium hydride (NaH) respectively. Examples of solvent used are THF and the like. The amount of HWE reagent used is usually about 1.0 to 1.5 molar equivalents with respect to 1 mole of the compound (10aaaaa). The amount of NaH used is usually about 1.0 to 1.5 molar equivalents with respect to 1 mole of the compound (10aaaaa). The reaction is performed at 0 ºC to room temperature and usually goes to completion overnight. Step 32-2 This step is a step of reducing the α, β-unsaturated ethyl ester moiety of compound (10bbbbb) to produce compound (10ccccc). The compound (10ccccc) can be generated by the reaction of compound (10bbbbb) with a reducing agent such as lithium aluminum hydride (LiAlH4), super hydride (Li(C2H5)3BH) and the like. Examples of the solvent may include THF and the like. The reaction can be performed at -78 ºC to room temperature and usually goes to completion from 30 min. to 18 h. Step 32- 3 This step is a step of converting compound (10ccccc) to compound (58m) under Glaser coupling conditions. The catalyst and ligand used are copper Iodide (CuI) and 3, 4, 7, 8-tetramethyl-1, 10-phenanthroline respectively. Examples of the solvent may include toluene, and the like. The reaction can be usually performed at 100 ºC to 110 ºC. The reaction time is usually 1 to 2 days. (33) General Procedure 33 The reaction conditions of Step 33-1, 33-2 and 33- 3 are carried out by utilizing of the method described in Example 25 of WO2018 / 136890. Step 33-1 This step is a step of N-alkylation of compound (65) with Glycidol (77) under Mitsunobu conditions to produce compound (78). Examples of the solvent may include THF, diethyl ether and the like. The amount of the Glycidol used is usually about 1 to 1.2 molar equivalents with respect to 1 mole of the compound (65). The reaction can be performed at 0 ºC and usually goes to completion in 3-4 hours. Step 33-2 This step is a step to ring opening of epoxide moiety in compound (78) in the presence of LiCl and acetic acid to produce compound (79). The reaction can be performed in THF at room temperature and usually goes to completion in 18-24 hours. Step 33- 3 This step is a step to formation of compound (58o) from compound (79) in the presence of K2CO3. The reaction can be performed in DMF at 125 ºC to 135 ºC and usually goes to completion in 24 to 36 hours. Step 33-4 This step is a step of protecting alcohol moiety in compound (58o) to produce the compound (58p) by the reaction with an alcohol protecting agent in a solvent in the presence of a base and catalyst. The alcohol protecting reagents used may include tert- butyl-chloro-diphenyl-silane (TBDPS-Cl) and the like. The base and catalyst used are imidazole and DMAP respectively. The amount of the alcohol protecting agent used is about 1.5 molar equivalents with respect to 1 mole of the compound (58o). The amount of the base used is about 2 to 2.2 molar equivalents with respect to 1 mole of compound (58o). The reaction can be usually performed at room temperature in the solvent such as DMF and the like. The reaction time varies depending on the starting materials, the alcohol protecting agent, the base and the solvent used. (34) General Procedure 34 Step 34-1 This step is a step of deprotecting alcohol moiety in compound (80) to produce compound (81) by the reaction with an alcohol deprotecting agent. The alcohol deprotecting agent may include tetra-n-butylammonium fluoride (TBAF), HCl and the like. The reaction can be usually performed at 0 ºC to room temperature with a solvent such as THF, DCM and the like. The reaction usually goes to completion in 1 h. (35) General Procedure 35 Step 35-1 This step is a step of reacting the compound (92) with silyl-ester compound (93) to produce the compound (94) using a copper halide in the presence of an additive heated at 80 ºC. The copper used may include CuI, copper and the like. Examples of additive may include potassium fluoride, sodium fluoride and the like. Examples of solvent may include DMF, DMSO and the like. The amount of copper halide and additive are about 1 to 3 molar equivalents each with respect to 1 mole of the compound (92). The amount of compound (93) used is about 1 to 3 molar equivalents with respect to 1 mole of the compound (92). The reaction time varies depending on the starting materials, the additive and the solvent used. Step 35-2 This step is a step of de-acetylation of the compound (94) to produce the compound (95) using an potassium salt in aqueous solvent. The potassium salt used may include potassium fluoride (KF), potassium chloride, and the like. The reaction can be usually performed at 100 °C to 130 °C in a solvent such as DMSO, DMF and the like. The amount of potassium salt and water used are about 3 to 5 molar equivalents each with respect to 1 mole of the compound (94). The reaction time varies depending on the starting materials, potassium halide and the solvent used. Step 35- 3 This step is a step of halogenation of compound (95) to produce the compound (96) using a halogenating agent such as N-iodosuccinimide (NIS), N-bromosuccinimide (NBS) and / or bromine (Br2). The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of the halogenating agent used is usually about 1 to 5 molar equivalents with respect to 1 mole of the compound (95). The reaction time varies depending on the starting materials, the halogenating agent and the solvent used. (36) General Procedure 36

[0014] Step 36-1 This step is a step of reacting the compound (10mmmmm) with a pinacol boronic ester compound (3u) to produce the compound (97) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3u) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (10mmmmm). The reaction can be usually performed at 70 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 36-2 This step is a step of converting the compound (97) to the compound (98) using mineral acid. Examples of mineral acid may include HCl, sulfuric acid (H2SO4) and the like. The reaction can be usually performed at 70 ºC to 100 ºC. The reaction time varies depending on the temperature of the reaction and the starting materials. Step 36- 3 This step is a step of protecting 1H-N of the compound (98) to produce the compound (99) by the reaction with an amine protecting agent in a solvent in the presence of a base. The amine protecting reagents used may include Boc2O, SEM-Cl, Fmoc-Cl, Cbz-Cl, BnCl and the like. The base used may include TEA, DIPEA, DMAP, NaH and the like. The amount of the amine protecting agent used is about 1.1 to 1.5 molar equivalents with respect to 1 mole of the compound (98). The amount of the base used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (98). The reaction can be usually performed at room temperature in the solvent such as DMF, THF and the like. The reaction time varies depending on the starting materials, the amine protecting agent, the base and the solvent used. Step 36-4 This step is a step is halogenation of the compound (99) to produce the compound (100) using a halogenating agent such as NIS, NBS and / or Br2. The reaction can be usually performed at room temperature in a solvent such as DCM, MeCN and the like. The amount of the halogenating agent used is usually about 1 to 5 molar equivalents with respect to 1 mole of the compound (99). The reaction time varies depending on the starting materials, the halogenating agent and the solvent used. Step 36-5 This step is a step of reacting the compound (100) with a pinacol boronic ester as compound (3) or a boronic acid as compound (4) to produce the compound (101) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3) or (4) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (100). The reaction can be usually performed at 70 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 36-6 This step is a step is halogenation of the compound (101) to produce the compound (102) using a halogenating agent such as NIS, NBS and / or Br2. The reaction can be usually performed at room temperature in a solvent such as DCM, DCE and the like. The amount of the halogenating agent used is usually about 1 to 5 molar equivalents with respect to 1 mole of the compound (101). The reaction time varies depending on the starting materials, the halogenating agent and the solvent used. Step 36-7 This step is a step of reacting the compound (102) with a pinacol boronic ester as compound (3’) or a boronic acid as compound (4’) to produce the compound (103) using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of compound (3’) or (4’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (102). The reaction can be usually performed at 70 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. Step 36-8 This step is a step of deprotecting amine of the compound (103) to produce compound (104) by the reaction with an amine deprotecting agent. The amine deprotecting agent can be acid with or without base such as TFA, HCl with or without ethylene diamine, NH4OH, NH3 and the like depending on the protecting groups. The reaction can be usually performed at room temperature to 50 ºC with or without a solvent such as MeOH, 1, 4-dioxane and water. The reaction time varies depending on the substrate, acid / base and reaction temperature. (37) General Procedure 37 Step 37-1 This step is a step of removing Boc protecting group from compound (5d) to produce compound (11) by the reaction with an acid. The acid used may include TFA, HCl and the like. The reaction can be usually performed at room temperature to 50 ºC with a solvent such as DCM, DCE and the like. The reaction time varies depending on the substrate, acid, and reaction temperature. Step 37-2 This step is a step of protecting 1H-N of the 7-azaindole compound (11) with SEM group to produce the compound (5e) by the reaction with SEM-Cl in a solvent in the presence of a base. The base used may include NaH and the like. The amount of SEM-Cl used is about 1.1 to 1.5 molar equivalents with respect to 1 mole of the compound (11). The amount of the base used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (11). The reaction can be usually performed at room temperature in the solvent such as DMF, THF and the like. The reaction time varies depending on the starting materials, the base and the solvent used. (38) General Procedure 38 Step 38-1 This step is a step of reacting the compound (10ppppp) with a Grignard reagent to produce the compound (10qqqqq) in solvents such as THF, ether and the like. The Grignard reagent (or its equivalent) used may include methylmagnesium bromide, benzylmagnesium bromide and the like. The amount of Grignard reagent used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (10ppppp). The reaction can be usually performed at 0 ºC to room temperature, and usually goes to completion in 0.5-2 hours. Step 38-2 This step is a step of oxidization of the alcohol moiety in compound (10qqqqq) to produce the compound (10rrrrr) at room temperature. Oxidizing reagent may include Dess-Martin periodinane, 2-Iodoxybenzoic acid (IBX), Pyridinium chlorochromate (PCC) and the like. The solvent used may include DCM, DMSO and the like. The amount of oxidizing reagent used is about 1.5 to 3 molar equivalents with respect to 1 mole of the compound (10qqqqq). The reaction time varies depending on the starting materials, oxidizing reagent and the solvent used. (39) General Procedure 39 Step 39-1 This step is a step of reacting the compound (104) with a H2or D2 (gas) to produce the compound (105) using a palladium catalyst in the presence of a ligand in solvents such as DMSO, DMF and the like. The palladium catalyst used may include Palladium on carbon (Pd / C), Pd2(dba)3and the like. Examples of ligand may includetBu3P, Me3P, P(Ph)3and the like. The reaction can be usually performed at 80 ºC to 90 ºC, and usually goes to completion in 1-2 hours. (40) General Procedure 40 Step 40-1 This step is a step of converting carboxylic acid moiety of compound (106) to the ester of the compound (107) in the presence of alcohol and catalytic amount of acid. The alcohol used, depending on the target ester, may include MeOH, EtOH and the like. The acid used may include H2SO4, HCl and the like. The reaction can be usually performed at 60 ºC to reflux temperature of the alcohol used. The reaction time varies depending on the starting materials, the temperature of the reaction and the solvent used. (41) General Procedure 41 Step 41-1 This step is a reductive amination between compound (108) with tetrahydropyran- 4-one to produce the compound (109) in the presence of an acid, reducing agent and in solvent such as methanol. The acid used may include acetic acid, PTSA and the like. The reducing agent used may include Sodium triacetoxyborohydride (NaBH(OAc)3), NaBH3CN and the like. The amount of the acid and reducing agent used are usually about 1 to 2 molar equivalents each with respect to 1 mole of the compound (108). The reaction time varies depending on the starting materials, the reducing agent and the acid used. (42) General Procedure 42 Ar1= aryl optionally substituted, heteroaryl optionally substituted, etc R1= CF3, CHF2, CH2F, CH3R2= amine Step 42-1 This step is a step of converting the carboxylic acid group of the compound (110) to produce the compound (111) by the reaction with an amine in a solvent under the influence of a coupling agent and a base. The coupling agent used may include oxalyl chloride, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), dicyclohexylcarbodiimide (DCC), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and the like. The base used may include TEA, DIPEA and the like. The amount of amine used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (110). The reaction can be usually performed at 0 ºC to 50 ºC in a solvent such as DMF, CH3CN and the like. The reaction time varies depending on the starting materials, the coupling agent, the base, the solvent used, and the reaction temperature. (43) General Procedure 43 Step 43-1 This step is a step of reducing the isolated olefin in the compound (121) to produce the compound (122) using a palladium catalyst under H2atmosphere. The palladium catalyst used may include Pd / C, Lindlar catalyst and the like. The reaction can be usually performed at room temperature in a solvent such as MeOH, EtOH and the like. The reaction time varies depending on the starting materials, pressure of H2gas, and the solvent used. Step 44-1 This step is a step of deprotecting alcohol of compound (125) to produce the compound (125a) by the reaction with an alcohol deprotecting agent. The alcohol deprotecting agent used may include HCl, H2SO4and the like. The reaction can be usually performed at 0 ºC to room temperature with a solvent such as THF. The reaction usually goes to completion in 1-2 h. (45) General Procedure 45 The reaction conditions of all steps are carried out by utilizing of the method described in Example 42 of WO2018 / 136890. Step 45-1 This step is a step of mesylation of compound (58q) to produce compound (58r) by the reaction with a mesylating reagent in a solvent in the presence of a base. The mesylating reagents used may include methanesulfonyl chloride (MsCl), methanesulfonyl triflate and the like. The base used may include TEA, DIPEA and the like. The amount of the mesylating agent used is about 2 to 2.05 molar equivalents with respect to 1 mole of the compound (58q). The amount of the base used is about 2 to 2.05 molar equivalents with respect to 1 mole of the compound (58q). The reaction can be usually performed at 0 ºC to room temperature in the solvent such as DCM, THF and the like. The reaction time varies depending on the starting materials, the mesylating agent, the base and the solvent used. Step 45-2 This step is a step is azidation of the compound (58r) to produce the compound (58s) by the reaction with an azidation reagent in a solvent. The azidation reagents used may include sodium azide (NaN ), toluenesulfonyl azide (TsN ) and the like. The amount of the azidation agent used is about 2 to 3 molar equivalents with respect to 1 mole of the compound (58r). The reaction can be usually performed at room temperature to 120 °C in the solvent such as DMF, DMSO and the like. The reaction time varies depending on the reaction temperature, starting materials, the azidation agent and the solvent used. Step 45- 3 This step is a step is hydrogenation of the azide moiety of compound (58s) to produce compound (58t) using a palladium catalyst under H2atmosphere. The palladium catalyst used may include Pd / C, Lindlar catalyst and the like. The reaction can be usually performed at room temperature in a solvent such as MeOH, EtOH and the like. The reaction time varies depending on the starting materials, pressure of H2gas, and the solvent used. (46) General Procedure 46 Step 46-1 This step is a step of converting the halide compound (19g) to the boronic acid compound (126). The compound (126) can be produced by first exposing compound (19g) to n-buthyllithium (n-BuLi) at -78 °C then triisopropyl borate. If necessary, HPMC may be used in this step. The amount of n-BuLiand HMPA used is usually about 2 molar equivalents with respect to 1 mole of the compound (19g). The lithiation and borylation can be performed at -78 ºC to room temperature, and usually goes to completion in 1-2 hours at room temperature Step 46-2 This step is a step of reacting the compound (126) with an aryl halide or heteroaryl halide compound (10’) to produce the compound (7bb), an intermediate used in the procedure 1, using a palladium catalyst in the presence of a base in mixed solvents such as 1,4-dioxane and water. The palladium catalyst used may include Pd(dppf)Cl2-DCM, Pd2(dba)3with XPhos, Pd(PPh3)4and the like. Examples of base may include Cs2CO3, K2CO3and the like. The amount of aryl halide or heteroaryl halide compound (10’) used is about 1 to 2 molar equivalents with respect to 1 mole of the compound (126). The reaction can be usually performed at 80 ºC to the reflux temperature of the solvent, and usually goes to completion in 1-2 hours. (47) General Procedure 47 Step 47-1 This step is a step of difluoromethylation of compound (10qqqqqq) to produce compound (10rrrrrr) using a difluromethylating agent and base. Examples difluromethylating agent used may include Diethyl (bromodifluoromethyl)phosphonate, 2- halo-2,2-difluoroacetophenone, 2-Bromo-2,2-difluoroacetic acid and the like. The base used may include various bases such as KOH, NaOH, Cs2CO3, K2CO3and the like. The reaction can be usually performed at -20 °C to room temperature in a solvent such as mixture of MeCN, Water and DMF. The amount of the difluromethylating agent used is usually about 1 to 2 molar equivalents with respect to 1 mole of the compound (10qqqqqq). The reaction time varies depending on the starting materials, the difluromethylating agent and the solvent used. (48) General Procedure 48 Step 48-1 This step is a step of converting the amide moiety of the compound (20f) to the nitrile in compound (20g) under the influence of dehydrating agent and base. The dehydrating agent used may include Phosphoryl Chloride (POCl3), Phosphorous Chloride (PCl3) and the like. Examples of base may include diethyl amine, pyridine and the like. The reaction can be usually performed at room temperature to the reflux temperature of the solvent such as DCM, CHCl3and the like. The amount of the dehydrating reagent used is usually about 1 to 1.5 molar equivalents with respect to 1 mole of the compound (20f). The reaction time varies depending on the starting materials, the coupling agents and the solvent used. (49) General Procedure 49

[0015] This procedure is another rout that is different from General Procedure 28 to produce compound (58k). The Mitsunobu reaction is proceeding from the enol form of compound (65) to give the O-alkylating product (67’). The reaction conditions for each step are the same as those described in General Procedure 28. The reaction conditions of 28-2 are carried out by utilizing of the method described in Example 25 of WO2018 / 136890. Step 28-2 This step is a step where compound (65) is reacted with compound (66) under Mitsunobu conditions at room temperature to obtain compound (67’) in the presence of a solvent. The reagents used may include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and the like in the presence of triphenylphosphine (TPP). Examples of the solvent may include THF, DCM and the like. The reaction time varies depending on the starting materials. Step 28- 3 This step is a step where deprotection of Boc and acetonide groups of compounds (67’) was achieved by the reaction of p-toluenesulfonic acid (pTSA) at room temperature in a solvent. Examples of the solvent may include MeOH and the like. After complete deprotection of acetyl and Boc groups, protection of the amine with a Boc group was achieved by reaction with Boc2O in the presence of base and solvent at room temperature. Examples of the base may include Et3N, and the like. Examples of the solvent may include THF and the like. Step 28-4 This step is a step where the alcohol of compound (68’) is converted to a mesyl group in the presence of MesylCl and a base to generate compound (69’) at room temperature. Examples of the base may include Et3N, pyridine and the like. Examples of the solvent may include THF, DCM and the like. The reaction time varies depending on the starting material. Step 28-5 This step is a step where compound (69’) is converted to compound (58k) in the presence of base and solvent. Examples of the base may include K2CO3, and the like. Examples of the solvent may include DMF and the like. The reaction time varies depending on the starting material and temperature of the reaction (80 ºC ~ 100 ºC). (50) General Procedure 50 This procedure is another rout that is different from General Procedure 33 to produce compound (58o). The Mitsunobu reaction is proceeding from the enol form of compound (65) to give the O-alkylating product (78’) . The reaction conditions for each step are the same as those described in General Procedure 33. The same method as above is described in Example A of WO2020018975. The reaction conditions of Step 33-1, 33-2 and 33- 3 are carried out by utilizing of the method described in Example 25 of WO2018 / 136890. Step 33-1 This step is a step of N-alkylation of compound (65) with Glycidol (77) under Mitsunobu conditions to produce compound (78’). Examples of the solvent may include THF, diethyl ether and the like. The amount of the Glycidol used is usually about 1 to 1.2 molar equivalents with respect to 1 mole of the compound (65). The reaction can be performed at 0 ºC and usually goes to completion in 3-4 hours. Step 33-2 This step is a step to ring opening of epoxide moiety in compound (78’) in the presence of LiCl and acetic acid to produce compound (79’). The reaction can be performed in THF at room temperature and usually goes to completion in 18-24 hours. Step 33- 3 This step is a step to formation of compound (58o) from compound (79’) in the presence of K2CO3. The reaction can be performed in DMF at 125 ºC to 135 ºC and usually goes to completion in 24 to 36 hours. Experimental Procedures (1) Experimental Procedure of EX.1 EX.1 was prepared in accordance with the general procedure 1 using the method described below in detail. Synthesis of 2-(2-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin- 3- yl)benzonitrile (EX.1) Step 1-1 A mixture of 3-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.08 mmol) (1a), Boc2O (1.33 g, 6.09 mmol), TEA (1.06 mL, 7.61 mmol) and DMAP (61 mg, 0.51 mmol) in THF (20 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by silica gel column chromatography (0- 30% EtOAc / Hexane) to give the expected product as a white solid (1.49 g, 94%); LRMS (ESI): m / z [M+H]+297, 299. Step 1-2 A reaction vessel containing tert-butyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (2a) (217 mg, 1.0 mmol), (2-cyanophenyl)boronic acid (4a) (118 mg, 1.1 mmol) and Cs2CO3(712 mg, 3.0 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2·DCM (80 mg, 0.10 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 70 ºC for 1 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (0- 35% EtOAc / Hexane) to give the expected product as a tan solid (175 mg, 71%); LRMS (ESI): m / z [M+H]+320. Step 1- 3 A mixture of tert-butyl 3-(2-cyanophenyl)pyrrolo[2,3-b]pyridine-1-carboxylate (5a) (87 mg, 0.27 mmol), NBS (48 mg, 0.27 mmol) and Br2(28 µL, 0.54 mmol) in DCM (1 mL) was stirred at room temperature for 1 h. The reaction mixture was adsorbed on silica gel, dried, and purified by silica gel column chromatography (0- 30% EtOAc / Hexane) to give the expected product as a light brown solid (54 mg, 47%); LRMS (ESI): m / z [M+H]+398, 400. Step 1-4 A reaction vessel containing tert-butyl 2-bromo- 3-(2-cyanophenyl)pyrrolo[2,3- b]pyridine-1-carboxylate (6a) (20 mg, 0.05 mmol), (5-fluoro-2-methoxy-phenyl)boronic acid (4b) (17 mg, 0.10 mmol) and Cs2CO3(49 mg, 0.15 mmol) in 1,4-dioxane (0.3 mL) and water (0.1 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (4.1 mg, 0.005 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ºC for 2 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (0-70% EtOAc / Hexane) to give the expected product as a white solid (12 mg, 50%); LRMS (ESI): m / z [M+H]+444. Step 1-5 A mixture of tert-butyl 3-(2-cyanophenyl)-2-(5-fluoro-2-methoxy- phenyl)pyrrolo[2,3-b]pyridine-1-carboxylate (7a) (12 mg, 0.026 mmol) and neat TFA (0.3 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.1 as a white solid (6 mg, 58%). 1H NMR (400 MHz, DMSO-d6): δ 3.36 (3H, s), 7.01 (1H, dd, J = 8.9, 4.3 Hz), 7.09-7.26 (3H, m), 7.37 (1H, d, J = 7.8 Hz), 7.49 (1H, t, J = 7.7 Hz), 7.68 (1H, t, J = 7.7 Hz), 7.81 (1H, d, J = 7.9 Hz), 7.87 (1H, d, J = 7.8 Hz), 8.33 (1H, dd, J = 4.6, 1.4 Hz), 12.29 (1H, s); LRMS (ESI): m / z [M+H]+344. The following compounds were synthesized using conditions analogous to (7a) in accordance with the general procedure 1.

[0016] The following compounds were synthesized using conditions analogous to EX.1 in accordance with the general procedure 1.

[0017] (2) Experimental Procedure of EX.19 EX.19 was prepared in accordance with the general procedure 1 using the method described below in detail. Synthesis of 2-(5-fluoro-2-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine- 3- yl)benzonitrile (EX.19)

[0018] Step 1-1 To a solution of 3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (1b) (158 mg, 0.73 mmol) in DMF (3.5 mL) was added NaH, 60% dispersion in mineral oil (44.1 mg, 1.10 mmol) and the mixture was stirred at room temperature for 10 min. To this, SEM-Cl (0.16 mL, 0.88 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 h. The mixture was poured into brine and the product was extracted with DCM (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was used for the next reaction without further purification (235 mg, quantitative yield); LRMS (ESI): m / z [M+H]+345, 347. Step 1-2 A reaction vessel containing 2-[(3-bromo-5-fluoro-pyrrolo[2,3-b]pyridin-1- yl)methoxy]ethyl-trimethyl-silane (2b) (100.0 mg, 0.29 mmol), (2-cyanophenyl)boronic acid (4a) (46.8 mg, 0.32 mmol) and Cs2CO3(283.1mg, 0.87 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (23.6 mg, 0.03 mmol), the mixture was purged with nitrogen three times. The resulting mixture was stirred and heated at 80 ºC for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0- 20% EtOAc / Hexane) to give the expected product as colorless oil (20.4 mg, 19%); LRMS (ESI): m / z [M+H]+368. Step 1- 3 To a solution of 2-[5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin- 3-yl]benzonitrile (5b) (20.4 mg, 0.06 mmol) in DCM (1 mL) was added 2M Br2in DCM (0.09 mL, 0.18 mmol) at room temperature and the mixture was stirred at room temperature overnight. The mixture was then diluted with DCM and washed with sat. aq. NaHCO3(x2). The organic layer was dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-20% EtOAc / Hexane) to give the expected product as yellow oil (14.2 mg, 57%); LRMS (ESI): m / z [M+H]+446, 448. Step 1-4 A reaction vessel containing 2-[2-bromo-5-fluoro-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (6b) (14.2 mg, 0.03 mmol), O-methoxyphenylboronic acid (4d) (4.8 mg, 0.03 mmol) and Cs2CO3(31.1 mg, 0.10 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (2.6 mg, 3.20 µmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 80 ºC for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc / Hexane) to give the expected product as yellow oil (9.4 mg, 62%); LRMS (ESI): m / z [M+H]+474. Step 1-5 (i) A mixture of 2-[5-fluoro-2-(2-methoxyphenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (7b) (9.4 mg, 0.02 mmol) and neat TFA (0.15 mL, 1.98 mmol) was stirred at room temperature for 1h. After concentration to dryness, the residue was used for the next reaction without further purification; LRMS (ESI): m / z [M+H]+374. Step 1-5 (ii) To a solution of 2-(5-fluoro-1-(hydroxymethyl)-2-(2-methoxyphenyl)-1H- pyrrolo[2,3-b]pyridin- 3-yl)benzonitrile (8a) in MeOH (0.15 mL) was added ethylenediamine (0.13 mL, 1.98 mmol) at room temperature and the mixture was stirred at room temperature for 30 min. The mixture was then poured into brine and the product was extracted with DCM (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-25% EtOAc / Hexane) to give the expected product as a white solid (6.0 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ 3.37 (3H, br s), 6.97 (1H, t, J = 7.5 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.25 (1H, dd, J = 7.6, 1.6 Hz), 7.32 (1H, d, J = 7.9 Hz), 7.35-7.42 (1H, m), 7.47 (1H, td, J = 7.7, 1.2 Hz), 7.60-7.70 (2H, m), 7.86 (1H, d, J = 7.8 Hz), 8.30 (1H, dd, J = 2.7, 1.6 Hz), 12.37 (1H, br s); LRMS (ESI): m / z [M+H]+344. The following compounds were synthesized using conditions analogous to EX.19 in accordance with the general procedure 1.

[0019] (3) Experimental Procedure of EX.106 EX.106 was prepared in accordance with the general procedures 2 and 1 using the method described below in detail. Synthesis of 2-(5-fluoro-2-methoxyphenyl)- 3-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3- b]pyridine (EX.106) Step 2-1 A reaction vessel containing tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (9) (150 mg, 0.44 mmol), 2-bromo-4- methylpyridine (10a) (97.4 mg, 0.57 mmol) and Cs2CO3(426 mg, 1.31 mmol) in 1,4- dioxane (1 mL) and water (0.5 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (71.2 mg, 0.09 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ºC for 1.5 h. After cooling to room temperature, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-60% EtOAc / Hexane) to give the expected product as colorless oil (79 mg, 59%); LRMS (ESI): m / z [M+H]+310. Step 1- 3 A mixture of tert-butyl 3-(4-methyl-2-pyridyl)pyrrolo[2,3-b]pyridine-1- carboxylate (5c) (79 mg, 0.26 mmol), NBS (50 mg, 0.28 mmol) and 1M Br2 in DCM (0.38 mL, 0.38 mmol) in DCM (1 mL) was stirred at room temperature for 3 h. The reaction mixture was then quenched with sat. aq. Na2S2O3, and the product was extracted with DCM (x3). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-70% EtOAc / Hexane) to give the expected product as pale yellow oil (60 mg, 60%); LRMS (ESI): m / z [M+H]+389, 391. Step 1-4 A reaction vessel containing tert-butyl 2-bromo- 3-(4-methylpyridin-2-yl)-1H- pyrrolo[2,3-b]pyridine-1-carboxylate (6c) (60 mg, 0.15 mmol), (5-fluoro-2-methoxy- phenyl)boronic acid (4b) (34 mg, 0.20 mmol) and Cs2CO3(151 mg, 0.46 mmol) in 1,4- dioxane (0.4 mL) and water (0.2 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (25.2 mg, 0.03 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ºC for 1 h. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (0-70% EtOAc / Hexane) to give the expected product as a white solid (16 mg, 24%); LRMS (ESI): m / z [M+H]+434. Step 1-5 A mixture of tert-butyl 2-(5-fluoro-2-methoxy-phenyl)- 3-(4-methyl-2- pyridyl)pyrrolo[2,3-b]pyridine-1-carboxylate (7e) (16 mg, 0.04 mmol) and TFA (0.2 mL) in DCM (0.3 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.106 as a white solid (12.4 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 2.54 (3H, s), 3.33 (3H, s), 7.08 (1H, dd, J = 9.2, 4.6 Hz), 7.29 (1H, dd, J = 8.0, 4.7 Hz), 7.35 (1H, td, J = 8.7, 3.1 Hz), 7.45 (1H, dd, J = 9.1, 3.1 Hz), 7.69-7.70 (2H, m), 8.24 (1H, dd, J = 8.2, 1.5 Hz), 8.42 (1H, dd, J = 4.6, 1.5 Hz), 8.63 (1H, d, J = 6.5 Hz), 12.80 (NH, br s); LRMS (ESI): m / z [M+H]+334. (4) Experimental Procedure of EX.107 EX.107 was prepared in accordance with the general procedure 3 using the method described below in detail. Synthesis of 2-(2-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl)-4- methoxybenzonitrile (EX.107) Step 3-1 A reaction vessel containing tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (9) (100 mg, 0.29 mmol), 2-bromo-4-methoxy- benzonitrile (10b) (73.9 mg, 0.35 mmol) and Cs2CO3(236.6 mg, 0.73mmol) in 1,4- dioxane (1.5 mL) and water (0.8 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (47.5 mg, 0.058 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ºC for 40 min. After cooling to room temperature, the mixture was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give the expected product as an off-white solid (50 mg, 69%); LRMS (ESI): m / z [M+H]+250. Step 3-2 A solution of 4-methoxy-2-(1H-pyrrolo[2,3-b]pyridin- 3-yl)benzonitrile (11a) (48 mg, 0.19 mmol) and NBS (41.1 mg, 0.23 mmol) in DCM (2.4 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give the expected product as a white solid (20.4 mg, 32%); LRMS (ESI): m / z [M+H]+328, 330. Step 3- 3 A reaction vessel containing 2-(2-bromo-1H-pyrrolo[2,3-b]pyridin- 3-yl)-4- methoxy-benzonitrile (12a) (12.9mg, 0.039 mmol), (5-fluoro-2-methoxy-phenyl)boronic acid (4b) (8.7 mg, 0.051 mmol), and Cs2CO3(32 mg, 0.098 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (6.4 mg, 0.008 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 80 ºC for 30 minutes. After cooling to room temperature, the mixture was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.107 as a pale-yellow solid (0.82 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ 3.42 (3H, s), 3.76 (3H, s), 6.86 (1H, d, J = 2.6 Hz), 7.01-7.03 (1H, m), 7.03-7.06 (1H, m), 7.11 (1H, dd, J = 9.1, 3.1 Hz), 7.16 (1H, dd, J = 7.9, 4.7 Hz), 7.22 (1H, td, J = 8.6, 3.2 Hz), 7.78 (1H, d, J = 8.7 Hz), 7.85 (1H, d, J = 6.4 Hz), 8.32 (1H, dd, J = 4.7, 1.5 Hz), 12.27 (NH, s); LRMS (ESI): m / z [M+H]+374. The following compounds were synthesized in a similar manner to EX.107 using Br2instead of NBS in step 3-2 in accordance with the general procedure 3.

[0020] (5) Experimental Procedure of EX.118 EX.118 was prepared in accordance with the general procedure 4 using the method described below in detail. Synthesis of 2-(6-methyl- 3-phenyl-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol (EX.118) Step 4-1 A reaction vessel containing tert-butyl 2-bromo-6-methyl- 3-phenyl-pyrrolo[2,3- b]pyridine-1-carboxylate (6d) (35 mg, 0.09 mmol), O-hydroxyphenylboronic acid (4e) (15 mg, 0.11 mmol) and Cs2CO3(88.3 mg, 0.27 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (7.4 mg, 0.01 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 80 °C for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.118 as a pale-yellow solid (3.8 mg, 13%). 1H NMR (400 MHz, DMSO-d6): δ 2.54 (3H, s), 6.73 (1H, t, J = 7.4 Hz), 6.92 (1H, d, J = 8.1 Hz), 6.98 (1H, d, J = 7.9 Hz), 7.08 (1H, d, J = 6.6 Hz), 7.13-7.24 (2H, m), 7.26-7.37 (4H, m), 7.87 (1H, d, J = 7.9 Hz), 9.80 (1H, br s), 11.53 (1H, br s); LRMS (ESI): m / z [M+H]+301. The following compounds were synthesized using conditions analogous to EX.118 in accordance with the general procedure 4.

[0021] (6) Experimental Procedure of EX.123 EX.123 was prepared in accordance with general procedure 5 using the method described below in detail.Synthesis of 2-[2-(5-methoxy-1-methyl-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile (EX.123) Step 5-1 A mixture of 2-[2-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (6e) (1.92 g, 4.48 mmol) and neat TFA (10.29 mL, 134.45 mmol) was stirred at room temperature for 1 h. After concentration to dryness, the residue was dissolved in MeOH (10 mL) and ethylenediamine (9.0 mL, 134.45 mmol) was added. The mixture was then stirred at room temperature for 30 min. The mixture was poured into brine and the product was extracted with DCM (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hexane, then 0-10% MeOH / DCM) to give the expected product as a white solid (1.30 g, 97%); LRMS (ESI): m / z [M+H]+298, 300. Step 5-2 A reaction vessel containing 2-(2-bromo-1H-pyrrolo[2,3-b]pyridin- 3- yl)benzonitrile (12b) (507 mg, 1.70 mmol), bis(pinacolato)diboron (518.2 mg, 2.04 mmol) and potassium acetate (334.0 mg, 3.40 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (138.9 mg, 0.17 mmol), the reaction mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 °C for 2 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0- 30% MeOH / DCM / 0.5% TFA) to give the expected product as a beige solid (145 mg, 32%); LRMS (ESI): m / z [M+H]+264. Step 5- 3 A reaction vessel containing [3-(2-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-2- yl]boronic acid (13a) (35 mg, 0.13 mmol), 4-bromo-5-methoxy-1-methyl-pyrazole (10c) (28 mg, 0.15 mmol), and Cs2CO3(78 mg, 0.24 mmol) in 1,4-dioxane (1.4 mL) and water (0.7 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (21.7 mg, 0.027 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 60 °C for 1 h. After cooling to room temperature, the mixture was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.123 as a pale-yellow solid (1.3 mg, 3%). 1H NMR (400 MHz, DMSO-d6): δ 3.48 (3H, s), 3.70 (3H, s), 7.09 (1H, dd, J = 7.9, 4.7 Hz), 7.45 (1H, d, J = 7.2 Hz), 7.52 (1H, td, J = 7.9, 1.6 Hz), 7.63 (1H, s), 7.64- 7.73 (2H, m), 7.89 (1H, d, J = 7.8 Hz), 8.23 (1H, dd, J = 4.6, 1.5 Hz), 11.86 (NH, s); LRMS (ESI): m / z [M+H]+330. The following compounds were synthesized using conditions analogous to EX.123 in accordance with the general procedure 5.

[0022] 3-Bromo-7-methyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine for preparation of EX.173 was synthesized according to literature procedure WO2018 / 136890. 3-Bromo-5-methyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine for preparation of EX.174 was synthesized according to literature procedure WO2018 / 136890. 3-Bromo-6-methoxy-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine for preparation of EX.195 was obtained according to the method described in the patent WO 2018 / 136890 (PCT / US2018 / 014728). 3-Bromo-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (10wwww) for preparation of EX.196 was obtained according to the method described in the patent WO 2018 / 136890 (PCT / US2018 / 014728). EX.261 was synthesized using conditions analogous to EX.123 in accordance with general procedure 5 (using 10ee and 10ff in step 5- 3), followed by SEM-deprotection step in accordance with methods used in step 6-4 of making EX.273. 1HNMR (400 MHz, CDCl3): δ 3.78 (3H, s), 6.79 (1H, s), 6.94 (1H, d, J = 8.3 Hz), 7.09 – 7.18 (1H, m), 7.55 – 7.66 (2H, m), 7.90 (1H, d, J = 7.9 Hz), 8.16 – 8.23 (1H, m), 11.60 (2H, br s); LRMS (ESI): m / z [M+H]+384. Methyl 3-(3-(2-cyano-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (EX.262) EX.262 is a transesterification product of EX.255 during purification via silica gel column chromatography (eluent: 0%- 30% MeOH / DCM).1H NMR (400 MHz, DMSO- d6): δ 2.14 (2H, s), 3.53 (3H, s), 3.79 (3H, s), 3.98 – 4.28 (4H, m), 6.85 (1H, d, J = 2.6 Hz), 7.02 (1H, dd, J = 8.7, 2.6 Hz), 7.13 (1H, dd, J = 7.9, 4.7 Hz), 7.75 (1H, d, J = 8.7 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 8.28 (1H, dd, J = 4.7, 1.5 Hz), 12.00 (1H, s). LRMS (ESI): m / z [M+H]+430. The following compounds were synthesized in accordance with procedure 5 (steps 5-1, 5-2, 5- 3) using 2-[[3-bromo-4-(trifluoromethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl- silane in step 5- 3, followed by SEM-deprotection as described in step 7-5. The following compounds were synthesized in accordance with the general procedures 1 (steps 1-1, 1-2, 1- 3) and 5.

[0023] The following compounds were synthesized in accordance with the general procedures 2 (step 2-1), 1 (step 1- 3), and 5 (step 5-1, step 5-2, and step 5- 3).

[0024] The following compounds were synthesized in accordance with the general procedures 3 (steps 3-1, 3-2), and 5 (steps 5-2, 5- 3). (7) Experimental Procedure of EX.273 EX.273 was prepared in accordance with general procedure 6 using the method described below in detail. Synthesis of 3-(2-fluoro-5-methoxyphenyl)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine (EX.273) Step 6-1 A reaction vessel containing [1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-2-yl]boronic acid (17b) (360 mg, 1.23 mmol), 4-bromo- 3-methoxy-1- methylpyrazole (10k) (254.2 mg, 1.33 mmol) and Cs2CO3(1.20 g, 3.70 mmol) in 1,4- dioxane (2 mL) and water (0.5 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (100.6 mg, 0.12 mmol), the mixture was purged with nitrogen three times. The resulting mixture was stirred and heated at 80 ºC for 2 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0- 50% EtOAc / Hexane) to give the expected product as a white solid (50 mg, 11%); LRMS (ESI): m / z [M+H]+359. Step 6-2 A mixture of 2-[2-(3-methoxy-1-methyl-pyrazol-4-yl)pyrrolo[2,3-b]pyridin-1- yl]methoxyethyltrimethylsilane (18b) (142 mg, 0.40 mmol) and NBS (69.6 mg, 0.44 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by silica gel column chromatography (0-40% EtOAc / Hexane) to give the expected product as colorless oil (149 mg, 86%); LRMS (ESI): m / z [M+H]+438, 440. Step 6- 3 A reaction vessel containing 2-[3-bromo-2-(3-methoxy-1-methyl-pyrazol-4- yl)pyrrolo[2,3-b]pyridin-1-yl]methoxyethyltrimethylsilane (19b) (50 mg, 0.11 mmol), (2- fluoro-5-methoxy-phenyl)boronic acid (4h) (25.2 mg, 0.15 mmol) and Cs2CO3(111.7 mg, 0.34 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (18.7 mg, 0.02 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ºC for 3 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give the expected product as a white solid (19 mg, 34%); LRMS (ESI): m / z [M+H]+483. Step 6-4 A mixture of 2-[3-(2-fluoro-5-methoxy-phenyl)-2-(3-methoxy-1-methyl-pyrazol-4- yl)pyrrolo[2,3-b]pyridin-1-yl]methoxyethyltrimethylsilane (20b) (12 mg, 0.02 mmol) and TFA (0.2 mL, 2.58 mmol) in DCM (0.3 mL) was stirred at room temperature for 1 h. After concentration to dryness, the residue was treated with NH3in methanol (1 mL), and the mixture was stirred at 50 ºC for 2 h. After concentration, the residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.273 as a white solid (2.2 mg, 25%); LRMS (ESI): m / z [M+H]+353. 1H NMR (400 MHz, DMSO-d6): δ 4.21 (3H, s), 4.32 (3H, s), 4.55 (3H, s), 7.55 (1H, dd, J = 5.8, 3.2 Hz), 7.56-7.66 (1H, m), 7.76-7.86 (2H, m), 7.96 (1H, dd, J = 7.9, 5.8 Hz), 8.71 (1H, d, J = 7.8 Hz), 8.77 (1H, d, J = 5.8 Hz), 13.24 (NH, br s); LRMS (ESI): m / z [M+H]+353. The following compounds were synthesized using conditions analogous to EX.273 in accordance with general procedure 6.

[0025] (8) Experimental Procedure of EX.298 EX.298 was prepared in accordance with general procedure 7 using the method described below in detail. Synthesis of 3-(2-fluoro-5-methoxyphenyl)-2-(3-methoxypyridin-2-yl)-1H- pyrrolo[2,3-b]pyridine (EX.298)

[0026] Step 7-1 A reaction vessel containing (1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-2- yl)boronic acid (17c) (489 mg, 1.86 mmol), 2-bromo- 3-methoxypyridine (10l) (421 mg, 2.24 mmol) and Cs2CO3(1.83 g, 5.60 mmol) in 1,4-dioxane (2 mL) and water (0.7 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (152 mg, 0.18 mmol), the mixture was purged with nitrogen three times. The resulting mixture was stirred and heated at 80 ºC for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hexane) to give the expected product as a tan solid (308 mg, 67%); LRMS (ESI): m / z [M+H]+226. Step 7-2 A mixture of 2-(3-methoxypyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (21a) (306 mg, 1,36 mmol) and NBS (242 mg, 1.36 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by silica gel column chromatography (0-100% EtOAc / Hexane) to give the expected product as a light brown solid (378 mg, 87%); LRMS (ESI): m / z [M+H]+304, 306. Step 7- 3 To a solution of 3-bromo-2-(3-methoxy-2-pyridyl)-1H-pyrrolo[2,3-b]pyridine (22a) (378 mg, 1.24 mmol) in DMF (5 mL) was added NaH, 60% dispersion in mineral oil (32.8 mg, 1.37 mmol) at room temperature and the mixture was stirred at room temperature for 10 min. To this, SEMCl (0.16 mL, 1.86 mmol) was added dropwise, and the mixture was stirred at room temperature for 20 min. The mixture was poured into brine and the product was extracted with EtOAc (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-25% EtOAc / Hexane) to give the expected product as colorless oil (90 mg, 17%); LRMS (ESI): m / z [M+H]+434. Step 7-4 A reaction vessel containing 3-bromo-2-(3-methoxypyridin-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (19c) (90 mg, 0.20 mmol), (2- fluoro-5-methoxy-phenyl)boronic acid (4h) (39 mg, 0.22 mmol) and Cs2CO3(195 mg, 0.60 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (16 mg, 0.02 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ºC for 2 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc / Hexane) to give the expected product as colorless oil (3 mg, 1.5%); LRMS (ESI): m / z [M+H]+480. Step 7-5 A mixture of 2-[[3-(2-fluoro-5-methoxy-phenyl)-2-(3-methoxy-2- pyridyl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (20c) (3 mg, 0.01 mmol) and neat TFA (0.25 mL, 3.30 mmol) was stirred at room temperature for 2 h. After concentration to dryness, the residue was dissolved in MeOH (0.25 mL). To this, ethylenediamine (0.22 mL, 3.30 mmol) was added at room temperature and the mixture was stirred at room temperature for 2 h. The mixture was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.298 as a white solid (1.3 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 3.49 (3H, s), 3.64 (3H, s), 6.74 (1H, dd, J = 6.0, 3.2 Hz), 6.82-6.86 (1 H, m), 7.07-7.20 (2H, m), 7.41 (1H, dd, J = 8.4, 4.8 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.87 (1H, d, J = 8.3 Hz), 8.22 (1H, d, J = 4.7 Hz), 8.32 (1H, dd, J = 4.7, 1.2), 12.20 (NH, br s); LRMS (ESI): m / z [M+H]+350. The following compounds were synthesized using the appropriate starting materials and reaction conditions analogous to EX.298, in accordance with general procedure 7. (9) Experimental Procedure of EX.301 EX.301 was prepared in accordance with the general procedure 8 and procedure 6 using the method described below in detail. Synthesis of 3-(cyclohex-1-en-1-yl)-2-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3- b]pyridine (EX.301) Step 8-1 To a suspension of NaH, 60% dispersion in mineral oil (609 mg, 15.23 mmol) in DMF (16 mL) was added 2-bromo-1H-pyrrolo[2,3-b]pyridine (23) (2.0 g, 15.23 mmol) at 0 ºC and the mixture was stirred for 20 min. To this, SEMCl (2.34 mL, 13.20 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into brine and the product was extracted with EtOAc (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-15% EtOAc / Hexane) to give the expected product as colorless oil (2.58 g, 78%); LRMS (ESI): m / z [M+H]+327, 329. Step 8-2 A reaction vessel containing 2-[(2-bromopyrrolo[2,3-b]pyridin-1- yl)methoxy]ethyl-trimethyl-silane (24a) (1.35 g, 4.12 mmol), (5-fluoro-2- mehoxyphenyl)boronic acid (4b) (911.3 mg, 5.36 mmol) and Cs2CO3(4.03 g, 12.37 mmol) in 1,4-dioxane (9 mL) and water (4 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (673.7 mg, 0.82 mmol), the mixture was purged with nitrogen three times. The resulting mixture was stirred and heated at 90 ºC for 1.5 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0- 30% EtOAc / Hexane) to give the expected product as colorless oil (2.77 g, 67%); LRMS (ESI): m / z [M+H]+373. Step 6-2 To a solution of 2-[[2-(5-fluoro-2-methoxyphenyl)pyrrolo[2,3-b]pyridin-1- yl]methoxy]ethyl-trimethyl-silane (18d) (1.03 g, 2.77 mmol) in DMF (7 mL) was added NBS (541.4 mg, 3.04 mmol) at room temperature and the mixture was stirred at room temperature for 1 h. The mixture was then diluted with EtOAc and washed with sat. aq. NaHCO3(x2). The organic layer was dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0- 30% EtOAc / Hexane) to give the expected product as red oil (1.13 g, 91%); LRMS (ESI): m / z [M+H]+451, 453. Step 6- 3 A reaction vessel containing 2-[[3-bromo-2-(5-fluoro-2-methoxy- phenyl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (19d) (20.0 mg, 0.04 mmol), 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3d) (11.1 mg, 0.05 mmol) and Cs2CO3(43.3 mg, 0.13 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2- DCM (3.6 mg, 4.40 µmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 80 ºC for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-15% EtOAc / Hexane) to give the expected product as yellow oil (16.7 mg, 83%); LRMS (ESI): m / z [M+H]+453. Step 6-4 (i) A mixture of 2-[[3-(cyclohexen-1-yl)-2-(5-fluoro-2-methoxy-phenyl)pyrrolo[2,3- b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (20d) (16.7 mg, 0.04 mmol) and neat TFA (0.28 mL, 3.69 mmol) was stirred at room temperature for 1 h. After concentration to dryness, the residue was used for the next reaction without further purification; LRMS (ESI): m / z [M+H]+353. Step 6-4 (ii) To a solution of (3-(cyclohex-1-en-1-yl)-2-(5-fluoro-2-methoxyphenyl)-1H- pyrrolo[2,3-b]pyridin-1-yl)methanol (25) in MeOH (0.5 mL) was added ethylenediamine (0.25 mL, 3.69 mmol) at room temperature and the mixture was stirred at room temperature for 30 min, then 50 ºC for 10 min. The mixture was then poured into brine and the product was extracted with DCM (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.301 as an off-white solid (9.2 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 1.60 (4H, br s), 2.08 (4H, br s), 3.76 (3H, s), 5.65 (1H, s), 7.05 (1H, dd, J = 7.9, 4.7 Hz), 7.11 (1H, dd, J = 9.0, 4.7 Hz), 7.15-7.27 (2H, m), 7.94 (1H, dd, J = 7.9, 1.5 Hz), 8.20 (1H, dd, J = 4.6, 1.5 Hz), 11.64 (NH, br s); LRMS (ESI): m / z [M+H]+323. The following compound was synthesized using conditions analogous to the compound (25) in accordance with the general procedure 8 and procedure 6. The following compounds were synthesized using conditions analogous to EX.301 in accordance with general procedure 8 and procedure 6.

[0027] (10) Experimental Procedure of EX.337 EX.337 was prepared in accordance with the general procedure 10 using the method described below in detail. Synthesis of 2-(2-(5-fluoro-2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin- 3- yl)benzonitrile (EX.337) Step 10-1 To a solution of 2-(2-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin- 3- yl)benzonitrile (EX.1) (14 mg, 0.041 mmol) in DMF (0.2 mL) was added NaH, 60% dispersion in mineral oil (1.8 mg, 0.045 mmol). After the addition of MeI (5.1 µL, 0.081 mmol), the mixture was stirred at room temperature for 30 min. The mixture was quenched with MeOH and purified by silica gel chromatography to give EX.337 as a white solid (11 mg, 72%). (Mixture of atropisomers)1H NMR (400 MHz, DMSO-d6): δ 3.58- 3.70 (6H, m), 6.97-7.30 (5H, m), 7.46 (1H, m), 7.64 (1H, br s), 7.85 (1H, d, J = 7.6 Hz), 8.40 (1H, dd, J = 4.7, 1.5 Hz); LRMS (ESI): m / z [M+H]+358. The following compounds were synthesized using conditions analogous to EX.337 and the appropriate alkylating reagents in accordance with the general procedure 10.

[0028] 2-(2-(5-Fluoro-2-methoxyphenyl)- 3-(2-fluoro-5-methylphenyl)-1H-pyrrolo[2,3- b]pyridin-1-yl)ethan-1-ol (EX.340) 2-(2-(5-Fluoro-2-methoxyphenyl)- 3-(2-fluoro-5-methylphenyl)-1H-pyrrolo[2,3- b]pyridin-1-yl)ethan-1-ol (EX.340) was prepared by reacting EX.21 with 2-(2- bromoethoxy)tetrahydropyran in accordance with the general procedure 10, followed by treatment with 4M HCl. 1H NMR (400 MHz, DMSO-d6): δ 2.18 (3H, s), 3.48- 3.56 (1H, m), 3.57- 3.66 (1H, m), 3.70 (3H, s), 3.94 (1H, dt, J = 14.0, 7.1 Hz), 4.31-4.41 (1H, m), 4.86 (OH, t, J = 5.6 Hz), 6.97 (1H, d, J = 7.6 Hz), 7.03-7.10 (3H, m), 7.13-7.22 (2H, m), 7.31 (1H, td, J = 8.7, 3.2 Hz), 7.82 (1H, d, J = 7.8 Hz), 8.35 (1H, dd, J = 4.7, 1.5 Hz); LRMS (ESI): m / z [M+H]+395. (11) Experimental Procedure of EX.341 EX.341 was prepared in accordance with the general procedure 10 using the method described below in detail. Synthesis of 1-[2-(5-fluoro-2-methoxyphenyl)- 3-(2-fluoro-5- methylphenyl)pyrrolo[2,3-b]pyridin-1-yl]ethanone (EX.341) Step 10-1 The solution of 2-(5-fluoro-2-methoxy-phenyl)- 3-(2-fluoro-5-methyl-phenyl)-1H- pyrrolo[2,3-b]pyridine (EX.21) (15 mg, 0.04 mmol) in acetic anhydride (0.2 mL) was heated at 125 ºC for 5 h. After cooling to room temperature, the mixture was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.341 as a white solid (12 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 2.22 (3H, s), 3.04 (3H, s), 3.68 (3H, s), 6.87 (1H, dd, J = 8.9, 3.1 Hz), 7.00-7.03 (2H, m), 7.09-7.20 (3H, m), 7.38 (1H, dd, J = 7.9, 4.8 Hz), 7.81-7.84 (1H, m), 8.49 (1H, dd, J = 4.8, 1.6 Hz); LRMS (ESI): m / z [M+H]+393. (12) Experimental Procedure of EX.342 EX.342 was prepared in accordance with the general procedure 11 using the method described below in detail. Synthesis of 2-(2-(5-fluoro-2-hydroxyphenyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine- 3-yl)benzonitrile (EX.342) Step 11-1 To a suspension of 2-[2-(5-fluoro-2-methoxy-phenyl)-4-methoxy-1H-pyrrolo[2,3- b]pyridine- 3-yl]benzonitrile (37b) (22.0 mg, 0.06 mmol) in 1,4-dioxane (2 mL) was added 1M BBr3in DCM (1.2 mL, 1.20 mmol) at room temperature and the mixture was stirred at 120 ºC overnight. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (0-20% MeOH / DCM) to give the expected product as a tan solid (7.8 mg, 36%). 1H NMR (400 MHz, DMSO-d6): δ 3.75 (3H, s), 6.72 (1H, d, J = 5.4 Hz), 6.76-6.83 (2H, m), 6.99 (1H, td, J = 8.6, 3.1 Hz), 7.24 (1H, d, J = 7.8 Hz), 7.40 (1H, t, J = 7.7 Hz), 7.51 (1H, t, J = 7.7 Hz), 7.78 (1H, d, J = 7.7 Hz), 8.17 (1H, d, J = 5.4 Hz), 9.62 (OH, s), 12.01 (1H, br s); LRMS (ESI): m / z [M+H]+360. The following compounds were synthesized using conditions analogous to EX.342 in accordance with the general procedure 11.

[0029] (13) Experimental Procedure of EX.345 EX.345 was prepared in accordance with the general procedure 12 using the method described below in detail. Synthesis of 2-(5-fluoro-2-(methoxy-d3)phenyl)- 3-(2-fluoro-5-methoxyphenyl-1H- pyrrolo[2,3-b]pyridine (EX.345) Step 12-1 To a solution of 4-fluoro-2-[3-(2-fluoro-5-methoxyphenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-2-yl]phenol (7i) (16.8 mg, 0.03 mmol) in DMF (1 mL) was added NaH, 60% dispersion in mineral oil (2.1 mg, 0.05 mmol) and the mixture was stirred at room temperature for 10 min. After the addition of CD3I (6.5 µL, 0.10 mmol), the mixture was further stirred at room temperature for 2 h. The mixture was quenched with brine and the product was extracted with DCM (x3). The combined organic extracts were dried over Na2SO4and concentrated. The residue was used for the next reaction without further purification (16.5 mg, 95%); LRMS (ESI): m / z [M+H]+500. Step 12-2 2-[[3-(2-fluoro-5-methoxy-phenyl)-2-[5-fluoro-2- (trideuteriomethoxy)phenyl]pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (7j) (16.5 mg, 0.03 mmol) and neat TFA (0.25 mL, 3.30 mmol) was stirred at room temperature for 30 min. After concentration to dryness, the residue was dissolved in MeOH (0.25 mL). To this, ethylenediamine (0.22 mL, 3.30 mmol) was added at room temperature and the mixture was stirred at room temperature for 30 min. The mixture was then poured into brine and the product was extracted with DCM (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hexane) to give the expected product as a white solid (6.3 mg, 49%). 1H NMR (400 MHz, DMSO-d6): δ 3.62 (3H, s), 6.71 (1H, dd, J = 5.5, 3.1 Hz), 6.81-6.90 (1H, m), 7.03-7.27 (5H, m), 7.82 (1H, d, J = 7.5 Hz), 8.29 (1H, d, J = 4.2 Hz), 12.12 (1H, br s); LRMS (ESI): m / z [M+H]+370. The following compounds were synthesized using conditions analogous to EX.345 in accordance with the general procedure 12. EX.350 was prepared in accordance with the general procedure 13 using the method described below in detail. Synthesis of 3-(2-cyanophenyl)-2-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3- b]pyridine 7-oxide (EX.350) Step 13-1 To a solution of 2-(2-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin- 3- yl)benzonitrile (EX.1) (50 mg, 0.15 mmol) in DME (2mL) was added mCPBA (40.2 mg, 0.23 mmol) and the mixture was stirred at room temperature for 1.5 h. The mixture was then poured into water and basified to pH 9-10 with sat. aq. K2CO3. The precipitate was filtered off and the filtrate was extracted with DCM (x3). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.350 as a white solid (5 mg, 10%). 1H NMR (400 MHz, CD3CN): δ 3.38 (3H, s), 6.81-7.33 (3H, m), 7.35-7.56 (2H, m), 7.57-7.85 (3H, m), 7.87-8.01 (1H, m), 8.06-8.27 (1H, m); LRMS (ESI): m / z [M+H]+360. (15) Experimental Procedure of EX.351 EX.351 was prepared in accordance with the general procedure 14 using the method described below in detail. Synthesis of 2-(5-fluoro-2-methoxyphenyl)- 3-(6-methoxy- 3,3-dimethylcyclohex-1-en- 1-yl)-1H-pyrrolo[2,3-b]pyridine (EX.351)

[0030] Step 14-1 To a solution of 2-[2-(5-fluoro-2-methoxy-phenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]-4,4-dimethyl-cyclohex-2-en-1-one (38a) (127 mg, 0.26 mmol) in methanol (3 mL) was added CeCl3·7H2O (114.8 mg, 0.31 mmol) and NaBH4(11.6 mg, 0.31 mmol) under nitrogen at 0 ºC. The mixture was stirred at 0 ºC for 30 min then room temperature for 1 h. After concentration, the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc / Hexane) to give the expected product as colorless oil (102 mg, 80%); LRMS (ESI): m / z [M+H]+497. Step 14-2 To a solution of 2-[2-(5-fluoro-2-methoxy-phenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]-4,4-dimethyl-cyclohex-2-en-1-ol (39a) (25 mg, 0.05 mmol) in DMF (0.5 mL) was added NaH, 60% dispersion in mineral oil (2.6 mg, 0.07 mmol) and the mixture was stirred at room temperature for 10 min. After the addition of MeI (4.1 µL, 0.065 mmol), the mixture was further stirred at room temperature for 2 h. The mixture was then poured into water and the product was extracted with EtOAc (x2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was used for the next reaction without further purification (20 mg, 47%); LRMS (ESI): m / z [M+H]+511. Step 14- 3 A mixture of 2-[[2-(5-fluoro-2-methoxy-phenyl)- 3-(6-methoxy- 3,3-dimethyl- cyclohexen-1-yl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (40a) (20 mg, 0.02 mmol) and TFA (0.3 mL, 3.92 mmol) in DCM (0.5 mL) was stirred at room temperature for 1 h. After concentration to dryness, the residue was treated with NH3in methanol (1 mL), and the mixture was stirred at room temperature for 1 h. After concentration, the residue was purified by prep HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA) to give EX.351 as a white solid (5.6 mg, 61%). 1H NMR (400 MHz, DMSO-d6): δ 0.88 (3H, s), 0.92 (3H, s), 1.30-1.41 (1H, m), 1.51- 1.63 (1H, m), 1.65-1.77 (1H, m), 1.78-1.89 (1H, m), 2.99 (3H, s), 3.74- 3.79 (4H, m), 5.31 (1H, s), 7.06 (1H, dd, J = 7.9, 4.7 Hz), 7.11 (1H, dd, J = 8.9, 4.5 Hz), 7.18-7.31 (2H, m), 7.95 (1H, dd, J = 8.1, 1.3 Hz), 8.21 (1H, dd, J = 4.7, 1.6 Hz), 11.67 (1H, s); LRMS (ESI): m / z [M+H]+381. (16) Experimental Procedure of EX.352 EX.352 was prepared in accordance with the general procedure 14 using the method described below in detail. Synthesis of 2-[2-[2-(1-hydroxyethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3- yl]-1H-pyrrolo[2,3-b]pyridin- 3-yl]-4-methoxy-benzonitrile: (EX.352 ) Step 14-1 (ref.: Angew. Chem. Int. Ed.2019, 58, 17567) To a solution of the 2-[2-(2-acetyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3- yl)-1H-pyrrolo[2,3-b]pyridin- 3-yl]-4-methoxy-benzonitrile (38b) (19.6 mg, 0.05 mmol) in THF (3 mL) and Methanol (1 mL) with H2O (3.42 uL, 0.19 mmol) was added NaBH4 (3.59 mg, 0.09 mmol) at once. After 15 min, the reaction mixture was quenched with 1 mL of sat. NH4Cl and concentrated under reduced pressure. The crude material was purified by ISCO-column chromatography (normal-phase silica gel) using 0- 30% MeOH on DCM gave pure compound EX.352 as an off-white solid, 18 mg 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (3H, s), 2.03 (2H, bs), 3.66 – 3.96 (5H, m), 4.03 (2H, t, J = 5.8 Hz), 4.65 (1H, bs), 5.63-5.83 (1H, m), 6.80 – 7.01 (1H, m), 7.05 (1H, dd, J = 8.7, 2.6 Hz), 7.12 (1H, dd, J = 7.9, 4.7 Hz), 7.79 (2H, d, J = 7.7 Hz), 8.24 (1H, dd, J = 4.7, 1.5 Hz), 11.76 (1H, s). LRMS (ESI): m / z [M+H]+416. (17) Experimental Procedure of EX.353 and EX.354 EX.353 and EX.354 were prepared in accordance with the general procedures 5 and 29 using the method described below in detail. Synthesis of 2-[2-[6-amino-2-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl]- 1H-pyrrolo[2,3-b]pyridin- 3-yl]-4-methoxy-benzonitrile (EX.353 ) and N-[3-[3-(2- cyano-5-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-methyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-6-yl]acetamide (EX.354 )

[0031] Step 5- 3 A reaction vessel containing (3-(2-cyano-5-methoxyphenyl)-1H-pyrrolo[2,3- b]pyridin-2-yl)boronic acid (4m) (220 mg, 0.59 mmol), tert-butyl N-[3-iodo-2-methyl-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl]carbamate (10llll) (244.5 mg, 0.64 mmol) and Cs2CO3(573 mg, 1.76 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and backfilled with N2 three times. After the addition of PdCl2(dppf).DCM (95.7 mg, 0.12 mmol), the mixture was purged with N2three times again, and heated at 90 °C for 98 min. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (0- 100% EtOAc / hexanes) to obtain expected product as a brown solid (130 mg, 44%); LCMS (ESI): m / z [M+H]+501. Step 29-1 A solution containing tert-butyl N- 3-[3-(2-cyano-5-methoxy-phenyl)-1H- pyrrolo[2,3-b]pyridin-2-yl]-2-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6- yl]carbamate (70a) (178 mg, 0.36 mmol) in DCM (3.7 mL) was cooled to 0 °C and added TFA (0.54 mL, 7.11 mmol). After addition ice bath was removed and reacted at room temperature for 2 h. The reaction mixture was cooled at 0 °C, added sat. NaHCO3dropwise (pH = ~7-8) and extracted with EtOAc. Organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford an orange oil which was further purified by prep-HPLC (CH3CN / 0.1% TFA - H2O / 0.1% TFA). Fractions containing product were combined, concentrated, and added saturated NaHCO3(pH 7-8). Resulting solution was transferred to a separatory funnel and extracted with EtOAc. Combined organic layers were further washed with water (x3), dried over anhydrous Na2SO4and concentrated under reduced pressure to afford EX.353 as a white solid (31 mg.21%);1H NMR (400 MHz, DMSO-d6): δ 1.77-1.92 (5H, m), 3.28- 3.32 (1H, m), 3.64- 3.69 (2H, m), 3.82 (3H, s), 3.95-4.14 (2H, m), 6.96 (1H, d, J = 2.5 Hz), 7.04 (1H, dd, J = 8.7, 2.6 Hz), 7.12 (1H, dd, J = 7.9, 4.7 Hz), 7.77-7.83 (2H, m), 8.25 (1H, dd, J = 4.7, 1.6 Hz), 11.93 (1H, br s); LRMS (ESI): m / z [M+H]+401. Step 29-2 A solution of 4-methoxy-2-[2-[6-amino-2-methyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin- 3-yl]-1H-pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (EX.353 ) (47 mg, 0.12 mmol), THF (3.3 mL), Et3N (18 uL, 0.13 mmol) was cooled to 0 °C and stirred for 6 min, added dropwise CH3COCl (8.3 uL, 0.12 mmol) in THF (0.67 mL). Reacted at 0 °C for 4 min and then at room temperature for 46 min additional CH3COCl (0.8 uL) was added and stirred for 15 min. Further addition of CH3COCl (2.2 uL) and reacted for another 35 min. The reaction was partitioned between water and extracted with EtOAc. Organic layer was washed with water (x3) and evaporated solvent in vacuo. Crude residue was purified by silica gel column chromatography (0-8% MeOH / DCM), fractions were dried and lyophilized. The white solid was further dried in the rotavapor at 50 °C for 2 h to obtain EX.354 as an off-white solid (37.5 mg, 70%);1H NMR (400 MHz, DMSO-d6): δ 1.80 (3H, br s), 1.82 (3H, br s), 3.79- 3.90 (4H, m), 3.98-4.04 (2H, m), 4.21-4.28 (2H, m), 6.93-7.02 (1H, m), 7.05 (1H, dd, J = 8.7, 2.5 Hz), 7.13 (1H, dd, J = 7.9, 4.7 Hz), 7.78- 7.84 (2H, m), 8.04 (0.5H, br s), 8.26 (1H, dd, J = 4.7, 1.5 Hz), 8.31 (0.5H, br s), 11.94 (1H, br s); LRMS (ESI): m / z [M+H]+443. The following compounds were synthesized using conditions analogous to EX.353 and EX.354 in accordance with the general procedures 5 and 29. (18) Experimental Procedure of EX.365 EX.365 was prepared in accordance with the general procedure 31 using the method described below in detail. Synthesis of 2-[2-[4-(difluoromethyl)-1H-pyrazol- 3-yl]-1H-pyrrolo[2,3-b]pyridin- 3- yl]-4-(trideuteriomethoxy)benzonitrile (EX.365 ) Step 31-1 To a solution of 2-[2-[4-(difluoromethyl)-1-tetrahydropyran-2-yl-pyrazol- 3-yl]-1H- pyrrolo[2,3-b]pyridin- 3-yl]-4-(trideuteriomethoxy)benzonitrile (EX.207 ) in THF / H2O / EtOH (0.5 mL / 0.1 mL / 0.5 mL) was added conc. HCl (25 uL of 12.4 M, 0.31mmol). Resulting solution was stirred at room temperature for 48 h. Thereafter, reaction mixture was slowly poured to a 30 mL saturated solution of sodium bicarbonate and extracted thrice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford a white solid which was purified by prep- HPLC [Kinetex 5u C18100A RXI, 150 x 21.20 mm, 30-70% CH3CN w / 0.1% TFA in H2O w / 0.1% TFA over 20 min, flow rate 20 mL / min, UV 225]. Pure fractions were passed through the PL-HCO3MP flash, concentrated, and lyophilized to afford a white solid (3.5 mg, 28%) as product (EX.365 ). 1H NMR (400 MHz, DMSO-d6): δ 6.59 (1H, t, JH-F= 55.8 Hz), 6.90 (1H, d, J = 2.6 Hz), 7.06 (1H, dd, J = 8.7, 2.6 Hz), 7.20 (1H, dd, J = 8.0, 4.7 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.89 (1H, dd, J = 8.0, 1.1Hz), 8.13 (1H, s), 8.37 (1H, dd, J = 4.6, 1.4 Hz), 12.62 (1H, s), 13.53 (1H, s); LRMS (ESI): m / z [M+H]+369. (19) Experimental Procedure of EX.366 EX.366 was prepared in accordance with the general procedures 5 and 34 using the method described below in detail. Synthesis of 2-[2-[(6S)-6-hydroxy-2-methyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin- 3-yl]-1H-pyrrolo[2,3-b]pyridin- 3-yl]-4- (trideuteriomethoxy)benzonitrile (EX.366 ) Step 5- 3 A 10 ml round bottom flask containing 4-(methoxy-d3)-2-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin- 3-yl)benzonitrile (4mi) (50 mg, 0.13 mmol), tert-butyl-[[(6S)- 3-iodo-2-methyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-6-yl]oxy]-diphenyl-silane (10iiiii) (133 mg, 0.26 mmol) and Cs2CO3(180 mg, 0.55 mmol) in 1,4-Dioxane / H2O (1 mL / 0.2 mL) was thrice evacuated and backfilled with nitrogen. After the addition of Pd(dppf)Cl2-DCM (32 mg, 0.04 mmol), the mixture was again thrice evacuated and backfilled with nitrogen and stirred at 90 ºC for 1 h. Thereafter, the aqueous layer was pipetted out and the remaining liquid (dark colored) was purified by silica gel column chromatography [4g pre-pack silica gel column (gold), eluted with 100% Hexanes (2 min.), 70% EtOAc / Hexanes (5 min.), 80% EtOAc / Hexanes (5 min.), 90% EtOAc / Hexanes (5 min.), 100% EtOAc / Hexanes (5 min.), 0 to 5% MeOH / DCM (5 min.), 10% MeOH / DCM (5 min.), 30% MeOH / DCM (5 min.)] to afford a light tan colored oil (20.5 mg, 24%) as product. LRMS (ESI): m / z [M+H]+643. Step 34-1 A 10 mL round bottom flask containing 2-[2-[(6S)-6-[tert- butyl(diphenyl)silyl]oxy-2-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl]-1H- pyrrolo[2,3-b]pyridin- 3-yl]-4-(trideuteriomethoxy)benzonitrile (80a) (20 mg, 0.03 mmol) in THF (1.5 mL) at 0 ºC was treated with TBAF (0.09 mL, 0.09 mmol) and stirred for 1 h at 0 ºC. Thereafter, the reaction mixture was quenched with cold water and extracted thrice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Residue was purified by silica gel chromatography [ 4g pre- pack silica gel column (gold) , eluted with 100% Hexanes (2 min.), 70% EtOAc / Hexanes (5 min.), 80% EtOAc / Hexanes (5 min.), 90% EtOAc / Hexanes ( 5 min.), 100% EtOA EtOAc / Hexanes ( 5 min.), 0 to 5% MeOH / DCM ( 5 min.), 10% MeOH / DCM ( 5 min.), 30% MeOH / DCM ( 5 min.)] to afford a yellow oil which was re-purified by prep- HPLC [Kinetex 5u C18100A RXI, 150 x 21.20 mm, 30-70% CH3CN w / 0.1% TFA in H2O w / 0.1% TFA over 20 min, flow rate 20 mL / min, UV 240]. Pure fractions were passed through the PL-HCO3MP column, concentrated, and lyophilized to afford a white solid (3.6 mg, 28%) as product. (mixture of atropisomers)1H NMR (400 MHz, DMSO-d6): δ 1.80 (1.5H, br s), 1.92 (1.5H, br s), 3.83 – 3.97 (3H, m), 4.11 – 4.23 (2H, m), 5.49 (1H, br s), 6.90 (1H, br s), 7.03 (1H, dd, J = 8.6, 2.6 Hz), 7.12 (1H, dd, J = 7.9, 4.7 Hz), 7.72 – 7.86 (2H, m), 8.25 (1H, dd, J = 4.7 Hz, 1.5 Hz), 11.93 (1H, s); LRMS (ESI): m / z [M+H]+405. The following compounds were synthesized using conditions analogous to EX.366 in accordance with the general procedures 5 (step 5- 3) and 34.

[0032] (20) Experimental Procedure of EX.372 EX.372 was prepared in accordance with the general procedures 36 using the method described below in detail. Synthesis of 2-[5-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl)-4H-pyrrolo[2,3- d]thiazol-6-yl]benzonitrile (EX.372 )

[0033] Step 36-1 A reaction vessel containing tert-butyl N-(5-iodothiazol-4-yl)carbamate (10nnnnn) (1.6 g, 4.91 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (3u) (1.17 g, 5.89 mmol) and Cs2CO3(4.8 g, 14.72 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was thrice evacuated and backfilled with nitrogen. After the addition of Pd(dppf)Cl2-DCM (600 mg, 0.74 mmol), mixture was again thrice evacuated & backfilled with nitrogen and stirred at 80 ºC for 1h. Thereafter, the aqueous layer was pipetted out and remaining liquid (dark colored) was concentrated. The residue was purified by silica gel column chromatography (eluted with 0-50% EtOAc / Hexanes) to afford a red oil (1.15 g, 87%) as the expected product. LRMS (ESI): m / z [M+H-tBu]+215. Step 36-2 A mixture of tert-butyl N-[5-[(E)-2-ethoxyvinyl]thiazol-4-yl]carbamate (97a) (7.38 g, 27.3 mmol) and 70 ml (2N HCl, 140 mmol) was stirred at 90 ºC for 1h. Thereafter, mixture was decanted to a separatory funnel and extracted thrice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 0-40% EtOAc / Hexanes) to afford a brown oil (1.08 g, 32%); LRMS (ESI): m / z [M+H]+125. Step 36- 3 To a solution of 4H-pyrrolo[2,3-d]thiazole (98a) (500 mg, 4.03 mmol) in DMF (15 mL) at 0 ºC was added slowly NaH (60% in mineral oil) (193 mg, 4.83 mmol) and stirred at 0 ºC for 10 min. Afterwards, SEM-Cl (0.78mL, 4.43mmol) was added and stirred at room temperature for 1 h. The mixture was then diluted with DCM, decanted into a separatory funnel, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 0- 30% EtOAc / Hexanes) to afford a tan-colored oil (965 mg, 94%) as the expected product. LRMS (ESI): m / z [M+H]+255. Step 36-4 A mixture of trimethyl-[2-(pyrrolo[2,3-d]thiazol-4-ylmethoxy)ethyl]silane (99a) (965 mg, 3.79 mmol) and NIS (896 mg, 3.98 mmol) in DCM (20 ml) was stirred for 1 h. Afterwards, additional 500 mg of NIS was added and further stirred for 1 h. Thereafter, mixture was decanted into a separatory funnel containing Na2S2O3(sat. aqueous) and extracted twice with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 0-20% EtOAc / Hexanes) to afford a red oil (1.12 g, 77%); LRMS (ESI): m / z [M+H]+381. Step 36-5 A reaction vessel containing 2-[(6-iodopyrrolo[2,3-d]thiazol-4-yl)methoxy]ethyl- trimethyl-silane (100a) (400 mg, 1.05 mmol), (2-cyanophenyl)boronic acid (4a) (185 mg, 1.26 mmol) and Cs2CO3(1.03 g, 3.16 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was thrice evacuated and backfilled with nitrogen. After the addition of Pd(dppf)Cl2- DCM (171 mg, 0.21 mmol), mixture was again thrice evacuated and backfilled with nitrogen and stirred at 80 ºC for 1h Thereafter, the aqueous layer was pipetted out and remaining liquid (dark colored) was concentrated. The residue was purified by silica gel column chromatography (eluted with 0-70% EtOAc / Hexanes) to afford a yellow oil (127.3 mg, 34%) as the expected product. LRMS (ESI): m / z [M+H]+356. Step 36-6 A mixture of 2-[4-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]thiazol-6- yl]benzonitrile (101a) (127 mg, 0.36 mmol) and NBS (76 mg, 0.43 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. Afterwards, mixture was concentrated and purified by silica gel column chromatography (eluted with 0-20% EtOAc / Hexanes) to afford a dark brown oil (119.7 mg, 77%) as the expected product. LRMS (ESI): m / z [M+H]+434, 436. Step 36-7 A reaction vessel containing 2-[5-bromo-4-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-d]thiazol-6-yl]benzonitrile (102a) (50 mg, 0.12 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine (3v) (58 mg, 0.23 mmol) and Cs2CO3(112 mg, 0.35 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was thrice evacuated and backfilled with nitrogen. After the addition of Pd(dppf)Cl2-DCM (18.8mg, 0.02 mmol), mixture was again thrice evacuated and backfilled with nitrogen and stirred at 80 ºC for 1h. Thereafter, the aqueous layer was pipetted out and remaining liquid (dark colored) was concentrated. The residue was purified by silica gel column chromatography (eluted with 0-50% EtOAc / Hexanes) to afford a dark brown oil (25.2 mg, 46%) as the expected product. LRMS (ESI): m / z [M+H]+478. Step 36-8 A mixture of 2-[5-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl)-4-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-d]thiazol-6-yl]benzonitrile (103a) (25 mg, 0.05 mmol) and neat TFA (0.2 mL, 2.64 mmol) was stirred at room temperature for 30 min. Afterwards, mixture was concentrated, dissolved in MeOH (0.5 mL), treated with ethylenediamine (0.12 mL, 1.75 mmol) and stirred for 30 min at room temperature Thereafter, mixture was directly purified by silica gel column chromatography (eluted with 0-100% EtOAc / Hexanes). Fractions with product were concentrated and re-purified by prep-HPLC (Kinetex 5u C18100A RXI, 150 x 21.20 mm, 30-70% CH3CN w / 0.1% TFA in H2O w / 0.1% TFA for 8 min, flow rate 20 mL / min). Pure fractions of product were passed through a PL-HCO3MP column and lyophilized to afford an off-white solid (10.2 mg, 54%) as the expected product. 1H NMR (400 MHz, DMSO-d6) δ 2.03 – 2.11 (2H, m), 3.93 – 4.01 (2H, m), 4.06 (2H, t, J = 6.0 Hz), 7.28 (1H, s), 7.46 (2H, apparent t, J = 7.3 Hz), 7.65 (1H, apparent t, J = 7.6 Hz), 7.85 (1H, d, J = 7.9 Hz), 8.79 (1H, s), 12.20 (1H, s) ; LRMS (ESI): m / z [M+H]+348. The following compound was synthesized using conditions analogous to EX.372 in accordance with the general procedure 36.

[0034] (21) Experimental Procedure of EX.375 EX.375 was prepared in accordance with the general procedures 3, 37 and 1 using the method described below in detail. Synthesis of 4-chloro-2-[2-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-1H- pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (EX.375)

[0035] Step 3-1 A reaction vessel containing tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (9) (5 g, 14.53 mmol), 2-bromo-4-chloro- benzonitrile (10ooooo) (3.77 g, 17.43 mmol) and Cs2CO3(14.2 g, 43.58 mmol) in 1,4- dioxane (30 mL) and water (10 mL) was thrice evacuated & backfilled with nitrogen. After the addition of Pd(dppf)Cl2-DCM (1.78 g, 2.18 mmol), mixture was again thrice evacuated & backfilled with nitrogen and stirred at 80 ºC for 1h. Thereafter, the aqueous layer was pipetted out and remaining liquid (dark colored) was concentrated. The residue was purified by silica gel column chromatography (eluted with 0-100% EtOAc / Hexanes) to afford an orange solid (4.87 g, 95%) as the expected product. LRMS (ESI): m / z [M+H]+354. Step 37-1 To a solution of tert-butyl 3-(5-chloro-2-cyano-phenyl)pyrrolo[2,3-b]pyridine-1- carboxylate (5f) (5.09 g, 14.39 mmol) in DCM (50 mL) was added TFA (22 mL, 287.73 mmol) at room temperature and stirred for 1 h. Afterwards, mixture was concentrated, treated with saturated aqueous solution of NaHCO3and stirred vigorously for 10 min. Thereafter, solids were filtered, washed with water and dried to afford product as a TFA salt (5.13 g, 97%, orange solid); LRMS (ESI): m / z [M+H]+254. Step 37-2 To a solution of 4-chloro-2-(1H-pyrrolo[2,3-b]pyridin- 3-yl)benzonitrile (11d) (2.07 g, 8.16 mmol) in DMF (40 mL) was added NaH (60% in mineral oil) (489.57 mg, 12.24 mmol) at 0 ºC and stirred for 10 min. Afterwards, SEM-Cl (1.73 mL, 9.79 mmol) was added slowly, and the resulting mixture was stirred further at 0 ºC for 1 h. The reaction was quenched with water and extracted thrice with DCM (x3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 0- 30% EtOAc / Hexanes) to afford a pale-yellow solid (824 mg, 26%) as the expected product. LRMS (ESI): m / z [M+H]+384. Step 1- 3 To a solution of 4-chloro-2-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin- 3-yl]benzonitrile (5g) (824 mg, 2.15 mmol) in DCM (10 mL) was added NBS (420 mg, 2.36 mmol, see note) and stirred for a total 2 h and 40 min. at room temperature. Reaction mixture diluted with DCM, washed with NaHCO3(sat. aqueous solution), dried over Na2SO4, filtered, and concentrated. The residue was then purified by silica gel column chromatography (eluted with 0-20% EtOAc / Hexanes) to afford a peach-colored oil (956 mg, 96%) as the expected product. LRMS (ESI): [M+H]+462, 464. Note: Additional 2 drops of bromine were added after 2 h and followed by 5 drops after 10 min. Step 1-4 A reaction vessel containing 2-[2-bromo-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]-4-chloro-benzonitrile (6f) (50 mg, 0.11 mmol), [3-(difluoromethyl)-1-methyl-pyrazol-4-yl]boronic acid (4n) (23 mg, 0.13 mmol) and Cs2CO3(105 mg, 0.32 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was thrice evacuated and backfilled with nitrogen. After the addition of Pd(dppf)Cl2- DCM (18 mg, 0.02 mmol), mixture was again thrice evacuated and backfilled with nitrogen and stirred at 80 ºC for 1 h. Thereafter, the aqueous layer was pipetted out and remaining liquid (dark colored) was directly purified by silica gel column chromatography (eluted with 0-70% EtOAc / Hexanes) to afford a colorless oil (32.8 mg, 59%) as the expected product. LRMS (ESI): m / z [M+H]+514. Step 1-5 A mixture of 4-chloro-2-[2-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (7z) (32.8 mg, 0.06 mmol) and neat TFA (0.24 mL, 3.19 mmol) was stirred at room temperature for 30 min. Afterwards. Afterwards, the mixture was concentrated, dissolved in MeOH (0.5 mL) treated with ethylenediamine (0.12 mL, 1.75 mmol), and stirred for 30 min at room temperature. Thereafter, mixture was directly purified by silica gel column chromatography (eluted with 0-100% EtOAc / Hexanes). Fractions with product were concentrated and re-purified by prep HPLC (Kinetex 5u C18100A RXI, 150 x 21.20 mm, 20-70% CH3CN w / 0.1% TFA in H2O w / 0.1% TFA for 8 min, flow rate 20 mL / min). Pure fractions of product were passed through a PL-HCO3MP column and lyophilized to afford a white solid (3.9 mg, 15%) as the expected product. LRMS (ESI): m / z [M+H]+384. 1H NMR (400 MHz, DMSO-d6): δ 3.93 (3H, s), 6.69 (1H, t, JH-F= 53.9 Hz), 7.18 (1H, dd, J = 7.9, 4.7 Hz), 7.49 (1H, d, J = 2.1 Hz), 7.60 (1H, dd, J = 8.4, 2.1 Hz), 7.82 (1H, dd, J = 7.9, 1.5 Hz), 7.93 (1H, d, J = 8.4 Hz), 8.01 (1H, s), 8.33 (1H, dd, J = 4.7, 1.5 Hz), 12.30 (1H, s); LRMS (ESI): m / z [M+H]+384. The following compounds were synthesized analogous to EX.375 in accordance with the general procedures 1, 3 and 37 using the appropriate starting material.

[0036] (22) Experimental Procedure of EX.387 EX.387 was prepared in accordance with the general procedure 39 using the method described below in detail. Synthesis of 2-[6-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-7H-pyrrolo[2,3- d]pyrimidin-5-yl]-4-methoxy-benzonitrile (EX.387 ) Step 39-1 To a solution of 2-[2-chloro-6-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-4-methoxy-benzonitrile (EX.82 ) (6.4 mg, 0.02 mmol) in methanol (0.5 mL) was added 10% Pd / C (1.64 mg, 0.015 mmol) under N2was thrice evacuated and backfilled with hydrogen and the mixture was stirred under H2atmosphere (balloon) at room temperature for a total of ~4 days. Thereafter, mixture was filtered through a pad of Celite, concentrated and purified by silica gel column chromatography (eluted with 0-100% EtOAc / Heaxnes followed by 0-20% MeOH in DCM). Fractions with product was concentrated and re-purified by prep-HPLC (Kinetex 5u C18100A RXI, 150 x 21.20 mm, 20-70% CH3CN w / 0.1% TFA in H2O w / 0.1% TFA for 8 min, flow rate 20 mL / min). Pure fractions were passed through a PL-HCO3MP column and lyophilized to afford EX.387 (3.5 mg, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 3.80 (3H, s), 3.93 (3H, s), 6.67 (1H, t, JH-F = 53.9 Hz), 6.98 (1H, d, J = 2.6 Hz), 7.10 (1H, dd, J = 8.7, 2.6 Hz), 7.83 (1H, d, J = 8.7 Hz), 8.03 (1H, s), 8.87 (2H, d, J = 9.7 Hz), 12.69 (1H, s); LRMS (ESI): m / z [M+H]+381. (23) Experimental Procedure of EX.388 EX.388 was prepared in accordance with the general procedure 39 using the method described below in detail. Synthesis of 3-(3-(3-(difluoromethoxy)pyridazin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)- 2-(difluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (EX.388 ) Step 39-1 A solution of 3-(3-(6-chloro- 3-(difluoromethoxy)pyridazin-4-yl)-1H-pyrrolo[2,3- b]pyridin-2-yl)-2-(difluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (EX.389) (2 mg) and 10% Pd / C (1 mg) in ethanol ( 0.2 mL) was thrice degassed and backfilled with N2. Afterwards, mixture was thrice degassed and backfilled with hydrogen (balloon). The reaction mixture was stirred at room temperature overnight. Thereafter, mixture was filtered through celite and purified by prep-HPLC to afford EX.388 (1.18 mg, 62%) as a yellow oil. 1H NMR (400 MHz, CD3OD): δ 2.15 – 2.30 (2H, m), 4.08 – 4.25 (4H, m), 6.59 (2H, t, J = 54.1 Hz), 7.31 (1H, dd, J = 8.0, 5.0 Hz), 7.68 (1H, d, J = 4.9 Hz), 7.73 (1H, t, J = 72.1 Hz), 8.14 (1H, dd, J = 8.0, 1.4 Hz), 8.34 (1H, d, J = 4.4 Hz), 8.96 (1H, d, J = 4.9 Hz); LRMS (ESI): m / z [M+H]+435. (24) Experimental Procedure of 2-(2-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin- 3- yl)-4-methoxybenzonitril 2-(2-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl)-4- methoxybenzonitrile was prepared in accordance with the general procedures 38, 6 and 48 using the method described below in detail. Synthesis of 2-(2-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl)-4- methoxybenzonitrile

[0037] Step 38-1 To a solution of N-methoxy-N-methyl-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-2-carboxamide (21d) (130 mg, 0.39 mmol) in THF (5 mL) in ice bath was slowly added cyclopropylmagnesium bromide solution (1M in 2-methyltetrahydrofuran) (2.6 mL, 2.6 mmol). Then the reaction was warmed up to room temperature and stirred for 3.5 hr. The mixture was concentrated and purified by ISCO normal-phase silica flash chromatography (0~40% EA in HX) to obtain product (21e) as yellow solid (88 mg, 71%); LRMS (ESI): m / z [M+H]+317; m / z [M+Na]+339. Step 6-2 as per general procedure 6. Step 6- 3 A vial containing of (2-cyano-5-methoxy-phenyl)boronic acid (4o) (12.1 mg, 0.07 mmol), [3-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-2-yl]- cyclopropyl-methanone (19f) (17 mg, 0.04 mmol), potassium carbonate (17.8 mg, 0.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.5 mg, 0.01 mmol) was vacuumed and refilled with N2 three times. Afterwards, 1, 4-Dioxane (2 mL) and Water (0.5 mL) were added into the vial and the mixture was again vacuumed and refilled with N2 three times. The resulting mixture was heated at 95 ºC for 2h43min. After reaction was cooled down, the organic layer was separated, concentrated, and purified by silica gel column chromatography (0~90% EtOAc / Hexanes) to obtain product (20j) as colorless film (12.8 mg, 60%); LRMS (ESI): m / z [M+H]+466. Step 48-1 To a solution of 2-[2-(cyclopropanecarbonyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]-4-methoxy-benzamide (20j) (12.8 mg, 0.03 mmol) in DCM (0.6 mL) was added POCl3(1.14 mL). The mixture was stirred at room temperature for ~ 3 h. Then it was concentrated and purified by silica gel column chromatography (0~65% ethyl acetate / hexanes) and then prep-TLC plate to obtain 2-(2-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl)-4-methoxybenzonitrile as white solid (0.58 mg, 6%). 1H (400 MHz, DMSO-d6) δ 0.86 – 0.99 (2H, m), 0.99 – 1.13 (2H, m), 2.19 – 2.29 (1H, m), 3.89 (3H, s), 7.18 (1H, dd, J = 8.7, 2.6 Hz), 7.20 – 7.25 (2H, m), 7.87 (1H, dd, J = 8.1, 1.5 Hz), 7.90 (1H, d, J = 8.6 Hz), 8.52 (1H, dd, J = 4.6, 1.6 Hz), 12.78 (1H, s); LRMS (ESI): m / z [M+H]+318. (25) Experimental Procedure of EX.391 EX.391were prepared in accordance with the general procedures 40 using the method described below in detail. Synthesis of methyl 2-(4-(3-(2-cyano-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2- yl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (EX.391 ) Step 40-1 To a solution of 2-[4-[3-(2-cyano-5-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin- 2-yl]- 3-(trifluoromethyl)pyrazol-1-yl]acetic acid (EX.229 ) (40 mg, 0.09 mmol) in methanol (2 mL) was added conc. H2SO4(0.03 mL). The solution was heated at 68 ºC for 1 h. After the mixture was cooled down, it was purified by Prep HPLC to obtain EX.391 as white solid (2.86 mg, 7%). 1H (400 MHz, DMSO-d6) δ 3.70 (3H, s), 3.75 (3H, s), 5.28 (2H, s), 6.81 (1H, d, J = 2.5 Hz), 7.04 (1H, dd, J = 8.7, 2.6 Hz), 7.18 (1H, dd, J = 8.0, 4.7 Hz), 7.80 (1H, d, J = 8.7 Hz), 7.83 (1H, dd, J = 8.0, 1.5 Hz), 8.16 (1H, d, J = 0.9 Hz), 8.34 (1H, dd, J = 4.7, 1.6 Hz), 12.38 (1H, s); LRMS (ESI): m / z [M+H]+456. (26) Experimental Procedure of EX.392 EX.392 was prepared in accordance with the general procedures 41 using the method described below in detail. Synthesis of 4-methoxy-2-(2-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl)-1H-pyrrolo[2,3-b]pyridin- 3- yl)benzonitrile (EX.392 )

[0038] Step 41-1 (J. Med. Chem.2019, 62, 1761−1780) A solution of 2-[2-(6-amino-2-methyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin- 3-yl)-1H-pyrrolo[2,3-b]pyridin- 3-yl]-4-methoxy-benzonitrile (108a) (36 mg, 0.09 mmol) and tetrahydropyran-4-one (0.01 mL, 0.06mmol) and NaBH(OAc)3(25.4 mg, 0.12 mmol) and AcOH (0.01mL, 0.12mmol) in DCE (1 mL) and methanol ( 0.2 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel column chromatography (0-12% MeOH in DCM) to obtain EX.392 as light- yellow solid (1.25 mg, 4%). 1HNMR(400 MHz, CD3OD) δ 1.29 (3H, s), 1.63 – 1.91 (4H, m), 2.84 – 2.97 (1H, m), 3.44 (2H, td, J = 11.8, 2.1 Hz), 3.50 – 3.58 (1H, m), 3.89 (3H, s), 3.90 – 4.09 (3H, m), 4.13 – 4.38 (3H, m), 7.03 (1H, dd, J = 8.7, 2.6 Hz), 7.11 (1H, s), 7.18 (1H, dd, J = 7.9, 4.9 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.94 (1H, d, J = 6.9 Hz), 8.24 (1H, d, J = 4.0 Hz); LRMS (ESI): m / z [M+H]+485. (27) Experimental Procedure of EX.393 EX.393 was prepared in accordance with the general procedure 42 using the method described below in detail. Synthesis of 2-(4-(3-(2-cyano-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)- 3- (trifluoromethyl)-1H-pyrazol-1-yl)acetamide (EX.393 ) Step 42-1 A solution of 2-[4-[3-(2-cyano-5-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-2- yl]- 3-(trifluoromethyl)pyrazol-1-yl]acetic acid (EX.229 ) (40 mg, 0.09 mmol) in DMF (1.5 mL) was stirred in ice bath for 10 minutes before oxalyl chloride (0.01 mL, 0.1 mmol) was added. The mixture was stirred in ice bath for another 10 minutes before NH4OH (28% aq. solution) (0.22 mL, 1.72 mmol) was added. The reaction was warmed up to room temperature and stopped after 1h40min. The reaction mixture was concentrated and purified by silica gel column chromatography (0~8% MeOH in DCM) and then by Agilent Prep HPLC to obtain EX.393 as white solid (2.9 mg, 7%). 1HNMR (400 MHz, DMSO-d6) δ 3.74 (3H, s), 4.92 (2H, s), 6.81 (1H, d, J = 2.6 Hz), 7.02 (1H, dd, J = 8.7, 2.6 Hz), 7.17 (1H, dd, J = 8.0, 4.7 Hz), 7.39 (1H, s), 7.65 (1H, s), 7.79 (1H, d, J = 8.7 Hz), 7.82 (1H, dd, J = 7.9, 1.6 Hz), 8.13 (1H, d, J = 0.8 Hz), 8.33 (1H, dd, J = 4.7, 1.6 Hz), 12.34 (1H, s); LRMS (ESI): m / z [M+H]+441. EX.394 was synthesized using conditions analogous to EX.393 in accordance with the general procedure 42. 4-(3-(2-fluoro-5-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-pyrazole- 3- carboxamide 1H (400 MHz, CD3OD) δ 2.40 (3H, s), 3.87 (3H, s), 7.22 (1H, dd, J = 9.6, 8.5 Hz), 7.29 (1H, dd, J = 6.6, 1.9 Hz), 7.33 – 7.40 (2H, m), 7.45 (1H, s), 8.07 (1H, d, J = 7.9 Hz), 8.32 (1H, dd, J = 5.5, 1.3 Hz); LRMS (ESI): m / z [M+H]+350. (28) Experimental Procedure of EX.395 EX.395 was prepared in accordance with the general procedure 42 using the method described below in detail. Synthesis of 2-(4-(3-(2-cyano-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)- 3- (trifluoromethyl)-1H-pyrazol-1-yl)-N-methylacetamide (EX.395 ) Step 42-1 To a solution of 2-[4-[3-(2-cyano-5-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin- 2-yl]- 3-(trifluoromethyl)pyrazol-1-yl]acetic acid (EX.229 ) (15 mg, 0.03 mmol) and methylamine HCl salt (3.1 mg, 0.05 mmol) in DMF (1.5 mL) was added DIPEA (0.01 mL, 0.07 mmol) and then HATU (19.6 mg, 0.05 mmol). The mixture was stirred at room temperature for ~ 2 h before it was concentrated and purified by Agilent Prep HPLC to obtain EX.395 as white solid (5.6 mg, 36%). 1H (400 MHz, DMSO-d6) δ 2.64 (3H, d, J = 4.6 Hz), 3.75 (3H, s), 4.92 (2H, s), 6.82 (1H, d, J = 2.6 Hz), 7.03 (1H, dd, J = 8.7, 2.6 Hz), 7.18 (1H, dd, J = 8.0, 4.7 Hz), 7.80 (1H, d, J = 8.7 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 8.15 (1H, s), 8.22 (1H, q, J = 4.5 Hz), 8.33 (1H, dd, J = 4.7, 1.6 Hz), 12.37 (1H, s); LRMS (ESI): m / z [M+H]+455. The following compounds were synthesized using conditions analogous to EX.395 in accordance with the general procedure 42. (29) Experimental Procedure of EX.398 and EX.399 EX.398 and EX.399 were prepared in accordance with the general procedures 1 and 43 using the method described below in detail. Synthesis of 2-[2-(cyclopenten-1-yl)-1H-pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (EX.398) and 2-(2-cyclopentyl-1H-pyrrolo[2,3-b]pyridin- 3-yl)benzonitrile (EX.399 ) Step 1-4 (J. Nat. Prod., 2017, 80.2561-2565.) A reaction vial containing 2-[2-bromo-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (6e) (100 mg, 0.23 mmol), cyclopenten-1-ylboronic acid (4p) (52.3 mg, 0.47 mmol), and tert-butylamine (0.07 mL, 0.7 mmol), IPA (2 mL), Water (1 mL) was degassed for two minutes. Subsequently, added Pd(dppf)Cl2-DCM(9.5 mg, 0.01 mmol) and the reaction mixture was degassed for two minutes. The resulting mixture was then heated at 100 °C for 30 min. under microwave conditions. The reaction mixture was directly concentrated and purified by silica gel column chromatography (0- 30% EtOAc / hex), pure fraction was concentrated and dried to obtain product (7aa) as a pale, yellow oil, (71 mg, 73%). Step 1-5 A mixture of 2-[2-(cyclopenten-1-yl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (7aa) (70 mg, 0.17 mmol) and neat TFA (0.77 mL, 10.11 mmol) was stirred at room temperature for 1 h. After concentration, the residue was dissolved in MeOH (0.5 mL) and reacted with ethylenediamine (0.67 mL, 10.11 mmol) at room temperature for 30 min. Thereafter, mixture was concentrated and directly subjected to prep HPLC (Kinetex 5u C18100A RXI, 150 x 21.20 mm, 30-80% CH3CN w / 0.1% TFA in H2O w / 0.1% TFA for 8 min run, flow rate 20 mL / min). Fractions containing the expected product were passed through a PL-HCO3MP column and lyophilized to give the product EX.398 as a light brown solid (36 mg, 73%). 1HNMR (400 MHz, DMSO-d6) δ 1.88-1.78 (2H, m), 2.30 (2H, dt, J = 7.9, 3.7 Hz), 2.36 – 2.46 (2H, m), 6.18 – 6.32 (1H, m), 7.06 (1H, dd, J = 7.9, 4.7 Hz), 7.49 – 7.68 (3H, m), 7.78 (1H, td, J = 7.7, 1.4 Hz), 7.88 – 8.01 (1H, m), 8.27 (1H, dd, J = 4.7, 1.5 Hz), 12.07 (1H, s). LRMS (ESI): m / z [M+H]+286. Step 43-1 In a 25 mL RB flask, 2-[2-(cyclopenten-1-yl)-1H-pyrrolo[2,3-b]pyridin- 3- yl]benzonitrile (EX.398) (12 mg, 0.04 mmol) was dissolved in 3 mL of MeOH and added carefully 10% Pd / C (0.45 mg, 0.0042 mmol). The mixture was degassed four times using N2 purging and charged with the H2balloon to the RB, purged the H2gas for two times, sealed and stirred at room temperature for 4 h. After concentration, the residue was dissolved in MeOH (0.5 mL) and the mixture was directly subjected to prep- HPLC. Pure fractions containing the expected product were passed through a PL-HCO3MP column and lyophilized to give the product EX.399 as a white solid (6.5 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ 1.44 – 1.68 (2H, m), 1.68 – 2.00 (5H, m), 2.14- 2.09 (1H, m), 2.98 – 3.14 (1H, m), 7.07 (1H, dd, J = 7.9, 4.7 Hz), 7.44 – 7.69 (3H, m), 7.79 (1H, td, J = 7.7, 1.4 Hz), 7.89 – 8.05 (1H, m), 8.22 (1H, dd, J = 4.7, 1.5 Hz), 11.98 (1H, s). LRMS (ESI): m / z [M+H]+288. (30) Experimental Procedure of EX.400 EX.400 was prepared in accordance with general procedures 6, 46, and 1 using the method described below in detail. Synthesis of 3-[3-[3-(difluoromethoxy)-1-ethyl-pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridin-2-yl]-2-(difluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (EX.400 ) Step 6-1 A vial containing of 2-(difluoromethyl)- 3-iodo-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine (10wwwi) (924 mg, 3.08 mmol), [1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-2-yl]boronic acid (17b) (750 mg, 2.57 mmol), Cs2CO3(2.5 g, 7.7 mmol) and Pd(dppf)Cl2-DCM (314 mg, 0.38 mmol) was vacuumed and refilled with N2 three times. Thereafter, 1, 4-Dioxane (8 mL) and Water (2 mL) were added into the vial and the resulting mixture was vacuumed and refilled with N2 three times. Mixture was then heated at 90 ºC for 2.0 h. Afterwards, it was cooled down to rt and concentrated. Crude residue was purified by silica gel chromatography using ethyl acetate in hexanes to give the expected product (18g) as dark brown oil, 650 mg (60%). LRMS (ESI): m / z [M+H]+421. Step 6-2 A solution containing 2-[[2-[2-(difluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin- 3-yl]pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (18g) (650 mg, 1.55 mmol) and NBS (296 mg, 1.85 mmol) in DCM (15 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with water, diluted with 50 mL of DCM and 50 mL of water and shaken. Layers were separated, and the organic layer was washed with saturated bicarbonate and followed by brine. The organic layer was concentrated and purified by silica gel chromatography to give the expected product (19h) as a yellow oil, 600 mg (78% yield). LRMS (ESI): m / z [M+H]+499, 500. Step 46-1 A solution of 2-[[3-bromo-2-[2-(difluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin- 3-yl]pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (19h) (520 mg, 1.04 mmol) in diethyl ether (10 mL) was cooled to –78 °C with a dry ice / acetone bath. To the stirred, heterogeneous mixture was added n-BuLi (0.83 mL, 2.08 mmol) dropwise. The mixture was stirred for a further 15 min at –78 °C, and then triisopropyl borate (0.48 mL, 2.08 mmol) was added slowly via syringe. After 15 min of stirring, the reaction mixture was allowed to warm to rt and stirred further for 1 h. Thereafter, reaction mixture was quenched with methanol, dried under vacuum to get crude product (126a) and used as for next step without further purifications. LRMS (ESI): m / z [M+H]+465. Step 46-2 A microwave vial containing of 3-(difluoromethoxy)-1-ethyl-4-iodo-pyrazole (10uu) (30 mg, 0.1 mmol), [2-[2-(difluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin- 3-yl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 3-yl]boronic acid (126a) (40 mg, 0.09 mmol), Cs2CO3(85 mg, 0.26 mmol) and Pd(dppf)Cl2-DCM (11 mg, 0.01 mmol) was vacuumed and refilled with N2three times. Then 1, 4-Dioxane (1 mL) and Water (0.25 mL) were added into the vial and the mixture was thrice evacuated and refilled with N2. The resulting mixture was heated at 90 ºC in microwave for 30 min. Thereafter, the reaction vial was removed from microwave and water phase was discarded. The organic phase was concentrated and purified by silica gel column chromatography using MeOH / DCM to obtain 38 mg (76%) of compound (7cc). LRMS (ESI): m / z [M+H]+581. Step 1-5 A solution of 2-[[3-[3-(difluoromethoxy)-1-ethyl-pyrazol-4-yl]-2-[2- (difluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl]pyrrolo[2,3-b]pyridin- 1-yl]methoxy]ethyl-trimethyl-silane (7cc) (38 mg, 0.07 mmol) in TFA (1 mL, 13.1 mmol) was stirred at room temperature for 3 h. Afterwards, the mixture was concentrated and used for the next step. The above concentrated crude reaction mixture was dissolved in methanol (1.5 mL) followed by the addition of ethylenediamine (0.44 mL, 6.54 mmol). l). The mixture was stirred at room temperature for 1.5 h, and then the clear reaction mixture was turned into a white-color cloudy suspension. The reaction mixture was concentrated under reduced pressure and purified the solid material by silica gel column chromatography using MeOH / DCM gave the desired compound (EX.400) as a white solid (22.1 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.35 (3H, t, J = 7.2 Hz), 2.13 – 2.28 (2H, m), 4.05 (2H, q, J = 7.2 Hz), 4.18 (2H, t, J = 6.0 Hz), 4.22 – 4.33 (2H, m), 6.62 (1H, t, JH-F = 54.0 Hz), 6.89 – 7.32 (2H, m), 7.63 (1H, s), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 8.23 (1H, dd, J = 4.7, 1.6 Hz), 11.75 (1H, s). LRMS (ESI): m / z [M+H]+451. The following compounds were synthesized using conditions analogous to EX.400 in accordance with the general procedures 6, 46 and 1.

[0039] (31) Experimental Procedure of EX.419 EX.419 was prepared in accordance with the general procedure 44 using the method described below in detail. Synthesis of 2-[2-[2-(Hydroxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3- yl]-1H-pyrrolo[2,3-b]pyridin- 3-yl]-4-methoxy-benzonitrile (EX.419) Step 44-1 To a stirred solution of 4-methoxy-2-[2-[2-(methoxymethoxymethyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin- 3-yl]-1H-pyrrolo[2,3-b]pyridin- 3-yl]benzonitrile (EX.249 ) (26 mg, 0.06 mmol) in methanol (2 mL), was added 4 N HCl in 1,4-dioxane (146 uL, 0.58 mmol) at 0 ºC and ice bath removed and stirring was continued for 2 h at rt. Reaction mixture was evaporated and added water (2 mL) and sat. bicarbonate, to adjust the pH to 8-9 and extracted with 5% MeOH in CH2Cl2(2 x 5 mL) and combined organic layers were washed with brine (10 mL), dried over Na2SO4and concentrated. The crude was purified by silica gel column chromatography using 0-5% MeOH in CH2Cl2gave pale yellow solid which was repurified by prep-HPLC to afford pure EX.419 as white solid (6 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 2.04 (2H, s), 3.80 (3H, s), 3.91 (2H, d, J = 21.0 Hz), 4.03 (2H, t, J = 6.1 Hz), 4.25 (2H, d, J = 17.9 Hz), 5.46 (1H, s), 6.95 (1H, d, J = 2.6 Hz), 7.04 (1H, dd, J = 8.7, 2.6 Hz), 7.12 (1H, dd, J = 7.9, 4.7 Hz), 7.79 (2H, dd, J = 8.2, 1.8 Hz), 8.24 (1H, dd, J = 4.7, 1.5 Hz), 11.70 (1H, s). LRMS (ESI): m / z [M+H]+402. (32) Reference procedure of (18‘d) 2-[3-(Difluoromethyl)-1-methyl-pyrazol-4-yl]-1-(2 trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-4-carbonitrile (18’d) for preparation of EX.278 was prepared in accordance with the general procedure 9 using the method described below in detail. Step 9-1 A reaction vessel containing 2-[[4-bromo-2-[3-(difluoromethyl)-1-methyl-pyrazol- 4-yl]pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (28b) (121.6 mg, 0.27 mmol), Zn(CN)2(93.6 mg, 0.8 mmol) and Zn (3.4 mg, 0.05 mmol) in DMF (1.6 mL) was degassed and backfilled with N2 three times. After the addition of Pd(dppf)Cl2-DCM (21.7 mg, 0.03 mmol), the reaction mixture was purged with N2three times. The resulting mixture was then stirred and heated at 90 °C for 1 h. No product formation was observed. The reaction mixture was transferred to a MW vial, degassed and back filled with N2three times and added bis(tri-tert-butylphosphine)palladium (27.1 mg, 0.05 mmol). The reaction was degassed and back filled with N2 three times and heated at 100 °C for 30 min under microwave irradiation. Solvent was evaporated in vacuo and purified by silica gel column chromatography (0-13% EtOAc / hexane) to obtain product as a yellow oil (69.2 mg, 64%); LRMS (ESI): m / z [M+H]+404. (33) Reference procedure of (18f) 2-Methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (18f) for preparation of EX.180 was prepared in accordance with the general procedure 9 using the method described below in detail. Step 9-1 A reaction vessel containing 6-bromo-2-methyl-pyrazolo[1,5-a]pyrimidine (28d) (400 mg, 1.89 mmol), dppf (209.1 mg, 0.38 mmol), Zn(CN)2(443 mg, 3.77 mmol) in DMF (15 mL) was degassed and backfilled with N2 three times. After the addition of Pd2(dba)3(172.7 mg, 0.19 mmol), the reaction mixture was purged with N2three times. The resulting mixture was then stirred and heated at 95 °C for 1.5 h. The reaction was partitioned between water and extracted with ether, evaporated solvent and purified by silica gel column chromatography (0-21% EtOAc / Hexane) to obtain product as a yellow solid (160.2 mg, 54%); LRMS (ESI): m / z [M+H]+159. (34) Reference procedure of (18c) 2-(5-fluoro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine-4-carbonitrile (18c) for the preparation of EX.274 was prepared in accordance with the general procedure 9 using the method described below in detail. , Step 9-1 A reaction vessel containing 2-[[4-bromo-2-(5-fluoro-2-methoxy- phenyl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (28a) (110 mg, 0.24 mmol), Zn(CN)2 (85.8 mg, 0.73 mmol) and Zn (3.2 mg, 0.05 mmol) in DMF (1.5 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2- DCM (19.9 mg, 0.02 mmol), the mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ° C for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-20% EtOAc / Hexane) to give the expected product as a pale-yellow solid (91.2 mg, 94%); LRMS (ESI): m / z [M+H]+398. (35) Reference Procedure of (3b) 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phen- 3,4,5,6-d4-ol (3b) for the preparation of EX.17 was prepared in accordance with the general procedure 15 using the method described below in detail. Step 15-1 To a solution of 1,2,3,4,5-pentadeuterio-6-deuteriooxy-benzene (41a) (318 mg, 3.18 mmol) in DCM (10 mL) was added 2M Br2in DCM (1.75 mL, 3.49 mmol) at room temperature and the mixture was stirred at room temperature for 2 h. The reaction mixture was directly loaded onto prepacked silica column and was purified by silica gel column chromatography (0-20% EtOAc / Hexane) to give the expected product as red oil (462 mg, 82%); LRMS (ESI): m / z [M+H]+177, 179. Step 15-2 A reaction vessel containing 2-bromo- 3,4,5,6-tetradeuterio-phenol (42a) (99.4 mg, 0.56 mmol), bis(pinacolato)diboron (171.2 mg, 0.67 mmol) and potassium acetate (110.3 mg, 1.12 mmol) in 1,4-dioxane (3 mL) was degassed and backfilled with nitrogen three times. After the addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41.1 mg, 0.06 mmol), the reaction mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 ° C for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0- 30% EtOAc / Hexane) to give the expected product (3b) as an off-white solid (79.1 mg, 62%); LRMS (ESI): m / z [M+H]+225. (36) Reference procedure of (3c) 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen- 3,4,6-d3-ol (3c) for the preparation of EX.56 was synthesized from commercially available 4- fluorophen-2,3,5,6-d4-ol in accordance with the methods described in the procedure 15 for the preparation of EX.56. LRMS (ESI): m / z [M+H]+242. (37) Reference procedure of (10d) 4-((2-bromo-4-fluorophenoxy)methyl)tetrahydro-2H-pyran (10d) for preparation of EX.124 was prepared in accordance with the general procedure 16 using the method described below in detail. Step 16-1 Step 16-1 A mixture of 2-bromo-4-fluoro-phenol (10n) (50 mg, 0.26 mmol), 4- (bromomethyl)tetrahydropyran (43a) (51.6 mg, 0.29 mmol) and K2CO3(65.1 mg, 0.47 mmol) in DMF (3 mL) was stirred and heated at 60 ºC overnight. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (0-70% EtOAc / Hexane) to give the expected product as colorless oil (50.8 mg, 67%); LRMS (ESI): m / z [M+H]+289, 291. The following compounds were synthesized using conditions analogous to (10d) in accordance with the general procedure 16. Tert-butyl 4-((2-bromo-4-fluorophenoxy)methyl)piperidine-1-carboxylate (10e) (for preparation of EX.125) LRMS (ESI): m / z [M+H]+388, 390. 3-((2-Bromo-4-fluorophenoxy)methyl)oxetane (10f) (for preparation of EX.126) LRMS (ESI): m / z [M+H]+261, 263. 1-(4-((2-Bromo-4-fluorophenoxy)methyl)piperidin-1-yl)ethan-1-one (10g) (for preparation of EX.127) LRMS (ESI): m / z [M+H]+330, 332. (38) Reference procedure of (3f) and (4j) 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trideuteriomethoxy)benzonitrile (3f) and [2-cyano-5- (trideuteriomethoxy)phenyl]boronic acid (4j) were prepared in accordance with the general procedures 15 and 16 using the method described below in detail. Step 16-1 A round bottom flask containing a pre-stirred (20 min) mixture of 2-bromo-4- hydroxy-benzonitrile (10o) (5 g, 25.25 mmol) and K2CO3(6.98 g, 50.5 mmol) in DMF (50 mL) was added CD3I (2.39 mL, 37.87 mmol) and stirred for 4.5 h. Thereafter, reaction mixture was filtered through a pad of Celite and washed twice with EtOAc. Filtrate and washes were combined, concentrated, and purified by silica gel column chromatography (eluted with 0-50% EtOAc / Hexanes) to afford a white solid (5.25 g, 96%) as the expected product. LRMS (ESI): m / z [M+H]+216. Step 15-2 A round bottom flask containing 2-bromo-4-(trideuteriomethoxy)benzonitrile (10p) (2.5 g, 11.62 mmol), bis(pinacolato)diboron (3.84 g, 15.11 mmol) and KOAc (3.42 g, 34.87 mmol) in 1,4-dioxane (40 mL) was thrice evacuated and backfilled with nitrogen. After addition of Pd(dppf)Cl2-DCM (1.9 g, 2.32 mmol), mixture was again thrice evacuated and backfilled with nitrogen. The resulting mixture was vigorously stirred overnight at 90 ºC. Thereafter, the mixture was cooled to room temperature, diluted with DCM, and extracted thrice with 2N NaOH. Aqueous layers were combined and treated with conc. HCl until precipitate formed (~ pH 4.5). The resulting slurry was filtered, washed twice with water, and vacuum dried to afford 1.2 g of an off-white solid (labeled as P1). The remaining filtrate and washes were combined and extracted thrice with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford a greyish oil material that solidified under vacuum drying (labeled as P2). Solids P1 and P2 were combined to afford 2-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trideuteriomethoxy)benzonitrile (3f) (2.07g, 67%) and [2-cyano-5- (trideuteriomethoxy)phenyl]boronic acid (4j) (0.69 g, 32%). LRMS (ESI): m / z [M+H]+263, 181. (39) Reference procedure of (10r) 2-Bromo-4-(fluoromethoxy)benzonitrile (10r) for preparation of EX.379 was prepared in accordance with the general procedure 16 using the method described below in detail. Step 16-1 To a mixture of the 2-bromo-4-hydroxy-benzonitrile (10q) (600 mg, 3.03 mmol) and Cs2CO3(1.085 g, 3.33 mmol) in dry acetonitrile, was treated slowly with fluoro(iodo)methane (0.23 mL, 3.33 mmol) and stirred for 12 h. Thereafter, reaction mixture was quenched with water and extracted thrice with Et2O. The combined organic extracts were washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 30% EtOAc / Hexanes) to afford an off-white solid (638 mg, 92 %) as the expected product. LRMS (ESI): m / z [M+H]+230, 232. (40) Reference procedure of (10t) 3-Iodo-2-(methoxymethoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine (10t) for preparation of EX.249 was prepared in accordance with the general procedure 16 using the method described below in detail. Step 16-1 To the stirred solution of (3-iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2- yl)methanol (10s) (100 mg, 0.36 mmol) in CH2Cl2(6 mL) was added DIPEA (124 uL, 0.71 mmol) and after stirring for 5 min, reaction mixture was cooled to 0°C and added chloromethyl methyl ether (35 uL, 0.46 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was concentrated and purified by silica gel column chromatography using 0-100% EtOAc in hexanes to give brown solid (10t), 106 mg 91% yield. (41) Reference procedure of (10u) 5-Ethoxy-4-iodo-1-methyl-1H-pyrazole (10u) for preparation of EX.154 was prepared in accordance with the general procedure 17 using the method described below in detail. Step 17-1 A mixture of 2-methylpyrazol- 3-ol (44) (2.0 g, 20.39 mmol) and neat POCl3(19 mL, 203.87 mmol) was stirred and heated at 100 °C overnight. After cooling to room temperature, extra POCl3was evaporated in vacuo. To the residue, water was added at 0 °C and the product was extracted with DCM (x3). The combined organic extracts were dried over Na2SO4and concentrated. The residue was used for the next reaction without further purification (1.23 g, 52%); LRMS (ESI): m / z [M+H]+117. Step 17-2 A mixture of 5-chloro-1-methyl-pyrazole (45) (227 mg, 1.95 mmol) and NIS (460 mg, 2.05 mmol) in DCM (10 mL) was stirred at room temperature for 1 h. After concentration, the residue was purified by silica gel column chromatography (0-20% EtOAc / Hexane) to give the expected product as a tan solid (275.8 mg, 58%); LRMS (ESI): m / z [M+H]+243. Step 17- 3 A mixture of 5-chloro-4-iodo-1-methyl-pyrazole (46) (100.0 mg, 0.41 mmol), KOtBu (139 mg, 1.24 mmol) and 18-crown-6 (163.5 mg, 0.62 mmol) in ethanol (1.2 mL) was stirred and heated at 120 °C overnight. After cooling to room temperature, the mixture was poured into brine and the product was extracted with DCM (x3). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-100% DCM / Hexane) to give the expected product as a yellow oil (8.2 mg, 7.9%); LRMS (ESI): m / z [M+H]+253. (42) Reference procedure of (10v) 5-(Cyclopropylmethoxy)-4-iodo-1-methyl-1H-pyrazole (10v) for preparation of EX.155 was prepared in accordance with the general procedure 17, step 17- 3 using the method described below in detail. Step 17- 3 A mixture of 5-chloro-4-iodo-1-methyl-pyrazole (46) (150.0 mg, 0.62 mmol), cyclopropylmethanol (0.1 mL, 1.24 mmol), KOtBu (138.8 mg, 1.24 mmol) and 18-crown- 6 (327.1 mg, 1.24 mmol) in 1,4-dioxane (2 mL) was stirred and heated at 120 °C overnight. After cooling to room temperature, the mixture was poured into brine and the product was extracted with DCM (x3). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (0-100% DCM / Hexane) to give the expected product as yellow oil (22.0 mg, 12.8%); LRMS (ESI): m / z [M+H]+279. (43) Reference procedure of (3a) 5-Methoxy-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indole (3a) for preparation of EX.12 was prepared in accordance with the general procedure 18 using the method described below in detail. Step 18-1 To a solution of 6-bromo-5-methoxy-1H-indole (47) (30 mg, 0.13 mmol) in THF (1 mL) was added NaH, 60% dispersion in mineral oil (3.5 mg, 0.15 mmol) and the mixture was stirred at room temperature for 10 min. After the addition of MeI (12.3 µL, 0.20 mmol), the mixture was further stirred at room temperature overnight. After concentration, the residue was purified by silica gel column chromatography (0-10% EtOAc / Hexane) to give the expected product as a white solid (25 mg, 75%); LRMS (ESI): m / z [M+H]+240, 242. Step 18-2 A reaction vessel containing 6-bromo-5-methoxy-1-methyl-indole (48) (25 mg, 0.099 mmol), bis(pinacolato)diboron (39 mg, 0.15 mmol) and potassium acetate (29 mg, 0.3 mmol) in 1,4-dioxane (0.4 mL) was degassed and backfilled with nitrogen three times. After the addition of Pd(dppf)Cl2-DCM (8 mg, 0.01mmol), the reaction mixture was purged with nitrogen three times. The resulting mixture was then stirred and heated at 90 °C for 6 h. After cooling to room temperature and concentration, the residue was purified by silica gel column chromatography (0-5% EtOAc / Hexane) to give the expected product as a white solid (12 mg, 40%); LRMS (ESI): m / z [M+H]+288. (44) Reference procedure of (10wi) 3-Bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (10wi) for preparation of EX.156 was prepared in accordance with the general procedure 19 using the method described below in detail. Step 19-1 To a mixture of 6,7-dihydro-5H-pyrazolo[1,5-a]pyridin-4-one (49a) (700 mg, 5.14 mmol) in DCM (29 mL) was added 1,2-ethanedithiol (0.65 mL, 7.71 mmol) and BF3.2AcOH (1.07 mL, 7.71 mmol) at room temperature. The reaction was stirred at room temperature over the weekend. The reaction was partitioned between brine and extracted with DCM. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-50% EtOAc / Hexane) to obtain the expected product as a yellow solid (942 mg, 86%); LRMS (ESI): m / z [M+H]+213. Step 19-2 To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (DBDMH) (1.09 g, 3.82 mmol) in DCM (2.18 mL) was added HF.pyridine (1.81 mL, 20.06 mmol) dropwise at -78 °C, followed by spiro[1,3-dithiolane-2,4'-6,7-dihydro-5H-pyrazolo[1,5- a]pyridine] (50a) (200 mg, 0.94 mmol). After stirring for 1h at -78 °C the reaction was quenched with water, extracted with DCM, dried over Na2SO4and concentrated in vacuo. Crude was purified by silica gel column chromatography (0-20% EtOAc / hexane) to obtain the expected product as a white solid (56.3 mg, 25%); LRMS (ESI): m / z [M+H]+237, 239. (45) Reference procedure of (10aa) Tert-butyl 3-(difluoromethoxy)-4-iodo-1H-pyrazole-1-carboxylate (10aa) for preparation of EX.157 was prepared in accordance with the general procedures 20 using the method described below in detail. Step 20-1 To a solution of 3-(difluoromethoxy)-1H-pyrazole (51a) (0.14 mL, 1.49 mmol) in DMF (3 mL) added NIS (336 mg, 1.49 mmol) and reacted at room temperature for 80 min. The reaction was quenched with water and extracted thrice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford a light-yellow color semisolid compound (261 mg, 67%) as a crude product which was used for the next step without further purification. LRMS (ESI): m / z [M+H]+261. Step 20-2a A solution of 3-(difluoromethoxy)-4-iodo-1H-pyrazole (10z) (289 mg, 0.97 mmol) in THF (4.6 mL) was cooled to 0 °C and added NaH (93.1 mg, 2.33 mmol) and stirred at 0 °C for 10 min. Subsequently, Boc2O (329.4 mg, 1.51 mmol) was added and stirred at 0 °C for 30 min. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-11% EtOAc / hexanes) to obtain the expected product as an orange oil (176.6 mg, 50%); LRMS (ESI): m / z [M+H- tBu]+304.9. (46) Reference procedure of (3g) and (3h) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)- 3-(trifluoromethyl)-1H- pyrazole (3g) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3- (trifluoromethyl)pyrazole-1-carboxylate (3h) were prepared in accordance with the general procedure 20 using the method described below in detail.

[0040] 90 ºC, overnight Step 20-2b A reaction vessel containing 4-bromo- 3-(trifluoromethyl)-1H-pyrazole (10bb) (200 mg, 0.93 mmol), bis(pinacolato)diboron (284 mg, 1.12 mmol) and potassium acetate (183 mg, 1.86 mmol) in 1,4-dioxane (5 mL) was thrice evacuated and backfilled with nitrogen. After addition of Pd(dppf)Cl2-DCM (76 mg, 0.09 mmol), mixture was again thrice evacuated and backfilled with nitrogen and stirred at 90 ºC overnight. Thereafter, mixture was concentrated and purified by silica gel column chromatography (eluted with 0-70% EtOAc / Hexanes) to afford the expected product (64 mg, 26%). LRMS (ESI): m / z [M+H]+263. Step 20- 3b To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3- (trifluoromethyl)-1H-pyrazole (3g) (500 mg, 1.91 mmol) in DMF (7 mL) was added 60% NaH in mineral oil (83 mg, 2.1 mmol) at 0 ºC, and stirred at the same temperature for 10 min. Afterwards, Boc2O (499 mg, 2.29 mmol) was added at 0 ºC and stirred at room temperature for 1 h. Thereafter, mixture was slowly treated with water and extracted thrice with 5% MeOH / DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 0- 30% EtOAc / Hexanes) to afford a white solid (320 mg, 46%) as the expected product. LRMS (ESI): m / z [M+H-Boc]+263, [M+H-tBu]+307, [M+Na]+385. (47) Reference procedure of (3j) and(4ja) Tert-butyl 5-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole-1-carboxylate (3j) and [1-tert-butoxycarbonyl-5-(difluoromethyl)pyrazol- 4-yl]boronic acid (4ja) were prepared in accordance with the general procedure 20 using the method described below in detail. Step 20-2b A reaction vessel containing 4-bromo-5-(difluoromethyl)-1H-pyrazole (10cc) (2 g, 10.15 mmol), bis(pinacolato)diboron (3.35 g, 13.2 mmol) and KOAc (2.99 g, 30.46 mmol) in 1,4-dioxane (40 mL) was thrice evacuated a backfilled with nitrogen. After addition of Pd(dppf)Cl2-DCM (0.83 g, 1.02 mmol), mixture was again thrice evacuated and backfilled with nitrogen. Resulting mixture was stirred overnight at 90 ºC. Thereafter, mixture was concentrated and purified by silica gel column chromatography (eluted with 0-100% EtOAc / Hexanes) to afford a red oil (2.13 g, 86%) as the expected product. LRMS (ESI): [M+H]+245. Step 20- 3b To a solution of 5-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (3i) (2 g, 8.2 mmol) in DMF (30 mL) at 0 ºC was added 60% NaH in mineral oil (0.36 g, 9.01 mmol) at 0 ºC and stirred at the same temperature for 10 min. Afterwards, Boc2O (2.15 g, 9.83 mmol) was added and stirred at room temperature for 1 h. Thereafter, mixture was slowly treated with water and extracted thrice with 5% MeOH / DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 0-100% EtOAc / Hexanes) to afford a mixture of tert-butyl 5-(difluoromethyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (3j) (630 mg, 22%) and [1- tert-butoxycarbonyl-5-(difluoromethyl)pyrazol-4-yl]boronic acid (4ja) (200 mg, 9%) which was used in the next step without further purification. LRMS (ESI): m / z [M+H-tBu]+289 for (3j), [M+H-tBu]+207 for (4ja). (48) Reference procedure of (10ee) and (10ff) 2-[[4-Bromo-5-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (10ee) and 2-[[5-bromo-4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl- silane (10ff) were prepared in accordance with the general procedure 20 using the method described below in detail. Step 20-2a To a solution of 5-bromo-4-(trifluoromethyl)-1H-imidazole (10dd) (700 mg, 3.26 mmol) in DMF (10 mL) stirred at 0 ºC and was added NaH (60% in mineral oil) (143.28 mg, 3.58 mmol) and stirring continued for 10 min. Afterwards, SEM-Cl (570 mg, 3.42 mmol) was added and stirred for another 1 h (during that time was allowed to warm to room temperature). The mixture was then poured into water and extracted twice with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-100% DCM / Hexanes) to afford a colorless oil (651 mg, 57.8%, mixture of 2-[[4-bromo-5- (trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (10ee) and 2-[[5-bromo-4- (trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (10ff) with approximately 1:1 ratio by1HNMR analysis) as products. LRMS (ESI): m / z [M+H]+345, 347. (49) Reference procedure of (3k) 5-Methyl- 3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2- carbonitrile (3k) was prepared in accordance with the general procedure 20 using the method described below in detail. Pd(dppf)Cl2.DCM Step 20-2b To a 20 mL vial containing 3-bromo-5-methyl-thiophene-2-carbonitrile (10gg) (500 mg, 2.47mmol), bis(pinacolato)diboron (816 mg, 3.22 mmol) and KOAc (728 mg, 7.42 mmol) in 1,4-dioxane (10 mL) was degassed by bubbling N2for 5 min. Afterwards, mixture was treated with Pd(dppf)Cl2.DCM (404 mg, 0.49 mmol) and stirred overnight at 90 ºC. Thereafter, mixturethe mixture was diluted with water (20 mL) and extracted thrice with EtOAc (20 mL each time). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (20% EtOAc / Hexanes) to afford the expected product (466 mg, 76%). LRMS (ESI): m / z : 250 and (M+Na)+277. (50) Reference procedure of (10ii) 3-Bromo-4-(2-trimethylsilylethoxymethyl)pyrazolo[1,5-a]pyrimidin-7-one (10ii) for preparation of EX.289 was prepared in accordance with the general procedure 20 using the method described below in detail. Step 20-2a To a solution of 3-bromo-4H-pyrazolo[1,5-a]pyrimidin-7-one (10hh) (500 mg, 2.34 mmol) in DMF (5 mL) was added NaH (120 mg, 4.68 mmol) and stirred at 0 ºC for 10 min. Afterwards, mixture was treated slowly (over 10 min.) at 0 ºC with the 2- (trimethylsilyl)ethoxymethyl chloride (408 mg, 2.45 mmol) and further at room temperature for 3 h. Thereafter, mixture was diluted with water (20 mL) and extracted thrice with (20 mL each time). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-15% EtOAc / Hexanes) to afford a yellow oil (529 mg, 66%) as product. LRMS (ESI): m / z [M+H - 2CH3]+316. (51) Reference procedure of (3m) 3-(Difluoromethoxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole (3m) for preparation of EX.291 was prepared in accordance with the general procedure 20 using the method described below in detail. Step 20- 3a A vial containing 3-(difluoromethoxy)-4-iodo-1-methyl-pyrazole (10jj) (200 mg, 0.73 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (222.4 mg, 0.88 mmol), KOAc (215 mg, 2.19 mmol) and Pd(dppf)Cl2- DCM (119.2 mg, 0.15 mmol) was vacuumed and backfilled with N2three times. Then, 1, 4-dioxane (5 mL) was added, and the solution was vacuumed and backfilled with N2 three times. The final mixture was stirred at 90 ºC for 4 h. After the reaction was cooled down, the mixture was diluted with DCM and extracted with 2N NaOH aqueous solution (25 mL x 2). The combined aqueous layers were combined and washed with DCM one more time. The aqueous phase was separated, filtered through Celite, and then acidified with 12 N HCl aq. solution to pH 3. This acidic aqueous solution was then extracted with DCM (30 mL x 2) and with EtOAc(30 mL x 2). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to obtain product as brown oil (102 mg, 50%); LRMS (ESI): m / z [M+H]+275. It was used as is in the next step without further purification. (52) Reference procedure of (10kk) 3-Ethyl-4-iodo-1-methyl-1H-pyrazole (10kk) for preparation of EX.260 was prepared in accordance with the general procedure 20 using the method described below in detail. Step 20-1 To a stirred solution of 3-ethyl-1-methyl-pyrazole (51b) (250 mg, 2.27 mmol), in ethanol (1 mL) and water (2 mL) was added molecular iodine (288 mg, 1.13 mmol), and cooled it to 15-20 ºC, added H2O2 (0.14 mL, 1.36 mmol) stirred at rt for 24 h. The reaction was quenched with NaHSO3solution (0.1 mL) and concentrate in vacuo. The crude was purified by flash chromatography using 0-5% MeOH in DCM to obtain the expected compound as brown oil, 295 mg, 55%. LCMS (ESI): m / z [M+H]+237. (53) Reference procedure of (10ll) 3-Iodo-6-methoxy-2-methylpyrazolo[1,5-a]pyrimidine (10ll) for preparation of EX.179 was prepared in accordance with the general procedures 16 and 20 using the method described below in detail. Step 16-1 A vial containing 2-methylpyrazolo[1,5-a]pyrimidin-6-ol (51c) (63.3 mg, 0.42 mmol) was dissolved in DMF (1.6 mL) cooled to 0 °C and added NaH (28.8 mg, 0.72 mmol). Reaction was stirred at 0 °C for 5 min and then added CH3I (0.04 mL, 0.72 mmol) and reacted at 0 °C for 40 min and then at room temperature for 1.25 h. Additional CH3I (12.4 uL), NaH (10.7 mg) was added at 0 °C and reacted at 0 °C for 1h and then at room temperature for 2.15 h. The reaction was quenched with water, extracted with ether and purified by silica gel column chromatography (0-25% EtOAc / hexanes) to obtain the expected product as a white solid (47 mg, 68%); LRMS (ESI): m / z [M+H]+164. Step 20-1 A reaction vial containing 6-methoxy-2-methyl-pyrazolo[1,5-a]pyrimidine (51d) (47 mg, 0.29 mmol) was dissolved in MeCN (0.79 mL), added NIS (72.2 mg, 0.32 mmol) and reacted at room temperature for 35 min. Crude reaction mixture was purified by silica gel column chromatography (0- 30% EtOAc / hexanes) to obtain the expected product as a yellow solid (78.4 mg, 94%); LRMS (ESI): m / z [M+H]+290. (54) Reference procedure of (10mm) 4-Bromo- 3-(difluoromethyl)-5-methoxy-1-methyl-pyrazole (10mm) for preparation of EX.232 was prepared in accordance with the general procedures 16 and 20 using the method described below in detail. Step 16-1 (following procedure in Journal of Fluorine Chemistry, 218 (2019), P1-10) To a solution of 5-(difluoromethyl)-2-methyl-pyrazol- 3-ol (51e) (300 mg, 2.03 mmol) and K2CO3(420 mg, 3.04 mmol) in MeCN (5 mL) was added dimethyl sulfate (0.19 mL, 2.03 mmol). The mixture was refluxed at 80 ºC for 2.5 h. After the reaction was cooled down, the mixture was diluted with water and then extracted with ethyl ether twice. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to obtain product (51f) as colorless liquid (310 mg, 94%). It was used as is in next step without further purification.1H (400 MHz, DMSO-d6): δ 3.57 (3H, t, J = 1.2 Hz), 3.89 (3H, s), 5.96 (1H, t, J = 0.9 Hz), 6.78 (1H, t, JH-F = 54.6 Hz); LRMS (ESI): m / z [M+H]+163. Step 20-1 A solution containing 3-(difluoromethyl)-5-methoxy-1-methyl-pyrazole (51f) (150 mg, 0.93 mmol) and NBS (177.4 mg, 1.11 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. It was concentrated and purified by ISCO normal-phase silica flash chromatography (0-40% ethyl acetate in hexanes) to obtain product (10mm) as light yellow oil (140 mg, 62%); LRMS (ESI): m / z [M+H]+241, 243. (55) Reference procedure of (3o) Trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl) pyrazol-1-yl]methoxy]ethyl]silane (3o) for preparation of EX.64 and EX.65 was prepared in accordance with the general procedure 20 using the method described below in detail. Step 20- 3b 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-pyrazole (3n) (200 mg, 0.76 mmol) was dissolved in DMF (0.5 mL) and cooled to 0 °C, added NaH (33.5 mg, 0.84 mmol) and reacted for 10 min. Subsequently, added (2- (chloromethoxy)ethyl)trimethylsilane (0.16 mL, 0.92 mmol) and reacted at 0 °C for 35 min. The reaction mixture was quenched with MeOH and purified by silica gel chromatography (0-15% EtOAc / hexanes) to obtain the expected product as a clear oil (128.3 mg, 43%); LRMS (ESI): m / z [M+H]+393. Tert-butyl 7-iodo-6-methyl-2,3-dihydroimidazo[1,2-b]pyrazole-1-carboxylate (10nn) for preparation of EX.168 was prepared in accordance with the general procedure 20. LRMS (ESI): m / z [M+H]+350. Tert-butyl 7-iodo-6-methyl-imidazo[1,2-b]pyrazole-1-carboxylate (10oo) for the preparation of EX.169 was prepared in accordance with the general procedure 20.

[0041] LRMS (ESI): m / z [M+H]+348. 3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan- 1-ol (3qa) was prepared in accordance with the general procedure 22. LRMS (ESI): m / z [M+H]+253. 3-(3-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)propan-1-ol (3qb) was prepared in accordance with the general procedure 22. LRMS (ESI): m / z [M+H]+303. (56) Reference procedure of (10qq) Tert-butyl 4-iodo- 3-(2,2,2-trifluoroethyl)-1H-pyrazole-1-carboxylate (10qq) for preparation of EX.160 was prepared in accordance with the general procedures 21 and 20 using the method described below in detail. Step 21-1 A reaction vessel under N2 containing trimethyl(2-trimethylsilylethynyl)silane (1.3 mL, 5.87 mmol), 3,3,3-trifluoropropanoyl chloride (52a) (0.67 mL, 6.46 mmol) was dissolved in DCM (15 mL), cooled to 0 °C, and added AlCl3(939 mg, 7.04 mmol). The reaction was stirred at 0 °C for 1.20 h. The reaction mixture was then poured into a mixture of 2M HCl (20 mL), ice, DCM. The mixture was left standing for 15 min. The aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4and evaporated solvent in vacuo to obtain the expected product as a yellow oil (732 mg, 60%) which was used for the next step without further purification. Step 21-2 A reaction vessel containing 5, 5, 5-trifluoro-1-trimethylsilyl-pent-1-yn- 3-one (53a) (0.73 g, 3.51 mmol) was dissolved in EtOH (10 mL), cooled to 0 °C and added NH2NH2.H2O (0.46 mL, 9.46 mmol). The reaction was stirred at room temperature for 1.10 h. Evaporated solvent in vacuo, added brine and extracted with DCM. Organic layer was dried over Na2SO4and evaporated in vacuo. The residue was purified by silica gel column chromatography (0- 3.5% MeOH / DCM) to obtain the expected product as a brown oily solid (193.2 mg, 36%); LRMS (ESI): m / z [M+H]+151. Step 20-1 To a solution of 3-(2,2,2-trifluoroethyl)-1H-pyrazole (51h) (190 mg, 1.27mmol) in DMF (0.3 mL) was added NIS (281.6 mg, 1.25 mmol) and reacted at room temperature for 1 h. The reaction was partitioned between brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo to obtain the expected product as a red solid (342.4 mg, 98%); LRMS (ESI): m / z [M+H]+276.9. Step 20-2 A solution of 4-iodo- 3-(2,2,2-trifluoroethyl)-1H-pyrazole (10pp) (342.4 mg, 1.24 mmol) in THF (5.6 mL) was cooled to 0 °C, added NaH (74.4 mg, 1.86 mmol) and stirred at 0 °C for 15 min. Subsequently Boc2O (431 mg, 1.97 mmol) was added and stirred at 0 °C for 30 min then at room temperature for 55 min. Additional Boc2O (18 mg) was added and reacted at room temperature for another 1.15 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-11% EtOAc / hexanes) to obtain the expected product as a pale-yellow solid (257.1 mg, 55%); LRMS (ESI): m / z [M+Na]+398.9. (57) Reference procedure of (10jj) and (10uu) 3-(Difluoromethoxy)-4-iodo-1-methyl-1H-pyrazole (10jj) for preparation of EX.161 and 3-(difluoromethoxy)-1-ethyl-4-iodo-1H-pyrazole (10uu) for preparation of EX.400 were prepared in accordance with the general procedure 22 using the method described below in detail. Step 22-1 3-(difluoromethoxy)-4-iodo-1H-pyrazole (10tt) (84.4 mg, 0.32 mmol) was dissolved in DMSO (0.19 mL), cooled to 0 °C, added K2CO3(68.5 mg, 0.5 mmol) and iodomethane (0.02 mL, 0.39 mmol). The reaction was stirred from 0 °C to room temperature. After 1 h additional CH3I (20 uL) was added and reacted at room temperature for 1.20 h. Further addition of CH3I (9.9 uL) and reacted at room temperature for another 1.5 h. The reaction was partitioned between water and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-1% EtOAc / DCM) to afford a yellow oil (52.6 mg, 59%) as product (10jj). LRMS (ESI): m / z [M+H]+274.9. Note: Iodoethane was used instead of Iodomethane for the conversion of compound (10tt) to product (10uu). (58) Reference procedure of (10ww) 3-Bromo-1-methyl-4-(trifluoromethyl)-1H-pyrazole (10ww) for preparation of EX.165 was prepared in accordance with the general procedure 22 using the method described below in detail. Step 22-1 5-bromo-4-(trifluoromethyl)-1H-pyrazole (10vv) (300 mg, 1.4 mmol) was dissolved in DMSO (1.0 mL) and cooled to 0 °C, added K2CO3(231.4 mg, 1.67 mmol) and iodomethane (0.1 mL, 1.54 mmol) and reacted from 0 °C to room temperature overnight. Additional CH3I (55 uL) was added and reacted for another 1.05 h. The reaction was partitioned between water and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0- 35% EtOAc / hexanes) to afford: (10xx) as a clear oil (41 mg, 13%);1H NMR (400 MHz, CDCl3): δ 3.94 (3H, s), 7.72 (1H, s). (10ww) as a yellow oil (55.1 mg, 17%);1H NMR (400 MHz, CDCl3): δ 3.92 (3H, s), 7.62 (1H, s); LRMS (ESI): m / z [M+H]+229, 231. Structures confirmed by HSQC and HMBC experiments. (59) Reference procedure of (10yy) 3-[4-Bromo- 3-(difluoromethyl)pyrazol-1-yl]propan-1-ol (10yy) for preparation of EX.212 and (7t) was prepared in accordance with the general procedure 22 using the method described below in detail. Step 22-1 To a solution of 3-bromo-1-propanol (0.25 mL, 2.83 mmol) in DMSO (1.2 mL) cooled to 0 °C added K2CO3(391 mg, 2.83 mmol) and 4-bromo- 3-(difluoromethyl)-1H- pyrazole (10cc) (464 mg, 2.36 mmol) and reacted from 0 °C to room temperature overnight. Additional 3-bromo-1-propanol (41.2 uL) was added and reacted for 55 min. Additional K2CO3(60.8 mg) was added at room temperature and reacted at room temperature for 3 h. The reaction mixture was partitioned between water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (0- 32% EtOAc / hexanes) to afford: 3-[4- bromo- 3-(difluoromethyl)pyrazol-1-yl]propan-1-ol (10yy) (300.2 mg, 50%) and 3-[4- bromo-5-(difluoromethyl)pyrazol-1-yl]propan-1-ol (10zz) (44.2 mg, 7%) as clear oils. (10xx):1H NMR (400 MHz, CDCl3): δ 2.00-2.07 (2H, m), 3.22 (1H, br s), 3.56- 3.60 (2H, m), 4.23-4.27 (2H, m), 6.66 (1H, t, JH-F= 53.7 Hz), 7.51 (1H, s). (10yy):1H NMR (400 MHz, CDCl3): δ 2.07-2.13 (2H, m), 2.63 (1H, br s), 3.63- 3.66 (2H, m), 4.46-4.49 (2H, m), 6.80 (1H, t, JH-F= 52.3 Hz), 7.50 (1H, s). LRMS (ESI): m / z [M+H]+255, 257. Structure confirmed by HSQC and HMBC. (60) Reference procedure of (10ccc) 3-Iodo-4-methyl-1-(oxetan- 3-ylmethyl)pyrazole (10ccc) for preparation of EX.204 was prepared in accordance with the general procedure 22. Step 22-1 To a round bottom flask containing 3-iodo-4-methyl-1H-pyrazole (10aaa) (300 mg, 1.44 mmol), Cs2CO3(1.03 g, 3.16 mmol) in MeCN (6.5 mL) was added 3- (iodomethyl)oxetane (0.29 mL, 2.88 mmol). Resulting mixture was stirred for 2 days at room temperature. Thereafter, mixture was filtered through a pad of Celite and washed twice with DCM. Filtrate and washes were combined, concentrated, and purified by prep-TLC (30% EtOAc / hexanes) to afford a colorless oil (153 mg, 38%) as the expected product (10ccc). 1H NMR (400 MHz, CDCl3): δ 1.97 (3H, d, J = 0.7 Hz), 4.37 (2H, d, J = 7.6 Hz), 4.46 (2H, t, J = 6.2 Hz), 4.80 (2H, dd, J = 7.7, 6.5 Hz), 7.07 (1H, s);13C NMR (101 MHz, CDCl3): δ 11.01, 35.5, 54.8, 74.6, 100.4, 121.6, 128.4. HMBC confirmed correct regiochemistry of (10ccc). LRMS (ESI): m / z [M+H]+279. TLC analysis: Rf = 0.07 in 30% EtOAc / hexanes. Note: Compound (10bbb) eluted with unreacted starting material (10aaa). 3-Iodo-1-(2-methoxyethyl)-4-methyl-pyrazole (10ddd) was synthesized from commercially available 3-iodo-4-methyl-1H-pyrazole and 2-bromoethyl methyl ether in accordance with the methods described in the general procedure 22 for the preparation of EX.205. LRMS (ESI): m / z [M+H]+267. The coupling agent, 3-iodo-4-methyl-1-(oxetan- 3-yl)pyrazole (10eee) was synthesized from commercially available 3-iodo-4-methyl-1H-pyrazole and 3- iodooxetane in accordance with the methods described in the general procedure 22 for the preparation of EX.206. LRMS (ESI): m / z [M+H]+265. (61) Reference procedure of (10hhh) The coupling agent, 4-(difluoromethyl)-5-iodo-1-methyl-pyrazole (10hhh) for preparation of EX.219 was prepared in accordance with the general procedure 22 using the method described below in detail. Step 22-1 To a mixture of 4-(difluoromethyl)- 3-iodo-1H-pyrazole (10fff) (307.mg, 1.26 mmol) and K2CO3(347 mg, 2.52 mmol) in DMSO (5 mL) was added iodomethane (0.12 mL, 1.89 mmol) and stirred at room temperature for 2 h. Thereafter, mixture was poured into water and extracted thrice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc / Hexanes) to afford product (10hhh) (113 mg, purity = ~ 55%, yield = 19%) followed by compound (10ggg) (120 mg, 37%). LRMS (ESI): m / z [M+H]+259. (62) Reference procedure of (10iii) and (3r) 4-Bromo- 3-(difluoromethyl)-1-(trideuteriomethyl)pyrazole (10iii) (for preparation of EX.222 and EX.284 ) and 3-(Difluoromethyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole (3r) (for preparation of EX.377 and EX.378 ) were prepared in accordance with the general procedures 22 and 20 using the method described below in detail. Step 22-1 A vial containing 3-(difluoromethyl)-1H-pyrazole (51i) (600 mg, 5.08 mmol), K2CO3(842 mg, 6.1 mmol), trideuterio(iodo)methane (0.35 mL, 5.59 mmol) at 0 °C was diluted with 4 mL of DMSO. The resulting mixture was slowly warmed to room temperature and stirred for 24 h. Thereafter, the reaction mixture was quenched with iced water (10 mL) and extracted twice with EtOAc (15 mL each time). The organic extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford crude product (150 mg, 22%) which was used in the next step without further purification. LRMS (ESI): m / z [M+H]+136. Step 20-1 A solution of NBS (591 mg, 3.7 mmol) in dry DMF (2 mL) was added dropwise to a stirring solution of compound 3-(difluoromethyl)-1-(trideuteriomethyl)pyrazole (51j) (500 mg, 3.7 mmol) in dry DMF (1 mL) at 0 °C and stirred for 2 h at room temperature thereafter, reaction mixture was quenched with water and extracted with diethyl ether. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude product (512 mg, 64%) which was used in the next step without further purification. LRMS (ESI): m / z [M+H]+196, 198. Step 22-2 A reaction vessel containing 4-bromo- 3-(difluoromethyl)-1- (trideuteriomethyl)pyrazole (10iii) (300 mg, 1.4 mmol), bis(pinacolato)diboron (462 mg, 1.82 mmol) and KOAc (413 mg, 4.21 mmol) in 1,4-dioxane (15 mL) was thrice evacuated and backfilled with nitrogen. After addition of Pd(dppf)Cl2-DCM (114 mg, 0.14 mmol), mixture was purged thrice with nitrogen and then stirred at 90 ºC overnight. Thereafter, mixture was concentrated, and residue was purified by silica gel column chromatography (eluted with 0-25% EtOAc / Hexanes) to afford a red oil (210 mg, 57%) as the expected product. LRMS (ESI): [M+H]+262. (63) Reference procedure of (10’jjj) 3-Iodo-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (10’jjj) for preparation of EX.163 was prepared in accordance with the general procedure 23 using the method described below in detail. Step 23- 3 To a solution of 1,2-dihydropyrazol- 3-one (2.0 g, 23.7 mmol) (55a), DMF (66 mL), K2CO3(11.5 g, 83.2 mmol) was added 1,4-dibromobutane (57a) (3.4 mL, 28.5 mmol) dropwise at room temperature, then the resulting reaction mixture was heated at 127 °C overnight. The reaction was partitioned between brine and extracted with EtOAc and CHCl3. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-11% EtOAc / hexanes) to obtain the expected product as a yellow oil (849 mg, 25%); LRMS (ESI): m / z [M+H]+139. Step 23-4 A reaction vial containing 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (58a) (276.2 mg, 2.0 mmol) was dissolved in MeCN (4.4 mL) and added NIS (458.7 mg, 2.04 mmol) at room temperature The reaction was stirred at room temperature for 1.40 h. Additional NIS (35.3 mg) was added and reacted at room temperature for another 1.10 h. After concentration, the residue was purified by silica gel column chromatography (0- 10% EtOAc / hexanes) to obtain the expected product as a white solid (269.3 mg, 51%); LRMS (ESI): m / z [M+H]+264.9. (64) Reference procedure of (10kkk) and (10lll) 7-iodo-2,6-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (10kkk) for preparation of EX.167 and 7-iodo- 3,6-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (10lll) for preparation of EX.166 were prepared in accordance with the general procedure 23 using the method described below in detail. Step 23- 3 5-methyl-1, 2-dihydropyrazol- 3-one (55b) (1 g, 10.19 mmol) was dissolved in MeCN (20 mL), added K2CO3(2.8 g, 20.26 mmol), TBAB (657.2 mg, 2.04 mmol), 1,2- dibromopropane (57b) (1.59 mL, 15.3 mmol) and heated at 50 °C overnight. Additional 1,2-dibromopropane (1.59 mL), K2CO3(1.38 g) was added and heated at 95 °C for 2 h. To the solution DMF (1 mL) was added and heated at 90 °C overnight. After concentration, the residue was purified by silica gel column chromatography (0-28% EtOAc / hexanes) to obtain 3,6-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (58b-2) (73 mg, 5%) and 2,6- dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (58b-1) (81.8 mg, 6%) both as clear oils. (58b-2):1H NMR (400 MHz, CDCl3): δ 1.44 (3H, d, J = 6.0 Hz), 2.13 (3H, s), 4.37-4.42 (2H, m), 4.93-4.99 (1H, m), 5.06 (1H, s). (58b-1):1H NMR (400 MHz, CDCl3): δ 1.52 (3H, d, J = 6.4 Hz), 2.13 (3H, s), 3.67- 3.71 (1H, m), 4.20-4.24 (1H, m), 5.06 (1H, s), 5.21-5.30 (1H, m); LRMS (ESI): m / z [M+H]+139. Step 23-4a A reaction vial containing 2,6-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (58b- 1) (75 mg, 0.54 mmol) was dissolved in MeCN (1.8 mL) and added NIS (122 mg, 0.54 mmol) at room temperature and reacted at room temperature for 55 min. Additional NIS (11 mg) was added and reacted for another 2 h. Solvent was evaporated in vacuo and was purified by silica gel column chromatography (0-50% EtOAc / hexanes) to obtain product (10kkk) as a clear oil (138.1 mg, 96%); LRMS (ESI): m / z [M+H]+265. Step 23-4b A reaction vial containing 3,6-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (58b- 2) (72 mg, 0.52 mmol) was dissolved in MeCN (1.1 mL) and added NIS (117 mg, 0.52 mmol) at room temperature and reacted at room temperature for 40 min. Solvent was evaporated in vacuo and was purified by silica gel column chromatography (0-51% EtOAc / hexanes) to obtain product (10lll) as a white solid (104.5 mg, 76%); LRMS (ESI): m / z [M+H]+265 (65) Reference procedure of (10mmm) and (10nnn) (1) 3-Bromo-2, 7-dimethyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (10mmm) for preparation of EX.170 and EX.172, (2) 3-bromo-2, 5-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (10nnn) for preparation of EX.171 were prepared in accordance with the general procedure 23 using the method described below in detail. Step 23- 3 A solution containing 5-methyl-1, 2-dihydropyrazol- 3-one (55b) (1 g, 10.19 mmol), K2CO3(4.9 g, 35.6 mmol) in DMF (25 mL) was heated at 120 °C for 20 min, and then added 1,3-dibromobutane (57c) (1.47 mL, 12.2 mmol) dropwise at room temperature and heated at 120 °C overnight. The reaction mixture was partitioned between water and extracted with DCM, EtOAc and ether. The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (0-100% EtOAc / hexanes) to obtain 2,7-dimethyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine (58c) (415.5 mg, 27%) and 2,5-dimethyl-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine (58d) (60 mg, 4%) both as clear oils. (58c):1H NMR (400 MHz, CDCl3): δ 1.58 (3H, d, J = 6.5 Hz), 1.92-2.00 (1H, m), 2.20 (3H, s), 2.26-2.33 (1H, m), 4.17-4.22 (1H, m), 4.26-4.34 (2H, m), 5.29 (1H, s);13C (100 MHz, CDCl3): δ 13.6, 20.3, 29.4, 49.2, 63.5, 85.7, 147.3, 151.3. (58d):1H NMR (400 MHz, CDCl3): δ 1.32 (3H, d, J = 6.3 Hz), 1.90-1.93 (2H, m), 1.99-2.02 (1H, m), 2.05 (3H, s), 3.88- 3.95 (1H, m), 4.15-4.23 (1H, m), 5.13 (1H, s); LRMS (ESI): m / z [M+H]+153. Step 23-4a A reaction vial containing 2,7-dimethyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine (58c) (407.6 mg, 2.68 mmol) was dissolved in MeCN (4.8 mL) cooled to 0 °C and added NBS (427.2 mg, 2.67 mmol) and reacted at 0 °C for 22 min. Solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (0- 48% EtOAc / hexanes) to obtain product (10mmm) as a clear oil (547 mg, 88%);1H NMR (400 MHz, CDCl3): δ 1.58 (3H, d, J = 6.5 Hz), 1.96 – 2.04 (1H, m), 2.20 (3H, s), 2.30- 2.37 (1H, m), 4.25–4.33 (2H, m), 4.39-4.44 (1H, m); LRMS (ESI): m / z [M+H]+231, 233. Step 23-4b A reaction vial containing 2,5-dimethyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine (58d) (60 mg, 0.39 mmol) was dissolved in MeCN (0.7 mL), cooled to 0 °C and added NBS (62.8 mg, 0.39 mmol) and reacted at 0 °C for 30 min. Solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (0- 100% EtOAc / hexanes) to obtain product (10nnn) as a clear oil (77.3 mg, 85%);1H NMR (400 MHz, CDCl3): δ 1.53 (3H, d, J = 6.3 Hz), 2.03-2.13 (1H, m), 2.16-2.18 (1H, m), 2.20 ...

Claims

CLAIMS 1. A compound represented by structural formula (I*):or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; Rb is selected from H, C1-C6alkyl, and C(=O)O(C1-C6alkyl), wherein each C1-C6alkyl is optionally substituted with one or more substituents independently selected from group Q; CyA is selected from one of the following moieties: ,CyB is selected from 5- to 12-membered heteroaryl and C6-C12aryl, wherein the 5- to 12- membered heteroaryl or C6-C12aryl is optionally substituted with one or more substituents independently selected from group Q; Ra is selected from H, deuterium, F, Cl, Br, CN, NO2, C1-C6alkyl, and C1-C6alkoxy, whereineach C1-C6alkyl or C1-C6alkoxy is optionally substituted with one or more substituents independently selected from group Q; R5and R6are each independently selected from deuterium, F, Cl, Br, OH, CN, NO2, NR10aR10b, C(=O)NR11aR11b, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12- membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2- C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from group Q, or R5and R6together with the atoms to which they are attached form C4-C12carbocyclyl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein the C4-C12carbocyclyl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from group Q; n is 0, 1, 2, 3, or 4; R7and R8together with the atoms to which they are attached form 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl is optionally substituted with one or more substituents independently selected from group Q;R7is selected from H, deuterium, F, Cl, Br, OH, CN, NO2, NR10cR10d, C(=O)NR11cR11d, C1- C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; R8is selected from H and C1-6alkyl optionally substituted with one or more substituents independently selected from a group Q; R9is selected from C1-C6alkyl, F, Cl, Br, OH, CN, NO2, NR10eR10f, C(=O)NR11eR11f, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12- membered heteroaryl, and 4- to 12-membered heterocyclyl, wherein each C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C12cycloalkyl, C6-C12aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; and R10a, R10b, R10c, R10d, R10e, R10f, R11a, R11b, R11c, R11d, R11e, and R11fare each independently selected from H and C1-C6alkyl optionally substituted with one or more substituents independently selected from a group Q, or one or more of the pairs of variables selected from R10aand R10b, R10cand R10d, R10eandR10f, R11aand R11b, R11cand R11d, and R11eand R11f, together with the nitrogen to which they are attached, form 5- to 12-membered heteroaryl or 4- to 12-membered heterocyclyl, wherein each 5- to 12-membered heteroaryl or 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from a group Q; wherein each of the one or more substituents of group Q is independently selected from deuterium, F, Cl, Br, OH, NH2, NH(C=O)(C1-C6alkyl), NH(C=O)(C3-C8cycloalkyl), NH(C=O)(O-C1-C6alkyl), C1-C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1- C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy- carbonyl-N-methylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, C1-C6alkylsulfinyl- C1-C6alkyl, C1-C6alkylsulfonyl- C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, N-methylamino-carbonyl-C1-C6alkyl, N,N- dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring.

2. The compound of claim 1, wherein Ra is selected from H, F, Cl, Br, CN, and NO2.

3. The compound of claim 1, wherein Ra is C1-C6alkyl.

4. The compound of claim 1, wherein Ra is C1-C6alkoxy.

5. The compound of claim 1, wherein the compound is represented by structural formula (Ia*):or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein Rb is C1-C3alkyl.

7. The compound of claim 1, wherein the compound is represented by structural formula (Ib*):or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, wherein CyB is C6-C12aryl.

9. The compound of claim 8, wherein CyB is phenyl optionally substituted with one or more substituents independently selected from group Q.

10. The compound any one of claims 1-7, whereinwherein V is CH or N; Rv1is selected from CN, F, Cl, Br, C1-C3haloalkyl, and C1-C3haloalkoxy; and Rv2is selected from H, F, Cl, Br, NH2, C1-C3alkyl, C1-C3alkoxy, and C1-C3deteuroalkoxy.

11. The compound of claim 10, wherein V is CH.

12. The compound of claim 10, wherein V is N.

13. The compound of any one of claims 10-12, wherein Rv1is selected from CN, F, and OCHF2.

14. The compound of claim 13, wherein Rv1is OCHF2.

15. The compound of claim 13, wherein Rv1is CN.

16. The compound of any one of claims 10-15, wherein Rv2is H.

17. The compound of any one of claims 10-15, wherein Rv2is OCH3.

18. The compound of any one of claims 10-15, wherein Rv2is OCD3.

19. The compound of any one of claims 1-7, wherein R3is 5- to 12-membered heteroaryl.

20. The compound of claim 19, wherein CyB is 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from group Q.

21. The compound of claim 20, wherein CyB is 5-membered heteroaryl.

22. The compound of claim 20, wherein CyB is selected from the following moieties: , , ,wherein each of the listed moieties, as valence permits, is optionally substituted with one or more substituents independently selected from group Q. .The compound of claim 22, wherein CyB is,wherein RN1is selected from H and C1-C3alkyl; andRN2is selected from CN and C1-C3haloalkoxy.

24. The compound of claim 23, wherein the compound is represented by structural formula (Ic*):or a pharmaceutically acceptable salt thereof.

25. The compound of claim 23 or 24, wherein RN1is C1-C3alkyl.

26. The compound of claim 25, wherein RN1is methyl.

27. The compound of any one of claims 23-26, wherein RN2is CN.

28. The compound of any one of claims 23-26, wherein RN2is C1-C3haloalkoxy.

29. The compound of claim 28, wherein RN2is OCHF2.

30. The compound of claim 1, wherein the compound is represented by structuralformula (Id*):or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 1- 30, wherein the compound is represented by structural formula (Ie*):(Ie*), or a pharmaceutically acceptable salt thereof.

32. The compound of claim 31, wherein the compound is represented by structural formula (If*):or a pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 1- 30, wherein CyA is selected from.

34. The compound of any one of claims 31- 33, wherein R5is selected from F, OH, C1- C3alkoxy, and C1-C3haloalkyl, wherein the C1-C3alkyl and C1-C3haloalkyl optionally substituted with one or more substituents independently selected from group Q.

35. The compound of any one of claims 31- 34, wherein R5is selected from F, deuterium, C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl.

36. The compound of any one of claims 31- 35, wherein R6is selected from deuterium and F.

37. The compound of claim 31 or 32, wherein R5and R6together with the atoms to which they are attached form 5- to 6-membered heteroaryl.

38. The compound of any one of claims 31- 35, wherein n is 0.

39. The compound of any one of claims 1- 30, wherein CyA is selected from40. The compound of any one of claims 1- 30, wherein the compound is represented by structural formula (Ig*):or a pharmaceutically acceptable salt thereof.

41. The compound of claim 1, wherein the compound is represented by structural formula (Ih*):(Ih*), or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 39-41, wherein R9is selected from F, Cl, Br,OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy.

43. The compound of claim 42, wherein R9is selected from C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl.

44. The compound of claim 43, wherein R9is C1-C3haloalkyl.

45. The compound of claim 44, wherein R9is selected from CH2F, CHF2, and CF3.

46. The compound of claim 45, wherein R9is CHF2.

47. The compound of claim 43, wherein R9is C1-C3alkyl.

48. The compound of claim 47, wherein R9is ethyl.

49. The compound of any one of claims 39-48, wherein R8is H.

50. The compound of any one of claims 39-48, wherein R8is C1-C3alkyl.

51. The compound of any one of claims 39-50, wherein R7is selected from H, F, Cl, Br, OH, CN, NO2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy.

52. The compound of any one of claims 39-50, wherein R7is H.

53. The compound of any one of claims 39-50, wherein R7is selected from C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl.

54. The compound of any one of claims 39-48, wherein R7and R8together with the atoms to which they are attached form 5- to 12-membered heteroaryl.

55. The compound of claim 54, wherein R7and R8together with the atoms to which they are attached form 5- to 6-membered heteroaryl optionally substituted, as valence permits, with one or more substituents independently selected from group Q.

56. The compound of any one of claims 39-48, wherein R7and R8together with the atoms to which they are attached form 4- to 12-membered heterocyclyl.

57. The compound of any one of claims 38-44, wherein R7and R8together with theatoms to which they are attached form 5- to 8-membered heterocyclyl optionally substituted with one or more substituents independently selected from group Q.

58. The compound of any one of claims 1- 30, wherein the compound is represented by structural formula (Ii*):or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3; and Ro1and Ro2are each independently selected from H, OH, F, Cl, Br, C1-C3alkyl, C1-C3alkoxy, NRx1Rx2, NRx3C(=O)Rx5, and NRx6C(=O)ORx7, wherein Rx1, Rx2, Rx3, Rx5, Rx6, and Rx7is each independently selected from H, C1-3alkyl, and C3-C6cycloalkyl, and wherein each C1-C3alkyl, C1-C3alkoxy, or C3-C6cycloalkyl is substituted with one or more substituents independently selected from group Q.

59. The compound of claim 58, wherein the compound is represented by structural formula (Ij*):or a pharmaceutically acceptable salt thereof, wherein k is 1 or 2; R9is selected from C1-C3alkyl and C1-C3haloalkyl; RN2is selected from OCHF2and CN; and Ro1and Ro2are each independently selected from H, OH, F, Cl, Br, C1-C3alkyl, C1-C3alkoxy, NRx1Rx2, NRx3C(=O)Rx5, and NRx6C(=O)ORx7, wherein Rx1, Rx2, Rx3, Rx5, Rx6, and Rx7is each independently selected from H, C1-C3alkyl, and C3- C6cycloalkyl, and wherein each C1-C3alkyl, C1-C3alkoxy, or C3-C6cycloalkyl is substituted with one or more substituents independently selected from group Q.

60. The compound of claim 59, wherein the compound is represented by structural formula (Ik*):or a pharmaceutically acceptable salt thereof, wherein Ro1is selected from H and C1-C2alkyl; and Ro2is selected from OH, F, NHC(=O)O(C1-C2alkyl), NHC(=O)O(C3-C6cycloalkyl), C1-C3alkoxy, and -O(C1-C3hydroxyalkyl).

61. The compound of claim 59 or 60, wherein RN2is OCHF2.

62. The compound of claim 69 or 60, wherein RN2is CN.

63. The compound of any one of claims 59-62, wherein Ro1is H.

64. The compound of any one of claims 59-62, wherein Ro1is methyl.

65. The compound of any one of claims 59-63, wherein Ro1and Ro2are each H.

66. The compound of claim any one of claims 54-57, wherein Ro2is OH.

67. The compound of any one of claims 59-64, wherein Ro2is F.

68. The compound of any one of claims 59-64, wherein Ro2is methoxy.

69. The compound of any one of claims 59-64, wherein Ro2is -OCH2CH2OH.

70. The compound of any one of claims 59-64, wherein Ro2is -OCH2C(Me)2OH.

71. The compound of any one of claims 59-64, wherein Ro2is NHC(=O)OCH3.

72. The compound of any one of claims 59-64, wherein Ro2is NHC(=O)O(C3cycloalkyl).

73. The compound of any one of claims 58-72, wherein R9is CHF2.

74. The compound of any one of claims 58-72, wherein R9is ethyl.

75. The compound of claim 1, wherein the compound is selected from, or a pharmaceutically acceptable salt thereof.

76. The compound of claim 1, wherein the compound is77. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

78. The compound of claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

79. The compound of claim 1, wherein the compound is80. The compound of claim 1, wherein the compound is81. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

82. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

83. The compound of claim 1, wherein the compound is84. The compound of claim 1, wherein the compound is85. The compound of claim 1, wherein the compound is86. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

87. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

88. The compound of claim 1, wherein the compound is89. The compound of claim 1, wherein the compound is90. A pharmaceutical composition, comprising a compound of any one of claims 1-89 and a pharmaceutically acceptable carrier.

91. The pharmaceutical composition of claim 90, wherein the pharmaceutical composition is formulated for the treatment of MRGPRX2-mediated disease or disorder.

92. The pharmaceutical composition of claim 91, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis.

93. The pharmaceutical composition of claim 92, wherein the MRGPRX2-mediated disease or disorder is chronic spontaneous urticaria or chronic inducible urticaria.

94. The pharmaceutical composition of claim 93, wherein the chronic inducible urticaria is cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria.

95. The pharmaceutical composition of claim 92, wherein the chronic pruritus is chronic pruritus of unknown origin.

96. The pharmaceutical composition of claim 92, wherein the rosacea is papulopustular rosacea.

97. A method of treating an MRGPRX2-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-89 or a pharmaceutically acceptable composition of claim 90.

98. The method of claim 96, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis.

99. The method of claim 98, wherein the MRGPRX2-mediated disease or disorder ischronic spontaneous urticaria or chronic inducible urticaria.

100. The method of claim 99, wherein the chronic inducible urticaria is cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria.

101. The method of claim 98, wherein the chronic pruritus is chronic pruritus of unknown origin.

102. The method of claim 98, wherein the rosacea is papulopustular rosacea.

103. A compound of any one of claims 1-89 or a pharmaceutical composition of claim 90 for use in the treatment of an MRGPRX2-mediated disease or disorder.

104. The compound of claim 103, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis.

105. The compound of claim 104, wherein the MRGPRX2-mediated disease or disorder is chronic spontaneous urticaria or chronic inducible urticaria.

106. The compound of claim 105, wherein the chronic inducible urticaria is cold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria.

107. The compound of claim 104, wherein the chronic pruritus is chronic pruritus of unknown origin.

108. The compound of claim 104, wherein the rosacea is papulopustular rosacea.

109. Use of a compound of any one of claims 1-89 or a pharmaceutical composition of claim 90 in the manufacture of a medicament for use in the treatment of an MRGPRX2- mediated disease or disorder.

110. The use of claim 109, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, chronic inducible urticaria, mastocytosis, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, and pseudo anaphylaxis.

111. The use of claim 110, wherein the MRGPRX2-mediated disease or disorder is chronic spontaneous urticaria or chronic inducible urticaria.

112. The use of claim 111, wherein the chronic inducible urticaria iscold urticaria, cholinergic urticaria, heat urticaria, solar urticaria, symptomatic demographism urticaria, pressure urticaria, or contact urticaria.

113. The use of claim 110, wherein the chronic pruritus is chronic pruritus of unknown origin.

114. The compound of claim 110, wherein the rosacea is papulopustular rosacea.

115. A compound of Formula (Ia),or a pharmaceutically acceptable salt thereof, wherein X is S, -CRd=CRe-, -CRd=N-, or -N=CRd-; Rd and Re are independently hydrogen, deuterium, halo, CN, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy; Ra is hydrogen, halo, C1-C6alkyl or C1-C6alkoxy; Rb is hydrogen, C1-C6alkyl, hydroxy-C1-C6alkyl, C1-C6alkoxy- C1-C6alkyl, C1-C6alkyl-carbonyl or C1-C6alkoxy- carbonyl; CyA and CyB are independently C6-C10aryl optionally having at least one substituent selected from a group Q, heteroaryl optionally having at least one substituent selected from the group Q, C3-C8cycloalkyl optionally having at least one substituent selected from the group Q, C3-C8cycloalkenyl optionally having at least one substituentselected from the group Q, heterocyclyl optionally having at least one substituent selected from the group Q, fused heterocyclic ring consisting of 9 or 10 atoms optionally having at least one substituent selected from the group Q, where the group Q is deuterium, halo, C1- C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, C1-C6alkylsulfinyl- C1-C6alkyl, C1-C6alkylsulfonyl- C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, N-methylamino-carbonyl-C1-C6alkyl, N,N- dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring; and n is 0 or 1.

116. The compound or a pharmaceutically acceptable salt thereof according to Claim 115, wherein the Formula (Ia) is selected from the group consisting of Formulas (Ib), (Ic), (Id) and (Ie),）117. The compound or a pharmaceutically acceptable salt thereof according to Claim 115 or 116, wherein CyA is fused non-aromatic heterocyclyl-aryl optionally having at least one substituent selected from the group Q, fused non-aromatic heterocyclyl-heteroaryl optionally having at least one substituent selected from the group Q, fused arylheteroaryl optionally having at least one substituent selected from the group Q, or fused heteroarylheteroaryl optionally having at least one substituent selected from the group Q, wherein the group Q is C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1- C6alkoxy-carbonyl-N-methylamino, C3-C8cyloalkyl, C3-C8cyloalkyl-C1-C3alkoxy, C1- C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl- C1-C3alkyl, phenyl-C1-C6alkoxy, C1-C3alkoxy-carbonyl-C1-C3alkyl, N-methylamino- carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring.

118. The compound or a pharmaceutically acceptable salt thereof according to Claim 115 or 116, wherein CyA is selected from the group consisting ofwherein each Rf is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1- C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, oxo, C1-C6alkyl- carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, or phenyl-C1-C6alkoxy or two Rf are taken together with the carbon atom to which they are attached to form a spiro ring; Rg is hydrogen, C1-C6alkyl, C1-C6haloalkyl, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, carboxy-C1-C6alkyl, N-methylamino-carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl- C1-C6alkyl, heterocyclyl or heterocyclyl-C1-C3alkyl; m is an integer of 0 to 5; and asterisks denote the points of attachment.

119. The compound or a pharmaceutically acceptable salt thereof according to claim 115 or 116, wherein CyB is C6-C10aryl optionally having at least one substituent selected from the group Q, or heteroaryl optionally having at least one substituent selected from the group Q, and the group Q is halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, or C3-C8cycloalkyl.

120. The compound or a pharmaceutically acceptable salt thereof according to claim 115, 116 or 118, wherein CyB is selected from the group consisting of, wherein each Rh is independently halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfonyl, or C3-C8cycloalkyl; Rj is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; p is an integer of 0 to 5; and asterisks denote the points of attachment.

121. The compound or a pharmaceutically acceptable salt thereof according to Claim 115 or 120, wherein the Formula (Ia) is Formula (Ib)）.

122. The compound or a pharmaceutically acceptable salt thereof according to Claim 121, wherein Ra, Rb, Rd and Re are hydrogens; and n is 0.

123. The compound or a pharmaceutically acceptable salt thereof according to Claim 122, wherein CyB is phenyl optionally having at least one substituent selected from the group Q.

124. The compound or a pharmacologically acceptable salt thereof according to Claim 115, wherein the compound has a structure selected from the group consisting of structures,125. A pharmaceutical composition, comprising: the compound or pharmaceutically acceptable salt thereof according to any one of claims 115-124; and a pharmaceutically acceptable excipient.

126. A method of treating an MRGPRX2-mediated disease or disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 115- 124.

127. The method according to claim 126, wherein the MRGPRX2-mediated disease or disorder is a pseudo-allergic reaction, an itch-associated condition, a pain-associated condition, or an inflammatory or autoimmune disorder.

128. The method according to claim 126, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, and contact urticaria.

129. The compound or pharmaceutically acceptable salt thereof according to any one of claims 115-124 for use in the treatment of an MRGPRX2-mediated disease or disorder.

130. The compound or pharmaceutically acceptable salt for use according to claim 129, wherein the disease or disorder is selected from the group consisting of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, or contact urticaria.

131. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 115-124, in the manufacture of a medicament for use in the treatment of an MRGPRX2-mediated disease or disorder.

132. The use according to claim 131, wherein said disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphylactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphylaxis, or contact urticaria.

133. A compound of Formula (IIa),or a pharmaceutically acceptable salt thereof, wherein X is S, -CRd=CRe-, -CRd=N-, or -N=CRd-; Rd and Re are independently hydrogen, deuterium, halo, CN, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy; Ra is hydrogen, halo, C1-C6alkyl or C1-C6alkoxy; Rb is hydrogen, C1-C6alkyl, hydroxy-C1-C6alkyl, C1-C6alkoxy- C1-C6alkyl, C1-C6alkyl-carbonyl or C1-C6alkoxy- carbonyl; CyC and CyD are independently C6-C10aryl optionally having at least one substituent selected from a group W, heteroaryl optionally having at least one substituent selected from the group W, C3-C8cycloalkyl optionally having at least one substituent selected from the group W, C3-C8cycloalkenyl optionally having at least one substituent selected from the group W, heterocyclyl optionally having at least one substituent selected from the group W, fused heterocyclic ring consisting of 8 to 10 atoms optionally having at least one substituent selected from the group W, where the group W is deuterium, halo, C1- C6alkyl optionally substituted with one or more deuterium, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with one or more deuterium, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-C6alkyl, amino optionally having at least one C1-C3alkyl or hydroxy-C1-C3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, aminocarbonyloxy substituted with at least one C1-C6alkyl , C1-C6alkyl-carbonylamino, hydroxy-C1-C6alkyl-carbonylamino, hydroxy-C1-C6alkyl- carbony-N-methylamino, hydroxy-C1-C6alkyl- N-methylamino-carbonylamino, C3-C8cycloalkyl- carbonylamino, C1-C6alkoxy-carbonylamino, heterocycloxy-carbonylamino, hydroxy heterocyclo-carbonylamino, heteroaryl-carbonylamino, C1-C6alkyl-heteroaryl- carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N- methylamino, C1-C6alkyl-sulfonylamino, hydroxy-C1-C6alkyl-sulfonylamino, C3-C8cycloalkyl-sulfonylamino, C1-C6alkyl- C3-C8cycloalkyl-sulfonylamino, N,N- dimethylaminosulfonyl amino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, C1-C6alkylsulfinyl- C1-C6alkyl, C1-C6alkylsulfonyl- C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, C1-C6alkoxy-carbonyl-C1-C6alkoxy, amino-carbonyl-C1-C6alkoxy, C1-C6alkoxy-C1-C6alkoxy, C1-C6alkylsulfonylamino-C1-C6alkoxy, C1-C6alkyl- carbonylamino-C1-C6alkoxy, N,N-dimethylamino-C1-C6alkoxy, N-methylamino- carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl optionally substituted with one or more oxo group, heterocyclyl-C1-C3alkyl, ureido, or a spiro ring, where C3-C8cycloalkyl of C3-C8cycloalky-carbonylamino may be substituted by one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, a C1-C6alkyl, and an aminocarboxyl group, where C1-C6alkoxy of C1-C6alkoxy-carbonylamino may be substituted by one or more substituents selected from a hydroxy group, an amino group, a N-methylamino group, an amino-carbonyl group, a N-methylamino-carbonyl group, and oxo group, where ureido may be substituted by one or more substituents selected from a C1-C6alkyl and a hydroxy-C1-C6alkyl group; and n is 0 or 1.

134. The compound or a pharmaceutically acceptable salt thereof according to Claim 133, wherein the Formula (IIa) is selected from the group consisting of Formulas (IIb), (IIc),(IId) and (IIe),135. The compound or a pharmaceutically acceptable salt thereof according to Claim 133 or 134, wherein CyC is fused non-aromatic heterocyclyl-aryl optionally having at least one substituent selected from the group W, fused non-aromatic heterocyclyl- heteroaryl optionally having at least one substituent selected from the group W, fusedarylheteroaryl optionally having at least one substituent selected from the group W, or fused heteroarylheteroaryl optionally having at least one substituent selected from the group W, wherein the group W is halo, C3-C8cycloalkyl-carbonylamino, C1-C6alkyl, C1- C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1-C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, aminocarbonyl substituted with at least one C1-C6alkyl, oxo, C1-C6alkyl- carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl-carbonylamino, C1-C6alkoxy- carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N- methylamino, C3-C8cyloalkyl, C3-C8cyloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, phenyl-C1-C6alkoxy, C1-C3alkoxy-carbonyl-C1-C3alkyl, N-methylamino-carbonyl-C1-C6alkyl, N,N- dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C3alkyl or a spiro ring.

136. The compound or a pharmaceutically acceptable salt thereof according to Claim 133 or 134, wherein CyC is selected from the group consisting ofwherein each Rf is independently hydrogen, halo, C3-C8cycloalkyl-carbonylamino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, C1- C6hydroxyalkoxy, carboxy-C1-6alkyl, amino optionally having at least one C1-3alkyl, NO2, CN, CONH2, oxo, C1-C6alkyl-carbonyl, C1-C6alkoxy-carbonyl, C1-C6alkyl- carbonylamino, C1-C6alkoxy-carbonylamino, C1-C6alkyl-carbonyl-N-methylamino, C1-C6alkoxy-carbonyl-N-methylamino, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C3alkoxy, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-C1-C3-alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, or phenyl-C1-C6alkoxy or two Rf are taken together with the carbon atom to which they are attached to form a spiro ring; Rg is hydrogen, C1-C6alkyl, C1-C6haloalkyl, carboxy- C1-C6alkyl, amino optionally having at least one C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, C1-C3alkoxy-carbonyl-C1-C3alkyl, carboxy-C1-C6alkyl, N-methylamino-carbonyl-C1-C6alkyl, N,N-dimethylaminocarbonyl-C1-C6alkyl, heterocyclyl or heterocyclyl-C1-C3alkyl; m is an integer of 0 to 5; and asterisks denote the points of attachment.

137. The compound or a pharmaceutically acceptable salt thereof according to claim 133 or 134, wherein CyD is C6-C10aryl optionally having at least one substituent selected from the group W, or heteroaryl optionally having at least one substituent selected from the group W, and the group W is halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkoxy-carbonylamino, C1-C6hydroxyalkoxy, C3-C8cycloalkyl-carbonylamino,or C3-C8cycloalkyl.

138. The compound or a pharmaceutically acceptable salt thereof according to claim 133, 134 or 136, wherein CyD is selected from the group consisting of, wherein each Rh is independently halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkenyl, hydroxyl, C1-C6hydroxyalkyl, amino optionally having at least one C1-C3alkyl, CN, oxo, C1-C6alkylsulfonyl, or C3-C8cycloalkyl; Rj is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; p is an integer of 0 to 5; and asterisks denote the points of attachment.

139. The compound or a pharmaceutically acceptable salt thereof according to Claim 133 or 138, wherein the Formula (IIa) is Formula (IIb)）.

140. The compound or a pharmaceutically acceptable salt thereof according to Claim 139, wherein Ra, Rb, Rd and Re are hydrogens; and n is 0.

141. The compound or a pharmaceutically acceptable salt thereof according to Claim 140, wherein CyD is phenyl optionally having at least one substituent selected from the group W, pyridyl optionally having at least one substituent selected from the group W, or pyrazolyl optionally having at least one substituent selected from the group W.

142. The compound or a pharmaceutically acceptable salt thereof according to Claim 133, wherein the compound has a structure selected from the group consisting of structures,

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