SIK2 modulators and uses thereof

Abstract

The present invention provides compounds of formula (I), compositions thereof, and methods of using the same for the inhibition of SIK2 and the treatment of SIK2-mediated disorders.

Description

SIK2 MODULATORS AND USES THEREOF REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application 63 / 669,101, filed July9, 2024, the contents of which are herein incorporated by reference. SEQUENCE LISTING

[0002] This application contains a Sequence Listing which has been submitted in .xml format viaEFS and is hereby incorporated by reference. The ST.26 copy, created on March 22, 2023, is named 97-SK-P1.xml and is 1,989 bytes in size. TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to compounds and methods useful for inhibiting salt-inducible kinase 2 (SIK2). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION

[0004] A protein kinase is an enzyme that catalyzes the transfer of phosphate groups to proteinsor other organic molecules. Consequently, defective control of protein phosphorylation leads to uncontrolled signaling is involved in a number of diseases, including for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.

[0005] The salt-inducible kinases (SIKs) are Ser / Thr kinases members of the adenosinemonophosphate-activated kinase (AMPK) subfamily of kinases and three isoforms have been described, i.e., SIK1, SIK2 (QIK), and SIK3 (QSK). The SIKs play a number of roles in different cell types have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins, and also histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes.

[0006] For example, SIK2 is known to play a role in the secretion of high levels of anti-inflammatory cytokines such as interleukin-10 (IL-10), very low levels of pro-inflammatory cytokines such as TNF-α, and in the regulation of IFN^ and IL-12 signaling, suggesting SIK2 may 33184274.1Page 1 of 177407531-97SKWO (219686)be an interesting target for inflammatory diseases. See e.g., Darling, et al, Biochem. J.2017, 474(4):521-537 and Yao, et al., Nat. comm.2013, 4(1):1-15.

[0007] The lack of selectivity towards salt inducible kinase isoforms, and in particular towardsSIK2 may be a possible limitation in the use of such compounds. The aim of the present invention is to provide new compounds which are potent SIK2 inhibitors, and which also show selectivity over SIK1 and SIK2. There is a need for selective small molecule kinase inhibitors that inhibit SIK2. SUMMARY OF THE INVENTION

[0008] It has now been found that compounds of this invention, and pharmaceutically acceptablecompositions thereof, are effective as inhibitors of SIK2. In certain embodiments, the invention provides for compounds of the formulae presented herein.

[0009] In one aspect, the disclosure provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof:wherein X, Y, X1, X2, X3, Z, R1A, L1, L2, L3, L4, L5, R3B, R3A, a, b, c, R4, Ring C, and Ring D are as described and defined herein.

[0010] Compounds of the present invention, and pharmaceutically acceptable compositionsthereof, are useful for treating a variety of diseases, disorders or conditions, associated with modulating SIK2. Such diseases, disorders, or conditions include those described herein. Compounds provided by this invention are also useful for the study of SIK2 kinase in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new SIK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 33184274.1Page 2 of 177407531-97SKWO (219686)1. General Description of Certain Embodiments of the Invention:

[0011] In certain aspects, the present invention provides a compound of formula I:or aX is N or C; Y is N or C, where one of X and Y is N and the other of X and Y is C; is a single or double bond; L1is selected from -O-, -S-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, and -C(R1)2- ;L2 and L3 are independently selected from absent, -O-, -S-, -NR1-, and -C(R1)2-; L4 and L5 are independently selected from the group consisting of -O-, -S-, -NR1-, C(O)NR1-, - NR1C(O)-, -NR1C(O)NR1- and -C(R1)2-; wherein when one of L1, L2, L3, L4, or L5, is -O- , -S-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, or -NR1C(O)NR1-, the others are -C(R1)2-; R1is independently selected from the group consisting of hydrogen, C1–3 alkyl, and haloC1- C3alkyl; a is 1, 2, or 3; b is 0, 1, 2, or 3; c is 0 or 1; X1, X2, and X3 are independently selected from N and CR2provided that none are N or only one of X1, X2, and X3 may be N; each R2is independently selected from hydrogen, OH, C1–3alkyl, C1–3alkoxy, and halogen; Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7– 12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 3 of 177407531-97SKWO (219686)each R1Ais independently hydrogen, halogen, –CN, oxo, –OR, –SR, –NR2, –SO2R, –SO2NR2, – S(O)R, –S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, – N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, – N(R)CN, –P(O)(OR)2, –P(O)R2, haloC1-C6alkyl, haloC3-C6cycloalkyl, haloC1-C6alkoxy, or an optionally substituted group selected from C1–6 aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3Bis independently hydrogen, halogen, oxo, –CN, –NO2, –OR, –SR, –NR2, –SO2R, –SO2NR2, – S(O)R, –S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, – N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, – N(R)CN, –P(O)(OR)2, –P(O)R2, haloC1-C6alkyl, haloC3-C6cycloalkyl, haloC1-C6alkoxy, or an optionally substituted group selected from C1–6aliphatic; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3Ais a C1-6 aliphatic-cyclic group or a cyclic group; wherein the cyclic group is selected from: ^a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 4 of 177407531-97SKWO (219686)^ a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that isoptionally bridged or spirocyclic; and ^a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring thatis optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R3Ais substituted with y instances of RA; each instance of RAis independently selected from hydrogen; a C1-6aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and - OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; – CN; –NO2; –OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; –C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon the same atom together form oxo or a cyclic group selected from: ^3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAon the same atom is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; – C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon adjacent atoms optionally form a cyclic group selected from: 33184274.1Page 5 of 177407531-97SKWO (219686)^ 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^phenyl; and^ an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAon adjacent atoms is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; – C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; y is 0, 1, 2, or 3; Z is #C(R6)2-[C(R7)2]1-2-, #O-[C(R7)2]1-2-, or #NR6-[C(R8)2]1-2-, provided that # is a direct bond to Ring C; R4is an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^an optionally substituted phenyl;^ an optionally substituted 3-8 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-8 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–5heteroatoms independently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 6 of 177407531-97SKWO (219686)^ an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^and optionally substituted 5–11 membered saturated or partially unsaturatedbicyclic ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R6is independently selected from hydrogen, C1–4alkyl, and C1–4haloalkyl, or two R6groups may combine to form oxo; each R7is independently selected from hydrogen and C1–4alkyl, or two R7groups may combine to form oxo; each R8is independently selected from hydrogen and C1–4 alkyl; each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3, -C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH3, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^an optionally substituted phenyl;^ an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4heteroatoms independently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 7 of 177407531-97SKWO (219686)^ an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 6–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 6–11 membered saturated or partially unsaturated bicyclicring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from: ^an optionally substituted 4-7 membered saturated or partially unsaturatedcarbocycyl; ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

[0012] In some embodiments, the present invention provides a pharmaceutical compositioncomprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0013] In some embodiments, the present invention provides a method of treating a SIK2-mediated disease, disorder, or condition comprising administering to a patient in need thereof, a compound of formula I, or a pharmaceutically acceptable salt thereof. 2. Compounds and Definitions:

[0014] Compounds of the present invention include those described generally herein, and arefurther illustrated by the classes, subclasses, and species disclosed herein. As used herein, the 33184274.1Page 8 of 177407531-97SKWO (219686)following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0015] Stereocenters marked with “abs” intend to cover material wherein the marked stereocenteris of the stereochemistry shown in the diagram.

[0016] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0017] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e.,carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, 33184274.1Page 9 of 177407531-97SKWO (219686)oxygen, or sulfur Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. The term “alkyl” refers to a C1-12straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C1-8straight or branched saturated aliphatic group or a C1-6 straight or branched saturated aliphatic group. The term “lower alkyl” refers to a C1-4 straight or branched alkyl group.

[0018] Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl (also referred tointerchangeably herein as 2-propyl, iPr,iPr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu,iBu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2-butyl, tBu,tBu and t-Bu).

[0019] The term “alkenyl” refers to a C2-12 straight or branched partially unsaturated aliphaticgroup comprising at least one unsaturated carbon carbon double bond. In certain instances, alkenyl refers to a C2-8 or a C1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. The term “lower alkenyl” refers to a C2-4straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. Alkenyl groups include both cis (Z) and trans (E) regioisomers. Exemplary lower alkenyl groups are vinyl, allyl, 2-propenyl, and butenyl isomers (-CH2CH2CH=CH2, - CH2CH=CHCH3 and -CH=CHCH2CH3).

[0020] The term “alkynyl” refers to a C2-12 straight or branched partially unsaturated aliphaticgroup comprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C2-8or a C1-6straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. The term “lower alkynyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and 3-butynyl.

[0021] The term “haloalkyl” refers to a straight or branched alkyl group that is substituted withone or more halogen atoms. The term “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0022] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized 33184274.1Page 10 of 177407531-97SKWO (219686)form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0023] The term "unsaturated," as used herein, means that a moiety has one or more units ofunsaturation.

[0024] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight orbranched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0025] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is apolymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0026] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chainis a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0027] The term “halogen” means F, Cl, Br, or I.

[0028] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0029] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g.,“heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic 33184274.1Page 11 of 177407531-97SKWO (219686)nitrogen. Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3triazolyl), 1,2,4triazolyl, 1,2,5triazolyl, 1,3,4triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3oxadiazolyl, 1,2,4oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-1-only, 1,2-dihydro-3H- pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-only, imidazo[1,2- a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2- a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0030] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0031] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atomthat results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, 33184274.1Page 12 of 177407531-97SKWO (219686)oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0032] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at leastone double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0033] As described herein, compounds of the invention may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0034] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; 33184274.1Page 13 of 177407531-97SKWO (219686)–N3; (CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; – N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; –N(R^)N(R^)C(O)NR^2; – N(R^)N(R^)C(O)OR^; –N(R^)C(NR^)N(R^)2;–(CH2)0–4C(O)R^; –C(S)R^; –(CH2)0–4C(O)OR^; – (CH2)0–4C(O)SR^; –(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; –SC(S)SR°, –(CH2)0–4OC(O)NR^2; –C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; –(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; –(CH2)0–4S(O)R^; – N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; –(CH2)0–4P(O)2R^; –(CH2)0–4P(O)R^2; –(CH2)0–4OP(O)R^2; –(CH2)0–4OP(O)(OR^)2; –SiR^3; –(C1–4 straight or branched alkylene)O–N(R^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 3–12–membered saturated, partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0035] Suitable monovalent substituents on R^ (or the ring formed by taking two independentoccurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; –O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S. 33184274.1Page 14 of 177407531-97SKWO (219686)

[0036] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted”group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on the aliphatic group of R* include halogen, –R^, (haloR^), OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on a substitutable nitrogen of an “optionally substituted” groupinclude –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, S(O)2R†, S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independentlybelow, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] Suitable substituents on the aliphatic group of R† are independently halogen,–R^, (haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– 33184274.1Page 15 of 177407531-97SKWO (219686)membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are,within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0041] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammoniumand N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric(e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and Ra(or M) and Sa(or P) atropisomers. Therefore, single 33184274.1Page 16 of 177407531-97SKWO (219686)stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0043] The structures as drawn represent absolute configurations unless indicated otherwise. Theinvention contemplates individual enantiomers and diastereomers, enantiomerically enriched enantiomers and diastereomers, and racemic mixtures of enantiomers and diastereomers.

[0044] As used herein, a "SIK2 inhibitor" is a molecule that reduces, inhibits, or otherwisediminishes one or more of the biological activities of SIK2 (e.g., protein phosphorylation). Inhibition using the SIK2 inhibitor does not necessarily indicate a total elimination of the SIK2 activity. Instead, the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of SIK2 compared to an appropriate control.

[0045] A compound of the present invention may be tethered to a detectable moiety. It will beappreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term “suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click 33184274.1Page 17 of 177407531-97SKWO (219686)chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed.2002, 41:2596-99 and Sun et al., Bioconjugate Chem., 2006, 17:52-57.

[0046] As used herein, the term “detectable moiety” is used interchangeably with the term "label"and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium,32P,33P,35S, or14C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.

[0047] The term “secondary label” as used herein refers to moieties such as biotin and variousprotein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.

[0048] The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” as used herein refer tomoieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone- fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X. 33184274.1Page 18 of 177407531-97SKWO (219686)

[0049] The term “mass-tag” as used herein refers to any moiety that is capable of being uniquelydetected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in United States Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass- tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.

[0050] The terms “measurable affinity” and “measurably inhibit,” as used herein, means ameasurable change in a SIK2 protein kinase activity between a sample comprising a compound of the present invention, or composition thereof, and a SIK2 protein kinase , and an equivalent sample comprising a SIK2 protein kinase, in the absence of said compound, or composition thereof. 3. Description of Exemplary Embodiments:

[0051] As described above, in certain embodiments, the present invention provides a compound offormula I: or aX is N or C; Y is N or C, where one of X and Y is N and the other of X and Y is C; is a single or double bond; 33184274.1Page 19 of 177407531-97SKWO (219686)L1is selected from -O-, -S-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, and -C(R1)2- ; L2 and L3 are independently selected from absent, -O-, -S-, -NR1-, and -C(R1)2-; L4and L5are independently selected from the group consisting of -O-, -S-, -NR1-, C(O)NR1-, - NR1C(O)-, -NR1C(O)NR1- and -C(R1)2-; wherein when one of L1, L2, L3, L4, or L5, is -O- , -S-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, or -NR1C(O)NR1-, the others are -C(R1)2-; R1is selected from the group consisting of hydrogen, C1–3alkyl, and haloC1-C3alkyl; a is 1, 2, or 3; b is 0, 1, 2, or 3; c is 0 or 1; X1, X2, and X3are independently selected from N and CR2provided that none are N or only one of X1, X2, and X3 may be N; each R2is independently selected from hydrogen, OH, C1–3 alkyl, C1–3 alkoxy, and halogen, provided when R2is halogen, c may be 0, also provided that when all available R2groups are hydrogen, Y is C, X, and X3 are N, c may be 0; Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7– 12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1Ais independently hydrogen, halogen, –CN, oxo, –OR, –SR, –NR2, –SO2R, –SO2NR2, – S(O)R, –S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, – N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, – N(R)CN, –P(O)(OR)2, –P(O)R2, or an optionally substituted group selected from C1–6 aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 20 of 177407531-97SKWO (219686)Ring D is a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3Bis independently hydrogen, halogen, oxo, –OR, –SR, –NR2, –SO2R, –SO2NR2, –S(O)R, – S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, – N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, –N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, – P(O)(OR)2, –P(O)R2, haloC1-C6alkyl, haloC3-C6cycloalkyl, haloC1-C6alkoxy, or an optionally substituted group selected from C1–6 aliphatic; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3Ais a C1-6aliphatic-cyclic group, or a cyclic group; wherein the cyclic group is selected from: ^a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that isoptionally bridged or spirocyclic; and ^a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring thatis optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R3Ais substituted with y instances of RA; each instance of RAis independently selected from hydrogen; a C1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and - OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered 33184274.1Page 21 of 177407531-97SKWO (219686)saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; – CN; –NO2; –OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; –C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon the same atom together form oxo or a cyclic group selected from: ^3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAon the same atom is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; – C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon adjacent atoms optionally form a cyclic group selected from: ^3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^phenyl; and^ an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAon adjacent atoms is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; –33184274.1Page 22 of 177407531-97SKWO (219686)C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; y is 0, 1, 2, or 3; Z is #C(R6)2-[C(R7)2]1-2-, #O-[C(R7)2]1-2-, or #NR6-[C(R8)2]1-2-, provided that # is a direct bond to Ring C; R4is an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^an optionally substituted phenyl;^ an optionally substituted 3-8 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-8 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–5heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^and optionally substituted 5–11 membered saturated or partially unsaturatedbicyclic ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R6is independently selected from hydrogen, C1–4alkyl, and C1–4haloalkyl, or two R6groups may combine to form oxo; 33184274.1Page 23 of 177407531-97SKWO (219686)each R7is independently selected from hydrogen and C1–4alkyl, or two R7groups may combine to form oxo; each R8is independently selected from hydrogen and C1–4 alkyl; each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3, -C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH3, an optionally substituted C1-6 aliphatic group, an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^an optionally substituted phenyl;^ an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 6–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 6–11 membered saturated or partially unsaturated bicyclicring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from: 33184274.1Page 24 of 177407531-97SKWO (219686)^ an optionally substituted 4-7 membered saturated or partially unsaturatedcarbocycyl; ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

[0052] In some embodiments, the compound of formula I is a compound of formula I-a or I-b:a, b, c, X1, X2, X3, Z, R4, and Ring D are as defined herein, both singly and in combination, and Ring C is a 5-membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0053] In some embodiments, the compound of formula I is a compound of formula I-a or I-b:a, b, c, X1, X2, X3, Z, Ring D, and R4are as defined herein, both singly and in combination, and Ring C is a 6-membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0054] In some embodiments, the compound of formula I is a compound of formula I-a or I-b:33184274.1Page 25 of 177407531-97SKWO (219686)5, a, b, c, X1, X2, X3, Z, Ring D, and R4are as defined herein, both singly and in combination, and Ring C is an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0055] In some embodiments, the compound of formula I is a compound of formula I-a or I-b:a, b, c, X1, X2, X3, Z, Ring D, and R4are as defined herein, both singly and in combination, and Ring C is a 7–12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the compound of formula I is a compound of formula I-a-1 or I-b-1:or or a pharmaceutically acceptable salt thereof, wherein each of R1A, R3A, R3B, L2, L3, L4, L5, a, b, c, X1, X2, X3, Z, and R4are as defined herein, both singly and in combination, Ring C is a 5- membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, 33184274.1Page 26 of 177407531-97SKWO (219686)oxygen, and sulfur and Ring D is a 5 or 6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0057] In some embodiments, the compound of formula I is a compound of formula I-a-2 or I-b-2:or a pharmaceutically acceptable salt thereof, wherein each of R1A, R3A, R3B, L2, L3, L4, L5, a, b, c, X1, X2, X3, Z, R4, and R2are as defined herein, both singly and in combination, Ring C is a 5- membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and Ring D is an 5 or 6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0058] As defined generally above, X is N or C.

[0059] In some embodiments, X is N. In some embodiments, X is C.

[0060] As defined generally above, Y is N or C.

[0061] In some embodiments, X is N. In some embodiments, X is C.

[0062] In certain embodiments, one of X and Y is N and the other of X and Y is C;

[0063] In some embodiments, X and Y are as depicted in the compounds of Table 1, below.As defined generally above, is a single or double bond. In some embodiments, is a single bond. In some embodiments, is a double bond.

[0064] In some embodiments, is as depicted in the compounds of Table 1, below.

[0065] As defined generally above, X1, X2 and X3 are independently selected from N and CR2provided that none are N or only one of X1, X2 and X3 may be N.

[0066] In some embodiments, X1 is N. In some embodiments, X1 is CR2.

[0067] In some embodiments, X2 is N. In some embodiments, X2 is CR2.

[0068] In some embodiments, X3 is N. In some embodiments, X3 is CR2.33184274.1Page 27 of 177407531-97SKWO (219686)

[0069] In some embodiments, X1, X2 and X3 are CR2. In some embodiments, X1 is N, and X2 andX3 are CR2. In some embodiments, X2 is N, and X1 and X3 are CR2. In some embodiments, X3 is N, and X1 and X2 are CR2.

[0070] In some embodiments, X1 is as depicted in the compounds of Table 1, below.

[0071] In some embodiments, X2 is as depicted in the compounds of Table 1, below.

[0072] In some embodiments, X3 is as depicted in the compounds of Table 1, below.

[0073] As defined generally above, each R2 is independently selected from hydrogen, OH, C1–3alkyl, C1–3 alkoxy, and halogen.

[0074] In some embodiments, R1 is hydrogen. In some embodiments, R1 is C1–3 alkyl. In someembodiments, R2is haloC1-C3alkyl.

[0075] In some embodiments, L1 is -O-, -S-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, or -C(R1)2-.

[0076] In some embodiments, L1 is -O-.

[0077] In some embodiments, L1 is -S-.

[0078] In some embodiments, L1 is -NR1-.

[0079] In some embodiments, L1 is -C(O)-.

[0080] In some embodiments, L1 is -C(O)NR1-.

[0081] In some embodiments, L1 is -NR1C(O)-.

[0082] In some embodiments, L1 is -NR1C(O)NR1-.

[0083] In some embodiments, L1 is -C(R1)2-.

[0084] In some embodiments, L1 is -CH2-.

[0085] In some embodiments, L1 is -C(H, CH3)-.

[0086] In some embodiments, L1 is as depicted in the compounds of Table 1, below.

[0087] In some embodiments, L2 is absent, -O-, -S-, -NR1-, or -C(R1)2-.

[0088] In some embodiments, L2 is absent.

[0089] In some embodiments, L2 is -O-.

[0090] In some embodiments, L2 is -S-.

[0091] In some embodiments, L2 is -NR1-.

[0092] In some embodiments, L2 is -C(R1)2-.

[0093] In some embodiments, L2 is -CH2-.

[0094] In some embodiments, L2 is -C(H, CH3)-.33184274.1Page 28 of 177407531-97SKWO (219686)

[0095] In some embodiments, L2 is as depicted in the compounds of Table 1, below.

[0096] In some embodiments, L3 is absent, -O-, -S-, -NR1-, or -C(R1)2-.

[0097] In some embodiments, L3 is absent.

[0098] In some embodiments, L3 is -O-.

[0099] In some embodiments, L3 is -S-.

[0100] In some embodiments, L3 is -NR1-.

[0101] In some embodiments, L3 is -C(R1)2-.

[0102] In some embodiments, L3 is -CH2-.

[0103] In some embodiments, L3 is -C(H, CH3)-.

[0104] In some embodiments, L3 is as depicted in the compounds of Table 1, below.

[0105] In some embodiments, L4 is -O-, -S-, -NR1-, C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, or -C(R1)2-.

[0106] In some embodiments, L4 is -O-.

[0107] In some embodiments, L4 is -S-.

[0108] In some embodiments, L4 is -NR1-.

[0109] In some embodiments, L4 is -C(O)NR1-.

[0110] In some

[0111] In some .

[0112] In some

[0113] In some

[0114] In some embodiments, L4 is -C(H, CH3)-.

[0115] In some embodiments, L4 is as depicted in the compounds of Table 1, below.

[0116] In some embodiments, L5 is -O-, -S-, -NR1-, C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, or -C(R1)2-.

[0117] In some embodiments, L5 is -O-.

[0118] In some embodiments, L5 is -S-.

[0119] In some embodiments, L5 is -NR1-.

[0120] In some embodiments, L5 is -C(O)NR1-.

[0121] In some embodiments, L5 is -NR1C(O)-.

[0122] In some embodiments, L5 is -NR1C(O)NR1-.

[0123] In some embodiments, L5 is -C(R1)2-.33184274.1Page 29 of 177407531-97SKWO (219686)

[0124] In some embodiments, L5 is -CH2-.

[0125] In some embodiments, L5 is -C(H, CH3)-.

[0126] In some embodiments, L5 is as depicted in the compounds of Table 1, below.

[0127] In some embodiments, R1 is hydrogen, CH3, or CF3.

[0128] In some embodiments, R1 is hydrogen.

[0129] In some embodiments, R1 is CH3.

[0130] In some embodiments, R1 is CF3.

[0131] In some embodiments, R1 is as depicted in the compounds of Table 1, below.

[0132] In some embodiments, R2 is hydrogen. In some embodiments, R2 is OH. In someembodiments, R2is C1–3alkyl. In some embodiments, R2is C1–3alkoxy. In some embodiments, R2is halogen.

[0133] In some embodiments, R2 is hydrogen, F, Cl, CH3, OCH3, or CH2CH3.

[0134] In some embodiments, R2 is F.

[0135] In some embodiments, R2 is Cl.

[0136] In some embodiments, R2 is CH3.

[0137] In some embodiments, R2 is OCH3.

[0138] In some embodiments, R2 is CH2CH3.

[0139] In some embodiments, R2 is as depicted in the compounds of Table 1, below.

[0140] As defined generally above, R6 is independently selected from hydrogen, C1–4 alkyl, or C1–4haloalkyl, or two R6groups may combine to form oxo.

[0141] In some embodiments, R6 is hydrogen. In some embodiments, R6 is C1–4 alkyl. In someembodiments, R6is C1–4 haloalkyl. In some embodiments, R6is two R6groups form oxo.

[0142] In some embodiments, R6 is hydrogen, F, Cl, CH3, or two R6 form oxo.

[0143] In some embodiments, two R6 form oxo.

[0144] In some embodiments, R6 is F.

[0145] In some embodiments, R6 is Cl.

[0146] In some embodiments, R6 is CH3.

[0147] In some embodiments, R6 is as depicted in the compounds of Table 1, below.

[0148] As defined generally above, Z is #C(R6)2-[C(R7)2]1-2-, #O-[C(R7)2]1-2-, or #NR6-[C(R8)2]1-2-, provided that # is a direct bond to Ring C. 33184274.1Page 30 of 177407531-97SKWO (219686)

[0149] In some embodiments, Z is #C(R6)2-[C(R7)2]1-2-. In some embodiments, Z is #O-[C(R7)2]1-2-. In some embodiments, Z is #NR6-[C(R8)2]1-2-.

[0150] In some embodiments, Z is -CH2-CH2-, -CH2-, -C(O)-CH2-, -O-CH2-, -O-CH2-CH2-, -NH-CH2-, -NH-CH2-CH2-, -N(CH)3-CH2-, or -N(CH)3-CH2-CH2-.

[0151] In some embodiments, Z is -CH2-CH2-.

[0152] In some embodiments, Z is -CH2-.

[0153] In some embodiments, Z is -C(O)-CH2-.

[0154] In some embodiments, Z is -O-CH2-.

[0155] In some embodiments, Z is -O-CH2-CH2-.

[0156] In some embodiments, Z is -NH-CH2-.

[0157] In some embodiments, Z is -NH-CH2-CH2-.

[0158] In some embodiments, Z is -N(CH3)-CH2-.

[0159] In some embodiments, Z is -N(CH3)-CH2-CH2-.

[0160] In some embodiments, Z is as depicted in the compounds of Table 1, below.

[0161] As defined generally above, each R7 is independently selected from hydrogen and C1–4alkyl, or two R7groups may combine to form oxo.

[0162] As defined generally above, each R8 is independently selected from hydrogen and C1–4alkyl.

[0163] In some embodiments, R7 is hydrogen. In some embodiments, R7 is C1–4 alkyl. In someembodiments, two R7groups combine to form oxo.

[0164] In some embodiments, R7 is hydrogen, methyl, or two R7 groups combine to form oxo.

[0165] In some embodiments, R7 is as depicted in the compounds of Table 1, below.

[0166] As defined generally above, Ring C is a 5–6 membered monocyclic heteroaryl ring having1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7–12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0167] In some embodiments, Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 7–12 membered saturated 33184274.1Page 31 of 177407531-97SKWO (219686)or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0168] In some embodiments, Ring C is a 5–membered monocyclic heteroaryl ring having 1–3nitrogen atoms. In some embodiments, Ring C is a 5–membered monocyclic heteroaryl ring having 2–3 nitrogen atoms. , , , or33184274.1Page 32 of 177407531-97SKWO (219686),or

[0172] As defined generally above, Ring D is a 5–6 membered monocyclic heteroaryl ring having1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0173] In some embodiments, Ring D is a 5–6 membered monocyclic heteroaryl ring having 1–4heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. , ,33184274.1Page 33 of 177407531-97SKWO (219686)or ,

[0178] As defined generally above, R3A is a C1-6 aliphatic-cyclic group or a cyclic group; whereinthe cyclic group is selected from: ^a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that isoptionally bridged or spirocyclic; and 33184274.1Page 34 of 177407531-97SKWO (219686)^ a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring thatis optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0179] In some embodiments, R3A is a C1-6 aliphatic-cyclic group. In some embodiments, R3A is acyclic group. In some embodiments, R3Ais a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3Ais an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3Ais a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3Ais a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic. In some embodiments, R3Ais a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0180] In some embodiments, R3A is substituted with y instances of RA.,,

[0183] As defined generally above, c is 0 or 1.

[0184] In some embodiments, when c is 0. In some embodiments, c is 1.

[0185] In some embodiments, c is as depicted in the compounds of Table 1, below.

[0186] As defined generally above, R3B is independently hydrogen, halogen, oxo, –OR, –SR, –NR2, –SO2R, –SO2NR2, –S(O)R, –S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, – 33184274.1Page 35 of 177407531-97SKWO (219686)OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, – N(R)C(NR)NR2, –N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, – N(R)S(O)R, –N(R)CN, –P(O)(OR)2, –P(O)R2, haloC1-C6alkyl, haloC3-C6cycloalkyl, haloC1- C6alkoxy, or an optionally substituted group selected from C1–6aliphatic; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0187] In some embodiments, R3B is hydrogen. In some embodiments, R3B is halogen. In someembodiments, R3Bis oxo. In some embodiments, R3Bis –OR. In some embodiments, R3Bis –SR. In some embodiments, R3Bis –NR2. In some embodiments, R3Bis –SO2R. In some embodiments, R3Bis –SO2NR2. In some embodiments, R3Bis –S(O)R. In some embodiments, R3Bis –S(O)NR2. In some embodiments, R3Bis –C(O)R. In some embodiments, R3Bis –CO2R. In some embodiments, R3Bis –C(O)NR2. In some embodiments, R3Bis –C(O)N(R)OR. In some embodiments, R3Bis –OC(O)R. In some embodiments, R3Bis –OC(O)NR2. In some embodiments, R3Bis –N(R)CO2R. In some embodiments, R3Bis –N(R)C(O)R. In some embodiments, R3Bis – N(R)C(O)NR2. In some embodiments, R3Bis –N(R)C(NR)R. In some embodiments, R3Bis – N(R)C(NR)NR2. In some embodiments, R3Bis –N(R)NR2. In some embodiments, R3Bis – N(R)SO2NR2. In some embodiments, R3Bis –N(R)SO2R. In some embodiments, R3Bis – N=S(O)R2. In some embodiments, R3Bis –S(NR)(O)R. In some embodiments, R3Bis –N(R)S(O)R. In some embodiments, R3Bis –N(R)CN. In some embodiments, R3Bis –P(O)(OR)2. In some embodiments, R3Bis –P(O)R2. In some embodiments, R3Bis an optionally substituted group selected from C1–6 aliphatic. In some embodiments, R3Bis a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R3Bis a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3Bis a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments, R3B is as depicted in the compounds of Table 1, below.

[0189] As defined generally above, b is 0, 1, 2, or 3.33184274.1Page 36 of 177407531-97SKWO (219686)

[0190] In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2.In some embodiments, b is 3.

[0191] In some embodiments, b is 0. In some embodiments, b is 1 or 2. In some embodiments, bis 2 or 3.

[0192] In some embodiments, b is as depicted in the compounds of Table 1, below.

[0193] As defined generally above, each instance of RA is independently selected from hydrogen;a C1-6aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; -SR; - NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; –C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon the same atom together form oxo or a cyclic group selected from: ^3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAthe same atoms is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; – C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon adjacent atoms optionally form a cyclic group selected from: ^3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;33184274.1Page 37 of 177407531-97SKWO (219686)^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^phenyl; and^ an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAon adjacent atoms is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; – C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R.

[0194] In some embodiments, RA is hydrogen. In some embodiments, RA is a C1-6 aliphatic groupoptionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR. In some embodiments, RAis a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR. In some embodiments, RAis a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR. In some embodiments, RAis a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR. In some embodiments, RAis halogen. In some embodiments, RAis –CN. In some embodiments, RAis –NO2. In some embodiments, RAis –OR. In some embodiments, RAis -SR. In some embodiments, RAis -NR2. In some embodiments, RAis -S(O)2R. In some embodiments, RAis -S(O)2NR2. In some embodiments, RAis -S(O)R. In some embodiments, RAis -S(O)NR2. In some embodiments, RAis -C(O)R. In some embodiments, RAis -C(O)OR. In some embodiments, RAis –C(O)NR2. In some embodiments, RAis -C(O)N(R)OR. In some embodiments, RAis -OC(O)R. In some embodiments, RAis -OC(O)NR2. In some embodiments, RAis -N(R)C(O)OR. In some embodiments, RAis -N(R)C(O)R. In some embodiments, RAis N(R)C(O)NR2. In some embodiments, RAis N(R)C(NR)NR2. In some embodiments, RAis 33184274.1Page 38 of 177407531-97SKWO (219686)N(R)S(O)2NR2. In some embodiments, RAis –N(R)S(O)2R. In some embodiments, two instances of RAon the same atom together form oxo.

[0195] In some embodiments, two instances of RA on the same atom together form a cyclic groupselected from 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0196] In some embodiments, the cyclic group formed by two instances of RA on the same atomis substituted with 1, 2, or 3 groups independently selected from a C1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; –C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R.

[0197] In some embodiments, two instances of RA on adjacent atoms optionally form a cyclicgroup selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl; and an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0198] In some embodiments, the cyclic group formed by two instances of RA on adjacent atomsis substituted with 1, 2, or 3 groups independently selected from a C1-6aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; –C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R.

[0199] In some embodiments, Ring RA is as depicted in the compounds of Table 1, below.

[0200] As defined generally above, y is 0, 1, 2, or 3.

[0201] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.In some embodiments, y is 3. In some embodiments, y is 0 or 1. In some embodiments, y is 1 or 2. In some embodiments, y is 2 or 3. 33184274.1Page 39 of 177407531-97SKWO (219686)

[0202] In some embodiments, y is depicted in the compounds of Table 1, below.

[0203] As defined generally above, each R1A are independently hydrogen, halogen, –CN, oxo, –OR, –SR, –NR2, –SO2R, –SO2NR2, –S(O)R, –S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, – C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, – N(R)C(NR)R, –N(R)C(NR)NR2, –N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, – S(NR)(O)R, –N(R)S(O)R, –N(R)CN, –P(O)(OR)2, –P(O)R2, or an optionally substituted group selected from C1–6aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0204] In some embodiments, R1A is CH2CH3. In some embodiments, R1A is CH3. In someembodiments, R1Ais CF3. In some embodiments, R1Ais CHF2. In some embodiments, R1Ais CH2CF3. In some embodiments, R1Ais CH2CHF2.

[0205] In some embodiments, Ring R1A is as depicted in the compounds of Table 1, below.

[0206] In some embodiments, Ring C together with its R1A and R4 substituents are as depicted inthe compounds of Table 1, below.

[0207] In some embodiments, R1A is halogen. In some embodiments, R1A is –CN. In someembodiments, R1Ais oxo. In some embodiments, R1Ais –OR. In some embodiments, R1Ais –SR. In some embodiments, R1Ais –NR2. In some embodiments, R1Ais –SO2R. In some embodiments, R1Ais –SO2NR2. In some embodiments, R1Ais –S(O)R. In some embodiments, R1Ais –S(O)NR2. In some embodiments, R1Ais –C(O)R. In some embodiments, R1Ais –CO2R. In some embodiments, R1Ais –C(O)NR2. In some embodiments, R1Ais –C(O)N(R)OR. In some embodiments, R1Ais –OC(O)R. In some embodiments, R1Ais –OC(O)NR2. In some embodiments, R1Ais –N(R)CO2R. In some embodiments, R1Ais –N(R)C(O)R. In some embodiments, R1Ais –N(R)C(O)NR2. In some embodiments, R1Ais –N(R)C(NR)R. In some embodiments, R1Ais –N(R)C(NR)NR2. In some embodiments, R1Ais –N(R)NR2. In some embodiments, R1Ais –N(R)SO2NR2. In some embodiments, R1Ais –N(R)SO2R. In some embodiments, R1Ais –N=S(O)R2. In some embodiments, R1Ais –S(NR)(O)R. In some embodiments, R1Ais –N(R)S(O)R. In some embodiments, R1Ais –N(R)CN. In some embodiments, R1Ais –P(O)(OR)2. In some embodiments, R1Ais –P(O)R2. In some embodiments, 33184274.1Page 40 of 177407531-97SKWO (219686)R1Ais an optionally substituted C1–6aliphatic. In some embodiments, R1Ais an optionally substituted phenyl. In some embodiments, R1Ais an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R1Ais an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1Ais an optionally substituted 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0208] In some embodiments, R1A is halogen, –CN, oxo, –OR, –SO2R, –C(O)NR2, an optionallysubstituted C1–6 alkyl, a 3–7 membered saturated monocyclic carbocyclic ring, or an optionally substituted 3–7 membered saturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0209] In some embodiments, R1A is halogen, –CN, –C(O)NR2, an optionally substituted C1–6alkyl, a 3–7 membered saturated monocyclic carbocyclic ring, or an optionally substituted 3–7 membered saturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0210] In some embodiments, R1A is fluoro, chloro, –CN, oxo, –OMe, –O(CH2)2NMe2, –O(CH2)2NEt2, –O(CH2)2pyrrolidinyl, –O(CH2)2piperidinyl, –SO2cyclopropyl, –SO2Ph, – C(O)NH(CH2)2NMe2, –C(O)NH(CH2)3NMe2, methyl, ethyl, propyl, isopropyl, isobutyl, tert- butyl, isopentyl, cyclopentyl, cyclobutyl, methyloxycyclobutyl, –CHF2, –CF3, –CH2CH2F, – CH2CHF2, –CH2CF3, –CH2NHMe, –CH2NMeCO2tBu, –CH2SO2Me, –CH2CO2H, –CH2CO2Me, –CH2CONHMe, –CH2CONMe2, –CH2CN, –CH(Me)CN, –CH(Me)2CN, –CH2cyclobutyl, – CH2(methyloxycyclobutyl), –CH2oxetanyl, –CH2(methyloxetanyl), –CH2(fluorooxetanyl), – CH2azetidinyl, –CH2tetrahydrofuranyl, –CH2pyrrolidinyl, –CH2(N-methylpyrrolidinyl), – CH2pyrazolyl, –CH2tetrahydro-2H-pyranyl, –CH2morpholinyl, –CH2(N-methylmorpholinyl), – CH2(N-methylpiperazinyl), –CH2(N,N-dimethylpiperazinyl), –CH2(N-acetylpiperazinyl), – CH2pyridyl, benzyl, –CH2(cyclopropylenyl)CN, –(CH2)2pyrrolidin-2-onyl, –(CH2)2CN, – (CH2)2NH2, –(CH2)2oxetanyl, –(CH2)2azetidinyl, –(CH2)3NMe2, piperazinyl, or N- methylpiperazinyl.

[0211] In some embodiments, R1A is fluoro, chloro, –CN, –C(O)NH(CH2)2NMe2, –C(O)NH(CH2)3NMe2, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, isopentyl, cyclopentyl, cyclobutyl, –CHF2, –CF3, piperazinyl, or N-methylpiperazinyl. 33184274.1Page 41 of 177407531-97SKWO (219686)

[0212] In some embodiments, R1A is as depicted in the compounds of Table 1, below.

[0213] As defined generally above, a is 1, 2, or 3.

[0214] In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3.

[0215] In some embodiments, a is 1 or 2. In some embodiments, a is 2 or 3.

[0216] In some embodiments, a is depicted in the compounds of Table 1, below.

[0217] As defined generally above R4 is an optionally substituted cyclic group, or an optionallysubstituted C1-6alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^phenyl;^ an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 6–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^and optionally substituted 6–11 membered saturated or partially unsaturatedbicyclic ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0218] In some embodiments, R4 an optionally substituted cyclic group selected from oxetanyl,azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, 33184274.1Page 42 of 177407531-97SKWO (219686)tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, quinuclidinyl, phenyl, pyridyl, N-acetylpiperazinyl, methyloxycyclobutyl, and methyloxetanyl.

[0219] In some embodiments, R4 is , wherein:each R1Bare independently hydrogen, halogen, –CN, –OR, –SR, –NR2, –SO2R, –SO2NR2, – S(O)R, – S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, – N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, – N(R)CN, –P(O)(OR)2, –P(O)R2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or an optionally substituted group selected from C1–6aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R1Btogether form oxo; d is 0, 1, 2, 3, or 4; and p and q are each independently 0, 1, or 2 such that p + q is an integer of between 1 and 4.

[0220] In some embodiments, R4 is,33184274.1Page 43 of 177407531-97SKWO (219686)

[0221] As defined generally above, each R1B are independently hydrogen, halogen, –CN, –OR, –SR, –NR2, –SO2R, –SO2NR2, –S(O)R, – S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, – N(R)C(NR)NR2, –N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, – N(R)S(O)R, –N(R)CN, –P(O)(OR)2, –P(O)R2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or an optionally substituted group selected from C1–6 aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R1Btogether form oxo.

[0222] In some embodiments, R1B is hydrogen. In some embodiments, R1B is halogen. In someembodiments, R1Bis –CN. In some embodiments, R1Bis –OR. In some embodiments, R1Bis – SR. In some embodiments, R1Bis –NR2. In some embodiments, R1Bis –SO2R. In some embodiments, R1Bis –SO2NR2. In some embodiments, R1Bis –S(O)R. In some embodiments, R1Bis –S(O)NR2. In some embodiments, R1Bis –C(O)R. In some embodiments, R1Bis –CO2R. In some embodiments, R1Bis –C(O)NR2. In some embodiments, R1Bis –C(O)N(R)OR. In some embodiments, R1Bis –OC(O)R. In some embodiments, R1Bis –OC(O)NR2. In some embodiments, R1Bis –N(R)CO2R. In some embodiments, R1Bis –N(R)C(O)R. In some embodiments, R1Bis –N(R)C(O)NR2. In some embodiments, R1Bis –N(R)C(NR)R. In some embodiments, R1Bis –N(R)C(NR)NR2. In some embodiments, R1Bis –N(R)NR2. In some embodiments, R1Bis –N(R)SO2NR2. In some embodiments, R1Bis –N(R)SO2R. In some embodiments, R1Bis –N=S(O)R2. In some embodiments, R1Bis –S(NR)(O)R. In some embodiments, R1Bis –N(R)S(O)R. In some embodiments, R1Bis –N(R)CN. In some embodiments, R1Bis –P(O)(OR)2. In some embodiments, R1Bis –P(O)R2. In some embodiments, R1Bis C1-4 alkyl. In some embodiments, R1Bis C1-4 alkoxy. In some embodiments, R1Bis C1-4 haloalkyl. In some embodiments, R1Bis an optionally substituted C1–6aliphatic. In some embodiments, R1Bis an optionally substituted phenyl. In some embodiments, R1Bis an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R1Bis an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, 33184274.1Page 44 of 177407531-97SKWO (219686)oxygen, and sulfur. In some embodiments, R1Bis an optionally substituted 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R1Btogether form oxo.

[0223] In some embodiments, R1B is C1-4 alkyl, C1-4 alkoxy, or C1-4 haloalkyl.

[0224] In some embodiments, R1B is as depicted in the compounds of Table 1, below.

[0225] As defined generally above, d is 0, 1, 2, 3, or 4.

[0226] In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2.In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 0 or 1. In some embodiments, d is 1 or 2. In some embodiments, d is 2 or 3.

[0227] In some embodiments, d is as depicted in the compounds of Table 1, below.

[0228] As defined generally above, p and q are each independently 0, 1, or 2 such that p + q is aninteger of between 1 and 4.

[0229] In some embodiments, p is 0 and q is 1. In some embodiments, p is 0 and q is 2. In someembodiments, p is 0 and q is 3. In some embodiments, p is 0 and q is 4. In some embodiments, p is 1 and q is 0. In some embodiments, p is 2 and q is 0. In some embodiments, p is 3 and q is 0. In some embodiments, p is 4 and q is 0. In some embodiments, p is 1 and q is 1. In some embodiments, p is 1 and q is 2. In some embodiments, p is 2 and q is 1. In some embodiments, p is 2 and q is 2. In some embodiments, p is 3 and q is 1. In some embodiments, p is 1 and q is 3.

[0230] In some embodiments, p and q are as depicted in the compounds of Table 1, below.

[0231] As generally defined above, each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3,-C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH3, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^phenyl;^ an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 45 of 177407531-97SKWO (219686)^ an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 6–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 6–11 membered saturated or partially unsaturated bicyclicring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from: ^an optionally substituted 4-7 membered saturated or partially unsaturatedcarbocycyl; ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

[0232] In some embodiments, each R is independently hydrogen, or an optionally substitutedgroup selected from C1–6 aliphatic; phenyl; naphthyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7–12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1–4 heteroatoms 33184274.1Page 46 of 177407531-97SKWO (219686)independently selected from nitrogen, oxygen, and sulfur; a 5–8 membered saturated or partially unsaturated bridged bicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6–10 membered saturated or partially unsaturated spirocyclic ring having 0– 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6–11 membered saturated or partially unsaturated bicyclic ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same atom are optionally taken together with the atom to form an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0233] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substitutedC1–6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted naphthyl. In some embodiments, R is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7–12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5–8 membered saturated or partially unsaturated bridged bicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6–10 membered saturated or partially unsaturated spirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6–11 membered saturated or partially unsaturated bicyclic ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom are taken together with the atom to form an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, two R groups on the same atom 33184274.1Page 47 of 177407531-97SKWO (219686)are taken together with the atom to form an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom are optionally taken together with the atom to form an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0234] In some embodiments, R is as depicted in the compounds of Table 1, below.

[0235] In some embodiments, the compound of formula I is a compound of formulae I-a-3 or I-b-3:each of R1A, R3A, R3B, Z, R4, L2, L3, L4, L5, a, b, c, and Ring D are as defined herein, both singlyand in combination; X1 and X3 are independently selected from N, CF, CCl, CH3, and CH; Ring C is a 5–6 membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and R2is independently selected from hydrogen, F, CH3, and Cl.

[0236] In some embodiments, the compound of formula I is a compound of formulae I-a-4 or I-b-4:33184274.1Page 48 of 177407531-97SKWO (219686)each of R1A, R3A, R3B, Z, R4, a, b, c, and Ring D are as defined herein, both singly and incombination; L2 and L3 are independently selected from absent, -O-, or -C(R1)2-; wherein when one of L2 or L3 is -O-, the other is absent or -C(R1)2-; X1 and X3 are independently selected from N, CF, CCl, CH3, and CH; Ring C is a 5–6 membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and R2is independently selected from hydrogen, F, CH3, and Cl.

[0237] In some embodiments, the compound of formula I is a compound of formulae I-a-5 or I-b-5:or a pharmaceutically acceptable salt thereof, wherein:each of R1A, R3A, R3B, Z, R4, L2, L3, L4, L5, a, b, c, and Ring D are as defined herein, both singlyand in combination; X1and X3are independently selected from N, CF, CCl, CH3, and CH; and R2is independently selected from hydrogen, F, CH3, and Cl.

[0238] In some embodiments, the compound of formula I is a compound of formulae I-a-6 or I-b-6: or aeach of R1A, R3A, R3B, Z, R4, a, b, c, and Ring D are as defined herein, both singly and incombination; 33184274.1Page 49 of 177407531-97SKWO (219686)L2and L3are independently selected from absent, -O-, or -C(R1)2-; wherein when one of L2or L3is -O-, the other is absent or -C(R1)2-; L3 is selected from absent, -C(R1)2- or when L2 is -C(R1)2-; X1and X3are independently selected from N, CF, CCl, CH3, and CH; R2is independently selected from hydrogen, F, CH3, and Cl.

[0239] In some embodiments, the compound of formula I is a compound of formulae I-a-7 or I-b-7:or a pharmaceutically acceptable salt thereof, wherein:each of R1A, R3A, R3B, Z, R4, a, b, c, and Ring D are as defined herein, both singly and incombination; L2is absent, or -C(R1)2-; L3, L4 and L5 are -C(R1)2-; X1 and X3 are independently selected from N, CF, CCl, CH3, and CH; Ring C is a 5–6 membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and R2is independently selected from hydrogen, F, CH3, and Cl.

[0240] In some embodiments, the compound of formula I is a compound of formulae I-a-8 or I-b-8: or a33184274.1Page 50 of 177407531-97SKWO (219686)each of R1A, R3A, R3B, Z, R4, L2, L3, L4, L5, a, b, c, and Ring D are as defined herein, both singlyand in combination; X1 and X3 are independently selected from N, CF, CCl, CH3, and CH; and R2is independently selected from hydrogen, F, CH3, and Cl.

[0241] In some embodiments, the compound of formula I is a compound of formulae I-a-9 or I-b-9: or aeach of R1A, R3A R3B, Z, R4, a, b, c, and Ring D are as defined herein, both singly and incombination; L2 is absent or -C(R1)2-; L3, L4, and L5 are -C(R1)2-; X1and X3are independently selected from N, CF, CCl, CH3, and CH; and R2is independently selected from hydrogen, F, CH3, and Cl.

[0242] In some embodiments, the present invention provides a compound of formulae I-a-4, I-b-4, I-a-6, or I-b-6, or a pharmaceutically acceptable salt thereof, wherein: wherein each of R1A, R3AR3B, Z, R4, b, a, and Ring D are as defined herein, both singly and in combination; X1and X3are independently selected from N, CF, CCl, CH3, and CH; Ring C is a 7–12 membered saturated or partially unsaturated bicyclic heterocyclyl having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and R2is independently selected from hydrogen, F, CH3, and Cl.

[0243] Exemplary compounds of the invention are set forth in Table 1, or a pharmaceuticallyacceptable salt thereof. Table 1 identifies compounds by their IUPAC name and Table 2 lists the same compounds and shows their chemical structure. In the event of any discrepancy between Table 1’s name for a compound and Table 2’s structure for that same compound, Table 2’s 33184274.1Page 51 of 177407531-97SKWO (219686)compound structures will dominate and identify the compound corresponding to each respective compound number (I-#) in Table 1. Compounds of the invention are named using ChemDraw Professional (Version 21.0.0.28) and / or ChemAxon name generator (J Chem 5.3.1.0). Table 1. Exemplary Compounds Ex-# IUPAC Name(9R)-321-dimeth l-7-oxa-34132024263233-33184274.1Page 52 of 177407531-97SKWO (219686)(9R)-3,20-dimethyl-7-oxa-3,4,13,19,23,27,31,32- I-9 octaazahexacyclo[24.3.1.1^{18,22}.1^{24,27}.0^{2,6}.0^{9,13}]dotriaconta-33184274.1Page 53 of 177407531-97SKWO (219686)(9R)-3-(difluoromethyl)-15-fluoro-21-methyl-7,17-dioxa-3,4,13,20,24,27,30,32,33- I-19 nonaazahexacyclo[25.3.1.1^{19,23}.1^{25,28}.0^{2,6}.0^{9,13}]tritriaconta-1,above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above.

[0245] In some embodiments, the present invention provides a pharmaceutical compositioncomprising a compound disclosed herein (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, 33184274.1Page 54 of 177407531-97SKWO (219686)excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I as defined above, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, excipient, or diluent. 4. General Methods of Providing the Present Compounds

[0246] The compounds of this invention may be prepared or isolated in general by synthetic and / orsemi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions

[0247] According to another embodiment, the invention provides a composition comprising acompound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit SIK2, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0248] The term “patient,” as used herein, means an animal, preferably a mammal, and mostpreferably a human.

[0249] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxiccarrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures 33184274.1Page 55 of 177407531-97SKWO (219686)of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0250] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an esteror other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof.

[0251] As used herein, the term "active metabolite or residue thereof" means that a metabolite orresidue thereof is also an inhibitor of SIK2, or a mutant thereof.

[0252] The subject matter disclosed herein includes prodrugs, metabolites, derivatives, andpharmaceutically acceptable salts of compounds of the invention. Metabolites include compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof. If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. 33184274.1Page 56 of 177407531-97SKWO (219686)

[0253] A compound of the invention can be in the form of a "prodrug," which includes compoundswith moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Prodrugs which are converted to active forms through other mechanisms in vivo are also included. In aspects, the compounds of the invention are prodrugs of any of the formulae herein.

[0254] Compositions of the present invention may be administered orally, parenterally, byinhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0255] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation 33184274.1Page 57 of 177407531-97SKWO (219686)of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0256] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0257] In order to prolong the effect of a compound of the present invention, it is often desirableto slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0258] Alternatively, pharmaceutically acceptable compositions of this invention may beadministered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0259] Pharmaceutically acceptable compositions of this invention may also be administeredtopically, especially when the target of treatment includes areas or organs readily accessible by 33184274.1Page 58 of 177407531-97SKWO (219686)topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0260] Topical application for the lower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0261] For topical applications, provided pharmaceutically acceptable compositions may beformulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0262] Dosage forms for topical or transdermal administration of a compound of this inventioninclude ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0263] For ophthalmic use, provided pharmaceutically acceptable compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. 33184274.1Page 59 of 177407531-97SKWO (219686)

[0264] Pharmaceutically acceptable compositions of this invention may also be administered bynasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0265] Most preferably, pharmaceutically acceptable compositions of this invention areformulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0266] Pharmaceutically acceptable compositions of this invention may be orally administered inany orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0267] Solid dosage forms for oral administration include capsules, tablets, pills, powders, andgranules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. 33184274.1Page 60 of 177407531-97SKWO (219686)

[0268] Solid compositions of a similar type may also be employed as fillers in soft and hard-filledgelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0269] The active compounds can also be in micro-encapsulated form with one or more excipientsas noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0270] Liquid dosage forms for oral administration include, but are not limited to,pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert 33184274.1Page 61 of 177407531-97SKWO (219686)diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0271] The compounds of this invention, or pharmaceutical compositions thereof, may also beincorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

[0272] The amount of compounds of the present invention that may be combined with the carriermaterials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg / kg, 0.01 and 50 mg / kg, or 1 and 25 mg / kg, body weight / day of the compound can be administered to a patient receiving these compositions.

[0273] It should also be understood that a specific dosage and treatment regimen for any particularpatient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

[0274] Compounds of the invention are preferably formulated in dosage unit form for ease ofadministration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. 4. Uses of Compounds and Pharmaceutically Acceptable Compositions

[0275] Compounds and compositions described herein are generally useful for the inhibition ofkinase activity of one or more enzymes. In some embodiments the kinase inhibited by the compounds and methods of the invention is SIK2. 33184274.1Page 62 of 177407531-97SKWO (219686)

[0276] The presently disclosed compounds find use in inhibiting SIK2 protein kinase. In oneembodiment, the subject matter disclosed herein is directed to a method of inhibiting SIK2, the method comprising contacting SIK2 with an effective amount of a compound of the invention or a pharmaceutical composition described herein.

[0277] The presently disclosed compounds can be used in a method for inhibiting SIK2. Suchmethods comprise contacting SIK2 with an effective amount of a presently disclosed compound. By "contact" is intended bringing the compound within close enough proximity to an isolated SIK2 kinase or a cell expressing SIK2 such that the compound is able to bind to and inhibit the SIK2. The compound can be contacted with SIK2 in vitro or in vivo via administration of the compound to a subject.

[0278] In one aspect, provided herein is a method of inhibiting SIK2 in a biological sample. Themethod comprises contacting the sample with a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0279] Any method known in the art to measure the kinase activity of SIK2 may be used todetermine if SIK2 has been inhibited, including in vitro assays, immunoblots with antibodies specific for phosphorylated targets of SIK2, or the measurement of a downstream biological effect of SIK2 kinase activity.

[0280] Provided herein are compounds and pharmaceutical compositions that inhibit SIK2 proteinkinase, as well as methods of treatment using such compounds and pharmaceutical compositions. The compounds and compositions can be used in methods of modulating the immune system, for treatment of diseases, and for treatment of cells in vivo, in vitro, or ex vivo.

[0281] The present disclosure provides methods of inhibiting SIK2 in a patient. The methodcomprises administering to a patient a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). 33184274.1Page 63 of 177407531-97SKWO (219686)

[0282] The presently disclosed compounds can be used to treat a SIK2-mediated disorder. As usedherein, a "SIK2-mediated disorder" is a pathological condition in which SIK2 activity is necessary for the genesis or maintenance of the pathological condition.

[0283] Accordingly, in one aspect, provided herein is a method of treating a SIK2-mediateddisorder, disease, or condition in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). In some embodiments, the present invention provided a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein for use in medicine.

[0284] In some embodiments, the SIK2-mediated disorder is selected from inflammatory diseases,autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases.

[0285] In some embodiments, the present invention provides a method of treating an inflammatorydisease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the present invention provides a method of treating anautoinflammatory disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the present invention provides a method of treating an autoimmunedisease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof. 33184274.1Page 64 of 177407531-97SKWO (219686)

[0288] In some embodiments, the present invention provides a method of treating cancer in apatient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is selected from solid tumors (e.g., bone cancer, skin cancer, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, kidney cancer, bladder cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bile duct cancer, bladder cancer), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.

[0289] In some embodiments, the SIK2-mediated disorder is a cancer selected from ovariancancer, breast cancer, acute myeloid leukemia, and multiple myeloma.

[0290] In some embodiments, the present invention provides a method of treating ovarian cancerin a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the present invention provides a method of treating breast cancer ina patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0292] In some embodiments, the present invention provides a method of treating acute myeloidleukemia in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the present invention provides a method of treating multiplemyeloma in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the present invention provides a method of treating fibrotic diseasesin a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof. 33184274.1Page 65 of 177407531-97SKWO (219686)

[0295] In some embodiments, the present invention provides a method of treating transplantationrejection diseases involving impairment of cartilage turnover in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the present invention provides a method of treating congenitalcartilage malformation in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the present invention provides a method of treating diseasesinvolving impairment of bone turnover in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the present invention provides a method of treating diseasesassociated with hypersecretion of TNFα, interferons, IL-6, IL-12 and / or IL-23 in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the present invention provides a method of treating respiratorydiseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the present invention provides a method of treating endocrine and / ormetabolic diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the present invention provides a method of treating cardiovasculardiseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the present invention provides a method of treating dermatologicaldiseases in a patient in need thereof, wherein the method comprises administering to the patient a 33184274.1Page 66 of 177407531-97SKWO (219686)compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the present invention provides a method of treating abnormalangiogenesis associated diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the SIK2-mediated disorder is inflammatory bowel diseases suchas Crohn’s disease and ulcerative colitis, diabetes, a skin pigmentation disease, osteoporosis, osteoarthritis, lupus (systemic lupus erythematosus), a musculoskeletal disease, or rheumatoid arthritis.

[0305] In some embodiments, the SIK2-mediated disorder is Bone-mineral disorders, includingchronic kidney disease. In some embodiments, the SIK2-mediated disorder is a mineral bone disorder. In some embodiments, the SIK2-mediated disorder is a mineral loss disorder, such as Malignancy-related and oncology drug-related bone loss, and osteoporosis (post-menopausal, glucocorticoid-induced, hypogonadal).

[0306] In some embodiments, the SIK2-mediated disorder is Ankylosing Spondylitis, PsoriaticArthritis, Crohn's Disease (Active and Maintenance), Plaque Psoriasis, Juvenile Idiopathic Arthritis, Ulcerative Colitis, Hidradenitis Suppurativa, Uveitis, and non-radiographic axial spondylarthritis.

[0307] In some embodiments, the present invention provides a method of treating inflammatorybowel disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the present invention provides a method of treating diabetes in apatient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the present invention provides a method of treating a skinpigmentation disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof. 33184274.1Page 67 of 177407531-97SKWO (219686)

[0310] In some embodiments, the present invention provides a method of treating osteoporosis ina patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the present invention provides a method of treating osteoarthritis ina patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the present invention provides a method of treating amusculoskeletal disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the present invention provides a method of treating rheumatoidarthritis in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0314] It is understood that appropriate doses of the active compound depends upon a number offactors within the knowledge of the ordinarily skilled physician or veterinarian. The dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.

[0315] It will also be appreciated that the effective dosage of a compound of the invention or apharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays.

[0316] In some embodiments, the SIK2 inhibitor is administered to the subject at a dose of betweenabout 0.001 ^ g / kg and about 1000 mg / kg, including but not limited to about 0.001 ^ g / kg, 0.01 ^ g / kg, 0.05 ^ g / kg, 0.1 ^ g / kg, 0.5 ^ g / kg, 1 ^ g / kg, 10 ^ g / kg, 25 ^ g / kg, 50 ^ g / kg, 100 ^ g / kg, 250 ^ g / kg, 500 ^ g / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0317] In some embodiments, the SIK2 inhibitor is administered to the subject at a dose of betweenabout 0.1 mg and about 10 g, including but not limited to about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1 g, 2 g, 5 g, and 10 g. 33184274.1Page 68 of 177407531-97SKWO (219686)

[0318] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating,delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0319] In some embodiments, the compounds of the invention are useful in preventing or reducingthe risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0320] Additionally, provided are SIK2 inhibitors for use as therapeutic active substances. A SIK2inhibitor for use in treating or preventing a SIK2-mediated disorder provided herein. Further provided is the use of a SIK2 inhibitor in the manufacture of a medicament for treating or preventing a SIK2-mediated disorder provided herein.

[0321] The term "administration" or "administering" includes routes of introducing thecompound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.

[0322] The term "effective amount" includes an amount effective, at dosages and for periods oftime necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.

[0323] The phrases "systemic administration," "administered systemically", "peripheraladministration" and "administered peripherally" as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes. 33184274.1Page 69 of 177407531-97SKWO (219686)

[0324] The phrase "therapeutically effective amount" means an amount of a compound of thepresent invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0325] The term "subject" refers to animals such as mammals, including, but not limited to,primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human. 5. Combination Therapies

[0326] Depending upon the particular condition, or disease, to be treated, additional therapeuticagents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0327] Those additional agents may be administered separately from a provided combinationtherapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another.

[0328] As used herein, the term “combination,” “combined,” and related terms refers to thesimultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[0329] The amount of additional therapeutic agent present in the compositions of this inventionwill be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic 33184274.1Page 70 of 177407531-97SKWO (219686)agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0330] In one embodiment, the present invention provides a composition comprising a compoundof formula I and one or more additional therapeutic agents. The therapeutic agent may be administered together with a compound of formula I, or may be administered prior to or following administration of a compound of formula I. In certain embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0331] A compound of the current invention may also be used in combination with knowntherapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[0332] A compound of the current invention can besides or in addition be administered especiallyfor tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. EXAMPLES

[0333] As depicted in the Examples below, in certain exemplary embodiments, compounds areprepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. 33184274.1Page 71 of 177407531-97SKWO (219686)Additional compounds of the invention were prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art. List of abbreviations Ac: acetyl CDI: carbonyldiimidazole AcOH: acetic acid COD: cyclooctadiene Ac2O: acetic anhydride Cs2CO3: Caesium carbonate ACN: acetonitrile d: days Ad: adamantly DABCO: 1,4-diazobicyclo[2.2.2]octane AIBN: 2,2'-azo bisisobutyronitrile DAST: diethylaminosulfur trifluoride AlMe3: Trimethylaluminium dba: dibenzylideneacetone Amphos: di-tert-butyl(4- DBU: 1,8-diazobicyclo[5.4.0]undec-7- dimethylaminophenyl)phosphine ene Anhyd: anhydrousAq: aqueous DCE: 1,2-dichloroethane BBr3: Boron tribromide B2Pin2: bis DCM: dichloromethane (pinacolato)diboron-4,4,4',4',5,5,5',5'- DEA: diethylamine octamethyl-2,2'-bi(1,3,2-dioxaborolane) DHP: dihydropyran BINAP: 2,2'-bis(diphenylphosphino)- DIBAL-H: diisobutylaluminum hydride 1,1'-binaphthyl DIPA: diisopropylamine BH3: borane DIPEA or DIEA: N,N- Bn: benzyl diisopropylethylamine Boc: tert-butoxycarbonyl DMA: N,N-dimethylacetamide Boc2O: di-tert-butyl dicarbonate DME: 1,2-dimethoxyethane BPO: benzoyl peroxide DMAP: 4-dimethylaminopyridine Brettphos: 2-Di-cyclohexylphosphino- DMF: N,N-dimethylformamide 3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′- DMP: Dess-Martin periodinane biphenyl)-2-(2′-amino-1,1′ -biphenyl) DMPU: N,N′-Dimethylpropyleneurea nBuOH: n-butanol DMSO-dimethyl sulfoxide Bu: Butyl DPPA: diphenylphosphoryl azide cataCXium: di-adamantylalkylphosphine DPPE: 1,2-Bis(diphenylphosphino)ethane CBr4: Carbon tetrabromide dppf: 1,1’- CDCl3: deuterated chloroform bis(diphenylphosphino)ferrocene 33184274.1Page 72 of 177407531-97SKWO (219686)EDC or EDCI: 1-(3- LiOH: lithium hydroxide dimethylaminopropyl)-3- m-CPBA: meta-chloroperbenzoic acid ethylcarbodiimide hydrochloride M: molar ee: enantiomeric excess MeCN: acetonitrile ESI: electrospray ionization MeOH: methanol Et3N_ Triethyl amine Me2S: dimethyl sulfide EA: ethyl acetate MeONa: sodium methylate EtOAc: ethyl acetate MeI: iodomethane EtOH: ethanol min: minutes FA: formic acid mL: milliliters h or hrs: hours mM: millimolar HATU: N,N,N’,N’-tetramethyl-O-(7- mmol: millimoles azabenzotriazol-1-yl)uronium MPa: mega pascal hexafluorophosphate MOMCl: methyl chloromethyl ether HCl: hydrochloric acid MS: molecular sieve HPLC: high performance liquid MsCl: methanesulfonyl chloride chromatography Ms2O: Methanesulfonic anhydride HOAc: acetic acid MTBE: methyl tert-butyl ether IBX: 2-iodoxybenzoic acid nBuLi: n-butyllithium IPA: isopropyl alcohol NaClO: Sodium hypochlorite KHMDS: potassium NaH: Sodium hydride hexamethyldisilazide NaCN: Sodium cyanide K2CO3: potassium carbonate NaNO2: sodium nitrite KF: potassium fluoride NaOH: sodium hydroxide KI: potassium iodide Na2SO4: sodium sulfate KOAc: potassium acetate NBS: N-bromosuccinimide KOH: potassium hydroxide NCS: N-chlorosuccinimide K3PO4: potassium phosphate NFSI: N-fluorobenzenesulfonimide LAH: lithium aluminum hydride NH4Cl: Ammonium chloride LDA: lithium diisopropylamide NMO: N-methylmorpholine N-oxide LiBH4: lithium borhydride NMP: N-methylpyrrolidine33184274.1Page 73 of 177407531-97SKWO (219686)NMR: Nuclear Magnetic Resonance PyBOP: (benzotriazol-1- o C: degrees Celsius yloxy)tripyrrolidinophosphonium o / n: overnight hexafluorophosphate Palladacycle G2 (Pd G2): [2-(2'-amino- Rel: relative 1,1'-biphenyl)]palladium chloride RuPhos: 2-Dicyclohexylphosphino-2′,6′- Palladacycle G3 (Pd G3): [2-(2'-amino- diisopropoxybiphenyl 1,1'-biphenyl)]palladium R.T. or rt: room temperature methanesulfonate sat: saturated P(Cy)3: Tricyclohexylphosphine SEMCl: chloromethyl-2- Pd / C: palladium on Carbon trimethylsilylethyl ether Pd(dba)2: palladium SFC: supercritical fluid chromatography bis(dibenzylideneacetone) SOCl2: sulfur dichloride Pd(dtdpf)Cl2: [1,1’-Bis(di-tert- TBDPS: tert-butyl diphenyl silyl butylphosphino)ferrocene]dichloro t-BuBrettPhos: [(2-Di-tert- palladium butylphosphino-3,6-dimethoxy-2′,4′,6′- Pd(OAc)2: palladium acetate triisopropyl-1,1′-biphenyl)-2-(2′-amino- Pd-PEPPSI-IPentCl: Dichloro[1,3- 1,1′-biphenyl)] palladium(II) bis(2,6-Di-3-pentylphenyl)imidazol-2- methanesulfonate ylidene](3-chloropyridyl)palladium tBuOK or t-BuOK: potassium tert- Pd(PPh3)2Cl2: palladium butoxide (bis(triphenylphosphine) dichloride TBAB: tetrabutylammonium bromide Pd(PPh3)4: palladium TBAF: tetrabutylammonium fluoride tetrakis(triphenylphosphine) TBAI: tetrabutylammonium iodide PBS: phosphate buffered saline TEA: triethylamine PE: petroleum ether Tf: trifluoromethanesulfonate PhMe: Toluene TfAA, TFMSA or Tf2O: POCl3: phosphorus oxychloride trifluoromethanesulfonic anhydride PPh3: triphenylphosphine TFA: trifluoracetic acid Py: Pyridine TIPS: triisopropylsilyl THF: tetrahydrofuran THP: tetrahydropyran33184274.1Page 74 of 177407531-97SKWO (219686)TLC: thin layer chromatography wt: weight TMEDA: tetramethylethylenediamine Xantphos: 4,5-bis(diphenylphosphino)- TMSCN: Trimethylsilyl cyanide 9,9-dimethylxanthene T3P: propylphosphonic anhydride XPhos: 2-dicyclohexylphosphino-2′,4′,6′- TsCl or TosCl: Tosyl chloride triisopropylbiphenyl pTSA: para-toluenesulfonic acid General Synthetic Methods

[0334] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents,and catalysts utilized to synthesis the compounds of the present invention were either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed.1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.

[0335] Proton NMR (1H NMR) was conducted in deuterated solvent. In certain compoundsdisclosed herein, one or more1H shifts overlap with residual proteo solvent signals; these signals have not been reported in the experimental provided hereinafter.

[0336] LCMS was conduct using the following methods:Method Instrument Mode Stationary PhaseMobile Phase Mobile N N N N N33184274.1Page 75 of 177407531-97SKWO (219686)Agilent 1290 Binary Zorbax E 10 mM F xtend C18 infinit II Gr di nt (50x46mm) 5 m NH4HCO3in 100% ACN N in in N N le N NGeneral Synthetic Methods of Producing Compounds of the Disclosure

[0337] Compounds of the present invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to those described in the accompanying synthetic schemes. Intermediate 1: 1-(tert-butyl) 2-methyl (2S,3R)-3-fluoropyrrolidine-1,2-dicarboxylate 33184274.1Page 76 of 177407531-97SKWO (219686)

[0338] To a solution of 1-(tert-butyl) 2-methyl (2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate(3.00 g, 12.2 mmol, 1.00 eq.) in dichloromethane (60.00 mL) was added DAST (9.86 g, 61.2 mmol, 8.08 mL, 5.00 eq.) at -60 °C under N2. The mixture was stirred at 25 °C for 12 h. The reaction mixture was adjusted to pH = 8 with aq. NaHCO3 and extracted with dichloromethane (60.00 mL*3) and the combined organic layer was washed with brine (60.00 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1 (Ninhydrin)).1-(tert-butyl) 2-methyl (2S,3R)-3-fluoropyrrolidine- 1,2-dicarboxylate (2.80 g, 11.32 mmol, 92.58% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 5.30 - 5.07 (1H), 4.68 - 4.38 (1H), 3.82 - 3.65 (4H), 3.56 (1H), 2.32 - 1.99 (2H), 1.49 - 1.41 (9H). Intermediate 2: tert-butyl (2S,3R)-3-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0339] To a solution of 1-(tert-butyl) 2-methyl (2S,3R)-3-fluoropyrrolidine-1,2-dicarboxylate(2.80 g, 11.3 mmol, 1.00 eq.) in THF (40.00 mL) was added dropwise LiBH4(2 M, 11.32 mL, 2.00 eq.) at 0 °C, the resulting mixture was stirred at 25 °C for 2 h. To the reaction mixture was slowly added NH4Cl (100.00 mL) at 0 °C and extracted with ethyl acetate (100.00 mL × 3). The combined organic layers were washed with brine (100.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Tert-butyl (2S, 3R) -3- fluoro-2-(hydroxymethyl) pyrrolidine-1-carboxylate (2.40 g, crude) was obtained as a yellow oil without further purification. Intermediate 3: Tert-butyl (2S,3R)-2-[[tert-butyl (dimethyl) silyl]oxymethyl]-3-fluoro- pyrrolidine-1-carboxylate 33184274.1Page 77 of 177407531-97SKWO (219686)

[0340] To a solution of tert- , hyl) pyrrolidine-1-carboxylate(2.40 g, 10.9 mmol, 1.00 eq.), DMAP (267.45 mg, 2.19 mmol, 0.20 eq.) and TEA (3.32 g, 32.8 mmol, 4.57 mL, 3.00 eq.) in dichloromethane (30.00 mL) was added TosCl (3.13 g, 16.42 mmol, 1.50 eq.). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 2 / 1). Tert-butyl (2S,3R)-2-[[tert-butyl (dimethyl) silyl]oxymethyl]-3-fluoro-pyrrolidine-1- carboxylate (2.70 g, 8.10 mmol, 73.96% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 7.77 (2H), 7.40 - 7.30 (2H), 5.26 - 4.92 (1H), 4.16 (2H), 4.07 - 3.87 (1H), 3.57 - 3.35 (2H), 2.46 (3H), 2.29 - 2.06 (2H), 1.46 - 1.35 (9H). Intermediate 4: Tert-butyl (2S,3R)-3-fluoro-2-[(1-methylpyrazol-4- yl)oxymethyl]pyrrolidine-1-carboxylate

[0341] To a solution of tert-butyl (2S,3R)-2-[[tert-butyl (dimethyl) silyl]oxymethyl]-3-fluoro-pyrrolidine-1-carboxylate (2.70 g, 8.10 mmol, 1.00 eq.) and 1-methyl-1H-pyrazol-4-ol (794.21 mg, 8.10 mmol, 1.00 eq.) in acetonitrile (40.00 mL) was added Cs2CO3(7.91 g, 24.29 mmol, 3.00 eq.), the mixture was stirred at 80 °C for 12 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 0 / 1). Tert-butyl (2S,3R)-3-fluoro-2-[(1-methylpyrazol-4- yl)oxymethyl]pyrrolidine-1-carboxylate (1.20 g, 3.98 mmol, 49.16% yield, 99.27% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.569 min, [M-56+H+] = 244.3. Intermediate 5: Tert-butyl (2S,3R)-2-[(5-bromo-1-methyl-pyrazol-4-yl) oxymethyl]-3- fluoro-pyrrolidine-1-carboxylate

[0342] To a[(1-methylpyrazol-4-yl)oxymethyl](1.20 g, 4.01 mmol, 1.00 eq.) in dichloromethane (20.00 mL) was added NBS (713.50 mg, 4.01 mmol, 1.00 eq.). The mixture was stirred at 25 °C for 2 h. 33184274.1Page 78 of 177407531-97SKWO (219686)The reaction mixture was diluted with aq. NaS2O3(40.00 mL) and extracted with ethyl acetate (50.00 mL × 3) and the combined organic layers were washed with brine (80.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 1 / 1). Tert-butyl (2S,3R)-2-[(5-bromo-1-methyl-pyrazol-4-yl) oxymethyl]-3-fluoro-pyrrolidine-1- carboxylate (1.30 g, 3.37 mmol, 84.02% yield, 98% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.615 min, [M-56+H+] = 324.0. Intermediate 6: [(2R)-5-oxopyrrolidin-2-yl] methyl 4-methylbenzene sulfonate

[0343] To a solution ofg, 69.49 mmol, 1.00 eq.)in dichloromethane (100.00 mL) was added TosCl (19.87 g, 104.23 mmol, 1.50 eq.), DMAP (1.70 g, 13.90 mmol, 0.20 eq.) and triethylamine (21.09 g, 208.46 mmol, 29.01 mL, 3.00 eq.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (150.00 mL) and extracted with ethyl acetate (100.00 mL × 3). The combined organic layers were washed with brine (50.00 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (40.00 mL) at 25 ℃ for 30 mins. [(2R)-5-Oxopyrrolidin-2-yl] methyl 4-methylbenzene sulfonate (18.00 g, 66.84 mmol, 96.19% yield) was obtained as a white solid.1H NMR (400 MHz, MeOH-d4) δ = 7.78 (2H), 7.43 (2H), 4.07 - 3.91 (2H), 3.90 - 3.81(1H), 2.42 (3H), 2.32 - 2.13 (3H), 1.84 - 1.73 (1H). Intermediate 7: (5R) -5-[(1-methylpyrazol-4-yl)oxymethyl]pyrrolidin-2-one

[0344] To a solution of(18.00 g,66.84 mmol, 1.00 eq.), 1-methylpyrazol-4-ol (7.21 g, 73.52 mmol, 1.10 eq.) in acetonitrile (180.00 mL) was added cesium carbonate (65.33 g, 200.51 mmol, 3.00 eq.). The mixture was stirred at 80 33184274.1Page 79 of 177407531-97SKWO (219686)°C for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~60% ethyl acetate / methanol @ 60 mL / min). (5R) -5-[(1-methylpyrazol-4-yl)oxymethyl]pyrrolidin-2- one (7.05 g, 35.75 mmol, 53.49% yield, 99% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.298 min, [M+H+] = 196.1. Intermediate 8: (5R)-5-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl] pyrrolidin-2-one

[0345] To a solution ofpyrrolidin-2-one (2.00 g,10.24 mmol, 1.00 eq.) in dichloromethane (80.00 mL) was added NBS (1.82 g, 10.24 mmol, 1.00 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (80.00 mL) and extracted with dichloromethane (80.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% methanol / ethyl acetate @ 36 mL / min). (5R) - 5-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl] pyrrolidin-2-one (2.24 g, 8.17 mmol, 79.76% yield, 100% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.383 min, [M+H+] = 273.9.1H NMR (400 MHz, CDCl3) δ = 7.28 - 7.23 (1H), 6.39 (1H), 4.07 - 3.91 (2H), 3.97 – 3.78 (4H), 2.43 -2.36 (3H), 1.91 - 1.80 (1H). Intermediate 9: tert-butyl (R)-2-((tosyloxy)methyl)azetidine-1-carboxylate

[0346] To a stirred1-carboxylate (1 g, 5.34mmol) and TEA (1.861 mL, 13.35 mmol) in CH2Cl2 (10 mL) was added 4-methylbenzenesulfonyl chloride (1.113 mL, 5.87 mmol) at 0 °C. The reaction mixture was allowed to stirred at room temperature for 16 h. Upon completion, as monitored by TLC , the reaction mixture was diluted with NaHCO3solution and extracted with CH2Cl2(3 x 50 mL). The combined organic layers were 33184274.1Page 80 of 177407531-97SKWO (219686)dried over anhydrous sodium sulphate and concentrated under vacuum to afford crude product. The crude product was purified by flash column chromatography (Biotage: Isolera using 60-120 mesh silica, Eluent: 30-40% EtOAc in petroleum ether) to afford tert-butyl (R)-2- ((tosyloxy)methyl)azetidine-1-carboxylate (1.6 g, 4.69 mmol, 88 % yield) as colorless liquid.LCMS (ESI): Rt: 2.519 min, [M-Boc+H+] = 242.1.1H NMR (400 MHz, DMSO-d6) δ = 7.81 (2H),7.50 (2H), 4.34 - 4.27 (1H), 4.25 - 4.16 (1H), 4.13 - 4.01 (1H), 3.72 - 3.56 (2H), 2.43 (3H), 2.24 - 2.14 (1H), 2.00 - 1.90 (1H), 1.30 (9H). Intermediate 10: tert-butyl (R)-2-(((1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate

[0347] To stirred solution of1-carboxylate (1.320 g,3.87 mmol) and 1H-pyrazol-4-ol (3) (0.65 g, 7.73 mmol) in DMF (10 mL) was added K2CO3(1.282 g, 9.28 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was stirred at 80 °C for 16 h. Upon completion of the reaction, as monitored by TLC and LCMS, the reaction mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude product. The crude product was purified by flash column chromatography (Biotage: Isolera, using 60-120 mesh silica, Eluent: 50-100% EtOAc in petroleum ether) to afford tert-butyl (R)-2-(((1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate (0.790 g, 3.12 mmol, 40 % yield) as pale yellow liquid. LCMS (ESI): Rt: 1.443 min, [M-tBu+H+] = 198.2.1H NMR (400 MHz, DMSO) δ = 12.36 (1H), 7.47 (1H), 7.38 - 7.17 (1H), 4.42 - 4.34 (1H), 4.16 - 4.00 (1H), 3.99 - 3.87 (1H), 3.83 - 3.65 (2H), 2.33 - 2.21 (1H), 2.18 - 2.05 (1H), 1.36 (9H). Intermediate 11: tert-butyl (R)-2-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)azetidine-1-carboxylate 33184274.1Page 81 of 177407531-97SKWO (219686)

[0348] To a stirr n of tert-butyl (R)-2-(((1H-pyr xy)methyl)azetidine-1-carboxylate (4) (0.780 g, 3.08 mmol) and potassium fluoride (0.358 g, 6.16 mmol) in CH3CN (10 mL) was added diethyl (bromodifluoromethyl)phosphonate (0.554 mL, 3.11 mmol) at room temperature . The reaction mixture was allowed to stir at room temperature for 16 h. Upon completion of the reaction, as monitored by TLC, the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (Biotage: Isolera using 60-120 mesh silica, Eluent: 20-30% EtOAc in petroleum ether) to afford tert-butyl (R)-2-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)azetidine-1- carboxylate (0.905 g, 2.98 mmol, 97 % yield) as yellow liquid. LCMS (ESI): Rt: 1.842 min, [M- tBu+H+] = 248.1.1H NMR (400 MHz, DMSO-d6) δ = 8.00 (1H), 7.87 - 7.46 (2H), 4.45 - 4.36 (1H), 4.29 - 4.15 (1H), 4.01 (1H), 3.81 - 3.66 (2H), 2.35 - 2.21 (1H), 2.19 - 2.05 (1H), 1.35 (9H). Intermediate 12: tert-butyl (R)-2-(((5-bromo-1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)azetidine-1-carboxylate

[0349] To a stirred-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate (0.950 g, 2.506 mmol) in CH3CN (3 mL) was added NBS (0.535 g, 3.01 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 16 h. Upon completion of the reaction, as monitored by TLC, the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (Biotage: Isolera using 60-120 mesh silica, Eluent:15-30 % EtOAc in 33184274.1Page 82 of 177407531-97SKWO (219686)petroleum ether) to afford tert-butyl (R)-2-(((5-bromo-1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)azetidine-1-carboxylate (0.780 g, 2.041 mmol, 81 % yield)) as yellow liquid. LCMS (ESI): Rt: 2.944min, [M-tBu+H+] = 328.0.1H NMR (400 MHz, DMSO-d6) δ = 7.94 - 7.63 (1H), 4.42 - 4.29 (2H), 4.27 - 4.19 (1H), 4.19 - 4.09 (1H), 3.75 (2H), 2.36 - 2.23 (1H), 2.20 - 2.10 (1H), 1.33 (9H). Intermediate 13: tert-butyl (2R)-2-(p-tolylsulfonyloxymethyl) pyrrolidine-1-carboxylate

[0350] To a solution of1-carboxylate (5.00 g,24.84 mmol, 1.00 eq.) and TEA (5.03 g, 49.69 mmol, 6.92 mL, 2.00 eq.) in dichloromethane (50.00 mL) was added TosCl (4.97 g, 26.09 mmol, 1.05 eq.) and DMAP (303.51 mg, 2.48 mmol, 0.10 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (100.00 mL) and extracted with dichloromethane (100.00 mL * 3), the combined organic layers were washed with saturated brine (200.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product tert-butyl (2R)-2-(p- tolylsulfonyloxymethyl)pyrrolidine-1-carboxylate (20.00 g, crude) was obtained as a yellow oil, which was used in the next step without further purification. LCMS (ESI): Rt: 0.598 min, [M- Boc+H+] = 256.2. Intermediate 14: tert-butyl (2R)-2-[(1-methylpyrazol-4-yl) oxymethyl]pyrrolidine-1- carboxylate

[0351] To a solution ofpyrrolidine-1-carboxylate(69.57 g, 195.71 mmol, 1.2 eq.) and 1-methylpyrazol-4-ol (16.00 g, 163.09 mmol, 1 eq.) in DMF (400.00 mL) was added Cs2CO3 (159.42 g, 489.28 mmol, 3 eq.). The mixture was stirred at 60 °C for 16 h. The reaction mixture was partitioned between ethyl acetate (1.00 L) and H2O (2.50 L). The organic phase was separated and washed with sat. NaCl (100.00 mL * 2), dried over Na2SO4, 33184274.1Page 83 of 177407531-97SKWO (219686)filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 / 1 - 1 / 1). tert-butyl (2R)-2-[(1- methylpyrazol-4-yl) oxymethyl]pyrrolidine-1-carboxylate (73.00 g, crude) was obtained as a colorless oil. LCMS (ESI): Rt: 0.499 min, [M+H+] = 281.9.1H NMR (400 MHz, CDCl3) δ = 7.20 (1H), 7.16 - 7.01 (1H), 4.02 (2H), 3.86 - 3.68 (4H), 3.45 - 3.28 (2H), 2.02 - 1.82 (4H), 1.47 (9H). Intermediate 15: tert-butyl (2R)-2-[ (5-bromo-1-methyl-pyrazol-4- yl)oxymethyl]pyrrolidine-1-carboxylate

[0352] To a solution ofoxymethyl]pyrrolidine-1-carboxylate (70.00 g, 248.80 mmol, 1 eq.) in CH3CN (30.00 mL) was added NBS (28.78 g, 161.72 mmol, 0.65 eq.). The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by addition H2O (50.00 mL) at 25 °C. The reaction mixture was partitioned between ethyl acetate (500.00 mL) and 0.5 M HCl (500.00 mL). The organic phase was separated, washed with sat. NaCl (100.00 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 / 1 - 3 / 1). Tert-butyl (2R)-2-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl]pyrrolidine-1- carboxylate (62.00 g, 154.89 mmol, 62.26% yield, 90% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.565 min, [M-tBu+H+] = 306.1.1H NMR (400 MHz, CDCl3) δ = 7.36 - 7.28 (1H), 4.09 - 3.96 (2H), 3.81 (4H), 3.44 - 3.29 (2H), 2.09 (1H), 2.04 - 1.94 (2H), 1.86 (1H), 1.47 (9H). Intermediate 16: tert-butyl (2R) -2-[[1-(difluoromethyl) pyrazol-4-yl]oxymethyl] pyrrolidine-1-carboxylate33184274.1Page 84 of 177407531-97SKWO (219686)

[0353] To a solution of tert-butyl (2R)-2-(p-tolylsulfonyloxymethyl) pyrrolidine-1-carboxylate(8.00 g, 22.51 mmol, 1.00 eq.) and 1-(difluoromethyl) pyrazol-4-ol (5.53 g, 24.76 mmol, 1.10 eq.) in acetonitrile (80.00 mL) was added Cs2CO3 (18.33 g, 56.27 mmol, 2.50 eq.). The mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 1: 0 - 1: 1). Tert-butyl (2R)-2-[[1-(difluoromethyl) pyrazol-4-yl]oxymethyl] pyrrolidine-1-carboxylate (4.00 g, 11.08 mmol, 71.24% yield, 87.97% purity) was obtained as a yellow solid. Intermediate 17: tert-butyl (2R)-2-[[5-bromo-1-(difluoromethyl) pyrazol-4- yl]oxymethyl]pyrrolidine-1-carboxylate

[0354] To apyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (4.50 g, 14.18 mmol, 1.00 eq.) in acetonitrile (50.00 mL) was added NBS (2.78 g, 15.60 mmol, 1.10 eq.). The mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 - 3: 1). Tert-butyl (2R) -2-[[5-bromo-1-(difluoromethyl) pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (10.50 g, 17.88 mmol, 63.03% yield, 67.46% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.591 min, [M-tBu+H+] = 340.1. Intermediate 18: tert-butyl (2R, 4R) -4-fluoro-2-(hydroxymethyl) pyrrolidine-1-carboxylate

[0355] To a solution of1,2-dicarboxylate(2.00 g, 8.09 mmol, 1.00 eq.) in tetrahydrofuran (20.00 mL) was added dropwise LiBH4(2.00 M, 8.49 mL, 2.10 eq.) at 0 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with sat. NH4Cl solution (20.00 mL) at 0 °C and extracted with ethyl acetate (30.00 mL × 3). The combined organic layers were washed with brine (10.00 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure 33184274.1Page 85 of 177407531-97SKWO (219686)to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 1 / 1). Tert-butyl (2R,4R)-4-fluoro-2-(hydroxymethyl) pyrrolidine-1- carboxylate (1.50 g, 6.84 mmol, 84.58% yield) was obtained as colorless oil.1H NMR (400 MHz, CDCl3) δ = 5.31 - 5.04 (1H), 4.34 - 4.16 (1H), 3.92 - 3.81 (1H), 3.78 - 3.70 (1H), 3.69 - 3.54 (2H), 2.33 - 2.15 (1H), 2.06 - 1.93 (1H), 1.48 (9H). Intermediate 19: tert-butyl (2R,4R)-4-fluoro-2-(p-tolylsulfonyloxymethyl) pyrrolidine-1- carboxylate

[0356] To a solution ofpyrrolidine-1-carboxylate(1.50 g, 6.84 mmol, 1.00 eq.), TEA (2.08 g, 20.52 mmol, 2.86 mL, 3.00 eq.) in dichloromethane (20.00 mL) was added TosCl (1.96 g, 10.26 mmol, 1.50 eq.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 3 / 1). Tert-butyl (2R,4R)-4-fluoro-2-(p-tolylsulfonyloxymethyl) pyrrolidine-1-carboxylate (2.20 g, 5.54 mmol, 80.94% yield, 94.00% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.591 min, [M-Boc+H+] = 274.1. Intermediate 20: tert-butyl (2R,4R)-4-fluoro-2-[(1-methylpyrazol-4- yl)oxymethyl]pyrrolidine-1-carboxylate

[0357] To a solution ofpyrrolidine-1-carboxylate (1.70 g, 4.55 mmol, 1.00 eq.), 1-methylpyrazol-4-ol (468.92 mg, 4.78 mmol, 1.05 eq.) in DMF (18.00 mL) was added Cs2CO3 (4.45 g, 13.66 mmol, 3.00 eq.). The mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with water (200.00 mL) and extracted with ethyl acetate (30.00 mL × 3). The combined organic layers were washed with brine (10.00 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate 33184274.1Page 86 of 177407531-97SKWO (219686)= 19 / 1 to 3 / 1). Tert-butyl (2R,4R)-4-fluoro-2-[(1-methylpyrazol-4-yl)oxymethyl]pyrrolidine-1- carboxylate (660.00 mg, 2.12 mmol, 46.47% yield, 95.95% purity) was obtained as yellow oil. LCMS (ESI): Rt: 0.483 min, [M +H+] = 300.2.1H NMR (400 MHz, CDCl3) δ = 7.35 (1H), 7.31 (1H), 5.43 - 5.22 (1H), 4.30 (2H), 3.95 - 3.81 (5H), 3.80 - 3.70 (1H), 2.57 (1H), 2.33 - 2.15 (1H), 1.57 (9H). Intermediate 21: tert-butyl (2R,4R)-2-[ (5-bromo-1-methyl-pyrazol-4-yl) oxymethyl]-4- fluoro-pyrrolidine-1-carboxylate

[0358] To a solution4-yl)oxymethyl]pyrrolidine-1-carboxylate (640.00 mg, 2.14 mmol, 1.00 eq.) in acetonitrile (12.00 mL) was added NBS (304.43 mg, 1.71 mmol, 0.80 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with sat. Na2S2O3 (30.00 mL) and extracted with ethyl acetate (30.00 mL × 3). The combined organic layers were washed with brine (10.00 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 3 / 1). tert- butyl (2R,4R)-2-[(5-bromo-1-methyl-pyrazol-4-yl) oxymethyl]-4-fluoro-pyrrolidine-1- carboxylate (600.00 mg, 1.53 mmol, 71.34% yield, 96.15% purity) was obtained as a colorless oil. LCMS (ESI): Rt: 0.520 min, [M-tBu+H+] = 322.1.1H NMR (400 MHz, CDCl3) δ = 7.43 - 7.29 (1H), 5.38 - 5.13 (1H), 4.39 - 4.17 (2H), 3.90 - 3.78 (4H), 3.76 - 3.54 (2H), 2.56 (1H), 2.27 - 2.07 (1H), 1.48 (9H). Intermediate 22: 2-(5-bromopentyl)-4-methoxy-6-methylpyrimidine

[0359] To a1.00 eq) and5-bromopentylboronic acid (5.53 g, 28.38 mmol, 1.50 eq) in toluene (80 mL) and H2O (2 mL) was added [2-(2-aminophenyl) phenyl]palladium (1+) ;bis (1-adamantyl)-butyl- 33184274.1Page 87 of 177407531-97SKWO (219686)phosphane;methanesulfonate (688.84 mg, 945.86 μmol, 0.05 eq) and K3PO4(10.04 g, 47.29 mmol, 2.50 eq). The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 50 / 1 to 3 / 1).2-(5-bromopentyl)-4-methoxy-6-methyl-pyrimidine (3.1 g, 10.78 mmol, 56.99% yield, 95% purity) was obtained as a colorless oil. LCMS (ESI): Rt: 0.434 min, [M+H+] = 275.2. Intermediate 23: 2-(5-bromopentyl)-6-methylpyrimidin-4-ol

[0360] Tog, 3.66 mmol,1.00 eq) in DCM (6 mL) was added BBr3 (2 M, 5.49 mL, 3.00 eq). The mixture was stirred at 25 °C for 24 h. Then BBr3 (2 M, 3.66 mL, 2.00 eq) was added into the mixture at -40°C. The mixture was stirred at 25 °C for 24 h. The reaction mixture was quenched by addition of sat. aq. NaHCO3(15 mL) solution at 0 °C. The mixture was partitioned between EA (100 mL) and H2O (150 mL). The organic phase was separated, washed with sat. NaCl (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.2-(5-bromopentyl)-6-methyl-pyrimidin-4- ol (905 mg, crude) was obtained as a white solid and used into the next step without further purification. LCMS (ESI): Rt: 0.381 min, [M+H+] = 259.0. Intermediate 24: 2-(5-bromopentyl)-6-methylpyrimidin-4-ol

[0361] To ammol, 1.00 eq)in MeCN (2 mL) was added POCl3 (6.58 g, 42.91 mmol, 4 mL, 12.36 eq). The mixture was stirred at 90 °C for 2 h. LCMS showed that the reactant was consumed and desired mass was detected. The reaction mixture was added into 20 mL H2O at 25°C. The mixture was partitioned between EA (50 mL) and H2O (35 mL). The organic phase was separated, washed with sat. NaCl (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The mixture was purified by column chromatography (SiO2, PE: EA = 25 / 1 to 2 / 1). 2-(5-bromopentyl)-4- chloro-6-methyl-pyrimidine (850 mg, 3.06 mmol, 88.17% yield) was obtained as a brown oil.1H33184274.1Page 88 of 177407531-97SKWO (219686)NMR (400 MHz, CDCl3) δ = 6.98 (1H), 3.34 (2H), 2.88 - 2.78 (2H), 2.42 (3H), 1.88 - 1.80 (2H), 1.80 - 1.71 (2H), 1.51 - 1.39 (2H). Intermediate 25: (4-bromobutoxy)(tert-butyl)diphenylsilane

[0362] To a solution of 4- 1.00 eq.) in dichloromethane(250.00 mL) was added g, , then TBDPS-Cl (49.40 g, 179.72 mmol, 45.99 mL, 1.10 eq.) was added at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with dichloromethane (500.00 mL), the organic layers were washed with sat. NH4Cl (aq, 200.00 mL * 2), then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~6% ethyl acetate / petroleum ether gradient @ 80 mL / min). (4-Bromobutoxy)(tert-butyl)diphenylsilane (50.00 g, 127.74 mmol, 78.19% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.73 - 7.66 (4H), 7.46 - 7.39 (6H), 3.72 (2H), 3.44 (2H), 2.06 - 1.96 (2H), 1.79 - 1.67 (2H), 1.08 (9H). Intermediate 26: 5-[tert-butyl (diphenyl) silyl]oxypentanenitrile

[0363] To a solution of 4-g, 76.64 mmol, 1.00 eq.)in DMSO (200.00 mL) was added NaCN (5.40 g, 110.18 mmol, 1.44 eq.) at 0 °C. The mixture was stirred at 25 °C for 16 h. To the reaction mixture was added H2O (200.00 mL), it was extracted with ethyl acetate (200.00 mL * 3). The combined organic layers were washed with brine (120.00 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The aqueous phase was combined and adjust to pH = 11~12 with NaOH (aq, 1 N), then sat. NaClO (aq) (400.00 mL) was slowly added to the water. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~9% Ethyl acetate / Petroleum ether gradient @ 90 mL / min). 5-[Tert-butyl (diphenyl) silyl]oxypentanenitrile (22.00 g, 65.18 mmol, 33184274.1Page 89 of 177407531-97SKWO (219686)85.04% yield) was obtained as a white oil.1H NMR (400 MHz, CDCl3) δ = 7.75 - 7.63 (4H), 7.47 - 7.35 (6H), 3.71 (2H), 2.35 (2H), 1.87 - 1.62 (4H), 1.09 - 1.02 (9H). Intermediate 27: 5-[tert-butyl (diphenyl) silyl]oxypentanamidine TBDPS TBDPS O O

[0364] To a solution of toluene (150.00 mL) wasslowly added AlMe3 at was stirred at 25 °C for 15 mins under N2. Then a solution of 5-[tert-butyl (diphenyl) silyl]oxypentanenitrile (16.00 g, 47.40 mmol, 1.00 eq.) in toluene (30.00 mL) was slowly added to the mixture. The mixture was stirred at 95 °C for 2 h. The reaction mixture was quenched with 70.00 mL of sat. NH4Cl (aq.) under N2 at 0 °C. The mixture was diluted with 80.00 mL of dichloromethane, filtered and the filter cake was washed with dichloromethane (10% methanol, 50.00 mL * 2). The filtrate was extracted with dichloromethane (10% methanol, 80.00 mL * 3). The combined organic layers were washed with brine (50.00 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. 5-[tert-butyl (diphenyl) silyl]oxypentanamidine (13.00 g, 36.67 mmol, 77.35% yield) was obtained as a white solid. Intermediate 28: 2-[4-[tert-butyl (diphenyl) silyl]oxybutyl]-6-methyl-pyrimidin-4-ol

[0365] To a mixtureg, 36.67 mmol, 1.00eq.), 4 A MS (36.67 mmol, 1.00 eq.) and ethyl 3-oxobutanoate (6.20 g, 47.66 mmol, 6.03 mL, 1.30 eq.) in ethanol (15.00 mL) was added KOH (3.09 g, 55.00 mmol, 1.50 eq.). The mixture was stirred at 25 °C for 0.5 h, then was stirred at 60 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-[4-[tert-butyl (diphenyl) silyl]oxybutyl]- 6-methyl-pyrimidin-4-ol (15.00 g, 35.66 mmol, 97.26% yield) as a white solid. The target compound was used without further purification. 33184274.1Page 90 of 177407531-97SKWO (219686)Intermediate 29: 2-(4-hydroxybutyl) -6-methyl-pyrimidin-4-ol

[0366] To a solution of pyrimidin-4-ol (15.00g, 35.66 mmol, 1.00 was 71.32 mL, 2.00 eq.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 100 / 1 to 10 / 1). 2-(4-hydroxybutyl) -6-methyl-pyrimidin-4-ol (6.00 g, 32.93 mmol, 92.33% yield) was obtained as a white solid. Intermediate 30: 2-(4-hydroxybutyl) -6-methyl-pyrimidin-4-ol

[0367] To a solution of(3.00 g, 16.46 mmol, 1 eq.)in dichloromethane (50.00 mL) was added Ac2O (1.85 g, 18.11 mmol, 1.70 mL, 1.10 eq.), pyridine (2.60 g, 32.93 mmol, 2.66 mL, 2.00 eq.) and DMAP (20.11 mg, 164.64 μmol, 0.01 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with HCl (1 mol / L, 50.00 mL) and extracted with ethyl acetate (30.00 mL * 3). The combined organic layers were washed with brine (30.00 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 0 / 1).4-(4-hydroxy-6-methyl-pyrimidin-2-yl) butyl acetate (3.00 g, 13.32 mmol, 80.93% yield, 99.6% purity) was obtained as a white solid. Intermediate 31: 4-(4-chloro-6-methyl-pyrimidin-2-yl)butyl acetate 33184274.1Page 91 of 177407531-97SKWO (219686)

[0368] A mixture of 4- etate (3.60 g, 16.05 mmol,1.00 eq.) and POCl3(23.03 g, 150.20 mmol, 14.00 mL, 9.36 eq.) were stirred at 100 °C for 1 h. The mixture was diluted with ethyl acetate (30.00 mL), then poured into water (200.00 mL) drop by drop (the temperature kept below 35 °C), extracted with ethyl acetate (50.00 mL × 4), washed with brine (50.00 mL× 3), dried over Na2SO4, filtered and concentrated under vacuum. 4-(4- chloro-6-methyl-pyrimidin-2-yl)butyl acetate (3.80 g, 15.47 mmol, 96.36% yield, 98.8% purity) was obtained as a brown oil. LCMS (ESI): Rt: 0.528 min, [M+H+] = 243.2. Intermediate 32: 4-(4-chloro-6-methyl-pyrimidin-2-yl)butan-1-ol

[0369] To a solution ofacetate (1.00 g, 4.12 mmol,1.00 eq.) in methanol (10.00 mL) was added K2CO3(1.71 g, 12.36 mmol, 3.00 eq.). The mixture was stirred at 5~10°C for 1 h and stirred at 25 °C for 1 h. The mixture was diluted with ethyl acetate (120.00 mL) and washed with cold water (40.00 mL × 3), the organic layers were dried over Na2SO4, filtered and concentrated under vacuum. 4-(4-chloro-6-methyl-pyrimidin-2- yl)butan-1-ol (650.00 mg, 2.86 mmol, 69.41% yield, 88.29% purity) was obtained as a yellow oil.LCMS (ESI): Rt: 0.385 min, [M+H+] = 201.1. 1H NMR (400 MHz, CDCl3) δ = 7.02 (1H), 3.65(2H), 2.91 (2H), 2.46 (3H), 1.87 (2H), 1.68 - 1.59 (2H). Intermediate 33: 2-(4-bromobutyl)-4-chloro-6-methyl-pyrimidine33184274.1Page 92 of 177407531-97SKWO (219686)

[0370] To a solution of 4-(4-chloro-6-methyl-pyrimidin-2-yl)butan-1-ol (650.00 mg, 3.24 mmol,1.00 eq.) in dichloromethane (7.00 mL) was added PPh3 (1.70 g, 6.48 mmol, 2.00 eq.) and CBr4 (2.15 g, 6.48 mmol, 2.00 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min).2-(4-bromobutyl)-4-chloro-6-methyl-pyrimidine (650.00 mg, 2.45 mmol, 75.79% yield, 99.54% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.545 min, [M+H+]= 265.0. 1H NMR (400 MHz, CDCl3) δ = 7.06 (1H), 3.48 - 3.40 (2H), 2.96 - 2.88 (2H), 2.49 (3H),2.01 - 1.90 (4H). Intermediate 34: (5R) -5-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl]-1-[5-(4-chloro-6- methyl-pyrimidin-2-yl) pentyl]pyrrolidin-2-one

[0371] To2-one(237.00 mg, 864.59 μmol, 1.20 eq.) and 2-(5-bromopentyl) -4-chloro-6-methyl-pyrimidine (200.00 mg, 720.49 μmol, 1.00 eq.) in acetonitrile (5.00 mL) was added Cs2CO3(704.25 mg, 2.16 mmol, 3.00 eq.). The mixture stirred at 80 °C for 12 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, dichloromethane: methanol = 1 / 0 to 5 / 1). (5R) -5-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl]-1-[5-(4-chloro-6- methyl-pyrimidin-2-yl) pentyl]pyrrolidin-2-one (290.00 mg, 369.59 μmol, 51.30% yield, 60% purity) was obtained as yellow oil. LCMS (ESI): Rt: 0.568 min, [M+H+] = 472.1. Intermediate 35: 4-(5-bromopentyl) -6-chloro-2-methyl-pyrimidine

[0372] To ammol, 1 eq.) and 5-bromopentylboronic acid (430.36 mg, 2.21 mmol, 1.2 eq.) in toluene (10.00 mL) was added 33184274.1Page 93 of 177407531-97SKWO (219686)Cs2CO3(1.80 g, 5.52 mmol, 3 eq.), tricyclohexylphosphane (51.61 mg, 184.04 μmol, 0.1 eq.) and Pd(OAc)2 (41.32 mg, 184.04 μmol, 0.1 eq.). The mixture was stirred at 100 °C for 5 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 / 1 - 5 / 1). 4-(5- Bromopentyl) -6-chloro-2-methyl-pyrimidine (150.00 mg, 513.35 μmol, 27.89% yield, 95% purity) was obtained as a red oil. LCMS (ESI): Rt: 0.580 min, [M+H+] = 279.1. Intermediate 36: 4-(4-bromobutyl) -6-chloro-2-methyl-pyrimidine

[0373] To ammol, 1 eq.) and 4-bromobutylboronic acid (399.38 mg, 2.21 mmol, 1.2 eq.) in toluene (10.00 mL) and THF (1.00 mL) was added Pd(OAc)2(41.32 mg, 184.04 μmol, 0.1 eq), tricyclohexylphosphane (103.22 mg, 368.09 μmol, 0.2 eq.) and K3PO4 (1.17 g, 5.52 mmol, 3 eq.). The mixture was stirred at 90 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove toluene. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 25 / 1 - 5 / 1).4-(4- bromobutyl) -6-chloro-2-methyl-pyrimidine (108.00 mg, 295.04 μmol, 16.03% yield, 72% purity) was obtained as a red oil. LCMS (ESI): Rt: 0.551 min, [M+H+] = 264.9. Intermediate 37: 2-(5-bromopentyl)-6-chloro-4-methylpyridine

[0374] To a1.00 eq) and 5-bromopentylboronic acid (707.84 mg, 3.63 mmol, 1.50 eq) in toluene (10 mL) and THF (1 mL) was added Pd(OAc)2(54.37 mg, 242.17 μmol, 0.100 eq), P(Cy)3(135.82 mg, 484.34 μmol, 157.02 μL, 0.200 eq) and Cs2CO3 (1.97 g, 6.05 mmol, 2.50 eq). The mixture was stirred at 100 °C for 3 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE: EA = 100 / 1 to 3 / 1). 2-(5-bromopentyl)-6- chloro-4-methyl-pyridine (320 mg, 1.04 mmol, 43.00% yield, 90% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.611 min, [M+H+] = 277.9. 33184274.1Page 94 of 177407531-97SKWO (219686)Intermediate 38: 2-(5-bromopentyl)-4-chloro-6-methyl-pyridine

[0375] To a solution of 3.09 mmol, 1.00 eq) and 5-bromopentylboronic acid (781.77 mg, 4.01 mmol, 1.30 eq) in toluene (10 mL) and THF (1 mL) was added Pd(OAc)2(69.29 mg, 308.61 μmol, 0.100 eq), P(Cy)3(173.09 mg, 617.22 μmol, 200.10 μL, 0.200 eq) and Cs2CO3(2.51 g, 7.72 mmol, 2.50 eq). The mixture was stirred at 100 °C for 3 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100 / 1 to 3 / 1). 2-(5-bromopentyl)-4- chloro-6-methyl-pyridine (190 mg, 666.31 μmol, 21.59% yield, 97% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.430 min, [M+H+] = 277.9.1H NMR (400 MHz, CDCl3) δ = 6.99 (2H), 3.42 (2H), 2.80 - 2.68 (2H), 2.52 (3H), 1.96 - 1.85 (2H), 1.79 - 1.68 (2H), 1.58 - 1.45 (2H). Intermediate 39: 4-(benzyloxy)-2-chloro-6-methylpyrimidine

[0376] A suspension ofmL, 2.00 eq) and tBuOK(20.65 g, 184.04 mmol, 1.20 eq) in THF (120 mL) was stirred at 70 °C for 0.5 h, the reaction mixture was cooled to 0°C and then added dropwise to a solution of 2,4-dichloro-6-methyl- pyrimidine (25 g, 153.37 mmol, 1.00 eq) in DMF (250 mL) at -60 °C, maintaining the temperature below -40 °C, after stirred for 1 h the mixture was allowed to warmed to 25°C and stirred for 16 h. The mixture was diluted with water (500 mL) and extracted with EA (200 mL × 3), organic layer was washed with brine (200 mL × 3), dried over Na2SO4and concentrated under vacuum. TLC (PE:EA=5:1) showed most reactant (Rf=0.55) was consumed and one main spot (Rf=0.56) was observed. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 3~11% Ethyl acetate / Petroleum ether gradient @ 80 mL / min).4-benzyloxy-2-chloro-6-methyl-pyrimidine (21.0 g, 87.57 mmol, 45.67% yield, 97.86% 33184274.1Page 95 of 177407531-97SKWO (219686)purity) was obtained as a yellow oil (PE:EA=5:1, Rf=0.56). LCMS (ESI): Rt: 0.562 min, [M+H+] = 235.0.1H NMR (400 MHz, CDCl3) δ = 7.09 - 6.99 (5H), 6.18 (s1H), 5.06 (2H), 2.07 (3H). Intermediate 40: 4-(benzyloxy)-2-chloro-6-methylpyrimidine

[0377] A mmol, 1.00 eq)and K2CO3g, g, mol, 118.59 mL, 15.00 eq) was stirred at 80°C for 3 h. The mixture was diluted with water (300 mL) and extracted with EA (200 mL × 3), organic layer was washed with brine and dried over Na2SO4, concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~42%, 42%~47% Ethylacetate / Petroleum ether gradient @ 70 mL / min). 4-(4-benzyloxy-6-methyl-pyrimidin-2-yl)oxybutan-1-ol (5.6 g, 18.94 mmol, 21.17% yield, 97.54% purity) was obtained as a colorless oil (PE:EA=1:1, Rf=0.4). LCMS (ESI): Rt: 0.474 min, [M+H+] = 289.3.1H NMR (400 MHz, CDCl3) δ = 7.45 - 7.30 (5H), 6.27 (1H), 5.40 (2H), 4.38 (2H), 3.72 (2H), 2.36 (3H), 1.94 - 1.86 (2H), 1.80 - 1.71 (2H). Intermediate 41: 4-(benzyloxy)-2-(4-bromobutoxy)-6-methylpyrimidine

[0378] To(5.6 g, 19.42mmol, 1.00 eq) in DCM (60.0 mL) was added PPh3 (7.64 g, 29.13 mmol, 1.50 eq) and CBr4 (9.66 g, 29.13 mmol, 1.50 eq) at 0°C and stirred at 25°C for 1 h. The mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~12% Ethylacetate / Petroleum ether gradient @ 60 mL / min).4- benzyloxy-2-(4-bromobutoxy)-6-methyl-pyrimidine (5.9 g, 16.73 mmol, 86.12% yield, 99.57% purity) was obtained as a colorless oil (PE:EA=1:1, Rf=0.9). LCMS (ESI): Rt: 0.562 min, [M+H+] = 353.0.1H NMR (400 MHz, CDCl3) δ = 7.46 - 7.30 (5H), 6.28 (1H), 5.40 (2H), 4.37 (2H), 3.48 (2H), 2.36 (3H), 2.12 - 2.03 (2H), 2.00 - 1.91 (2H). Intermediate 42: 2-(4-bromobutoxy)-6-methylpyrimidin-4-ol 33184274.1Page 96 of 177407531-97SKWO (219686)

[0379] benzyloxy-2-(4-bromobutoxy)-6-methyl-pyrimidine (5.9 g, 16.80 mmol, 1.00 eq), the mixture was degassed and purged with Ar for three times, then followed by H2for three times and stirred under H2(15 psi) at 25°C for 1 h. The mixture was filtered and washed with EtOAc (30 mL × 3), the filtrated was concentrated under reduced pressure. 2-(4-bromobutoxy)-6-methyl-pyrimidin-4-ol (4.3 g, 16.36 mmol, 97.40% yield, 99.35% purity) was obtained as a white solid (PE:EA=3:1, Rf=0.05) which was determined by LCMS and HNMR. The material was used in the next step without further purification. LCMS (ESI): Rt: 0.428 min, [M+H+] = 263.0.1H NMR (400 MHz, CDCl3) δ = 12.79 - 11.95 (1H), 5.97 (1H), 4.41 (2H), 3.47 (2H), 2.22 (3H), 2.03 - 1.89 (4H). Intermediate 43: 2-(4-bromobutoxy)-4-chloro-6-methylpyrimidine

[0380] A1.00 eq)in POCl3 (2.00 mL) was stirred at 40°C under N2 for 1 h. The mixture was added dropwise into sat. NaHCO3aqueous solution (150 mL), extracted with EA (30 mL × 3) and the organic layer was dried over Na2SO4, the organic layer was concentrated under vacuum.2-(4-bromobutoxy)-4- chloro-6-methyl-pyrimidine (510 mg, crude) was obtained as a brown oil which was determined by LCMS and which was used in the next step without any further purification. LCMS (ESI): Rt: 0.563 min, [M+H+] = 281.0. Intermediate 44: 2-(3-hydroxypropoxy)acetonitrile

[0381] To a solution of 1, 3-eq) in dichloromethane (900.00mL) was added TMSCN (40.92 g, 412.47 mmol, 51.60 mL, 1.21 eq) and BF3•Et2O (57.99 g, 408.60 mmol, 50.25 mL, 1.20 eq). The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted into sat. NH4Cl (360.00 mL) and extracted with ethyl acetate (100.00 mL × 3). The 33184274.1Page 97 of 177407531-97SKWO (219686)combined organic layers were washed with brine (50.00 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was treated with NaClO. The residue was purified by column chromatography. 2-(3- hydroxypropoxy)acetonitrile (30.00 g, 260.57 mmol, 76.53% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ = 4.27 (2H), 3.84 - 3.70 (4H), 1.90 (2H). Intermediate 45: 2-(3-((tert-butyldiphenylsilyl)oxy)propoxy)acetonitrile

[0382] To a solution260.57 mmol, 1.00 eq) indichloromethane (300.00 mL) was added TBDPSCl (85.95 g, 312.69 mmol, 80.02 mL, 1.20 eq) and imidazole (53.22 g, 781.72 mmol, 3.00 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted into water (1000.00 mL) and extracted with ethyl acetate (150.00 mL × 3). The combined organic layers were washed with brine (100.00 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 3 / 1).2-[3- [tert-butyl (diphenyl) silyl]oxypropoxy]acetonitrile (60.00 g, crude) was obtained as colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.70 - 7.63 (m, 4H), 7.39 (br s, 6H), 4.18 (s, 2H), 3.81 - 3.68 (m, 4H), 1.92 -1.80 (m, 2H), 1.07 (s, 9H). Intermediate 46: 2-(3-((tert-butyldiphenylsilyl)oxy)propoxy)acetimidamide

[0383] To a solution(250.00 mL) was slowlyadded AlMe3(2 M, 176.79 mL, 5.00 eq) at 0 °C, the mixture was stirred at 25 °C for 15 minutes under N2, then a solution of 2-[3-[tert-butyl (diphenyl) silyl]oxypropoxy]acetonitrile (25.00 g, 70.72 mmol, 1.00 eq) in toluene (125.00 mL) was slowly added to the mixture at 25 °C and the mixture was stirred at 95 °C for 2 h. The reaction mixture was quenched with 625 mL of sat. NH4Cl under N2 at 0 °C, the mixture was diluted with 200.00 mL of dichloromethane, filtered and 33184274.1Page 98 of 177407531-97SKWO (219686)the filter cake was washed with dichloromethane (10% methyl alcohol, 100.00 mL ×2). The mixture was extracted with dichloromethane (10% methyl alcohol, 100.00 mL ×3). The combined organic layers were washed with brine (100.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 2-[3-[tert-butyl(diphenyl)silyl] oxypropoxy]acetamidine (20.00 g, 53.97 mmol, 76.32% yield) was obtained as yellow oil (crude, used without any further purification). Intermediate 47: 2-((3-((tert-butyldiphenylsilyl)oxy)propoxy)methyl)-6-methylpyrimidin-4- ol

[0384] To a(20.00 g, 53.97mmol, 1.00 eq), ethyl 3-oxobutanoate (7.02 g, 53.97 mmol, 6.83 mL, 1.00 eq) and 4A MS (200.00 mg) in ethyl alcohol (300.00 mL) was added KOH (4.54 g, 80.96 mmol, 1.50 eq). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was diluted into water (50.00 mL) and it was acidified with aqueous HCl to pH = 3. The combined organic layers were washed with ethyl acetate (50.00 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 1 / 1).2-[3-[tert-butyl (diphenyl) silyl]oxypropoxy methyl]-6-methyl-pyrimidin-4-ol (8.00 g, 18.32 mmol, 33.95% yield) was obtained as colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.68 - 7.63 (4H), 7.43 - 7.35 (6H), 6.16 (1H), 4.36 (2H), 3.79 (2H), 3.73 (2H), 2.29 (3H), 1.87 (2H), 1.06 (9H). Intermediate 48: 2-((3-hydroxypropoxy)methyl)-6-methylpyrimidin-4-ol

[0385] To a-6-methyl-pyrimidin-4-ol (8.00 g, 18.32 mmol, 1.00 eq) in tetrahydrofuran (50.00 mL) was added TBAF (1.00 M, 27.48 33184274.1Page 99 of 177407531-97SKWO (219686)mL, 1.50 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum Dichloromethane / methyl alcohol = 19 / 1 to 1 / 1). 2-(3- hydroxypropoxymethyl)-6-methyl-pyrimidin-4-ol (8.00g, crude) was obtained as yellow oil and was directly used in the next step. Intermediate 49: 3-((4-hydroxy-6-methylpyrimidin-2-yl)methoxy)propyl acetate

[0386] To a4-ol (4.00 g, 20.18mmol, 1.00 eq), TEA (6.13 g, 60.54 mmol, 8.43 mL, 3.00 eq) in dichloromethane (40.00 mL) was added Ac2O (2.47 g, 24.22 mmol, 2.27 mL, 1.20 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 0 / 1). 3- [(4-hydroxy-6-methyl-pyrimidin-2-yl) methoxy]propyl acetate (1.40 g, 5.65 mmol, 28.01% yield, 97.00% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.371 min, [M+H+] = 241.1.1H NMR (400 MHz, CDCl3) δ = 6.18 (1H), 4.45 (2H), 4.24 (2H), 3.68 (2H), 2.29 (3H), 2.08 (3H), 2.04 - 1.97 (2H). Intermediate 50: 3-((4-chloro-6-methylpyrimidin-2-yl)methoxy)propyl acetate

[0387] To a solutionpropyl acetate (1.20 g,4.99 mmol, 1.00 eq) in dichloromethane (12.00 mL) was added POCl3 (2.30 g, 14.98 mmol, 1.40 mL, 3.00 eq). The mixture was stirred at 60 °C for 1 h. The reaction mixture was slowly added to 10.00 mL water, then extracted with ethyl acetate (10.00 mL x 3). The combined organic layer was washed with sat. NaHCO3 (5.00 mL x 2), dried over Na2SO4, filtered and concentrated under 33184274.1Page 100 of 177407531-97SKWO (219686)reduced pressure, the aqueous was combined and adjusted to pH = 9-10 with NaOH. The crude product was used into the next step and without purification.3-[(4-chloro-6-methyl-pyrimidin-2- yl)methoxy]propyl acetate (1.00 g, 3.71 mmol, 74.30% yield, 96.00 % purity) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.20 (1H), 4.71 (2H), 4.21 (2H), 3.73 (2H),2.60 (3H), 2.05 (3H), 2.03 - 1.96 (2H). Intermediate 51: 3-((4-chloro-6-methylpyrimidin-2-yl)methoxy)propyl acetate

[0388] To a solutionpropyl acetate (1.00 g,3.87 mmol, 1.00 eq) in acetonitrile (10.00 mL) was added KOH (1.50 M, 2.00 mL). The mixture was stirred at 10 °C for 2 h. The reaction was acidified with aqueous HCl to pH = 1. The combined organic layers were washed with ethyl acetate (10.00 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 0 / 1). 3-[(4-chloro-6-methyl- pyrimidin-2-yl)methoxy]propan-1-ol (450.00 mg, 2.04 mmol, 52.87% yield, 98.40% purity) was obtained as colorless oil. LCMS (ESI): Rt: 0.361 min, [M+H+] = 217.1. Intermediate 52: 2-((3-bromopropoxy)methyl)-4-chloro-6-methylpyrimidine

[0389] To a1-ol (300.00 mg,1.38 mmol, 1.00 eq) in dichloromethane (6.00 mL) was added CBr4 (505.10 mg, 1.52 mmol, 1.10 eq) and DPPE (606.82 mg, 1.52 mmol, 1.10 eq). The mixture was stirred at 10 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 19 / 1 to 1 / 1).2-(3- bromopropoxymethyl)-4-chloro-6-methyl-pyrimidine (150.00 mg, 536.56 μmol, 38.75% yield) 33184274.1Page 101 of 177407531-97SKWO (219686)was obtained as colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.14 (1H), 4.69 (2H), 3.76 (2H), 3.59 (2H), 2.56 (3H), 2.27 - 2.14 (2H). Intermediate 53: 2-(allyloxymethyl) -6-methyl-pyrimidin-4-ol Cl

[0390] To a solution of mL) was added prop-2 -en-1-ol (2.80 g, -6-methyl-pyrimidin-4- ol (5 g, 31.53 mmol, 1 eq.) at 25 °C. The mixture was stirred at 60 °C for 3 h. The mixture was adjusted to pH = 3 with 1 M HCl. The mixture was partitioned between DCM (180.00 mL) and H2O (150.00 mL). The organic phase was separated, washed with sat. NaCl (25.00 mL* 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The mixture was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 25 / 1 - 0 / 1, then dichloromethane : methanol = 10 / 1).2-(Allyloxymethyl) -6-methyl-pyrimidin-4-ol (3.60 g, 18.38 mmol, 58.29% yield, 92% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.343 min, [M+H+] = 181.3. Intermediate 54: 2-(allyloxymethyl) -4-chloro-6-methyl-pyrimidine

[0391] To a solution of 2-ol (1.00 g, 5.55 mmol, 1 eq.) inMeCN (10.00 mL) was added POCl3 (5.11 g, 33.30 mmol, 3.10 mL, 6 eq.). The mixture was stirred at 90 °C for 2 h. The reaction mixture was quenched by addition H2O (6.00 mL) at 25 °C. Themixture was adjusted to pH = 7 with sat. NaHCO3 and extracted with dichloromethane (20.00 mL* 3). The combined organic layers were washed with sat. NaCl (10.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The mixture was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 / 1 - 3 / 1).2-(Allyloxymethyl) 33184274.1Page 102 of 177407531-97SKWO (219686)-4-chloro-6-methyl-pyrimidine (950.00 mg, 4.59 mmol, 82.73% yield, 96% purity) was obtained as a yellow oil. Intermediate 55: 2-[ (3-bromo-2-fluoro-propoxy) methyl]-4-chloro-6-methyl-pyrimidine

[0392] To a solution of (500 mg, 2.52 mmol,1 eq.) in dichloromethane (8.00 mL) was added NBS (537.58 mg, 3.02 mmol, 1.2 eq.) and 1, 3- dimethylhexahydropyrimidin-2-one; hydrofluoride (1.86 g, 7.55 mmol, 60% purity, 3 eq.) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was partitioned between ethyl acetate (50.00 mL) and H2O (25.00 mL). The organic phase was separated, washed with sat. NaCl (10.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The mixture was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 / 1 - 1 / 1).2-[ (3-Bromo-2-fluoro-propoxy) methyl]-4-chloro-6-methyl-pyrimidine (350.00 mg, 1.09 mmol, 43.46% yield, 93% purity) was obtained as a colorless oil. LCMS (ESI): Rt: 0.566 min, [M+H+] = 296.9 / 298.9.1H NMR (400 MHz, CDCl3) δ= 7.17 (1H), 5.01 - 4.82 (1H), 4.78 (2H), 3.99 (1H), 3.94 (1H), 3.76 - 3.58 (2H), 2.57 (3H). Intermediate 56: 3-(2-hydroxyethoxy)propanenitrile

[0393] To a solution ofglycol (47 g, 757.24 mmol,42.23 mL, 1.00 eq) was added prop-2-enenitrile (10.0 g, 188.46 mmol, 12.50 mL, 2.49 e-1 eq) dropwise slowly, the reaction mixture was stirred at 45 °C for 5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with 6N HCl solution and evaporated to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~95% Ethyl 33184274.1Page 103 of 177407531-97SKWO (219686)acetate / Petroleum ether gradient @ 100 mL / min). 3-(2-hydroxyethoxy) propanenitrile (18 g, 156.34 mmol, 20.65% yield) was obtained as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ= 4.65 (1H), 3.60 (2H), 3.53 - 3.48 (2H), 3.47 - 3.44 (2H), 2.74 (2H). Intermediate 57: 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)propanenitrile

[0394] To a solution of 3- mmol, 1.00 eq) in DCM(300 mL) was added Imidazole (21.29 g, 312.69 mmol, 2.00 eq) and TBDPSCl (51.57 g, 187.61 mmol, 48.01 mL, 1.20 eq) and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). 3-[2-[tert-butyl (diphenyl) silyl]oxyethoxy]propanenitrile (60 g, crude) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ= 7.74 - 7.71 (4H), 7.46 - 7.41 (6H), 3.88 - 3.81 (2H), 3.73 (2H), 3.67 - 3.63 (2H), 2.57 (2H), 1.11 - 1.08 (9H). Intermediate 58: 3-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)propanimidamide

[0395] To a(300 mL) was addedAlMe3(2 M, 70.01 mL, 1.50 eq) at 0 °C slowly the mixture was stirred at 25 °C for 15 min under N2, then a solution of 3-[2-[tert-butyl (diphenyl) silyl]oxyethoxy]propanenitrile (33 g, 93.34 mmol, 1.00 eq) in toluene (300 mL) was added to the mixture slowly, the mixture was stirred at 95 °C for 12 h. The reaction mixture was quenched with 600 mL of Sat. NH4Cl (aq) under N2at 0 °C, the mixture was diluted with 500 mL of DCM, filtered and the filter cake was washed with DCM (10% MeOH, 500 mL *2). The filter was extracted with DCM (10% MeOH, 300 mL * 3). The combined organic Layers were washed with brine (300 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was used for next step directly without purification.3- 33184274.1Page 104 of 177407531-97SKWO (219686)[2-[Tert-butyl (diphenyl) silyl]oxyethoxy]propanamidine (36 g, crude) was obtained as a yellow oil. LCMS (ESI): Rt: 0.705 min, [M+H+] = 371.3. Intermediate 59: 2-(2-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)ethyl)-6-methylpyrimidin-4-ol

[0396] To a (30 g, 80.96mmol, 1.00 eq), ethyl 3-oxobutanoate (13.70 g, 105.25 mmol, 13.32 mL, 1.30 eq), 4A MS (3 g, 80.96 mmol, 1.00 eq) in EtOH (300 mL) was added KOH (6.81 g, 121.44 mmol, 1.50 eq). The mixture was stirred at 25 °C for 0.5 h, then the mixture was stirred at 60 °C for 2 h. The residue was purified by column chromatography (SiO2, DCM: MeOH = 20 / 1 to 10 / 1).2-[2-[2-[tert-butyl (diphenyl)silyl]oxyethoxy]ethyl]-6-methyl-pyrimidin-4-ol (9 g, 18.76 mmol, 23.17% yield, 91% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.606 min, [M+H+] = 437.7. Intermediate 60: 2-(2-(2-hydroxyethoxy)ethyl)-6-methylpyrimidin-4-ol

[0397] To a solution-6-methyl-pyrimidin-4-ol (9 g, 20.61 mmol, 1.00 eq) in THF (100 mL) was added TBAF (1 M, 41.23 mL, 2.00 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min, DCM / MeOH = 10 / 1, Rf = 0.4). 2-[2-(2-hydroxyethoxy)ethyl]-6-methyl-pyrimidin-4-ol (4.05 g, 20.03 mmol, 97.16% yield, 98.02% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.331 min, [M+H+] = 199.1. Intermediate 61: 2-(2-(4-hydroxy-6-methylpyrimidin-2-yl)ethoxy)ethyl acetate 33184274.1Page 105 of 177407531-97SKWO (219686)

[0398] To a solution n-4-ol (4 g, 20.18 mmol,1.00 eq) in DCM (40 mL) was added Ac2O (2.27 g, 22.20 mmol, 2.08 mL, 1.10 eq) and Py (3.19 g, 40.36 mmol, 3.26 mL, 2.00 eq) and DMAP (24.65 mg, 201.80 μmol, 0.01 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by column chromatography (SiO2, MeOH / DCM = 20 / 1 to 10 / 1, MeOH / DCM = 10 / 1, Rf = 0.6). 2-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl) ethoxy] ethyl acetate (4.5 g, 18.55 mmol, 91.91% yield, 99.02% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.328 min, [M+H+] = 241.3. Intermediate 62: 2-(2-(4-chloro-6-methylpyrimidin-2-yl)ethoxy)ethyl acetate

[0399] To a solutionethyl acetate (4.5 g,18.73 mmol, 1.00 eq) in CHCl3 (50 mL) was added POCl3 (14.36 g, 93.65 mmol, 8.73 mL, 5.00 eq) and the reaction mixture was stirred at 60 °C for 10 h. The mixture was diluted with DCM (50 mL), then poured into ice aqueous NaHCO3(150 mL) drop by drop. The temperature was kept at 0 °C. The aq. phase was extracted with DCM (120 mL × 4) and washed with brine (120 mL× 3), dried over Na2SO4 and concentrated under vacuum. The crude product was used to next step without purification. 2-[2-(4-chloro-6-methyl-pyrimidin-2-yl)ethoxy]ethyl acetate (3.5 g, 10.36 mmol, 55.32% yield, 76.59% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.432 min, [M+H+] = 259.0. Intermediate 63: 2-(2-(4-chloro-6-methylpyrimidin-2-yl)ethoxy)ethan-1-ol 33184274.1Page 106 of 177407531-97SKWO (219686)

[0400] To a solution of ]ethyl acetate (3.5 g, 13.53mmol, 1.00 eq) in THF (32 mL) and H2O (8 mL) was added KOH (2.28 g, 40.59 mmol, 3.00 eq) and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 36 mL / min, PE / EA = 1 / 1, Rf = 0.4). 2-[2-(4-chloro-6-methyl-pyrimidin-2-yl)ethoxy]ethanol (800 mg, 3.62 mmol, 26.75% yield, 98% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.363 min, [M+H+] = 217.1. Intermediate 64: 2-(2-(2-bromoethoxy)ethyl)-4-chloro-6-methylpyrimidine

[0401] To a solution ofethanol (800 mg, 3.69mmol, 1.00 eq) in DCM (10 mL) was added PPh3(1.07 g, 4.06 mmol, 1.10 eq) and CBr4 (1.35 g, 4.06 mmol, 1.10 eq) at 0 °C and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 60 mL / min, PE / EA = 1 / 1, Rf = 0.5). 2-[2-(2-bromoethoxy) ethyl]-4-chloro-6-methyl-pyrimidine (700 mg, 2.50 mmol, 67.81% yield, 100% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.481 min, [M+H+] = 281.0. Intermediate 65: 5-(4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo[1, 5-a]pyridin- 2-amine 33184274.1Page 107 of 177407531-97SKWO (219686)

[0402] To a solution of 5 -b (3.50 g, 16.51 mmol, 1 eq.) and4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (8.38 g, 33.01 mmol, 2 eq.) in dioxane (100.00 mL) was added KOAc (4.86 g, 49.52 mmol, 3 eq.) and Pd(dppf)Cl2 (603.87 mg, 825.29 μmol, 0.05 eq.). The mixture was stirred at 80 °C for 16 h. The reaction mixture was partitioned between ethyl acetate (200.00 mL) and H2O (150.00 mL). The organic phase was separated, washed with sat. NaCl (50.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 / 1 - 1 / 1).5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) pyrazolo[1, 5-a]pyridin-2-amine (4.60 g, crude) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ= 8.14 (1H), 7.75 (s, 1H), 6.88 - 6.83 (1H), 5.79 (1H), 1.36 (12H). Intermediate 66: tert-butyl (2R)-2-[[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl) -1-methyl- pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate

[0403] Topyrazol-4-yl)oxymethyl]pyrrolidine-1-carboxylate (4.00 g, 11.10 mmol, 1 eq.) and 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo[1, 5-a]pyridin-2-amine (2.88 g, 11.10 mmol, 1 eq.) in dioxane (50.00 mL) and H2O (5.00 mL) was added Pd(dppf)Cl2(406.23 mg, 555.18 μmol, 0.05 eq.) and K3PO4 (4.71 g, 22.21 mmol, 2 eq.). The mixture was stirred at 90 °C for 16 h. The reaction mixture was partitioned between EA (200.00 mL) and H2O (350.00 mL). The organic phase was separated, washed with sat. NaCl (30.00 mL* 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum 33184274.1Page 108 of 177407531-97SKWO (219686)ether : ethyl acetate = 15 / 1 - 0 / 1). Tert-butyl (2R)-2-[[5-(2-aminopyrazolo[1,5-a]pyridin-5-yl) -1- methyl-pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (4.20 g, 9.37 mmol, 84.37% yield, 92% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.492 min, [M+H+] = 413.2. Intermediate 67: (R)-5-(1-methyl-4-(pyrrolidin-2-ylmethoxy)-1H-pyrazol-5-yl)pyrazolo[1,5- a]pyridin-2-amine

[0404] To a 5-yl)-1-methyl-pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (2.30 g, 5.58 mmol, 1.00 eq) in DCM (15 mL) was added TFA (9.21 g, 80.77 mmol, 6.00 mL, 14.49 eq) and the mixture was stirred at 25°C for 1 h. The mixture was concentrated under vacuum to remove TFA, diluted with MeCN (6.00 mL) and basified by adding Na2CO3 solid to adjust pH = 6~7 under ice-bath, LCMS showed one main peak with the desired mass. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:0%- 25% B over 28 min). Fractions containing product were concentrated and lyophilized. (R)-5-(1- methyl-4-(pyrrolidin-2-ylmethoxy)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-amine (1.4 g, 4.36 mmol, 78.17% yield, 97.25% purity) was obtained as a brown solid (DCM:MeOH=10:1, Rf = 0.02). LCMS (ESI): Rt: 0.613 min, [M+H+] = 313.1. Intermediate 68: tert-butyl (2S,3R)-2-[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl) -1-methyl- pyrazol-4-yl]oxymethyl]-3-fluoro-pyrrolidine-1-carboxylate

[0405] To ayl) oxymethyl]-3-fluoro-pyrrolidine-1-carboxylate (650.00 mg, 1.72 mmol, 1.00 eq.), 4, 4, 5, 5-tetramethyl-2- (4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (654.59 mg, 2.58 mmol, 1.50 eq.), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline;dichloropalladium (121.68 mg, 171.85 33184274.1Page 109 of 177407531-97SKWO (219686)μmol, 121.68 μL, 0.10 eq.) and 5-bromopyrazolo[1, 5-a]pyridin-2-amine (364.40 mg, 1.72 mmol, 1.00 eq.) in dioxane (10.00 mL) was added KF (499.20 mg, 8.59 mmol, 5.00 eq.) in H2O (2.00 mL) under N2. The mixture was stirred at 100 °C for 2 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1). Tert-butyl (2S, 3R)-2-[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl) -1-methyl-pyrazol-4-yl]oxymethyl]-3-fluoro-pyrrolidine-1-carboxylate (500.00 mg, 1.10 mmol, 64.07% yield, 94.8% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.542 min, [M+Na+] = 453.4. Intermediate 69: 5-[4-[[(2S,3R)-3-fluoropyrrolidin-2-yl] methoxy]-2-methyl-pyrazol-3-yl] pyrazolo [1, 5-a] pyridin-2-amine

[0406] To a solutionpyridin-5-yl) -1-methyl-pyrazol-4-yl]oxymethyl]-3-fluoro-pyrrolidine-1-carboxylate (500.00 mg, 1.16 mmol, 1.00 eq.) in dichloromethane (5.00 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 23.18 eq.). The mixture was stirred at 25 °C for 4 h. The mixture was adjusted to pH = 8 with TEA at 0 °C, then was concentrated under vacuum at 40 °C. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 2%-32% B over 52 min). 5-[4-[[(2S,3R)-3-fluoropyrrolidin-2-yl] methoxy]-2-methyl-pyrazol-3- yl] pyrazolo [1, 5-a] pyridin-2-amine (360.00 mg, 1.08 mmol, 93.26% yield, 99.4% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.408 min, [M+H+] = 331.2. Intermediate 70: Tert-butyl (2R,4R)-2-[[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl) -1-methyl- pyrazol-4-yl]oxymethyl]-4-fluoro-pyrrolidine-1-carboxylate33184274.1Page 110 of 177407531-97SKWO (219686)

[0407] To a solution of 5-bromopyrazolo[1, 5-a]pyridin-2-amine (1.12 g, 5.29 mmol, 1.00 eq.),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (2.01 g, 7.93 mmol, 1.50 eq.), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline;dichloropalladium (374.41 mg, 528.77 μmol, 374.41 μL, 0.10 eq.) and tert-butyl (2R, 4R) -2-[ (5-bromo-1-methyl- pyrazol-4-yl) oxymethyl]-4-fluoro-pyrrolidine-1-carboxylate (2.00 g, 5.29 mmol, 1.00 eq.) in dioxane (30.00 mL) was added KF (1.54 g, 26.44 mmol, 5.00 eq.) in H2O (6.00 mL) under N2. The mixture was stirred at 100 °C under N2for 2 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1). Tert-butyl (2R,4R)-2-[[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl)-1-methyl- pyrazol-4-yl]oxymethyl]-4-fluoro-pyrrolidine-1-carboxylate (1.25 g, 2.83 mmol, 53.49% yield, 97.4% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.545 min, [M+H+] = 431.3. Intermediate 71: 5-[4-[[(2R,4R)-4-fluoropyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3- yl]pyrazolo[1, 5-a]pyridin-2-amine (HCl salt)

[0408] To a5-yl) -1-methyl-pyrazol-4-yl]oxymethyl]-4-fluoro-pyrrolidine-1-carboxylate (600.00 mg, 1.39 mmol, 1.00 eq.) in dichloromethane (2.00 mL) was added HCl / ethyl acetate (2 M, 6.00 mL, 8.61 eq.), the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue.5-[4-[[(2R,4R)-4-fluoropyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5- a]pyridin-2-amine (500.00 mg, crude, HCl) was obtained as a white solid without further purification Intermediate 72: tert-butyl (2R)-2-[[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl) -1- methylpyrazol-4-yl]oxymethyl]azetidine-1-carboxylate 33184274.1Page 111 of 177407531-97SKWO (219686)

[0409] To a s methyl]azetidine-1-carboxylate (1.00 g, 2.89 mmol, 1.00 eq) in dioxane (10 mL) and H2O (1 mL) was added 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyrazolo[1, 5-a]pyridin-2-amine (972.92 mg, 3.75 mmol, 1.30 eq), Pd(dppf)Cl2(211.34 mg, 288.83 μmol, 0.100 eq) and K3PO4(1.84 g, 8.67 mmol, 3.00 eq). The reaction mixture was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 1 h under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 20%-50% B over 20 min). tert-butyl (2R)-2-[[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl) -1-methylpyrazol-4- yl]oxymethyl]azetidine-1-carboxylate (400 mg, 1.00 mmol, 34.76%yield, 100% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.460 min, [M+H+] = 399.3. Intermediate 73: tert-butyl (R)-2-(((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)-1- (difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate

[0410] To a-1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate (0.770 g, 2.015 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-2-amine (0.681 g, 2.418 mmol) in 1,4-dioxane (6 mL) was added tripotassium phosphate (in water) (4.03 mL, 2.015 mmol, 0.5 M). The reaction mixture was purged with N2for 10 min., PdCl2(dppf).CH2Cl2(0.165 g, 0.201 mmol) was added and the reaction was stirred at 60 °C for 16 h. Upon completion of the reaction, as monitored by TLC and 33184274.1Page 112 of 177407531-97SKWO (219686)LCMS, the reaction mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (Biotage: Isolera using 60-120 mesh silica, Eluent: 60-100% EtOAc in petroleum ether) to afford tert-butyl (R)-2-(((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)-1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)azetidine-1-carboxylate (0.4 g, 0.921 mmol, 46 % yield) as yellow solid. LCMS (ESI): Rt: 1.684 min, [M+H+] = 435.2.1H NMR (400 MHz, DMSO-d6) δ= 8.37 (1H), 7.93 (1H), 7.86 - 7.56 (1H), 7.38 (1H), 6.59 (1H), 5.75 (1H), 5.41 (2H), 4.40 - 4.29 (2H), 4.13 - 4.09 (1H), 3.71 - 3.57 (2H), 2.28 - 2.19 (1H), 2.10 - 2.03 (1H), 1.29 (9H). Intermediate 74: tert-butyl (R)-2-(((5-(2-aminoimidazo[1,2-a]pyrazin-6-yl)-1-methyl-1H- pyrazol-4-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0411] tert-butyl(2R) -2-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl]pyrrolidine-1-carboxylate (1.69 g, 4.69 mmol, 1.00 eq), 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, 3, 2- dioxaborolane (1.19 g, 4.69 mmol, 1.00 eq), KF (1.36 g, 23.47 mmol, 5.00 eq) and 4-ditert- butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (332.37 mg, 469.41 μmol, 332.37 μL, 0.100 eq) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. LCMS showed the desired mass was observed. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~25 % MeOH / DCM gradient @ 60 mL / min MeOH / DCM = 1 / 10, Rf = 0.5). Tert-butyl (2R)- 2-[[5-(2-aminoimidazo[1, 2-a]pyrazin-6-yl)-1-methyl-pyrazol-4-yl]oxymethyl]pyrrolidine-1- carboxylate (3.5 g, 4.71 mmol, 50.22% yield, 55.70% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.452 min, [M+H+] = 414.3. 33184274.1Page 113 of 177407531-97SKWO (219686)Intermediate 75: (R)-6-(1-methyl-4-(pyrrolidin-2-ylmethoxy)-1H-pyrazol-5-yl)imidazo[1,2- a]pyrazin-2-amine

[0412] To a 6-yl)-1-methyl-pyrazol-4-yl] g, in DCM (15 mL) was added TFA (4.61 g, 40.39 mmol, 3 mL, 11.13 eq) and the reaction mixture was stirred at 25 °C for 2 h. LCMS showed the reactant was consumed completely and one main peak with desired mass. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*40 mm* 15um; mobile phase: [water (FA) - ACN]; gradient: 0%-23% B over 15 min). 6-[2-methyl-4-[[ (2R) -pyrrolidin-2- yl]methoxy]pyrazol-3-yl]imidazo[1, 2-a]pyrazin-2-amine (350 mg, 1.10 mmol, 30.36% yield, 98.61% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.413 min, [M+H+] = 314.1. Intermediate 76: tert-butyl (2R) -2-[[5-(2-aminoimidazo[1, 2-a]pyrazin-6-yl) -1- (difluoromethyl) pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate

[0413] To apyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (1.60 g, 4.04 mmol, 1.00 eq.), 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (1.54 g, 6.06 mmol, 1.50 eq.) and 6-bromoimidazo[1, 2-a]pyrazin-2-amine (860.25 mg, 4.04 mmol, 1.00 eq.) in DMF (16.00 mL) was added KOAc (1.19 g, 12.11 mmol, 3.00 eq.) and Ad2nBuP Pd G3 (cataCXium® A Pd G3) (294.08 mg, 403.81 μmol, 0.100 eq.) under N2 atmosphere. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with water (50.00 mL) and extracted with ethyl acetate (30.00 mL * 3). The combined organic layers were washed with saturated brine (100.00 mL), dried 33184274.1Page 114 of 177407531-97SKWO (219686)over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 1: 0 - 0: 1). Tert-butyl (2R) -2-[[5-(2-aminoimidazo[1, 2-a]pyrazin-6-yl) -1-(difluoromethyl) pyrazol-4- yl]oxymethyl]pyrrolidine-1-carboxylate (1.22 g, 2.40 mmol, 59.54% yield, 88.57% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.489 min, [M+H+] = 450.3 Intermediate 77: 6-[2-(difluoromethyl) -4-[[ (2R) -pyrrolidin-2-yl]methoxy]pyrazol-3- yl]imidazo[1, 2-a]pyrazin-2-amine (TFA salt)

[0414] To apyrazin-6-yl) -1-(difluoromethyl) pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (500.00 mg, 1.11 mmol, 1.00 eq.) in dichloromethane (5.00 mL) was added TFA (380.54 mg, 3.34 mmol, 247.91 μL, 3.00 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product 6-[2-(difluoromethyl) -4-[[ (2R) -pyrrolidin-2- yl]methoxy]pyrazol-3-yl]imidazo[1, 2-a]pyrazin-2-amine (550.00 mg, crude, TFA) was obtained as a yellow solid, and was used into the next step without further purification. Intermediate 78: tert-butyl (R)-2-(((5-(2-((tert-butoxycarbonyl)amino)imidazo[1,2- a]pyridin-6-yl)-1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0415] 1.00 eq),tert-butyl (2R)-2-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl]pyrrolidine-1-carboxylate (600 mg, 1.67 mmol, 1.05 eq) and 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan- 2-yl) -1, 3, 2-dioxaborolane (604.20 mg, 2.38 mmol, 1.50 eq) in dioxane (12 mL) and H2O (1 mL) was added KF (276.46 mg, 4.76 mmol, 3.00 eq) and 4-ditert-butylphosphanyl-N, N-dimethyl- aniline;dichloropalladium (89.85 mg, 126.90 μmol, 89.85 μL, 0.08 eq). The mixture was stirred at 33184274.1Page 115 of 177407531-97SKWO (219686)100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10um;mobile phase: [water (NH4HCO3) -ACN]; gradient:18%-48% B over 15 min). tert-butyl (2R)-2-[[5-(2-aminoimidazo[1,2-a] pyridin-6-yl)-1-methyl-pyrazol-4- yl]oxymethyl]pyrrolidine-1-carboxylate (80 mg, 108.61 μmol, 6.85% yield, 56% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.426 min, [(M-Boc)+H+] = 413.2. Intermediate 79: (R)-6-(1-methyl-4-(pyrrolidin-2-ylmethoxy)-1H-pyrazol-5-yl)imidazo[1,2- a]pyridin-2-amine (TFA salt)

[0416] To a6-yl)-1-methyl-pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (80 mg, 193.95 μmol, 1.00 eq) in DCM (1 mL) was added TFA (3.07 g, 26.92 mmol, 2.00 mL, 138.82 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated with DCM (2 mL*2) under reduced pressure to give a residue. 6-[2-methyl-4-[[(2R)-pyrrolidin-2-yl]methoxy]pyrazol-3-yl]imidazo[1, 2-a] pyridin-2- amine (65 mg, crude) was obtained as a white solid and used into the next step without further purification. LCMS (ESI): Rt: 0.353 min, [M+H+] = 313.2. Intermediate 80: 6-bromo-1-tosyl-1H-benzo[d]imidazol-2-amine

[0417] To a mixture of 5-bromo-1H-benzimidazol-2-amine (4.50 g, 21.22 mmol, 1.00 eq) andDMAP (518.52 mg, 4.24 mmol, 0.20 eq) in DCM (60.00 mL) was added TEA (6.44 g, 63.67 mmol, 8.86 mL, 3.00 eq) and TosCl (4.86 g, 25.47 mmol, 1.20 eq), the mixture was stirred at 25 °C for 2 h. The reaction was concentrated. The residue was purified by column chromatography to give 6-bromo-1-tosyl-1H-benzo[d]imidazol-2-amine (2 g, 5.46 mmol, 25.73% yield) as white solid.1H NMR (400 MHz, CDCl3) δ = 7.83 (2H), 7.58 (1H), 7.41 (1H), 7.30 (2H), 7.20 (1H), 6.21 (s, 2H), 2.40 (3H). 33184274.1Page 116 of 177407531-97SKWO (219686)Intermediate 81: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H- benzo[d]imidazol-2-amine

[0418] 5.46 mmol,1.00 , 2-yl)-1,3,2- dioxaborolane (2.08 g, 8.19 mmol, 1.50 eq) and Ad2nBuP Pd G3 (cataCXium® A Pd G3) (397.71 mg, 546.10 μmol, 0.10 eq) in dioxane (60.00 mL) was added AcOK (1.61 g, 16.38 mmol, 3.00 eq)and the mixture was stirred at 80 °C for 12 h under N2. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-benzo[d]imidazol-2-amine (1.9 g, 3.68 mmol, 67.35% yield, 80% purity) as white solid. LCMS (ESI): Rt: 0.538 min, [M+H+] =414.2. Intermediate 82: tert-butyl (R)-2-(((5-(2-amino-1-tosyl-1H-benzo[d]imidazol-6-yl)-1- methyl-1H-pyrazol-4-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0419] Topyrrolidine-1-carboxylate (1.20 g, 3.33 mmol, 1.00 eq), 1-(p-tolylsulfonyl)-5-(4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-yl) benzimidazol-2-amine (1.89 g, 3.66 mmol, 1.10 eq) and Xphos Pd G4 (286.63 mg, 333.11 μmol, 0.10 eq) in THF (40 mL) was added K3PO4(1.50 M, 6.66 mL, 3.00 eq) and the mixture was stirred at 60 °C for 12 h under N2. The reaction was concentrated. The residue was purified by column chromatography to give tert-butyl (2R)-2-[[5-[2-amino-3-(p-tolylsulfonyl) benzimidazol-5-yl]-1-methyl-pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (1.4 g, 2.32 mmol, 69.72% yield, 94% purity) was obtained as brown oil. LCMS (ESI): Rt: 0.686 min, [M+H+] =567.4. 33184274.1Page 117 of 177407531-97SKWO (219686)Intermediate 83: (R)-6-(1-methyl-4-(pyrrolidin-2-ylmethoxy)-1H-pyrazol-5-yl)-1-tosyl-1H- benzo[d]imidazol-2-amine

[0420] tert- methyl-pyrazol-4-yl] g, (12.00 mL) was added TFA (3.68 g, 32.31 mmol, 2.4 mL, 18.31 eq) at 25 °C, the mixture was stirred at 25 °C for 1 h. The mixture was adjusted to pH = 8 with TEA at 0 °C. Then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10um; mobile phase: [water (NH4HCO3) -ACN]; gradient:18%-48% B over 20 min). (R)-6-[2-methyl-4-[[(2R)-pyrrolidin-2-yl] methoxy]pyrazol-3-yl]-1-(p-tolylsulfonyl) benzimidazol-2-amine (500 mg, 1.07 mmol, 60.73% yield) was obtained as white solid. LCMS (ESI): Rt: 0.434 min, [M+H+] = 467.2. Intermediate 84: 6-fluoro-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyrazolo [1, 5- a]pyridin-2-amine

[0421] To amg, 869.43μmol, 1 eq.) and 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2- dioxaborolane (441.56 mg, 1.74 mmol, 2.00 eq.) in dioxane (6.00 mL) was added KOAc (170.65 mg, 1.74 mmol, 2.00 eq.), XPhos (49.74 mg, 104.33 μmol, 0.12 eq) and Pd2(dba)3 (79.61 mg, 86.94 μmol, 0.10 eq.). The mixture was degassed and purged with N2 for 3 times and stirred at 80 °C for 1 h. The mixture was filtered and the filtrate was concentrated to give a residue.6-fluoro- 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyrazolo [1, 5-a]pyridin-2-amine (240.00 mg, 866.11 μmol, 99.62% yield) was obtained as a brown liquid and it's used directly in the next step. Intermediate 85: tert-butyl (2R) -2-[[5-(2-amino-6-fluoro-pyrazolo[1,5-a]pyridin-5-yl)-1- methyl-pyrazol-4-yl]oxymethyl] azetidine-1-carboxylate 33184274.1Page 118 of 177407531-97SKWO (219686)

[0422] To a solu (212.62 mg, 924.27μmol, 0.8 eq.), tert-butyl (2R)-2-[ (5-bromo-1-methyl-pyrazol-4-yl) oxymethyl]azetidine-1- carboxylate (400.00 mg, 1.16 mmol, 1 eq.) and 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (469.41 mg, 1.85 mmol, 1.60 eq.) in dioxane (10.00 mL) and H2O (2.00 mL) was added [2-(2-aminophenyl) phenyl]palladium (1+) ; bis (1-adamantyl) -butyl-phosphane; methanesulfonate (67.31 mg, 92.43 μmol, 0.08 eq.) and K3PO4(735.72 mg, 3.47 mmol, 3 eq.). The mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*40 mm* 15um; mobile phase: [water (TFA) -ACN]; gradient: 35%-65% B over 22 min). Tert-butyl (2R) -2-[[5-(2-amino-6-fluoro-pyrazolo[1,5- a]pyridin-5-yl)-1-methyl-pyrazol-4-yl]oxymethyl] azetidine-1-carboxylate (108.00 mg, 207.47 μmol, 17.96% yield, 80% purity) was obtained as a white solid. Alternative Synthesis:

[0423] Toyl) pyrazolo[1,5-a]pyridin-2-amine (240.00 mg, 866.11 μmol, 1.00 eq.) in dioxane (2.00 mL) and H2O (1.50 mL) was added tert-butyl (2R) -2-[(5-bromo-1-methyl-pyrazol-4-yl)oxymethyl]azetidine-1- carboxylate (254.88 mg, 736.19 μmol, 0.85 eq.), K3PO4 (367.69 mg, 1.73 mmol, 2.00 eq.), Pd(dppf)Cl2 (63.37 mg, 86.61 μmol, 0.10 eq.), the mixture was degassed and purged with N2 for 3 times, stirred at 90 °C for 1 h. The mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether, then 5~15% methanol / dichloromethane gradient @ 40 33184274.1Page 119 of 177407531-97SKWO (219686)mL / min). Tert-butyl (R) -2-(((5-(2-amino-6-fluoropyrazolo[1, 5-a]pyridin-5-yl) -1-methyl-1H- pyrazol-4-yl) oxy) methyl) azetidine-1-carboxylate (270.00 mg, 505.25 μmol, 58.34% yield, 77.93% purity) was obtained as a brown oil. LCMS (ESI): Rt: 0.462 min, [M+H+] = 417.2. Intermediate 86: 5-[4-[[(2R)-azetidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]-6-fluoro- pyrazolo[1, 5-a]pyridin-2-amine

[0424] To a 5-a]pyridin-5-yl) -1-methyl-pyrazol-4-yl]oxymethyl]azetidine-1-carboxylate (80.00 mg, 192.10 μmol, 1 eq.) in dichloromethane (3.00 mL) was added TFA (921.00 mg, 8.08 mmol, 0.6 mL, 42.05 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.5-[4-[[(2R)-azetidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]-6- fluoro-pyrazolo[1, 5-a]pyridin-2-amine (80.00 mg, crude, TFA) was obtained as a white solid and used into the next step without further purification. LCMS (ESI): Rt: 0.330 min, [M+H+] = 317.0. Example 1: (R)-11,46-dimethyl-11H,21H-12-oxa-3-aza-2(6,2)-benzo[d]imidazola-4(4,2)- pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1:

[0425] To 2-μmol, 1.20 eq)and 6-[2-methyl-4-[[2R)-pyrrolidin-2-yl]methoxy]pyrazol-3-yl]-1-(p-tolylsulfonyl) benzimidazol-2-amine (100.00 mg, 214.34 μmol, 1.00 eq) in MeCN (5.00 mL) was added K2CO3 (148.11 mg, 1.07 mmol, 5.00 eq) and the mixture was stirred at 25 °C for 16 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give [2-methyl-4-[[(2R)-1-[5-(4-chloro-6-methyl-pyrimidin-2-yl)pentyl] pyrrolidin-2- 33184274.1Page 120 of 177407531-97SKWO (219686)yl]methoxy]pyrazol-3-yl]-1-(p-tolylsulfonyl)benzimidazol-2-amine (100 mg, 143.24 μmol, 66.83% yield, 95% purity) as yellow solid. LCMS (ESI): Rt: 0.818 min, [M+H+] =663.3. Step 2:2-yl)pentyl]pyrrolidin-2-yl] methoxy]pyrazol-3-yl]-1-(p-tolylsulfonyl) benzimidazol-2-amine (100.00 mg, 150.78 μmol, 1.00 eq) in dioxane (3.00 mL) was added BrettPhos Pd G3 (13.67 mg, 15.08 μmol, 0.10 eq) and Cs2CO3(147.38 mg, 452.33 μmol, 3.00 eq). The mixture was stirred at 60 °C for 3 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm* 10um;mobile phase: [water (FA) - ACN];gradient:8%-38% B over 9 min). Example 1 (24.41 mg, 51.65 μmol, 34.26% yield, 100% purity) was obtained as yellow solid. Note: The Tos protecting groups gets cleaved during the procedure.1H NMR (400 MHz, DMSO-d6) δ = 12.28 (1H), 11.70 -10.64 (1H), 7.63 (1H), 7.53 (1H), 7.44 (1H), 7.28 - 7.20 (1H), 6.70 (1H), 4.35 - 4.19 (1H), 4.05 (1H), 3.87 (3H), 3.69 - 3.42 (3H), 3.12 - 2.79 (4H), 2.35 (3H), 2.18 - 2.06 (1H), 2.04 - 1.85 (4H), 1.78 (2H), 1.74 - 1.59 (2H), 1.51 (1H). LCMS (ESI): Rt: 0.604 min, [M+H+] =473.3. Example 2: (22Z,25E,102R)-11,46-dimethyl-11H-12-oxa-3-aza-2(6,2)-imidazo[1,2- a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1:[1, 2-a]pyridin-2-amine (60 mg, 192.08 μmol, 1.00 eq) in ACN (10 mL) was added K2CO3(79.64 mg, 576.24 μmol, 3.00 eq) and 2-(5-bromopentyl)-4-chloro-6-methyl-pyrimidine (63.98 mg, 230.50 33184274.1Page 121 of 177407531-97SKWO (219686)μmol, 1.20 eq). The mixture was stirred at 40 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um;mobile phase: [water (NH4HCO3) - ACN];gradient:22%-52% B over 9 min). 6-[2-methyl-4-[[(2R) -1-[5-(4-chloro-6-methyl- pyrimidin-2-yl)pentyl]pyrrolidin-2-yl]methoxy]pyrazol-3-yl] imidazo[1, 2-a]pyridin-2-amine (35 mg, 61.19 μmol, 31.86% yield, 89% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.373 min, [M+H] = 509.2. Step 2:

[0428] 2-yl) pentyl]pyrrolidin-2-yl]methoxy]pyrazol-3-yl]imidazo[1, 2-a]pyridin-2-amine (35 mg, 68.76 μmol, 1.00 eq) in THF (3 mL) was added Cs2CO3 (56.01 mg, 171.89 μmol, 2.50 eq) and BrettPhos Pd G3 (6.23 mg, 6.88 μmol, 0.100 eq). The mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10um;mobile phase: [water (FA) -ACN];gradient:0%-25% B over 18 min). Example 2: (6.18 mg, 13.08 μmol, 19.02% yield, 100%purity, FA) was obtained as a yellow solid. LCMS (ESI): Rt: 0.363 min, [M+H+] = 473.4.1H NMR (400 MHz, CDCl3) δ = 8.66 (1H), 8.40 (1H), 8.36 (1H), 8.23 (1H), 7.53 (1H), 7.32 (1H), 7.23 (1H), 6.40 (1H), 3.95 (4H), 3.73 - 3.54 (1H), 3.40 - 3.18 (2H), 3.14 - 3.04 (1H), 2.99 - 2.89 (1H), 2.69 - 2.53 (3H), 2.41 (3H), 2.15 - 2.06 (4H), 2.02 - 1.94 (2H), 1.86 - 1.73 (3H), 1.57 - 1.45 (1H). Example 3: (22Z,25Z,102R)-11,46-dimethyl-11H-12-oxa-3-aza-2(6,2)-imidazo[1,2- a]pyrazina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1: 33184274.1Page 122 of 177407531-97SKWO (219686)[0429 azo[1, 2-a]pyrazin-2-amine (300 mg, 957.37 μmol, 1.00 eq) in CH3CN (5 mL) was added K2CO3(396.94 mg, 2.87 mmol, 3.00 eq), KI (79.46 mg, 478.69 μmol, 0.500 eq), 2-(5-bromopentyl)-4-chloro-6- methyl-pyrimidine (212.60 mg, 765.90 μmol, 0.800 eq) and the reaction mixture was stirred at 50 °C for 5 h. LCMS showed the reactant was consumed completely and 64.57% desired mass was observed. The reaction mixture was concentrated in vacuum to dryness. The residue was purified flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% MeOH / DCM gradient @ 40 mL / min MeOH / DCM = 10 / 1, Rf = 0.5).6-[2-methyl-4-[[(2R)-1-[5- (4-chloro-6-methyl-pyrimidin-2-yl)pentyl]pyrrolidin-2-yl]methoxy] pyrazol-3-yl]imidazo[1, 2- a]pyrazin-2-amine (230 mg, 378.98 μmol, 39.59% yield, 84.04% purity) was obtained as a yellowoil. LCMS (ESI): Rt: 0.388 min, [M+H+] = 510.3.Step 2:

[0430] 2-yl)pentyl]pyrrolidin-2-yl] methoxy]pyrazol-3-yl]imidazo[1, 2-a]pyrazin-2-amine (180 mg, 352.92 μmol, 1.00 eq) in dioxane (6 mL) was added BrettPhos Pd G3 (31.99 mg, 35.29 μmol, 0.100 eq) and Cs2CO3(344.96 mg, 1.06 mmol, 3.00 eq), the mixture was stirred at 60 °C for 3 h under N2. The reaction mixture was filter and the filtrate was concentrated in vacuum to dryness. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm* 10um; mobile phase: [water (FA) -ACN]; gradient: 0%-28% B over 9 min) then was further purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient:22%-52% B over 9 min). Example 3: (17.02 mg, 35.94 μmol, 10.18% yield, 100% purity) was33184274.1Page 123 of 177407531-97SKWO (219686)obtained as a white solid. LCMS (ESI): Rt: 0.351 min, [M+H+] = 474.2.1H NMR (400 MHz, DMSO-d6) δ = 8.89 (1H), 8.75 (1H), 8.66 (1H), 8.53 (1H), 7.25 - 7.23 (1H), 6.35 (1H), 4.20 (3H), 3.89 (2H), 3.27 (1H), 3.17 - 3.00 (3H), 2.99 - 2.88 (1H), 2.54 - 2.41 (2H), 2.35 (3H), 1.82 (8H), 1.59 - 1.46 (2H). Example 4: (R,23Z,24E)-11,46-dimethyl-11H-5,12-dioxa-3-aza-2(5,2)-pyrazolo[1,5- a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1:μmol,1.00 eq) and 5-[2-methyl-4-[[(2R)-pyrrolidin-2-yl]methoxy]pyrazol-3-yl]pyrazolo[1,5-a] pyridin- 2-amine (156.43 mg, 500.79 μmol, 0.70 eq) in MeCN (4.0 mL) was added K2CO3 (197.75 mg, 1.43 mmol, 2.00 eq) and KI (59.38 mg, 357.70 μmol, 0.50 eq) and the mixture was stirred at 50°C for 2 h. The suspension was diluted with water (50 mL) and extracted with EA (30 mL × 3), the organic layer was dried over Na2SO4and concentrated under vacuum. TLC (DCM:MeOH=10:1) showed some reactant (Rf = 0.9) remained and one main blue spot (Rf = 0.1) was observed. The residue was purified by flash silica gel chromatography (ISCO®; g SepaFlash® Silica Flash Column, Eluent of 0~100 % Ethyl acetate / Petroleum ether, 5~16% MeOH / DCM gradient @ 35 mL / min). 5-[4-[[(2R)-1-[4-(4-chloro-6-methyl-pyrimidin-2-yl)oxybutyl]pyrrolidin-2- yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1,5-a]pyridin-2-amine (210 mg, 399.03 μmol, 27.89% yield, 97.10% purity) was obtained as a brown oil (DCM:MeOH = 10:1, Rf = 0.1). LCMS (ESI): Rt: 0.399 min, [M+H+] = 511.3. Step 2: 33184274.1Page 124 of 177407531-97SKWO (219686)

[0432] To a so u o o - - - - - -c o o- - e y -py - -y o y u yl]pyrrolidin-2-yl] methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1,5-a]pyridin-2-amine (160 mg, 313.10 μmol, 1.00 eq) in THF (16.0 mL) was added t-BuOK (105.40 mg, 939.30 μmol, 3.00 eq) and the mixture was stirred at 60°C for 40 min. The mixture was diluted with brine (40 mL), extracted with EA (30 mL × 3) and the organic layer was washed with brine (30 mL), dried over Na2SO4and concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v / v)-ACN];gradient:18%-48% B over 10 min), eluent was lyophilized). The product containing fractions showed some impurity. Therefore, the material product was purified again by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];gradient:20%-50% B over 9 min).Example 4: (36.98 mg, 77.93 μmol, 24.89% yield, 100% purity) was obtained as a white solid.LCMS (ESI): Rt: 0.566 min, [M+H+] = 475.4.1H NMR (400 MHz, CDCl3) δ = 8.33 (1H), 8.20 - 8.05 (1H), 7.93 (1H), 7.28 (1H), 7.24 (1H), 6.77 - 6.71 (1H), 6.11 (1H), 4.76 - 4.60 (1H), 4.22 - 4.11 (1H), 3.99 (3H), 3.90 - 3.84 (1H), 3.77 (1H), 3.38 - 3.28 (1H), 3.13 - 3.01 (1H), 2.98 - 2.88 (1H), 2.41 - 2.28 (6H), 2.18 - 2.08 (1H), 2.01 - 1.90 (1H), 1.87 - 1.80 (2H), 1.76 - 1.66 (2H), 1.63 - 1.53 (1H). Example 5: (R,23Z,24E)-11,44-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(2,6)-pyridina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1: 33184274.1Page 125 of 177407531-97SKWO (219686)[043 razolo[1,5-a] pyridin-2-amine (200 mg, 640.27 μmol, 1.00 eq) in ACN (3 mL) was added K2CO3 (265.47 mg, 1.92 mmol, 3.00 eq) and 2-(5-bromopentyl)-6-chloro-4-methyl-pyridine (177.10 mg, 640.27 μmol, 1.00 eq). The mixture was stirred at 60 °C for 22 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10um;mobile phase: [water (NH4HCO3) - ACN];gradient:28%-58% B over 20 min). 5-[4-[[(2R)-1-[5-(6-chloro-4-methyl-2- pyridyl)pentyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (180 mg, 325.95 μmol, 50.91% yield, 92% purity) was obtained as a red solid. LCMS (ESI): Rt: 0.435 min, [M+H+] =508.3.1H NMR (400 MHz, DMSO-d6) δ = 8.31 (1H), 7.40 (1H), 7.35 (1H), 7.13 (1H), 7.05 (1H), 6.69 - 6.57 (1H), 5.68 (1H), 5.34 (2H), 3.88 - 3.78 (4H), 3.77 - 3.70 (1H), 3.03 - 2.94 (1H), 2.78 - 2.70 (1H), 2.68 - 2.60 (1H), 2.55 (2H), 2.27 (3H), 2.22 - 2.13 (1H), 2.12 - 2.04 (1H), 1.86 - 1.75 (1H), 1.63 (2H), 1.57 - 1.45 (3H), 1.41 - 1.30 (2H), 1.16 (2H). Step 2:

[0434] To a solution of 5-[4-[[(2R)-1-[5-(6-chloro-4-methyl-2-pyridyl)pentyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (150 mg, 295.24 μmol, 1.00 eq) in THF (20 mL) was added NaH (29.52 mg, 738.11 μmol, 60% purity, 2.50 eq). The mixture was 33184274.1Page 126 of 177407531-97SKWO (219686)stirred at 40 °C for 24 h. Then NaH (23.62 mg, 590.49 μmol, 60% purity, 2.00 eq) was added into the mixture. The mixture was stirred at 60°C for 48 h. The reaction mixture was quenched by addition sat. NH4Cl (5 mL) at 0°C, and the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40 mm* 15um;mobile phase: [water (FA) -ACN];gradient:5%-35% B over 15 min). Example 5: (58.10 mg, 123.20 μmol, 41.73% yield, 100% purity, FA) was obtained as a yellow solid. LCMS (ESI): Rt: 0.382 min, [M+H+] = 472.3.1H NMR (400 MHz, DMSO-d6) δ = 9.68 (1H), 8.56 (1H), 8.14 (1H), 7.72 (1H), 7.42 (1H), 7.27 (1H), 6.99 - 6.85 (1H), 6.54 (1H), 6.48 (1H), 3.99 (1H), 3.96 - 3.86 (4H), 3.09 (1H), 2.93 - 2.82 (1H), 2.82 - 2.60 (3H), 2.19 (3H), 2.08 - 1.77 (6H), 1.75 - 1.51 (4H), 1.47 - 1.13 (2H). Example 6: (R,23Z,24E)-11,46-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1:[1,5-a] pyridin-2-amine (200 mg, 640.27 μmol, 1.00 eq) and 2-(5-bromopentyl)-4-chloro-6-methyl- pyrimidine (195.50 mg, 704.30 μmol, 1.10 eq) in ACN (2 mL) was added K2CO3 (309.71 mg, 2.24 mmol, 3.50 eq). The mixture was stirred at 40 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The mixture was purified by column chromatography (SiO2, PE:EA = 15 / 1 TO 0 / 1, then DCM:MeOH = 100 / 1 to 5 / 1).5-[4-[[(2R)-1- [5-(4-chloro-6-methyl-pyrimidin-2-yl)pentyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3- yl]pyrazolo[1, 5-a]pyridin-2-amine (210 mg, 255.77 μmol, 39.95% yield, 62% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.407 min, [M+H+] = 509.2. Step2: 33184274.1Page 127 of 177407531-97SKWO (219686)

[0436] To a solution of 5-[2-methyl-4-[[(2R)-1-[5-(4-chloro-6-methyl-pyrimidin-2-yl)pentyl]pyrrolidin-2-yl]methoxy]pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (195 mg, 383.07 μmol, 1.00 eq) in THF (15 mL) was added t-BuOK (1 M, 383.07 μL, 1.00 eq). The mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10um;mobile phase: [water (FA) -ACN];gradient:0%-25% B over 20 min). Example 6: (117.83mg, 249.33 μmol, 65.09% yield, 100% purity, FA) was obtained as a yellow solid. LCMS (ESI): Rt: 0.373 min, [M+H+] = 473.4.1H NMR (400 MHz, DMSO-d6) δ = 10.28 (1H), 8.60 (1H), 8.18 (1H), 7.75 (1H), 7.38 (1H), 7.31 (1H), 6.98 (1H), 6.55 (1H), 3.94 (3H), 3.85 (1H), 3.72 (1H), 3.18 - 3.11 (1H), 3.03 - 2.90 (3H), 2.80 - 2.65 (1H), 2.42 -2.33 (2H), 2.26 (3H), 2.03 - 1.84 (3H), 1.79 - 1.61 (5H), 1.48 (1H), 1.35 - 1.21 (1H). Example 7: (R,23Z,24E)-11,46-dimethyl-11H-7,12-dioxa-3-aza-2(5,2)-pyrazolo[1,5- a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1:[1,5-a] pyridin-2-amine (300 mg, 960.40 μmol, 1.00 eq) in CH3CN (5 mL) was added K2CO3 (398.20 mg, 2.88 mmol, 3.00 eq), KI (79.71 mg, 480.20 μmol, 0.500 eq) and 2-[2-(2-bromoethoxy) ethyl]- 4-chloro-6-methyl-pyrimidine (214.79 mg, 768.32 μmol, 0.800 eq) and the reaction mixture was 33184274.1Page 128 of 177407531-97SKWO (219686)stirred at 50 °C for 10 h. The reaction mixture was concentrated in vacuum to dryness. The residue was purified flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% MeOH / DCM gradient @ 40 mL / min MeOH / DCM = 10 / 1, Rf = 0.5).5-[4-[[ (2R) -1-[2-[2-(4-chloro-6-methyl-pyrimidin-2-yl) ethoxy]ethyl]pyrrolidin-2-yl]methoxy]-2-methyl- pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (350 mg, 577.58 μmol, 60.14% yield, 84.33% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.394 min, [M+H+] = 511.4. Step 2:

[0438] To a solution of 5-[4-[[(2R)-1-[2-[2-(4-chloro-6-methyl-pyrimidin-2-yl)ethoxy]ethyl]pyrrolidin-2-yl]methoxy] -2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2- amine (300 mg, 587.06 μmol, 1.00 eq) in dioxane (10 mL) was added BrettPhos Pd G3 (53.22 mg, 58.71 μmol, 0.100 eq) and Cs2CO3 (573.83 mg, 1.76 mmol, 3.00 eq) and the mixture was stirred at 60 °C for 3 h under N2. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water(NH4HCO3) -ACN]; gradient: 22%-52% B over 9 min). Example 7: (43.86 mg, 92.42 μmol,15.74% yield, 100% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.348 min, [M+H+] =475.2.1H NMR (400 MHz, CDCl3) δ = 8.29 (2H), 8.08 (1H), 7.76 (1H), 7.27 (1H), 6.76 - 6.70 (1H), 6.25 (1H), 4.33 - 4.24 (1H), 4.09 - 4.03 (1H), 4.02 - 4.00 (3H), 3.92 - 3.86 (1H), 3.84 - 3.75 (2H), 3.74 - 3.65 (1H), 3.49 - 3.39 (1H), 3.36 - 3.16 (3H), 3.04 - 2.94 (1H), 2.77 - 2.68 (1H), 2.54 - 2.45 (1H), 2.33 (3H), 2.01 - 1.89 (1H), 1.86 - 1.75 (2H), 1.62 - 1.51 (1H). Example 8: (R,23Z,24E)-11,46-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,2)-pyridina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1: 33184274.1Page 129 of 177407531-97SKWO (219686)

[0439] yrazolo[1,5-a] pyridin-2-amine (200 mg, 640.27 μmol, 1.00 eq) and 2-(5-bromopentyl)-4-chloro-6-methyl- pyridine (177.10 mg, 640.27 μmol, 1.00 eq) in ACN (5 mL) was added K2CO3(309.71 mg, 2.24 mmol, 3.50 eq). The mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The filtrate was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10um;mobile phase: [water (NH4HCO3) - ACN];gradient:32%-62% B over 20 min). 5-[4-[[(2R) -1-[5-(4-Chloro-6-methyl-2- pyridyl)pentyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl] pyrazolo[1, 5-a]pyridin-2-amine (160 mg, 258.24 μmol, 40.33% yield, 82% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.362 min, [M+H+] = 508.2.1H NMR (400 MHz, DMSO-d6) δ = 8.31 (1H), 7.40 (1H), 7.34 (1H), 7.20 - 7.11 (2H), 6.67 - 6.59 (1H), 5.68 (1H), 5.34 (2H), 3.89 - 3.78 (4H), 3.77 - 3.69 (1H), 3.02 - 2.94 (1H), 2.74 (1H), 2.68 - 2.62 (1H), 2.59 (2H), 2.40 (3H), 2.22 - 2.13 (1H), 2.09 (1H), 1.86 - 1.75 (1H), 1.67 - 1.45 (5H), 1.36 (2H), 1.17 (2H). Step 2:

[0440] To a solution of 5-[4-[[(2R)-1-[5-(4-chloro-6-methyl-2-pyridyl)pentyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (150 mg, 295.24 μmol, 1.00 eq) in THF (20 mL) was added NaH (35.43 mg, 885.73 μmol, 60% purity, 3.00 eq). The mixture was stirred at 60 °C for 16 h. Then NaH (17.71 mg, 442.86 μmol, 60% purity, 1.50 eq) was added into 33184274.1Page 130 of 177407531-97SKWO (219686)the mixture and the mixture was stirred at 60°C for 24 h. The reaction mixture was quenched by addition sat. NH4Cl (5 mL). The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water (FA) -ACN];gradient:0%-30% B over 20 min). Example8: (26.62 mg, 56.45 μmol, 19.12% yield, 100% purity, FA) was obtained as a yellow solid. LCMS(ESI): Rt: 0.363 min, [M+H+] = 472.3.1H NMR (400 MHz, DMSO-d6) δ = 9.28 (1H), 8.65 (1H), 8.15 (2H), 7.78 (1H), 7.44 (1H), 7.04 - 6.98 (1H), 6.89 (1H), 6.58 (1H), 6.45 (1H), 3.92 (4H), 3.78 (1H), 2.70 - 2.62 (2H), 2.32 (3H), 2.00 - 1.89 (1H), 1.75 - 1.47 (9H), 1.37 - 1.26 (2H). Example 9: (R,23Z,24E)-11,46-dimethyl-11H-11-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,2)-pyrimidina-1(5,4)-pyrazola-9(1,2)-pyrrolidinacycloundecaphane Step 1:

[0441] To amg, 948.55μmol, 1.00 eq.) and 5-[2-methyl-4-[[(2R)-pyrrolidin-2-yl]methoxy]pyrazol-3-yl]pyrazolo[1,5- a]pyridin-2-amine (266.67 mg, 853.69 μmol, 0.90 eq.) in acetonitrile (7.00 mL) was added K2CO3(393.28 mg, 2.85 mmol, 3.00 eq.), the mixture was stirred at 40 °C for 4 h. The mixture was filtered and washed with ethyl acetate (20.00 mL × 3). The filtrate was washed with water (10.00 mL × 3), then the organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a yellow oil. The oil was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether, then 5~20% MeOH / DCM gradient @ 40 mL / min).5-[2-methyl-4-[[2R)-1-[4-(4-chloro-6-methyl-pyrimidin-2- yl)butyl]pyrrolidin-2-yl]methoxy]pyrazol-3-yl]pyrazolo[1,5-a]pyridin-2-amine (320.00 mg, 603.45 μmol, 63.62% yield, 93.35% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.377 min, [M+H+] = 495.2.1H NMR (400 MHz, CDCl3) δ = 8.22 (1H), 7.33 (1H), 7.29 (1H), 7.04 (1H), 6.69 - 6.62 (1H), 5.82 (1H), 4.07 - 3.92 (2H), 3.88 (3H), 3.84 - 3.72 (1H), 3.23 - 3.07 (1H), 2.97 - 2.67 (4H), 2.48 (3H), 2.42 - 2.14 (2H), 1.96 - 1.52 (8H). 33184274.1Page 131 of 177407531-97SKWO (219686)Step 2:

[0442] To2-yl)butyl]pyrrolidin-2-yl]methoxy]pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (100.00 mg, 202.01 μmol, 1.00 eq.) in DMF (7.00 mL) was added t-BuOK (68.00 mg, 606.04 μmol, 3.00 eq.). The mixture was heated to 60 °C and stirred for 1 h. The mixture was diluted with water (20.00 mL) and extracted with ethyl acetate (20.00 mL × 3), the organic layers were dried over anhydrousNa2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (ammonia hydroxide v / v) -ACN]; gradient: 23%-53% B over 10 min). Example 9: (8.98 mg, 19.28 μmol, 4.77% yield,98.47% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.650 min, [M+H+] = 459.3.1H NMR (400 MHz, CDCl3) δ = 8.31 (1H), 7.83 (1H), 7.39 - 7.32 (2H), 7.08 (1H), 6.72 - 6.66 (1H), 6.32 (1H), 4.00 (3H), 3.96 - 3.77 (2H), 3.21 - 3.03 (3H), 2.92 - 2.79 (1H), 2.75 - 2.63 (1H), 2.41 (3H), 2.27 - 1.90 (5H), 1.79 - 1.68 (4H), 1.53 - 1.47 (1H). Example 10: (R,23Z,24Z)-26-fluoro-11,46-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5- a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-azetidinacyclododecaphane Step 1:

[0443] -6-fluoro-pyrazolo[1, 5-a]pyridin-2-amine (120.00 mg, 379.35 μmol, 1 eq.) in MeCN (5.00 mL) was added 33184274.1Page 132 of 177407531-97SKWO (219686)K2CO3(157.28 mg, 1.14 mmol, 3 eq.) and 2-(5-bromopentyl)-4-chloro-6-methyl-pyrimidine (126.36 mg, 455.22 μmol, 1.2 eq.). The mixture was stirred at 40 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 15 / 1 - 0 / 1, then dichloromethane : methanol = 10 / 1). 5-[4-[[ (2R) -1-[5-(4-chloro-6-methyl-pyrimidin-2-yl) pentyl]azetidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]-6-fluoro-pyrazolo[1, 5-a]pyridin-2-amine (42.00 mg, 63.86 μmol, 16.83% yield, 78% purity) was obtained as a red solid. LCMS (ESI): Rt: 0.420 min, [M+H+] = 477.1. Step 2:

[0444] To a solution of 5 -[4-[[ (2R) - 1-[5-(4-chloro-6-methyl-pyrimidin-2-yl) pentyl]azetidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]-6-fluoro-pyrazolo[1, 5-a]pyridin-2-amine (39.00 mg, 76.02 μmol, 1 eq.) in THF (2.00 mL) was added BrettPhos Pd G3 (68.91 mg, 76.02 μmol, 1 eq.) and Cs2CO3 (24.77 mg, 76.02 μmol, 1 eq.). The mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 um;mobile phase: [water (FA) -ACN];gradient:2%-32% B over 9 min). Example 10: (8.97 mg, 18.82 μmol, 24.76% yield, 100%purity) was obtained as a white solid. LCMS (ESI): Rt: 0.367 min, [M+H+] = 477.3.1H NMR (400 MHz, MeOH-d4) δ = 8.70 (1H), 8.53 (1H), 7.68 (1H), 7.52 (1H), 7.27 (1H), 6.55 (1H), 4.34 - 4.14 (3H), 4.01 (1H), 3.86 (3H), 3.61 (1H), 3.14 - 2.96 (2H), 2.89 - 2.74 (2H), 2.52 - 2.39 (1H), 2.37 (3H), 2.31 (1H), 2.17 - 1.93 (2H), 1.88 - 1.68 (2H), 1.65 - 1.50 (1H), 1.43 - 1.24 (1H). Example 11: (R,23Z,24Z)-26-fluoro-11,46-dimethyl-11H-11-oxa-3-aza-2(5,2)-pyrazolo[1,5- a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-9(1,2)-azetidinacycloundecaphane Step 1: 33184274.1Page 133 of 177407531-97SKWO (219686)

[0445] To 0 mg, 341.48μmol, 1.00 eq.) and (R) -5-(4-(azetidin-2-ylmethoxy) -1-methyl-1H-pyrazol-5-yl) -6- fluoropyrazolo [1, 5-a]pyridin-2-amine (86.42 mg, 273.18 μmol, 0.80 eq.) in acetonitrile (7.00 mL) was added K2CO3 (141.58 mg, 1.02 mmol, 3.00 eq.). The mixture was stirred at 40 °C for 1 h, then stirred at 60 °C for 1 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (ammonia hydroxide v / v) -ACN]; gradient: 25%-55% B over 12 min). (R) -5-(4-((1-(4-(4-chloro-6-methylpyrimidin-2-yl) butyl) azetidin-2-yl) methoxy) -1-methyl-1H- pyrazol-5-yl) -6-fluoropyrazolo[1, 5-a]pyridin-2-amine (33.00 mg, 62.36 μmol, 18.26% yield, 94.30% purity) was obtained as a brown solid. LCMS (ESI): Rt: 0.406 min, [M+H+] = 499.3. Step: 2

[0446] azetidin-2-yl)methoxy) -1-methyl-1H-pyrazol-5-yl) -6-fluoropyrazolo[1, 5-a]pyridin-2-amine (15.00 mg, 30.06 μmol, 1.00 eq.) in dioxane (4.00 mL) was added BrettPhos Pd G3 (2.73 mg, 3.01 μmol, 0.1 eq.) and Cs2CO3(29.38 mg, 90.18 μmol, 3.00 eq.). The mixture was degassed and purged with N2for 3 times and stirred at 60 °C for 3 h. The mixture was filtered and washed with ethyl acetate (5.00 mL), then the filtrate was concentrated under vacuum. The crude product was purified by prep- HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (ammonia hydroxidev / v) -ACN]; gradient: 38%-68% B over 11 min). Example 11: (6.31 mg, 13.64 μmol, 45.38%yield, 100% purity) was obtained as an off-white solid. LCMS (ESI): Rt: 0.363 min, [M+H+] = 463.3.1H NMR (400 MHz, CDCl3) δ = 8.32 (1H), 7.71 (1H), 7.44 (1H), 7.33 (1H), 7.00 (1H), 33184274.1Page 134 of 177407531-97SKWO (219686)6.30 (1H), 3.95 - 3.85 (5H), 3.80 - 3.72 (1H), 3.46 - 3.35 (1H), 3.32 - 3.25 (1H), 3.22 - 3.12 (1H), 3.11 - 3.03 (1H), 2.88 - 2.77 (1H), 2.72 - 2.62 (1H), 2.40 (3H), 2.30 - 2.21 (1H), 2.19 - 2.10 (1H), 1.98 - 1.89 (2H), 1.86 - 1.77 (1H), 1.72 - 1.64 (1H). Example 12: (22Z,25Z,102R)-11-(difluoromethyl)-46-methyl-11H-7,12-dioxa-3-aza-2(6,2)- imidazo[1,2-a]pyrazina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)- pyrrolidinacyclododecaphane Step 1:

[0447] pyrazol-3-yl]imidazo[1, 2-a]pyrazin-2-amine (120.00 mg, 258.98 μmol, 1.00 eq., TFA) and K2CO3(71.58 mg, 517.95 μmol, 2.00 eq.) in acetonitrile (1.00 mL) was added 2-[2-(2-bromoethoxy) ethyl]-4- chloro-6-methyl-pyrimidine (72.40 mg, 258.98 μmol, 1.00 eq.). The mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane : methanol = 1: 0 - 10: 1).6- [4-[[ (2R) -1-[2-[2-(4-Chloro-6-methyl-pyrimidin-2-yl) ethoxy] ethyl]pyrrolidin-2-yl]methoxy]- 2-(difluoromethyl)pyrazol-3-yl]imidazo[1, 2-a]pyrazin-2-amine (50.00mg, 91.24 μmol, 35.23% yield, 100% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.412 min, [M+H+] = 548.3. Step 2:yl)ethoxy]ethyl]pyrrolidine-2-yl]methoxy]-2-(difluoromethyl) pyrazol-3-yl]imidazo[1, 2-a]pyrazin-2-amine (40.00 mg, 72.99 μmol, 1.00 eq.) and Cs2CO3(71.35 mg, 218.98 μmol, 3.00 eq.) in dioxane (1.00 mL) was added BrettPhos Pd G3 (6.62 mg, 7.30 μmol, 0.10 eq.) under N2 atmosphere. The mixture 33184274.1Page 135 of 177407531-97SKWO (219686)was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um;mobile phase: [water (NH4HCO3) -ACN]; gradient: 28%-58% B over 10 min). Example 12: (18.00mg, 35.19 μmol, 18.00% yield, 100% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.377 min, [M+H+] = 512.3.1H NMR (400 MHz, CDCl3) δ = 9.15 (1H), 9.03 (1H), 8.86 (1H), 8.83 - 8.49 (1H), 8.25 (1H), 7.64 (1H), 6.42 (1H), 4.20 (1H), 4.05 - 3.95 (3H), 3.93 - 3.86 (1H), 3.83 - 3.74 (1H), 3.51 - 3.41 (1H), 3.39 - 3.29 (2H), 3.29 - 3.20 (1H), 3.19 - 3.09 (1H), 2.98 - 2.88 (1H), 2.60 - 2.51 (1H), 2.42 (3H), 2.08 - 1.96 (1H), 1.93 - 1.82 (2H), 1.60 - 1.50 (1H). Example 13: (R,23Z,24E)-11,46-dimethyl-11H-6,12-dioxa-3-aza-2(5,2)-pyrazolo[1,5- a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1:

[0449] To a(150.00 mg,536.56 μmol, 1.00 eq), 5-[2-methyl-4-[[(2R)-pyrrolidin-2-yl]methoxy]pyrazol-3-yl]pyrazolo[1, 5- a] pyridin-2-amine (167.60 mg, 536.56 μmol, 1.00 eq) in acetonitrile (3.00 mL) was added K2CO3 (222.46 mg, 1.61 mmol, 3.00 eq) and NaI (16.09 mg, 107.31 μmol, 0.20 eq). The mixture was stirred at 10 °C for 1 h. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Dichloromethane / methyl alcohol = 19 / 1 to 0 / 1). 5-[4-[[(2R)-1-[3-[ (4-Chloro-6-methyl- pyrimidin-2-yl)methoxy]propyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5- a]pyridin-2-amine (150.00 mg, 272.98 μmol, 50.88% yield, 93.00% purity) was obtained as colorless oil. LCMS (ESI): Rt: 0.377 min, [M+H+] = 511.2. Step 2: Step 2: 33184274.1Page 136 of 177407531-97SKWO (219686)

[0450] y]propyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (150.00 mg, 293.53 μmol, 1.00 eq), BrettPhos Pd G3 (26.61 mg, 29.35 μmol, 0.10 eq), Cs2CO3 (286.91 mg, 880.60 μmol, 3.00 eq) in dioxane (2.00 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 1 h under N2atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm* 10um; mobilephase: [water (FA) -ACN]; gradient: 1%-30% B over 10 min). Example 13: (28.02 mg, 53.82μmol, 18.34% yield, 100% purity, FA) was obtained as a white solid. LCMS (ESI): Rt: 0.343 min, [M+H+] = 475.2.1H NMR (400 MHz, DMSO-d6) δ = 10.39 (1H), 8.61 (1H), 8.17 (1H), 7.80 (1H), 7.50 (1H), 7.38 (1H), 7.05 - 6.95 (1H), 6.57 (1H), 4.68 (1H), 4.40 (1H), 4.20 - 4.11 (1H), 3.95 (3H), 3.89 - 3.84 (1H), 3.69 (1H), 3.46 (1H), 3.15 - 3.10 (1H), 3.02 - 2.93 (2H), 2.43 - 2.31 (2H), 2.28 (3H), 2.07 - 1.82 (3H), 1.77 - 1.63 (2H), 1.53 - 1.38 (1H). Example 14: (22Z,25Z,102R)-11-(difluoromethyl)-8-fluoro-46-methyl-11H-6,12-dioxa-3- aza-2(6,2)-imidazo[1,2-a]pyrazina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)- pyrrolidinacyclododecaphane Step 1:33184274.1Page 137 of 177407531-97SKWO (219686)

[0451] To a solution of tert-butyl (2R) - 2 -[[5-(2-aminoimidazo[1, 2-a]pyrazin-6-yl) -1-(difluoromethyl) pyrazol-4-yl]oxymethyl]pyrrolidine-1-carboxylate (200.00 mg, 444.98 μmol, 1 eq.) and 2-[ (3-bromo-2-fluoro-propoxy) methyl]-4-chloro-6-methyl-pyrimidine (145.65 mg, 489.48 μmol, 1.1 eq.) in dioxane (5.00 mL) was added Cs2CO3(362.46 mg, 1.11 mmol, 2.5 eq.) and BrettPhos Pd G3 (40.34 mg, 44.50 μmol, 0.1 eq.). The mixture was stirred at 60 °C for 5 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40 mm* 15um;mobile phase: [water (TFA) -ACN];gradient:32%-62% B over 22 min). Tert-butyl (2R) -2-[[5-[2-[[2-[ (3-bromo-2-fluoro-propoxy) methyl]-6-methyl-pyrimidin-4- yl]amino]imidazo[1,2-a]pyrazin-6-yl]-1-(difluoromethyl)pyrazol-4-yl]oxymethyl] pyrrolidine-1- carboxylate (148.00 mg, 135.39 μmol, 30.43% yield, 65% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.0.528 min, [M+H+] = 710.2 / 712.2. Step 2:

[0452] To amethyl]-6-methyl-pyrimidin-4-yl]amino]imidazo[1,2-a]pyrazin-6-yl]-1-(difluoromethyl)pyrazol-4- yl]oxymethyl] pyrrolidine-1-carboxylate (140.00 mg, 197.03 μmol, 1 eq.) in dichloromethane (5.00 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 68.32 eq.). The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated with dichloromethane (5.00 mL* 2) under reduced pressure to give a residue. N-[2-[ (3-Bromo-2-fluoro-propoxy) methyl]-6-methyl- pyrimidin-4-yl]-6-[2-(difluoromethyl) -4-[[ (2R) -pyrrolidin-2-yl]methoxy]pyrazol-3- yl]imidazo[1, 2-a]pyrazin-2-amine (120.00 mg, crude, TFA) was obtained as a red solid. Step 3: 33184274.1Page 138 of 177407531-97SKWO (219686)

[0453] To a solution of N-[2 -[ (3-bromo- 2-fluoro-propoxy) methyl]-6-methyl-pyrimidin-4-yl]-6-[2-(difluoromethyl) -4-[[ (2R) -pyrrolidin-2-yl]methoxy]pyrazol-3-yl]imidazo[1, 2-a]pyrazin-2- amine (120.00 mg, 165.64 μmol, 1 eq., TFA) in DMF (1.00 mL) and ACN (5.00 mL) was added K2CO3(68.68 mg, 496.93 μmol, 3 eq.). The mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 um;mobile phase: [water(TFA) -ACN];gradient:0%-22% B over 10 min). Example 14: (20.78 mg, 38.46 μmol, 23.22%yield, 98% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.360 min, [M+H+] = 530.2.1H NMR (400 MHz, MeOH-d4) δ = 9.07 (1H), 9.00 (1H), 8.96 (1H), 8.68 - 8.34 (1H), 7.93 (1H), 6.86 (1H), 5.54 - 5.32 (1H), 5.00 - 4.93 (1H), 4.86 - 4.80 (1H), 4.52 - 4.36 (3H), 4.34 - 4.24 (1H), 4.10 - 3.92 (2H), 3.89 - 3.71 (2H), 3.63 - 3.55 (1H), 2.56 - 2.44 (4H), 2.38 - 2.20 (2H), 2.06 - 1.95 (1H). Example 15: (23Z,24E,102S,103R)-103-fluoro-11,46-dimethyl-11H-12-oxa-3-aza-2(5,2)- pyrazolo[1,5-a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)- pyrrolidinacyclododecaphane Step 1:

[0454] To apyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (150.00 mg, 454.05 μmol, 1.00 eq.) and 2-(5-bromopentyl) - 4-chloro-6-methyl-pyrimidine (138.64 mg, 499.46 μmol, 1.10 eq.) in acetonitrile (3.00 mL) was 33184274.1Page 139 of 177407531-97SKWO (219686)added K2CO3(188.26 mg, 1.36 mmol, 3.00 eq.). The mixture was stirred at 60 °C for 12 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, dichloromethane: methanol = 100 / 0 - 10 / 1). 5-[4-[[ (2S, 3R) -1-[5-(4- chloro-6-methyl-pyrimidin-2-yl)pentyl]-3-fluoro-pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3- yl]pyrazolo[1, 5-a]pyridin-2-amine (200.00 mg, 360.13 μmol, 79.31% yield, 94.9% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.595 min, [M+H+] = 527.3. Step 2:

[0455] To a- yl) pentyl]-3-fluoro-pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (150.00 mg, 284.61 μmol, 1.00 eq.) in dioxane (3.00 mL) was added BrettPhos Pd G3 (25.80 mg, 28.46 μmol, 0.10 eq.) and Cs2CO3(278.19 mg, 853.83 μmol, 3.00 eq.). The mixture was stirred at 60 °C for 3 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 1 / 0 to 10 / 1) to give a crude product (90 mg, 98% purity). The crude was further purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 22%-52% B over 15 min). The titled compound (67.89 mg, 138.39 μmol, 48.62% yield, 100.00% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.571 min, [M+H+] = 491.3.1H NMR (400 MHz, DMSO-d6) δ = 10.27 (1H), 8.61 (1H), 7.71 (s, 1H), 7.37 (1H), 7.32 (1H), 6.99 (1H), 6.55 (1H), 5.14 - 4.86 (1H), 4.01 - 3.95 (1H), 3.93 (3H), 3.64 (1H), 3.21 (1H), 3.06 - 2.87 (3H), 2.80 - 2.66 (1H), 2.49 -2.42 (1H), 2.42 - 2.31 (1H), 2.27 (3H), 2.06 - 1.80 (4H), 1.77 - 1.60 (3H), 1.39 - 1.26 (1H). Example 16: (23Z,24E,102S,103R)-103-fluoro-11,46-dimethyl-11H-7,12-dioxa-3-aza-2(5,2)- pyrazolo[1,5-a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)- pyrrolidinacyclododecaphane Step 1: 33184274.1Page 140 of 177407531-97SKWO (219686)

[0456] To a sol 2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (400.00 mg, 1.09 mmol, 1 eq., HCl) in CH3CN (8.00 mL) was added K2CO3 (1.51 g, 10.90 mmol, 10 eq.), DIPEA (140.93 mg, 1.09 mmol, 189.94 μL, 1 eq.) and 2-[2-(2-bromoethoxy) ethyl]-4-chloro-6-methyl-pyrimidine (304.85 mg, 1.09 mmol, 1 eq.). The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated in vacuum to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% dichloromethane / methanol gradient @ 40 mL / min).5-[4- [[ (2S, 3R) -1-[2-[2-(4-Chloro-6-methyl-pyrimidin-2-yl) ethoxy]ethyl]-3-fluoro-pyrrolidin-2- yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (210.00 mg, 204.16 μmol, 18.72% yield, 51.43% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.401 min, [M+H+] = 529.3. Step 2:

[0457] To2-yl)ethoxy]ethyl]-3-fluoro-pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin- 2-amine (180.00 mg, 340.26 μmol, 1 eq.) in dioxane (5.00 mL) was added BrettPhos Pd G3 (30.84 mg, 34.03 μmol, 0.1 eq.) and Cs2CO3(332.59 mg, 1.02 mmol, 3 eq.), the mixture was stirred at 60 °C for 3 h under N2atmosphere. The reaction mixture was diluted with H2O (10.00 mL) and extracted with ethyl acetate (10.00 mL * 3). The combined organic layers were washed with aqueous NaCl (10.00 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure 33184274.1Page 141 of 177407531-97SKWO (219686)to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; gradient: 1%-30% B over 10 min; purity confirmed by LCMS), then was further purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 22%-52% B over 9 min). The titled compound (16.78 mg, 34.07 μmol, 10.01% yield, 100% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.356 min, [M+H+] = 493.3.1H NMR (400 MHz, MeOH-d4) δ = 8.40 (1H), 8.03 (1H), 7.67 (1H), 7.37 (1H), 6.96 - 6.86 (1H), 6.56 (1H), 5.06 - 4.90 (1H), 4.16 - 4.07 (1H), 4.04 - 3.98 (1H), 3.97 (3H), 3.91 - 3.82 (3H), 3.81 - 3.72 (1H), 3.44 - 3.31 (2H), 3.22 - 3.04 (3H), 2.82 - 2.61 (2H), 2.36 (3H), 2.16 - 1.99 (1H), 1.98 - 1.77 (1H). Example 17: (23Z,24E,102R,104R)-104-fluoro-11,46-dimethyl-11H-7,12-dioxa-3-aza-2(5,2)- pyrazolo[1,5-a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)- pyrrolidinacyclododecaphane Step 1:

[0458] To amethyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (250.00 mg, 681.53 μmol, 1.00 eq., HCl) in acetonitrile (5.00 mL) was added K2CO3(941.92 mg, 6.82 mmol, 10.00 eq.) and DIPEA (88.08 mg, 681.53 μmol, 118.71 μL, 1.00 eq.). The mixture was stirred at 60 °C for 1 h. Then 2-[2-(2-bromoethoxy) ethyl]- 4-chloro-6-methyl-pyrimidine (190.53 mg, 681.53 μmol, 1 eq.) was added, the mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100 / 0 to 10 / 1).5- [4-[[ (2R, 4R) -1-[2-[2-(4-chloro-6-methyl-pyrimidin-2-yl) ethoxy]ethyl]-4-fluoro-pyrrolidin-2- yl]methoxy]-2-methyl-pyrazol-3-yl] pyrazolo[1, 5-a] pyridine-2-amine (130.00 mg, 245.74 μmol, 36.06% yield, 95.69% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.505 min, [M+H+] = 529.3. Step 2: 33184274.1Page 142 of 177407531-97SKWO (219686)

[0459] To pyrimidin-2-yl)ethoxy]ethyl]-4-fluoro-pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin- 2-amine (130.00 mg, 245.74 μmol, 1.00 eq.) in dioxane (2.00 mL) was added BrettPhos Pd G3 (22.28 mg, 24.57 μmol, 0.10 eq.) and Cs2CO3 (240.20 mg, 737.23 μmol, 3.00 eq.). The mixture was stirred at 60 °C for 3 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm* 10um; mobile phase: [water (FA) -ACN]; gradient:1%-30% B over 11 min). The titled compound (12.32 mg, 24.58 μmol, 10.00% yield, 98.26% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.343 min, [M+H+] = 493.1.1H NMR (400 MHz, MeOH-d4) δ = 8.42 (1H), 8.00 (1H), 7.70 (1H), 7.38 (1H), 6.98 - 6.88 (1H), 6.56 (1H), 5.33 - 5.11 (1H), 4.31 - 4.21 (1H), 4.02 (4H), 3.97 - 3.89 (2H), 3.84 - 3.76 (1H), 3.69 -3.61 (1H), 3.58 - 3.45 (2H), 3.22 - 3.10 (3H), 2.78 -2.58 (2H), 2.46 - 2.27 (4H), 1.95 - 1.80 (1H). Example 18: ((23Z,24E,102R,104R)-104-fluoro-11,46-dimethyl-11H-12-oxa-3-aza-2(5,2)- pyrazolo[1,5-a]pyridina-4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)- pyrrolidinacyclododecaphane Step 1:

[0460] To apyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (250.00 mg, 681.53 μmol, 1.00 eq., HCl) in acetonitrile (6.00 mL) was added K2CO3 (941.92 mg, 6.82 mmol, 10.00 eq.) and DIPEA (88.08 mg, 681.53 μmol, 118.71 μL, 1.00 eq.). The mixture was stirred at 60 °C for 1 h. Then 2-(5-bromopentyl) -4-chloro- 33184274.1Page 143 of 177407531-97SKWO (219686)6-methyl-pyrimidine (189.19 mg, 681.53 μmol, 1.00 eq) was added the mixture and stirred at 60 °C for 12 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100 / 0 to 10 / 1).5-[4-[[ (2R, 4R) -1-[5-(4-chloro-6-methyl-pyrimidin-2-yl) pentyl]-4-fluoro-pyrrolidin-2-yl]methoxy]-2-methyl- pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (150.00 mg, 284.61 μmol, 41.76% yield, 100% purity) was obtained as a yellow oil. LCMS (ESI): Rt: 0.560 min, [M+H+] = 527.3. Step 2:

[0461] Toyl) pentyl]-4-fluoro-pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (120.00 mg, 227.69 μmol, 1.00 eq.) in dioxane (2.00 mL) was added BrettPhos Pd G3 (20.64 mg, 22.77 μmol, 0.10 eq.) and Cs2CO3 (222.56 mg, 683.07 μmol, 3.00 eq.), the mixture was stirred at 60 °C for 3 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) - ACN]; gradient:28%-58% B over 9 min). The titled compound (38.66 mg, 75.64 μmol, 33.22% yield, 95.98% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.552 min, [M+H+] = 491.3.1H NMR (400 MHz, MeOH-d4) δ = 8.40 (1H), 7.79 (1H), 7.37 (1H), 7.23 (1H), 6.84 (1H), 6.49 (1H), 5.37 - 5.09 (1H), 4.01 - 3.87 (5H), 3.62 - 3.51 (1H), 3.18 - 3.07 (2H), 3.04 - 2.95 (1H), 2.78 - 2.49 (2H), 2.41 - 2.19 (5H), 2.12 - 1.97 (2H), 1.91 - 1.75 (m, 2H), 1.74 - 1.54 (m, 2H), 1.28 - 1.13 (1H). Example 19: (R,23Z,24E)-11,46-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphan-105-one Step 1: 33184274.1Page 144 of 177407531-97SKWO (219686)

[0462] To a pyrrolidin-2-one(237.00 mg, 864.59 μmol, 1.20 eq.) and 2-(5-bromopentyl) -4-chloro-6-methyl-pyrimidine (200.00 mg, 720.49 μmol, 1.00 eq.) in acetonitrile (5.00 mL) was added Cs2CO3(704.25 mg, 2.16 mmol, 3.00 eq.), the mixture stirred at 80 °C for 12 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, dichloromethane: methanol = 1 / 0 to 5 / 1). (5R) -5-[(5-Bromo-1-methyl-pyrazol-4-yl)oxymethyl]-1-[5-(4-chloro-6- methyl-pyrimidin-2-yl) pentyl]pyrrolidin-2-one (290.00 mg, 369.59 μmol, 51.30% yield, 60% purity) was obtained as yellow oil. LCMS (ESI): Rt: 0.568 min, [M+H+] = 472.1. Step 2:1.00eq.) and (5R) -5-[ (5-bromo-1-methyl-pyrazol-4-yl)oxymethyl]-1-[5-(4-chloro-6-methyl- pyrimidin-2-yl) pentyl] pyrrolidine-2-one (230 mg, 293.12 μmol, 1.00 eq.) in THF (3.00 mL) was added t-BuOK (1 M, 879.37 μL, 3.00 eq.), the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (10.00 mL) and extracted with ethyl acetate (10.00 mL*3). The combined organic layer was washed with brine (20.00 mL), dried over Na2SO4, filtered and concentrated. The residue purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 30%-60% B over 15 min). (5R) -5-[(5-bromo-1-methyl-pyrazol-4-yl) oxymethyl]-1-[5-[4-[ (5-bromopyrazolo[1, 5- a]pyridin-2-yl) amino]-6-methyl-pyrimidin-2-yl]pentyl]pyrrolidin-2-one (40.00 mg, 60.96 μmol, 20.80% yield, 98.5% purity) was obtained as yellow oil. LCMS (ESI): Rt: 0.628 min, [M+H+] = 647.1. 33184274.1Page 145 of 177407531-97SKWO (219686)Step 3:

[0464] [5-[4-[ (5-bromopyrazolo[1, 5-a]pyridin-2-yl) amino]-6-methyl-pyrimidin-2-yl]pentyl]pyrrolidin-2-one (40.00 mg, 48.89 μmol, 1.00 eq.), 4-ditert-butylphosphanyl-N, N-dimethyl- aniline;dichloropalladium (3.46 mg, 4.89 μmol, 3.46 μL, 0.10 eq.) and 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (18.62 mg, 73.33 μmol, 1.50 eq.) in dioxane (1.00 mL) was added KF (14.20 mg, 244.44 μmol, 5.00 eq.) in H2O (0.20 mL) under N2. The mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was poured into water (10.00 mL) and extracted with ethyl acetate (15.00 mL*3). The combined organic layer was washed with brine (30.00 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient:20%-50% B over 9 min). The titled compound (2.94 mg, 6.00 μmol, 12.28% yield, 99.38% purity) was obtained as white solid. LCMS (ESI): Rt: 0.508 min, [M+H+] = 487.3.1H NMR (400 MHz, CDCl3) δ = 8.35 (1H), 7.71 (1H), 7.34 (2H), 6.78 - 6.65 (1H), 6.35 (1H), 4.09 - 4.04 (1H), 4.00 (3H), 3.95 - 3.88 (1H), 3.85 - 3.76 (2H), 3.08 - 2.94 (3H), 2.60 - 2.46 (2H), 2.42 (3H), 2.40 - 2.15 (3H), 2.07 - 1.79 (5H). Example 20: (R,23Z,24E)-11,46-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,2)-pyrimidina-1(5,4)-pyrazola-10(1,2)-azetidinacyclododecaphane Step 1:33184274.1Page 146 of 177407531-97SKWO (219686)

[0465] To a solution of tert-butyl (2R)-2-[[5-(2-aminopyrazolo[1, 5-a]pyridin-5-yl)-1-methylpyrazol-4-yl]oxymethyl]azetidine-1-carboxylate (100.00 mg, 250.97 μmol, 1.00 eq) in dioxane (2 mL) was added 5-(4-chloro-6-methyl-pyrimidin-2-yl) pentyl acetate (77.32 mg, 301.16 μmol, 1.20 eq), BrettPhos Pd G3 (22.75 mg, 25.10 μmol, 0.100 eq) and Cs2CO3(245.31 mg, 752.90 μmol, 3.00 eq) was degassed and purged with N2 for 3 times and then the mixture was stirred at 90 °C for 1 h under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE: Ethyl acetate = 3: 1). Tert-butyl (2R)-2-[[5-[2-[[2-(5-acetoxypentyl) -6-methyl-pyrimidin-4-yl] amino]pyrazolo[1,5- a]pyridin-5-yl]-1-methyl-pyrazol-4-yl]oxymethyl]azetidine-1-carboxylate (150 mg, 201.22 μmol, 80.18% yield, 83% purity) was obtained as a yellow solid. LCMS (ESI): Rt: 0.468 min, [M+H+] = 619. Step 2:

[0466] To apyrimidin-4-yl]amino] pyrazolo[1,5-a]pyridin-5-yl]-1-methyl-pyrazol-4-yl]oxymethyl]azetidine-1- carboxylate (140 mg, 226.27 μmol, 1.00 eq) in MeOH (1 mL) was added K2CO3 (93.82 mg, 678.82 μmol, 3.00 eq). The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (10 mL), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mL×3). The organic layers were combined and washed with brine (10 mL), dried over Na2SO4 and concentrated to give a residue. The crude mixture was used in next step directly without workup and purification. Tert-butyl (2R)-2-[[5-[2-[[2-(5-hydroxypentyl)-6-methyl -pyrimidin-4- yl]amino]pyrazolo[1,5-a]pyridin-5-yl]-1-methyl-pyrazol-4-yl]oxymethyl] azetidine-1-carboxylate (130 mg, crude) was obtained as a yellow solid. LCMS (ESI): Rt: 0.445 min, [M+H+]= 577.4. Step 3: 33184274.1Page 147 of 177407531-97SKWO (219686)

[0467] To a s ethyl-pyrimidin-4-yl]amino] pyrazolo[1,5-a]pyridin-5-yl]-1-methyl-pyrazol-4-yl]oxymethyl]azetidine-1- carboxylate (90 mg, 156.06 μmol, 1.00 eq) and methylsulfonyl methanesulfonate (54.37 mg, 312.13 μmol, 2.00 eq) in DCM (2 mL) was added TEA (63.17 mg, 624.25 μmol, 86.89 μL, 4.00 eq). The mixture was stirred at 25 °C for 2 h. The mixture was poured into water (20 mL), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mL×3). The organic layers were combined and washed with brine (5 mL), dried over Na2SO4and concentrated to give a residue. The reaction mixture was used to next step directly without workup and purification. Tert-butyl (2R)-2-[[1-methyl-5-[2-[[6-methyl-2-(5-methylsulfonyl- oxypentyl)pyrimidin-4-yl]amino]pyrazolo[1,5-a]pyridin-5-yl]pyrazol-4-yl]oxymethyl] azetidine- 1-carboxylate (110 mg, crude) was obtained as a yellow solid. LCMS (ESI): Rt: 0.466 min, [M+H+] = 655.5. Step 4:

[0468] To[[6-methyl-2-(5-methylsulfonyloxypentyl) pyrimidin-4-yl]amino]pyrazolo[1,5-a]pyridin-5-yl]pyrazol-4- yl]oxymethyl]azetidine-1-carboxylate (110 mg, 168.00 μmol, 1.00 eq) in DCM (1 mL) was added TFA (57.47 mg, 503.99 μmol, 37.44 μL, 3.00 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The reaction mixture was used to next step directly without workup and purification.5-[4-[[5-[4-[[(2R)-Azetidin-2-yl] methoxy]- 2-methyl-pyrazol-3-yl]pyrazolo[1,5-a]pyridin-2-yl]amino]-6-methyl-pyrimidin-2-yl] 33184274.1Page 148 of 177407531-97SKWO (219686)pentylmethanesulfonate (100 mg, crude, TFA salt) was obtained as a yellow solid. LCMS (ESI): Rt: 0.371 min, [M+H+] = 555.4. Step 5:

[0469] To apyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-yl]amino]-6-methyl-pyrimidin-2-yl]pentyl methanesulfonate (100 mg, 180.29 μmol, 1.00 eq) in ACN (1 mL) was added K2CO3(74.75 mg, 540.87 μmol, 3.00 eq). The mixture was stirred at 60 °C for 1 h. The mixture was filtered. The filtrate was poured into water (100 mL), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (25 mL×3). The organic layers were combined and washed with brine (100 mL), dried over Na2SO4and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm* 10um; mobile phase: [water (FA) -ACN]; gradient: 0%-30% B over 15 min). The titled compound (15 mg, 32.71 μmol, 18.14% yield, 100% purity, FA) was obtained as a yellow solid. LCMS (ESI): Rt: 0.355 min, [M+H+] = 459.3.1H NMR (400 MHz, CDCl3) δ = 8.43 (1H), 8.32 (1H), 7.93 (1H), 7.51 (1H), 7.31 (1H), 7.25 (1H), 6.72 - 6.64 (1H), 6.32 (1H), 4.52 (1H), 4.23 - 4.13 (1H), 4.10 - 4.03 (1H), 3.97 (3H), 3.94 - 3.90 (1H), 3.33 - 3.20 (2H), 3.15 -3.05 (1H), 2.92 - 2.80 (1H), 2.55 (1H), 2.39 (3H), 2.36 - 2.28 (2H), 2.15 - 2.01 (2H), 1.99 - 1.88 (1H), 1.86 - 1.72 (1H), 1.58 - 1.45 (1H), 1.43 - 1.29 (1H). Example 21: (R,23Z,24E,44Z)-11-(difluoromethyl)-41-methyl-11H,41H-11-oxa-3,6-diaza- 2(5,2)-pyrazolo[1,5-a]pyridina-1(5,4),4(3,5)-dipyrazola-9(1,2)-azetidinacycloundecaphan-5- one Step 1: 33184274.1Page 149 of 177407531-97SKWO (219686)

[0470] To a s -a]pyridin-5-yl)-1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate (0.7 g, 1.128 mmol) andmethyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (0.296 g, 1.353 mmol) in 1,4-dioxane (7.0mL) was added Cs2CO3 (1.102 g, 3.38 mmol) under nitrogen atmosphere. The mixture was purged with nitrogen for a period of 10 min and tBuBrettPhos Pd G3 (0.096 g, 0.113 mmol) was added; the resulting mixture was purged with N2for additional 5 min and stirred at 100 °C for 16 h. Upon completion of the reaction as monitored by TLC and LCMS, the reaction mixture was filteredthrough a celite bed. The filtrate was dried in vacuum to afford the crude product. The crudeproduct was purified by flash column chromatography (Biotage: Isolera using 60 x 120 mesh size silica, eluent: 50-70% EtOAc in pet-ether) to afford methyl (R)-3-((5-(4-((1-(tert- butoxycarbonyl)azetidin-2-yl)methoxy)-1-(difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5-carboxylate (0.4 g, 0.699 mmol, 62% yield) as brown solid. LCMS (ESI): Rt: 2.27 min, [M+H+] = 573.2. DMSO-d6 Step 2:

[0471] Toazetidin-2-yl)methoxy)-1-(difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl- 1H-pyrazole-5-carboxylate (0.4 g, 0.699 mmol) in anhydrous CH2Cl2(5.0 mL) was added a solution of trifluoroacetic acid (1.016 mL, 13.27 mmol) at 0 °C under inert atmosphere. The 33184274.1Page 150 of 177407531-97SKWO (219686)reaction mixture was stirred at room temperature for 4 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under vacuum to get the crude product. The crude product was dissolved in 10% CH3OH in CH2Cl2 and basified with Amberlyst ion-exchange resin. The organic layer was dried over anhydrous sodium sulfate and solvent was distilled off under vacuum to get crude methyl (R)-3-((5-(4-(azetidin-2-ylmethoxy)-1- (difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5- carboxylate (0.35 g, 0.597 mmol, 85% yield)) as a brown solid. The crude product was taken as such to next step without further purification. LCMS (ESI): Rt: 1.32 min, [M+H+] = 473.2. Step 3:

[0472] To-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5-carboxylate (0.35 g, 0.597 mmol) in CH3CN (5 ml) was added K2CO3 (0.219 g, 1.587 mmol) at room temperature. The resulting reaction mixture was stirred for 15 min, and then tert-butyl (2-bromoethyl)carbamate (0.142 g, 0.635 mmol) was added and stirred at room temperature for 24 h. Upon completion of the reaction as monitored by TLC and LCMS, the reaction mixture was filtered through celite and the solvent was concentrated in vacuum to afford the crude product, which was purified by flash column chromatography (Biotage: Isolera using neutral alumina, eluent: 5-10% CH3OH in CH2Cl2) to afford methyl (R)-3-((5-(4-((1-(2-((tert-butoxycarbonyl)amino)ethyl)azetidin-2- yl)methoxy)-1-(difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5-carboxylate (0.3 g, 0.487 mmol, 92% yield) as brown gummy solid. LCMS (ESI):Rt: 1.57 min, [M+H+] = 616.4. Step 4: 33184274.1Page 151 of 177407531-97SKWO (219686)((1-(2-((tert-5- yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5-carboxylate (0.3 g, 0.341 mmol) in THF (3.0 mL), MeOH (0.8 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (0.029 g, 0.682 mmol) at 0 °C .The resulting reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was concentrated in vacuum, diluted with water and acidified with 1 N HCl and extracted with 20% MeOH in CH2Cl2. The organic layer was dried over anhydrous sodium sulfate and solvent was concentrated under vacuum to afford the crude product (R)-3-((5-(4-((1-(2-((tert- butoxycarbonyl)amino)ethyl)azetidin-2-yl)methoxy)-1-(difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5-carboxylic acid (0.230 g, 0.279mmol, 82% yield) as yellow solid. LCMS (ESI): Rt: 1.37 min, [M+H+] = 602.3. Step 5:

[0474] azetidin-2-yl)methoxy)-1-(difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl- 1H-pyrazole-5-carboxylic acid (0.230 g, 0.382 mmol) in anhydrous CH2Cl2 (2.0 mL) was added HCl (0.956 mL, 3.82 mmol, 4M in 1,4-dioxane) at 0 °C under inert atmosphere. The resulting reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction as 33184274.1Page 152 of 177407531-97SKWO (219686)monitored by LCMS, the reaction mixture was concentrated in vacuum and washed with MTBE to afford the crude product (R)-3-((5-(4-((1-(2-aminoethyl)azetidin-2-yl)methoxy)-1- (difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5- carboxylic acid (0.22 g, 0.315 mmol, 82%, HCl salt) as pink solid. LCMS (ESI): Rt: 0.99 min, [M+H+] = 502.2. Step 6:

[0475] Tomethoxy)-1-(difluoromethyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-pyrazole-5- carboxylic acid (0.04 g, 0.074 mmol, HCl salt) in anhydrous CH2Cl2 (8.0 mL) was added TEA (0.311 mL, 2.231 mmol) and T3P (50% in EtOAc) (0.657 mL, 1.115 mmol) at 0 °C under inert atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under vacuum and the residue obtained was diluted with water (20 mL), the aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and solvent was concentrated under vacuum to get the crude product (approximately 70 mg). The crude product was purified by RP-prep HPLC purification (Column: Zorbox C18, mobile phase: 0.1% formic acid in water: CH3CN). The Product containing fraction was lyophilized to afford (R,23Z,24E,44Z)-11-(difluoromethyl)-41-methyl-11H,41H-11-oxa-3,6-diaza-2(5,2)- pyrazolo[1,5-a]pyridina-1(5,4),4(3,5)-dipyrazola-9(1,2)-azetidinacycloundecaphan-5-one, formicacid salt (0.001g, 1.889 µmol, 2.54% yield, FA) as yellow solid. LCMS (ESI): Rt: 1.29 min,[M+H+] = 484.0.1H NMR (400 MHz, DMSO-d6) δ = 9.20 (1H), 8.51-8.46 (1H), 8.33-8.26 (1H), 8.14 (1H), 7.98-7.94 (1H), 7.87-7.56 (2H), 6.73-6.69 (1H), 6.54-6.42 (1H), 4.05 (2H), 3.85 (3H), 3.65-3.40 (3H), 3.20-3.04 (2H), 2.87-2.60 (2H), 2.04-1.82 (2H). Example 22: (R,23Z,24E)-11,42-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,6)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane 33184274.1Page 153 of 177407531-97SKWO (219686)Step 1:

[0476] To a 3-yl]pyrazolo[1,5-a]pyridin-2- mg, eq., mL) was added K2CO3 (209.12 mg, 1.51 mmol, 3 eq.) and 4-(5-bromopentyl) -6-chloro-2-methyl-pyrimidine (140.00 mg, 504.34 μmol, 1 eq.). The mixture was stirred at 60 °C for 16 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10um;mobile phase: [water (NH4HCO3) -ACN];gradient:18%-48% B over 20 min). 5-[4-[[ (2R) -1-[5-(6-Chloro-2-methyl- pyrimidin-4-yl) pentyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin- 2-amine (135.00 mg, 241.33 μmol, 47.85% yield, 91% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.402 min, [M+H+] = 509.3.1H NMR (400 MHz, DMSO-d6) δ = Step 2:

[0477] To apentyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (125.00 mg, 245.56 μmol, 1 eq.) in THF (20.00 mL) was added NaH (28.48 mg, 712.00 μmol, 60% purity, 2.90 eq.) at 0 °C under N2 atmosphere. The mixture was stirred at 40 °C for 18 h. The mixture was quenched by addition sat. NH4Cl (3.00 mL) at 0 °C and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um;mobile phase: [water (TFA) -ACN];gradient:3%-33% B over 15 min). The titled compound (37.07 mg, 61.68 μmol, 25.12% yield, 97.60% purity, TFA) was obtained as a white solid. LCMS 33184274.1Page 154 of 177407531-97SKWO (219686)(ESI): Rt: 0.363 min, [M+H+] = 473.4.1H NMR (400 MHz, DMSO-d6) δ = 11.46 (1H), 9.89 - 9.62 (1H), 8.80 (1H), 7.96 (1H), 7.52 (1H), 7.21 - 7.14 (1H), 6.73 (1H), 6.68 (1H), 4.38 - 4.25 (1H), 4.12 - 4.02 (1H), 3.95 (3H), 3.23 - 3.17 (2H), 3.11 - 3.04 (1H), 2.86 - 2.76 (1H), 2.75 - 2.66 (1H), 2.58 (3H), 2.52 (2H), 2.30 - 2.16 (1H), 2.10 - 1.96 (1H), 1.94 - 1.83 (1H), 1.82 - 1.73 (1H), 1.73 - 1.52 (4H), 1.46 - 1.23 (2H). Example 23: (S,23Z,24E)-11,42-dimethyl-11H-12-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,6)-pyrimidina-1(5,4)-pyrazola-10(1,2)-pyrrolidinacyclododecaphane Step 1:

[0478] Note:a solution of 5 -[4-[[ (2S) - 1-[5-(6-chloro-2-methyl-pyrimidin-4-yl) pentyl]pyrrolidin-2-yl]methoxy]-2-methyl- pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (52 mg, 102.15 μmol, 1 eq) in THF (10 mL) was added NaH (10 mg, 250.02 μmol, 60% purity, 2.45 eq) at 25 °C. The mixture was stirred at 40 °C for 18 hr. The reaction mixture was quenched by addition sat. NH4Cl 2 mL at 25°C. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (NH4HCO3) - ACN];gradient:18%-48% B over 9 min). Then the mixture was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water (TFA) -ACN];gradient:5%-35% B over 9 min). The titled compound (27.56 mg, 46.98 μmol, 45.99% yield, 100% purity, TFA) was obtained as a white solid. LCMS (ESI): Rt: 0.362 min, [M+H+] = 473.4.1H NMR (400 MHz, DMSO-d6) δ = 11.59 - 11.22 (1H), 9.86 - 9.57 (1H), 8.80 (1H), 7.96, 7.23 - 7.11 (1H), 6.70 (2H), 4.31 (1H), 4.07 (1H), 3.96 (3H), 3.13 - 3.03 (1H), 2.86 - 2.75 (1H), 2.71 (1H), 2.58 (3H), 2.52 (2H), 2.30 - 2.18 (1H), 2.10 - 1.98 (1H), 1.96 - 1.84 (1H), 1.82 - 1.74 (1H), 1.74 - 1.51 (4H), 1.46 - 1.24 (2H). Example 24: (R,23Z,24E)-11,42-dimethyl-11H-11-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,6)-pyrimidina-1(5,4)-pyrazola-9(1,2)-pyrrolidinacycloundecaphane 33184274.1Page 155 of 177407531-97SKWO (219686)Step 1:

[0479] To a 3-yl]pyrazolo[1,5-a]pyridin-2- mg, eq., mL) was added K2CO3 (183.54 mg, 1.33 mmol, 3.5 eq.) and 4-(4-bromobutyl) -6-chloro-2-methyl-pyrimidine (100 mg, 379.42 μmol, 1 eq.). The mixture was stirred at 60 °C for 16 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10 um;mobile phase: [water (NH4HCO3) - ACN];gradient:12%-42% B over 20 min). 5-[4-[[ (2R) -1-[4-(4-Chloro-6-methyl-pyrimidin-2- yl)butyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl] pyrazolo[1, 5-a]pyridin-2-amine (58.00 mg, 92.56 μmol, 24.40% yield, 79% purity) was obtained as a white solid. LCMS (ESI): Rt: 0.394 min, [M+H+] = 495.3. Step 2:

[0480] To a solution of 5 -[4-[[ (2R) - 1-[4-(4-chloro-6-methyl-pyrimidin-2-yl) butyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol-3-yl]pyrazolo[1, 5-a]pyridin-2-amine (56.00 mg, 113.13 μmol, 1 eq.) in THF (8.00 mL) was added NaH (13.58 mg, 339.38 μmol, 60% purity, 3 eq.) at 25 °C. The mixture was stirred at 40 °C for 20 h. The mixture was quenched by addition sat. NH4Cl (2.00 mL) at 0 °C and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 um;mobile phase: [water (TFA) - ACN];gradient:3%-33% B over 15 min). The titled compound (20.51 mg, 35.15 μmol, 31.07% yield, 98.14% purity, TFA) was obtained as a yellow solid. LCMS (ESI): Rt: 0.527 min, [M+H+] = 459.3.1H NMR (400 MHz, DMSO-d6) δ = 11.39 (1H), 9.91 - 9.60 (1H), 8.80 (1H), 8.24 (1H), 33184274.1Page 156 of 177407531-97SKWO (219686)7.55 (1H), 7.28 - 7.06 (1H), 6.65 (1H), 6.60 (1H), 4.26 (1H), 4.07 - 3.99 (1H), 3.97 (3H), 3.89 - 3.81 (1H), 3.75 (1H), 3.29 - 3.17 (2H), 2.87 (2H), 2.73 - 2.61 (1H), 2.57 (3H), 2.29 - 2.18 (1H), 2.07 (1H), 1.99 - 1.85 (2H), 1.65 (4H). Example 25: (S,23Z,24E)-11,42-dimethyl-11H-11-oxa-3-aza-2(5,2)-pyrazolo[1,5-a]pyridina- 4(4,6)-pyrimidina-1(5,4)-pyrazola-9(1,2)-pyrrolidinacycloundecaphane Step 1:

[0481] of 5 -[4-[[(2S) - 1-[4-(4-chloro-6-methyl-pyrimidin-2-yl) butyl]pyrrolidin-2-yl]methoxy]-2-methyl-pyrazol- 3-yl]pyrazolo[1, 5-a]pyridin-2-amine (40 mg, 80.81 μmol, 1 eq) in THF (5 mL) was added NaH (8.08 mg, 202.01 μmol, 60% purity, 2.5 eq) at 25 °C. The mixture was stirred at 40°C for 16 hr. The reaction mixture was quenched by addition sat. NaCl 1 mL at 25 °C. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um;mobile phase: [water (TFA) - ACN];gradient:6%-36% B over min). The titled compound (12.65 mg, 22.09 μmol, 27.34% yield, 100% purity, TFA) was obtained as a white solid. LCMS (ESI): Rt: 0.525 min, [M+H+] = 459.3.1H NMR (400 MHz, DMSO-d6) δ = 11.34 (1H), 9.80 (1H), 8.79 (1H), 8.24 (1H), 7.55 (1H), 7.23 - 7.12 (1H), 6.65 (1H), 6.59 (1H), 4.32 - 4.22 (1H), 4.08 - 4.00 (1H), 3.96 (3H), 3.78 - 3.71 (1H), 3.67 - 3.62 (1H), 3.25 - 3.17 (2H), 2.87 (2H), 2.72 - 2.63 (1H), 2.57 (3H), 2.31 - 2.19 (1H), 2.12 - 2.01 (1H), 2.00 - 1.89 (2H), 1.79 - 1.50 (4H). Table 2. Selected Compounds LCMS Mass Retention ]33184274.1Page 157 of 177407531-97SKWO (219686)33184274.1Page 158 of 177407531-97SKWO (219686)33184274.1Page 159 of 177407531-97SKWO (219686)33184274.1Page 160 of 177407531-97SKWO (219686)33184274.1Page 161 of 177407531-97SKWO (219686)Example 15: Biochemical Assays SIK2-FLAG (1 mM ATP) ADP-Glo Assay Protocol (Assay A)

[0482] Reagents were procured and 1X assay buffer was prepared as above except for theAMARAtide substrate and the human recombinant SIK2 (SIK2-FLAG). AMARAtide was purchased from Biopeptide (San Diego, CA) and SIK2-FLAG (UniProt ID Q9H0K1) (G13-L350) was codon optimized for expression in SF21 cells and lysed in a buffer containing 50 mM Tris- HCl (pH 7.5), 500 mM NaCl, 5% glycerol, 0.5% Tween-20, 1 mM TCEP and purified over Glutathione Sepharose FF cartridge and Size Exclusion Chromatography (HiLoad 16 / 600 Superdex 200pg) into a final storage buffer of 50mM Tris-HCl (pH 7.5), 300mM NaCl, 10% glycerol, 1mM TCEP. The final protein, stored at -80 °C, contains a single Glycine cloning artifact 33184274.1Page 162 of 177407531-97SKWO (219686)at the N-terminus and retains a c-terminal FLAG tag and consists of an amino acid sequence of SEQ ID NO: 1. Compounds (60 nL) in 100% DMSO were added to the assay plate (AlphaPlate- 384, Cat# 6005359 Perkin Elmer) using a LabCyte Echo 550. Similarly, DMSO (60 nL) was added to maximum signal control (MAX) wells and a reference compound producing 100% inhibition was added to minimum signal control (MIN) wells. SIK2 was diluted to 2X final concentration in 1X assay buffer and 3 µL was added to the compounds / DMSO in the assay plate. After incubation for 20 minutes at RT, 3 µL substrate mix containing 2X ATP and 2X AMARAtide in 1X assay buffer was added to the assay plate. After incubation for 60 minutes, the reaction was stopped by the addition of the ADP-Glo Kit components as directed and the relative luminescence units (RLU) were read on an Envision 2104. The final concentrations of the assay components were 3 nM SIK2-FLAG, 50 µM AMARAtide, 1 mM ATP, and 1% DMSO.

[0483] Inhibition calculation:%INH = (RLU MAX - RLU sample) / (RLU MAX - RLU MIN) × 100 Where RLU = relative luminescence units, sample = signal in sample well, and MIN and MAX are the minimum and maximum signal controls, respectively.

[0484] Four-parameter IC50 fit:Y = Bottom + (Top - Bottom) / (1 + (IC50 / X)^Hill Slope) Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0, respectively, in a 3-parameter fit. Y is the % inhibition and X is the compound concentration.

[0485] Table 3 shows the IC50 of selected compounds of this invention in the above assays.Compound activity designations have the following values: A (< 10 nM); B (10 nM to < 100 nM); C (100 nM to < 500 nM); D (> 500 nM); and ** (not tested). Table 3. Biochemical Assays Results I-# Assay A I-# Assay A I-# Assay A33184274.1Page 163 of 177407531-97SKWO (219686)I-# Assay A I-25 D

[0486] While we have described a number of embodiments of this invention, it is apparent thatour examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. 33184274.1Page 164 of 177407531-97SKWO (219686)

Claims

CLAIMS 1. A compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: X is N or C; Y is N or C, where one of X and Y is N and the other of X and Y is C; is a single or double bond; L1 is selected from -O-, -S-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, and -C(R1)2- ; L2and L3are independently selected from absent, -O-, -S-, -NR1-, and -C(R1)2-; L4 and L5 are independently selected from the group consisting of -O-, -S-, -NR1-, C(O)NR1-, - NR1C(O)-, -NR1C(O)NR1- and -C(R1)2-; wherein when one of L1, L2, L3, L4, or L5, is -O-, -S-, - NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, or -NR1C(O)NR1-, the others are -C(R1)2-; R1is independently selected from the group consisting of hydrogen, C1–3alkyl, and haloC1- C3alkyl; a is 1, 2, or 3; b is 0, 1, 2, or 3; c is 0 or 1; X1, X2, and X3 are independently selected from N and CR2provided that none are N or only one of X1, X2, and X3may be N; each R2is independently selected from hydrogen, OH, C1–3 alkyl, C1–3 alkoxy, and halogen, provided when R2is halogen, c may be 0, also provided that when all available R2groups are hydrogen, Y is C, X, and X3are N, c may be 0; 33184274.1Page 165 of 177407531-97SKWO (219686)Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7– 12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1Ais independently hydrogen, halogen, –CN, oxo, –OR, –SR, –NR2, –SO2R, –SO2NR2, – S(O)R, –S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, – N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, – N(R)CN, –P(O)(OR)2, –P(O)R2, or an optionally substituted group selected from C1–6aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3Bis independently hydrogen, halogen, oxo, –OR, –SR, –NR2, –SO2R, –SO2NR2, –S(O)R, – S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, – N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, –N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, – P(O)(OR)2, –P(O)R2, haloC1-C6alkyl, haloC3-C6cycloalkyl, haloC1-C6alkoxy, or an optionally substituted group selected from C1–6aliphatic; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3Ais a C1-6 aliphatic-cyclic group, or a cyclic group; wherein the cyclic group is selected from: ^a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 166 of 177407531-97SKWO (219686)^ an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; ^a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that isoptionally bridged or spirocyclic; and ^a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring thatis optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R3Ais substituted with y instances of RA; each instance of RAis independently selected from hydrogen; a C1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and - OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; – CN; –NO2; –OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; –C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon the same atom together form oxo or a cyclic group selected from: ^3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAon the same atom is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - 33184274.1Page 167 of 177407531-97SKWO (219686)SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; – C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; or two instances of RAon adjacent atoms optionally form a cyclic group selected from: ^3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;^ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^phenyl; and^ an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two instances of RAon adjacent atoms is optionally substituted with 1, 2, or 3 groups independently selected from a C1-6aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; –CN; –NO2; –OR; - SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; – C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and –N(R)S(O)2R; y is 0, 1, 2, or 3; Z is #C(R6)2-[C(R7)2]1-2-, #O-[C(R7)2]1-2-, or #NR6-[C(R8)2]1-2-, provided that # is a direct bond to Ring C; R4is an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^an optionally substituted phenyl;^ an optionally substituted 3-8 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-8 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 168 of 177407531-97SKWO (219686)^ an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–5heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 5–11 membered saturated or partially unsaturated bicyclicring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R6is independently selected from hydrogen, C1–4alkyl, and C1–4haloalkyl, or two R6groups may combine to form oxo; each R7is independently selected from hydrogen and C1–4 alkyl, or two R7groups may combine to form oxo; each R8is independently selected from hydrogen and C1–4alkyl; each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3, -C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH3, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group, or an optionally substituted C1-6alkyl-cyclic group, wherein the cyclic group is optionally selected from: ^an optionally substituted phenyl;^ an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclic ring; ^an optionally substituted 3-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; 33184274.1Page 169 of 177407531-97SKWO (219686)^ an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 7–12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 5–8 membered saturated or partially unsaturated bridgedbicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ^an optionally substituted 6–10 membered saturated or partially unsaturatedspirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 6–11 membered saturated or partially unsaturated bicyclicring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from: ^an optionally substituted 4-7 membered saturated or partially unsaturatedcarbocycyl; ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ^an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1, wherein said compound is of any one of the following formulae:, , 33184274.1Page 170 of 177407531-97SKWO (219686)or a pharmaceutically acceptable salt thereof, wherein: X1, X2, and X3 are independently selected from N, CF, CCl, CH3, and CH, provided that only one of X1, X2, and X3 may be N; and Ring C is a 5-6 membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

3. The compound of claim 1 or claim 2, wherein Ring C is a 5-membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4. The compound of any one of claims 1-3, wherein Ring C is ,5. The compound of any one of claims 1-4, wherein said compound is of any one of the following formulae: 33184274.1Page 171 of 177407531-97SKWO (219686), , , or a pharmaceutically acceptable salt thereof, wherein: X1 and X3 are independently selected from N, CF, CCl, and CH, provided that none of X1 and X3 are N or only one of X1 and X3 may be N.

6. The compound of any one of claims 1-5, wherein said compound is of any one of the following formulae: , , or aX1and X3are independently selected from N, CF, CCl, and CH, provided that none of X1and X3are N or only one of X1and X3may be N. 33184274.1Page 172 of 177407531-97SKWO (219686)7. The compound of any one of claims 1-6, wherein Z is -CH2-CH2-, -CH2-, -C(O)-CH2-, -O- CH2-, -O-CH2-CH2-, -NH-CH2-, -NH-CH2-CH2-, -N(CH3)-CH2-, or -N(CH3)-CH2-CH2-.

8. The compound of any one of claims 1-7, wherein R4is an optionally substituted cyclic group selected from oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, quinuclidinyl, phenyl, pyridyl, N-acetylpiperazinyl, methyloxycyclobutyl, and methyloxetanyl.

9. The compound of any one of claim 1-8, wherein R4,wherein: each R1Bare independently hydrogen, halogen, –CN,–SO2NR2, – S(O)R, – S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, – N(R)NR2, –N(R)SO2NR2, – N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, – N(R)CN, –P(O)(OR)2, –P(O)R2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or an optionally substituted group selected from C1–6 aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R1Btogether form oxo; d is 0, 1, 2, 3, or 4; and p and q are each independently 0, 1, or 2 such that p + q is an integer of between 1 and 4.

10. The compound of any one of claims 1-9, wherein said compound is of any one of the following formulae: 33184274.1Page 173 of 177407531-97SKWO (219686)or a pha X1and X3are independently selected from N, CF, CCl, and CH, provided that none of X1and X3are N or only one of X1 and X3 may be N; ,hydrogen, halogen, –CN, –OR, –SR, –NR2, –SO2R, –SO2NR2, – S(O)R, – S(O)NR2, –C(O)R, –CO2R, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)CO2R, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)R, –N(R)C(NR)NR2, – N(R)NR2, –N(R)SO2NR2, –N(R)SO2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, – N(R)CN, –P(O)(OR)2, –P(O)R2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or an optionally substituted group selected from C1–6aliphatic; phenyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R1Btogether form oxo; d is 0, 1, 2, 3, or 4; and p and q are each independently 0, 1, or 2 such that p + q is an integer of between 1 and 4. 33184274.1Page 174 of 177407531-97SKWO (219686)11. The compound of any one of the claims 1-10, wherein the compound is selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

13. The compound of any one of claims 1-11, or the pharmaceutical composition of claim 12, for use as a medicament.

14. A method of inhibiting SIK2 in a biological sample, comprising contacting the sample with the compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12.

15. A method of treating an SIK2-mediated disorder, disease, or condition in a patient, comprising administering to said patient the compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12.

16. The method of claim 15, wherein the SIK2-mediated disorder is selected from inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases.

17. The method of claim 15, wherein the SIK2-mediated disorder is a cancer selected from ovarian cancer, breast cancer, acute myeloid leukemia, and multiple myeloma. 33184274.1Page 175 of 177407531-97SKWO (219686)18. The method of claim 15, wherein the SIK2-mediated disorder is inflammatory bowel disease, diabetes, a skin pigmentation disease, osteoporosis, osteoarthritis, a musculoskeletal disease, or rheumatoid arthritis. 33184274.1Page 176 of 177407531-97SKWO (219686)

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