Substituted pyrazolopyridines as phosphoinosidide kinase (PIK) modulators

Abstract

Provided herein are compounds of formula (I) that modulate PlKfyve and methods of using the compounds in PlKfyve-associated disorders, such as fibro-inflammatory conditions (e.g., interstitial lung disease, or a liver, kidney, cardiac, or systemic fibrotic condition).

Description

SUBSTITUTED PYRAZOLOPYRIDINES AS PHOSPHOINOSIDIDE KINASE (PI K) MODULATORSBACKGROUND

[0001] The present disclosure relates to substituted pyrazolopyridines and their use as pharmaceutical agents. Specifically, the present disclosure relates to the use of these compounds to inhibit the activity of PlKfyve enzymes.

[0002] Lipid kinases of the phosphoinositide kinase (PIK) families generate important cellular signaling molecules, phosphoinositides. These secondary messenger molecules control a wide range of cellular activities and the enzymes generating these have proven to be tractable drug targets. PlKfyve is an endosomal located enzyme catalyzing the production of phosphatidylinositol 3,5-bisphosphate (PI (3,5)P2) from phosphatidylinositol 3-phosphate (PI3P). These phospholipids are found in cell membranes playing roles in protein trafficking, protein degradation and autophagy.

[0003] The importance of PlKfyve in maintaining endosomal structure and function were identified through observation of enlarged endosome / lysosome structures in cells expressing a dominant negative PlKfyve construct or through the use of siRNA knockdown. STA 5326, also referred to as apilimod, is a compound inhibitor of PlKfyve which was initially identified as a potent IL-12 / IL-23 inhibitor shown to suppress inflammation in a mouse inflammatory bowel disease model. Chemical genetics approaches identified the compound target as PlKfyve and showing highly potent and selective activity.

[0004] Clinical trials of apilimod have not proven efficacious across a number of inflammatory conditions including psoriasis, rheumatoid arthritis or Crohn’s disease. A number of these reports highlighted the possibility that apilimod had a narrow therapeutic index and therefore better molecules may prove efficacious. Subsequent to the identification of apilimod’s molecular target, many additional PlKfyve inhibitors have been identified. One additional potent, selective inhibitor has reached clinical trials from Verge Genomics for ALS, after some preclinical validation of PlKfyve in models of diverse forms of ALS.

[0005] PlKfyve inhibitors may also be useful in disease indications with a fibrotic component exemplified by preclinical studies. Apilimod could prevent TGF|3 signaling induced cardiac fibrotic remodeling (and reduce the contractile ability of myofibroblasts). These activities together with modulating the immune response suggest PlKfyve inhibitors may be widely applicable across a range of fibro-inflammatory conditions including interstitial lung diseases, liver, kidney, cardiac and systemic conditions.

[0006] Accordingly, there is a need for new compounds useful for treating fibro-inflammatory and fibrotic conditions, such as compounds that modulate, e.g., inhibit, PlKfyve.SUMMARY

[0007] Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof:whereinQ is a 5-membered heteroaryl comprising a ring nitrogen atom and one additional ring heteroatom selected from 0, N, and NR5, wherein the heteroaryl is optionally substituted with halo, Ci-3alkyl, Ci-3haloalkyl, Cisalkoxy, or cyclopropyl;RAis H, Ci-3alkyl, or Ci-3haloalkyl;R1is C2.6alkenyl, C2.6alkynyl, OR8, NHR8, N(R8)2, HET, O-HET, or N(RN)-HET, wherein HET is C3- scycloalkyl, 3- to 8-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from S, N, and 0, or 5- or 6-membered heteroaryl comprising 1-4 ring heteroatoms selected from N and 0, and HET is optionally substituted with 1-3 R6;R2is H or halo;R3is H or Ci-ealkyl;R4is Ce-waryl or 5- to 10-membered heteroraryl comprising a ring nitrogen atom and 0-2 additional ring heteroatoms selected from N and S, wherein the aryl and heteroaryl are optionally substituted with 1-3 R7;R5is H, Ci-ealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, or Cs-ehalocycloalkyl, wherein the alkyl, haloalkyl, cycloalkyl, and halocycloalkyl are optionally substituted with ORN; each R6is independently OH, oxo, CN, halo, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-ealkoxy, C3- ecycloalkyl, or 3-6-memebred heterocycle having 1-3 ring heteroatoms selected from N, 0, and S and the heterocycle is substituted with 0 or 1 Ci-salkyl; each R7is independently halo, CN, N(RN)2, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, C3- ecycloalkyl, O-Cs-ecycloalkyl or 3-6-memebred heterocycle having 1-2 ring heteroatoms selected from N, 0, and S, wherein the cycloalkyl and heterocycle are optionally substituted with 1 to 3 halo; each RNis independently H or Ci-ealkyl; and each R8is independently Ci-ealkyl or Ci-ehaloalkyl.

[0008] Also provided herein are methods of using the compounds of Formula (I) as inhibitors of a PIK enzyme, e.g., PlKfyve.DETAILED DESCRIPTION

[0009] Provided herein are compounds, and their use in treating or preventing diseases and disorders associated with aberrant PlKfyve activity, e.g., fibro-inflammatory conditions. Also provided are uses of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions comprising such a compound or a pharmaceutically acceptable salt thereof, for the treatment orprevention of diseases and disorders associated with aberrant PlKfyve activity, e.g., fibro-inflammatory conditions. Also provided are uses of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions comprising such a compound or a pharmaceutically acceptable salt thereof, in modulating PlKfyve, e.g., in inhibiting PlKfyveCompounds

[0010] Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof:whereinQ is a 5-membered heteroaryl comprising a ring nitrogen atom and one additional ring heteroatom selected from 0, N, and NR5, wherein the heteroaryl is optionally substituted with halo, Ci-3alkyl, Ci-ahaloalkyl, Ci. salkoxy, or cyclopropyl;scycloalkyl, 3- to 8-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from S, N, and 0, or 5- or 6-membered heteroaryl comprising 1-4 ring heteroatoms selected from N and 0, and HET is optionally substituted with 1-3 R6;R2is H or halo;R3is H or Ci-ealkyl;R4is Ce- aryl or 5- to 10-membered heteroraryl comprising a ring nitrogen atom and 0-2 additional ring heteroatoms selected from N and S, wherein the aryl and heteroaryl are optionally substituted with 1-3 R7;R5is H, Ci-ealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, or Ca-ehalocycloalkyl, wherein the alkyl, haloalkyl, cycloalkyl, and halocycloalkyl are optionally substituted with ORN; each R6is independently OH, oxo, CN, halo, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-ealkoxy, C3- ecycloalkyl, or 3-6-memebred heterocycle having 1-3 ring heteroatoms selected from N, 0, and S and the heterocycle is substituted with 0 or 1 Ci-salkyl; each R7is independently halo, CN, N(RN)2, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, C3- ecycloalkyl, O-Cs-ecycloalkyl or 3-6-memebred heterocycle having 1-2 ring heteroatoms selected from N, 0, and S, wherein the cycloalkyl and heterocycle are optionally substituted with 1 to 3 halo; each RNis independently H or C^alkyl; and each R8is independently Ci-ealkyl or Ci-ehaloalkyl.

[0011] For compounds of Formula (I), Q a 5-membered heteroaryl comprising a ring nitrogen atom and one additional ring heteroatom selected from 0, N, and NR5, wherein the heteroaryl is optionally substituted with halo, Ci-salkyl, Ci-shaloalkyl, Ci-salkoxy, or cyclopropyl. In some cases, Q is a 5-membered heteroaryl comprising two ring nitrogen atoms, and in some specific cases one of the ring nitrogen atoms is substituted withR5(i.e., is NR5). In some cases, Q is a 5-membered heteroaryl comprising one ring nitrogen atom and a ring oxygen atom In some cases, Q is not further substituted (i.e., may have a R5). In some cases, Q may be substituted or not with R5, but is substituted with halo, Ci-galkyl, Ci.3haloalkyl, Ci ^al koxy, or cyclopropyl, and in some specific cases, is substituted with halo In some cases, Q is substituted with F. In some cases, Q isR5Ci.3alkyl, Ci.3haloalkyl, Cualkoxy, or cyclopropyl. In some cases, Q is. In some cases, R5is methyl.

[0012] In some cases, the compound of Formula (I) has a structure of Formula (IA):

[0013] For compounds of Formula (I), RAis H, Ci-aalkyl, or Ci-3haloalkyl. In some cases, RAis H. In some cases, RAis Ci.3alkyl or Ci-shaloalkyl.

[0014] For compounds of Formula (I), R2is H or halo. In some cases, R2is H. In some cases, R2is halo. In some cases, R2is F.

[0015] For compounds of Formula (I), R1is C^alkenyl, C^alkynyl, OR8, NHR8, N(R8)2, HET, O-HET, or N(RN)-HET, wherein HET is Cg-scycloalkyl, 3- to 8-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from S, N, and 0, or 5- or 6-membered heteroaryl comprising 1-4 ring heteroatoms selected from N and O, and HET is optionally substituted with 1-3 R6. In some cases, R1is OR8, NHR8, or N(R8)2. In some cases, R1is OR8. In some cases, R1is NHR8. In some cases, R1is N(R8)2. In some cases, R1is HET, O-HET, or N(RN)-HET. In some cases, R1is OR8, O-HET, or N(RN)-HET. In some cases, R8is Ci-ealkyl or Ci-ehaloalkyl.In some cases, R8is Ci^alkyl. In some cases, R8is Ci^haloalkyl. In some cases, R1is —, orCF30^—I— . In some cases, R1is HET. In some cases, R1is O-HET. In some cases, R1is N(RN)-HET. In some cases, RNis H. In some cases, HET is 5- or 6-membered heteroaryl comprising 1-3 ring nitrogen atoms. In some cases, HET is 5-membered heteroaryl comprising 1-3 ring nitrogen atoms. In some cases, HET is, and R6is OH, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, or Cs-ecycloalkyl. In some cases, HET is C3- scycloalkyl or 3-8-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from N and 0. In some cases, HET is C3-8cycloalkyl. In some cases, HET is C3-6cycloalkyl. In some cases, HET is Cgcycloalkyl. In some cases, HET is C^ycloalkyl. In some cases, HET is Cscycloalkyl. In some cases, HET is Cecycloalkyl. In some cases, HET is cyclopentyl or cyclohexyl and is substituted with 1 or 2 R6. In some cases, HET is cyclobutyl or cyclopropyl. In some cases, HET is 3- to 8-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from N and O. In some cases, HET is 5- to 6-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from N and 0. In some cases, HET is tetrahydropyranyl. In some cases, HET is azetindinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrollidinyl, 2- oxaspiro[3.3]heptanyl, 4-oxaspiro[2.4]heptanyl, or oxabicyclo[3.1.1]heptanyl. In some cases, HET is cyclopropyl, cyclopentyl, cyclohexyl, tetrahhydrofuranyl, or tetrahydropyranyl. In some cases, HET is unsubstituted. In some cases, HET is substituted with 1-3 R6. In some cases, each R6is OH, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, or C3- ecycloalkyl. In some cases, each R6is Ci-ealkyl or OH. In some cases, at least one R6is OH.

[0016] For compounds of Formula (I), R3is H or Ci-ealkyl. In some cases, R3is H. In some cases, R3is Ci. ealkyl. In some cases, R3is methyl.

[0017] For compounds of Formula (I), R4is Ce-ioaryl or 5- to 10-membered heteroraryl comprising a ring nitrogen atom and 0-2 additional ring heteroatoms selected from N and S, wherein the aryl and heteroaryl are optionally substituted with 1-3 R7. In some cases, R4is Ce-waryl or 5- to 10-membered heteroraryl comprising 1- 3 ring nitrogen atoms, wherein the aryl and heteroaryl are unsubstituted. In some cases, R4is Ce-ioaryl or 5- to 10-membered heteroraryl comprising 1-3 ring nitrogen atoms, wherein the aryl and heteroaryl are substituted with 1-3 R7. In some cases, R4is Ce-ioaryl optionally substituted with 1-3 R7. In some cases, R4is unsubstituted Ce-ioaryl. In some cases, R4is phenyl optionally substituted with 1-3 R7. In some cases, R4is phenyl substituted with 1-3 R7. In some cases, R4is Ce-ioaryl substituted with 1-3 R7. In some cases, R4is 5- to 10-membered heteroraryl optionally substituted with 1-3 R7. In some cases, R4is unsubstituted 5- to 10-membered heteroraryl. In some cases, R4is 5- to 10-membered heteroraryl substituted with 1-3 R7. In some cases, R4is pyridyl, pyrimidinyl, pyrrolopyridinyl, 1 / - / -pyrrolo[2,3-b]pyridinyl, 1 / - / -pyrrolo[3,2-c]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 1 / 7-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrazolo[3,4-b]pyridinyl, 5 / 7-pyrrolo[2,3-d]pyrazinyl, quinolinyl, benzo[d][1 ,3]dioxole, or thieno[2,3-b]pyridinyl. In some cases, R4is pyridyl, pyrimidinyl, or pyrrolopyridinyl. In some cases, R4is pyridyl, pyrimidinyl, or pyrrolopyridinyl, and is optionally substituted with 1-3 R7. In some cases, R4is pyrimidyl In some cases, R4is pyrimidyl substituted with 1-3 R7In some cases, each R7is independently halo, Ci ealkyl, or Ci ealkoxy. In some cases, R7is halo. In some cases, R7is chloro. In somecases, R7is Ci-ealkyl. In some cases, R7is methyl. In some cases, R7is Ci-ealkoxy. In some cases, R7is methoxy. In some cases,some cases, R4is phenyl, chlorophenyl, or methylphenyl.

[0018] Specific compounds contemplated include compounds in the following Table A, or a pharmaceutically acceptable salt thereof. Compounds having a chiral center without indication of a particular stereoisomerism indicate a mixture of stereocenters at that chiral center.

[0019] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this disclosure, unless only one of the isomers is specifically indicated. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, cis / trans, conformational, and rotational mixtures of the present compounds are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein can exist as a single stereoisomer, or as a mixture of stereoisomers. Stereochemistry of the compounds shown herein indicates a relative stereochemistry, not absolute, unless discussed otherwise. As indicatedherein, a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least more than 50% of the indicated stereoisomer, diastereomer, or enantiomer, and in some cases, at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer.

[0020] Unless otherwise indicated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0021] Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopical ly enriched atoms. For example, compounds having the present structures except for 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 disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterium analogs, can also be therapeutically useful.

[0022] The compounds of the disclosure are defined herein by their chemical structures and / or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0023] The compounds disclosed herein can be useful as modulators of PlKfyve, such as inhibitors of PlKfyve. These compounds can also be useful in the treatment or prevention of diseases and disorders associated with aberrant PlKfyve activity, e.g., fibro-inflammatory conditions, in a patient.Definitions

[0024] As used herein, the term "alkyl” refers to straight chained and branched saturated hydrocarbon groups containing one to six carbon atoms. The term Cnmeans the alkyl group has “n” carbon atoms. For example, Ce alkyl refers to an alkyl group that has 6 carbon atoms. Ci-Ce alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1 to 6 carbon atoms), as well as all subgroups (e.g., 1-6, 2-6, 1-5, 3-6, 1 , 2, 3, 4, 5, and 6 carbon atoms). Nonlimiting examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), and t-butyl (1, 1 -dimethylethyl). Unless otherwise indicated, an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.

[0025] The term "haloalkyl" used herein refers to an alkyl group defined herein which is substituted with one or more halogen atoms. Nonlimiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 ,1 -difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl.

[0026] As used herein, the term "cycloal kyl” refers to an aliphatic cyclic hydrocarbon group containing three to eight carbon atoms (e.g , 3, 4, 5, 6, 7, or 8 carbon atoms). The term Cnmeans the cycloalkyl group has “n” carbon atoms. For example, Cs cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring. C3-C8 cycloalkyl refers to cycloalkyl groups having a number of carbon atoms encompassing the entire range (e.g., 3 to 8 carbon atoms), as well as all subgroups (e.g., 3-8, 4-8, 5-8, 6-8, 7-8, 3-7, 4-7, 5-7, 6-7, 3-6, 4-6, 5-6, 3-5, 4-5, 3-4, 1 , 2, 3, 4, 5, 6, 7, and 8 carbon atoms). Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, a cycloalkyl groupcan be an unsubstituted cycloalkyl group or a substituted cycloalkyl group. The cycloalkyl groups described herein can be isolated or fused to another cycloalkyl group, a heterocycloalkyl group, an aryl group and / or a heteroaryl group When a cycloalkyl group is fused to another cycloalkyl group, then each of the cycloalkyl groups can contain three to eight carbon atoms unless specified otherwise. Unless otherwise indicated, a cycloalkyl group can be unsubstituted or substituted.

[0027] The term "halocycloalkyl" used herein refers to a cycloalkyl group defined herein which is substituted with one or more halogen atoms. Nonlimiting examples of halocycloalkyls include fluorocyclohexyl, difluorocyclohexyl, trifluorocyclohexyl, pentafluorocyclohexyl, 1, 1 -difluorocyclohexyl, chlorocyclohexyl, chlorofluorocyclohexyl and trichlorocyclohexyl.

[0028] As used herein, the term “heterocycloalkyl” is defined similarly as cycloalkyl, except the ring contains one to five heteroatoms independently selected from oxygen and nitrogen. In particular, the term “heterocycloalkyl” refers to a ring containing a total of 3 to 8 ring atoms, of which 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms independently selected from oxygen and nitrogen, and the remaining atoms in the ring are carbon atoms. Nonlimiting examples of heterocycloalkyl groups include piperdine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, and the like.

[0029] Cycloalkyl and heterocycloalkyl groups can be saturated or partially unsaturated ring systems optionally substituted with, for example, one to three groups as described herein. Heterocycloalkyl groups optionally can be further N-substituted with alkyl (e.g., methyl or ethyl), al kylene-OH, alkylenearyl, alkyleneheteroaryl, and the like. The heterocycloalkyl groups described herein can be isolated or fused to another heterocycloalkyl group, a cycloalkyl group, an aryl group, and / or a heteroaryl group When a heterocycloalkyl group is fused to another heterocycloalkyl group, then each of the heterocycloalkyl groups can contain three to twelve total ring atoms, and one to three heteroatoms. Unless otherwise indicated, a heterocycloalkyl group can be unsubstituted or substituted.

[0030] As used herein, the term "aryl” refers to aromatic ring groups that have only carbon ring atoms (typically six to ten) and include monocyclic aromatic rings such as phenyl, and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another such as naphthyl. In some embodiments, aryl is phenyl. Unless otherwise indicated, an aryl ring can be unsubstituted or substituted as described herein.

[0031] As used herein, the term “heteroaryl” refers to a monocyclic or bicyclic aromatic ring having 5 to 10 total ring atoms, and containing one to four heteroatoms selected from nitrogen and oxygen atoms in the aromatic ring. In particular, heteroaryls described herein can contain 5 or 6 total ring atoms, and containing 1 , 2, 3, or 4 heteroatoms selected from nitrogen and oxygen in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to three, substituents as described herein. Examples of heteroaryl groups include, but are not limited to, furyl, pyridyl, pyrrolyl, oxazolyl, triazinyl, triazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyrimidinyl, 1 ,4-dihydropyrrolo[3,2-b]pyrrolyl, 1,6- dihydropyrrolo[2,3-b]pyrrolyl, 6 / 7-furo[2,3-b]pyrrolyl, 4 / 7-furo[3,2- ]pyrrolyl, 1 / 7-indolyl, 2 / 7-isoindolyl, indolizyl, 1 / 7-indazolyl, benzimidazolyl, 7-azaindolyl, 5-azaindolyl, 6-azaindolyl, 1,2-benzisoxazolyl, benzoxazolyl, adenyl, guanyl, quinolyl, isoquinolyl, quinoxalyl, phthalazyl, quinazolyl, cinnolyl, 1 ,8-naphthyridyl, pyrido[3,2-d|pyrimidyl, pyrido[4,3-d]pyrimidyl, pyrido[3,4-b]pyrazyl, pyrido[2,3-b]pyrazyl, pteridyl, 2 / 7-chromen-2-onyl, 2 / 7- benzo[e][1 ,2]oxazyl, quinolin-2(1 / 7)-onyl, and isoquinolin-1 (2 / 7)-onyl.

[0032] As used herein, the term "alkoxy” refers to a O-alkyl” group. The alkoxy group can be unsubstituted or substituted.

[0033] The term "haloalkoxy" used herein refers to an alkoxy group defined herein which is substituted with one or more halogen atoms. Nonlimiting examples of haloalkoxys include fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 1 ,1 -difluoroethoxy, chloromethoxy, chlorofluoromethoxy and trichloromethoxy.

[0034] As used herein, the terms “halo” and “halogen” refer to fluorine, chlorine, bromine, and iodine.

[0035] As used herein, the term “therapeutically effective amount” means an amount of a compound or combination of therapeutically active compounds that ameliorates, attenuates or eliminates one or more symptoms of a particular disease or condition (e.g., a fibro-i nflammatory condition), or prevents or delays the onset of one of more symptoms of a particular disease or condition.

[0036] As used herein, the terms “patient” and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (e.g., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans).

[0037] As used herein, the term “pharmaceutically acceptable” means that the referenced substance, such as a compound of the present disclosure, or a formulation containing the compound, or a particular excipient, are safe and suitable for administration to a patient or subject. The term “pharmaceutically acceptable excipient" refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.

[0038] As used herein, the term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API).Pharmaceutically Acceptable Salts

[0039] The compounds described herein can exist in free form, or, where appropriate, as salts. Those salts that are pharmaceutically acceptable are of particular interest since they are useful in administering the compounds described below for medical purposes. Salts that are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of the disclosure or intermediates thereof.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefi t / risk ratio.

[0041] 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, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0042] Where the compound described herein contains a basic group, or a sufficiently basic bioisostere, acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed. In practice, acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.

[0043] Examples of pharmaceutically acceptable, non-toxic 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, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0044] Where the compound described herein contains a carboxy group or a sufficiently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. In practice, use of the base addition salt might be more convenient and use of the salt form inherently amounts to use of the free acid form. Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N+(C i-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0045] Basic addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. The sodium and potassium salts are usually preferred. 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. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines which are frequently used in medicinal chemistrybecause of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

[0046] Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0047] It should be understood that a compound disclosed herein can be present as a mixture / combination of different pharmaceutically acceptable salts. Also contemplated are mixtures / combinations of compounds in free form and pharmaceutically acceptable salts.Pharmaceutical Formulations, Dosing, and Routes of Administration

[0048] Further provided are pharmaceutical formulations (alternatively referred to as compositions throughout herein) comprising a compound as described herein or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0049] The compounds described herein can be administered to a subject in a therapeutically effective amount, alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds can be administered all at once, multiple times, or delivered substantially uniformly over a period of time. It is also noted that the dose of the compound can be varied over time.

[0050] A particular administration regimen for a particular subject will depend, in part, upon the compound, the amount of compound administered, the route of administration, and the cause and extent of any side effects. The amount of compound administered to a subject (e.g., a mammal, such as a human) in accordance with the disclosure should be sufficient to affect the desired response over a reasonable time frame. Dosage typically depends upon the route, timing, and frequency of administration. Accordingly, the clinician titers the dosage and modifies the route of administration to obtain the optimal therapeutic effect, and conventional range-finding techniques are known to those of ordinary skill in the art.

[0051] Purely by way of illustration, the method comprises administering, for example, from about 0.1 mg / kg up to about 100 mg / kg of compound or more, depending on the factors mentioned above. In other embodiments, the dosage ranges from 1 mg / kg up to about 100 mg / kg; or 5 mg / kg up to about 100 mg / kg; or 10 mg / kg up to about 100 mg / kg. Some conditions require prolonged treatment, which may or may not entail administering lower doses of compound over multiple administrations. If desired, a dose of the compound is administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. The treatment period will depend on the particular condition and type of pain, and may last one day to several months.

[0052] Suitable methods of administering a physiologically-acceptable composition, such as a pharmaceutical composition comprising the compounds disclosed herein are well known in the art. Although more than one route can be used to administer a compound, a particular route can provide a more immediate and more effective reaction than another route. Depending on the circumstances, a pharmaceutical composition comprising the compound is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and / or introduced into circulation. For example, in certain circumstances, it will be desirable to deliver a pharmaceutical composition comprising the agent orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means, by sustained release systems, or by implantation devices. If desired, the compound is administered regionally via intrathecal administration, intracerebral (intra- parenchymal) administration, intracerebroventricular administration, or intraarterial or intravenous administration feeding the region of interest. Alternatively, the composition is administered locally via implantation of a membrane, sponge, or another appropriate material onto which the desired compound has been absorbed or encapsulated. Where an implantation device is used, the device is, in one aspect, implanted into any suitable tissue or organ, and delivery of the desired compound is, for example, via diffusion, timed-release bolus, or continuous administration.

[0053] To facilitate administration, the compound is, in various aspects, formulated into a physiologically- acceptable composition comprising a carrier (e.g., vehicle, adjuvant, or diluent). The particular carrier employed is limited only by physico-chemical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. Physiologically- acceptable carriers are well known in the art. Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent No. 5,466,468). Injectable formulations are further described in, e.g., Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia. Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)). A pharmaceutical composition comprising the compound is, in one aspect, placed within containers, along with packaging material that provides instructions regarding the use of such pharmaceutical compositions. Generally, such instructions include a tangible expression describing the reagent concentration, as well as, in certain embodiments, relative amounts of excipient ingredients or diluents (e.g., water, saline or PBS) that may be necessary to reconstitute the pharmaceutical composition.

[0054] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0055] These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0056] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be used 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.

[0057] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. The solid dosage forms may also contain opacifying agents. Further, the solid dosage forms may be embedding compositions, such that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound can also be in micro-encapsulated form, optionally with one or more excipients.

[0058] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0059] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition tothe active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

[0060] Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.

[0061] The compositions used in the methods of the invention may be formulated in micelles or liposomes. Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes. Such formulations can facilitate intracellular delivery, since lipid bilayers of liposomes and micelles are known to fuse with the plasma membrane of cells and deliver entrapped contents into the intracellular compartment.

[0062] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.

[0063] The frequency of dosing will depend on the pharmacokinetic parameters of the agents and the routes of administration. The optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and the desired dosage. See, for example, Remington’s Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, incorporated herein by reference. Such formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface areas or organ size. Further refinement of the calculations necessary to determine the appropriate treatment dose is routinely made by those of ordinary skill in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein, as well as the pharmacokinetic data observed in animals or human clinical trials.

[0064] The precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition, e.g., disease or disorder, being treated, the mode of administration and the particular active substance employed. The compounds may be administered by any conventional route, in particular enterally, and, in one aspect, orally in the form of tablets or capsules. Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of a disease of interest. These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.

[0065] It will be appreciated that the pharmaceutical compositions and treatment methods of the invention are useful in fields of human medicine and veterinary medicine Thus, the subject to be treated is in one aspect a mammal. In another aspect, the mammal is a human.

[0066] In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of "administering" of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.) The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.Methods of Use

[0067] The compounds described herein can modulate PIKtyve. In some embodiments, the compounds inhibit PlKfyve, i.e., the compounds are PlKfyve inhibitors.

[0068] The term “PlKfyve inhibitor” as used herein refers to a compound having the ability to inhibit the activity of PlKfyve enzymes.

[0069] Toll-like receptor (TLR) signaling is a key component of innate immunity. Aberrant TLR activation leads to immune disorders via dysregulation of cytokine production, such as IL-12 / IL-23. Inhibition of PlKfyve blocks its phosphotransferase activity, leading to selective inhibition of IL-12 / IL-23. Pharmacological or genetic inactivation of PlKfyve is necessary and sufficient for suppression of I L-12 / I L-23p40 expression. PlKfyve inhibition is thus a phosphoinositide-mediated regulatory mechanism that controls TLR signaling. Cai et al., Chem Biol . 2013 Jul 25;20(7):912-21 . PlKfyve is an emerging target for suppressing inflammation in a variety of conditions. The PlKfyve inhibitor apilimod has been evaluated in clinical trials for patients with inflammatory conditions, such as Crohn's disease or rheumatoid arthritis. Apilimod has also been studied for its use in fibrotic conditions, by preventing TGFp signaling induced cardiac fibrotic remodeling and reducing the contractile ability of myofibroblasts. Taken together, these results suggest that PlKfyve inhibitors such as apilimod may be useful for treating a variety of fibro-inflammatory conditions. However, apilimod itself has shown limitations in clinical trials, and so there is a need for alternative and more effective PlKfyve inhibitors.

[0070] The compounds disclosed herein are particularly advantageous for the treatment or prevention of diseases or disorders caused by aberrant PlKfyve activity, e.g., by inhibiting PlKfyve.

[0071] As used herein, “aberrant PlKfyve activity" refers to PlKfyve activity associated with the etiology or progression of fibro-inflammatory conditions. Such PlKfyve-linked etiology or progression is associated with a variety of fibro-inflammatory conditions.

[0072] Given the importance of the biological roles of PlKfyve, the compounds of the present disclosures are useful for a number of applications in a variety of settings. For example and most si mplistically, the active agents of the present disclosures are useful for inducing the inhibition of PlKfyve in a cell. In this regard, the presentdisclosures provide methods of inducing the inhibition of PlKfyve in a cell. The methods comprise contacting the cell with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to induce the inhibition. In some aspects, the cell is part of an in vitro or ex vivo cell culture or in vitro or ex vivo tissue sample. In some aspects, the cell is an in vivo cell. In certain embodiments, the method is intended for research purposes, and, in other embodiments, the method is intended for therapeutic purposes.

[0073] As shown herein, a compound that induces the inhibition of PlKfyve reduces inflammation and / or fibrosis. Thus, the present disclosure provides methods of reducing inflammation and / or fibrosis in a subject. The methods comprise administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to reduce inflammation and / or fibrosis in a subject.

[0074] In accordance with the foregoing, the present disclosures further provides methods of treating or preventing a fibro-inflammatory condition in a subject. As used herein, the term “fibro-inflammatory condition” means formation of fibrous connective tissue after chronic or acute inflammation leading to persistent inflammation and uncontrolled wound healing ultimately resulting in scarring and thickening of the affected tissue or organ. The methods comprise administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the fibro-inflammatory condition in the subject.

[0075] As used herein, the term "treat,” as well as words related thereto, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the methods of treating fibro- inflammatory conditions of the present disclosures can provide any amount or any level of treatment of a fibro- inflammatory condition Furthermore, the treatment provided by the method of the present disclosures may include treatment of one or more conditions or symptoms of the fibro-inflammatory condition being treated. Also, the treatment provided by the methods of the present disclosures may encompass slowing the progression of the fibro-inflammatory condition. For example, the methods can treat a fibro-inflammatory condition by virtue of dampening the magnitude of the inflammatory / collagen deposition cycle through reduction in circulating cytokines or collagen deposition.

[0076] The fibro-inflammatory conditions treatable by the methods disclosed herein may be any fibro- inflammatory conditions In some embodiments, the fibro-inflammatory condition is a fibro-inflammatory condition in which a PlKfyve is expressed by the cells implicated in the etiology or progression of the fibro- inflammatory conditions. In some aspects, the fibro-inflammatory condition is a fibro-inflammatory condition in which a Pl fyve enzyme is over-expressed, the gene encoding PlKfyve is amplified, and / or a PlKfyve mutant protein (e.g., truncated PlKfyve, point-mutated PlKfyve) is expressed.

[0077] The fibro-inflammatory condition in some aspects is one selected from the group consisting of interstitial lung disease, or a liver, kidney, cardiac, or systemic fibrotic condition such as liver cirrhosis, chronic kidney disease, lupus nephritis, diabetic kidney disease, heart failure with preserved ejection fraction, nonalcoholic steatohepatitis, scleroderma, primary biliary cholangitis, or primary sclerosing cholangitis.

[0078] Uses of the compounds disclosed herein in the preparation of a medicament for modulating PlKfyve, or for treating or preventing a disease or disorder associated with aberrant PlKfyve activity also are provided herein.

[0079] The disclosure herein will be understood more readily by reference to the following examples, below.

[0080] In view of the many possible embodiments to which the principles of the disclosure may be applied, it should be recognized that the illustrated embodiments are only examples and should not be taken as limiting the scope of the invention.

[0081] As used herein, the terms "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0082] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.Synthesis of Compounds of the Disclosure

[0083] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the synthetic schemes as described in the Examples section, with modification for specific desired substituents

[0084] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B. , March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001 ; and Greene, T.W., Wuts, P.G. M. , Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis knownto those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[0085] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.EXAMPLESAbbreviationsIntermediate 1

[0086] Preparation of 6-bromo-1-(difluorornethyl)pyrrolo[2,3-b]pyridine To a stirred solution of 6-bromo-1 H-pyrrolo[2,3-b]pyridine (200 mg, 1.02 mmol, 1 equiv) and f-BuOK (456 mg, 4.06 mmol, 4 equiv) in ACN (4 mL) was added ethyl 2-bromo-2,2-difluoroacetate (824 mg, 4.06 mmol, 4 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by column chromatography, eluted with petroleum ether / EtOAc (100:1) to afford 6-bromo-1-(difluoromethyl)pyrrolo[2,3- b]pyridine (55 mg, 21.93%). LCMS: (ES, m / z): [M+1]+: 247Intermediate 2

[0087] Preparation of 6-bromo-1 -methyl-1 H-py rrolo [2, 3-b]py rid i ne : A solution of 6-bromo-1 H-py r rol o [2, 3- b]pyridine (1.5 g, 7.65 mmol, 1 equiv) in THF (30 mL) was treated with NaH (60% in oil, 918 mg, 22.9 mmol, 3 equiv) for 30 min at rt under nitrogen atmosphere. To the above mixture was added iodomethane (3.26 g, 22.9 mmol, 3 equiv) at room temperature. The reaction was quenched with sat NH4CI (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, then concentrated under reduced pressure. The residue was purified by reverse flash chromatography using ACN in water, 10% to 20% gradient to afford 6-bromo-1 -methyl-1 H-pyrrolo[2, 3- b]pyridine (1.1 g, 73.3%). LCMS (ES, m / z): [M+1]+: 21Intermediate 3

[0088] Preparation of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine:A solution of 6-bromo-1 -methyl-1 H-pyrrolo[2,3-b]pyridine (1.1 g, 5.23 mmol, 1 equiv) in t-AmOH (22 mL) was treated with potassium acetate (1 54 g, 15.7 mmol, 3 equiv) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (2.66 g, 10.4 mmol, 2 equiv) and RuPhos-Pd-Gg (437 mg, 0.523 mmol, 0.1 equiv) at rt. The resulting mixture was stirred for 6 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt and quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, and concentratedunder reduced pressure. The residue was purified by reverse flash chromatography with ACN in water, 50% to 65% gradient to provide 1-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine (460 mg, 34 0%). LCMS: (ES, m / z): [M+1]+: 259Intermediate 4

[0089] Preparation of 1-methyl-3-(1-methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1H-pyrazol-5-amine: A solution of 1-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine (420 mg, 1.62 mmol, 1 equiv) in dioxane (9.3 mL) and H2O (3.1 mL) was treated with K2CO3 (449 mg, 3.25 mmol, 2 equiv) and 3-bromo- 1-methyl-1 H-pyrazol-5-amine (1.42 g, 8 14 mmol, 5 equiv) and Pd(dppf)Cl2 (1.32 g, 0.162 mmol, 0.1 equiv) at rt. The resulting mixture was stirred for 5 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to re and quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with ACN in water, 50% to 60% gradient to provide 1- methyl-3-(1 -methyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)-1 H-pyrazol-5-amine (180 mg, 48.7%). LCMS-: (ES, m / z): [M+1]+: 228Intermediate 5

[0090] Preparation of 6-chloro-1-cyclopropylpyrrolo[2,3-b]pyridine: A solution of 6-chloro-1 H-pyrrolo[2,3- b]pyridine (3 g, 19.7 mmol, 1 equiv), Na2CO3 (4.17 g, 39.3 mmol, 2 equiv) in DCE (150 mL) was treated with cyclopropylboronic acid (3.38 g, 39.3 mmol, 2 equiv) for 1 min at rt under nitrogen atmosphere followed by the addition of Cu(OAc)2 (3.57 g, 19.7 mmol, 1 equiv) and 2-(pyridin-2-yl)pyridine (3.07 g, 19.7 mmol, 1 equiv) at rt. The resulting mixture was stirred for an additional 2 h at 100°C then cooled to rt. The resulting mixture was filtered, washed with EtOAc (3 x100 mL), and concentrated under reduced pressure. The residue was purified by column chromatography, eluted with petroleum ether / EtOAc (15: 1) to afford 6-chloro-1 -cyclopropylpyrrolo[2,3- b]pyridine (2.20 g, 58.08%). LCMS ESI-MS m / z: = 193 [M+H]Intermediate 6

[0091] Preparation of 5-{1-cyclopropylpyrrolo[2,3-b]pyridin-6-yl}-2-methylpyrazol-3-amine: A solution of 6-chloro-1-cyclopropylpyrrolo[2,3-b]pyridine (1.20 g, 6.229 mmol, 1 equiv), KOAc (0.120 g, 1.25 mmol, 0.2 equiv) in DMF (42 mL) was treated with 5-bromo-2-methylpyrazol-3-amine (1.64 g, 9.34 mmol, 1.5 equiv) for 1 min at rt under nitrogen atmosphere followed by the addition of Sn2(n-Bu)e (5.42 g, 9 34 mmol, 1 .5 equiv),Pd (dppfJCkCHhCk (0.250 g, 0.311 mmol, 0.05 equiv) at rt. The resulting mixture was stirred for an additional 3 h at 90°C then cooled to rt. The mixture was concentrated and purified by reversed-phase chromatography withACN in water (0.1 % FA), 20% to 50% gradient to provide 5-{1-cyclopropylpyrrolo[2,3-b]pyridin-6-yl}-2- methylpyrazol-3-amine (200 mg, 12.68%). LCMS ESI-MS m / z: = 254 [M+H]Intermediate 7

[0092] Preparation of 4-methyl-2-(tributylstannyl)pyrimidine: To 2-bromo-4-methylpyrimidine (1 g, 5.78 mmol, 1 equiv) and toluene (20 mL) at rt was added n-BuLi (0.44 g, 6.94 mmol, 1 .2 equiv) at -78 °C. The resulting mixture was stirred for 0.5 h at -78 °C under nitrogen atmosphere. To the above mixture was added SnCI(n-Bu)3 (2.63 g, 8.09 mmol, 1.4 equiv) at -78 °C. The resulting mixture was stirred for an additional 1 h at - 78 °C then warmed to rt and quenched by the addition of water (40 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide 4-methyl-2-(tributylstannyl)pyrimidine (2.5 g, 90.31 %) which was used without further purification. LCMS: (ES, m / z): [M+1]+:385Intermediate 8

[0093] Preparation of 2-methyl-5-(4-methylpyrimidin-2-yl)pyrazol-3-amine: 4-Methyl-2- (tributylstannyl)pyrimidine (2.5 g, 6.53 mmol, 1 equiv), 5-bromo-2-methylpyrazol-3-amine (0.38 g, 2.15 mmol, 0.33 equiv) and (2E)-but-2-en-1-yl(chloro)palladium (0.26 g, 0.653 mmol, 0.1 equiv) in DMF (50 mL) stirred for 12 h at 100 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reversed-phase flash chromatography with MeCN in Water (0.05% NH4HCO3), 10% to 100% gradient to provide 2-methyl-5-(4- methylpyrimidin-2-yl)pyrazol-3-amine (300 mg, 21.87%). LCMS: (ES, m / z): [M+1]+:190Intermediate 9

[0094] Preparation of methyl 5-bromo-2-(difluoromethyl) pyrazole-3-carboxylate: Methyl 5-bromo-2H- pyrazole-3-carboxylate (1 g, 4.88 mmol, 1 equiv), sodium 2-chloro-2,2-difluoroacetate (1.12 g, 7.32 mmol, 1.5 equiv), CS2CO3 (4.77 g, 14.6 mmol, 3 equiv) and DMF (15 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere then cooled to rt. The resulting mixture was filtered; washed with ACN (1 x 5 mL), and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with ACN in Water (0.05 % FA), 10% to 70% gradient to provide methyl 5-bromo-2-(difluoromethyl) pyrazole-3-carboxylate (0.54 g, 43.41 %). LCMS: (ES, m / z): [M+1]+: 255.Intermediate 10

[0095] Preparation of methyl 2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl)pyrazole-3-carboxylate:Methyl 5-bromo-2-(difluoromethyl) pyrazole-3-carboxylate (0.5 g, 1.96 mmol, 1 equiv), 1 ,4-dioxane (10 mL), 4- methoxy-2-(tributylstannyl)pyrimidine (1.57 g, 3.92 mmol, 2 equiv) and Pd(PPha)4 (0.08 g, 0.196 mmol, 0.1 equiv) was stirred for 12 h at 100 °C under nitrogen atmosphere then cooled to rt. The resulting mixture was filtered; washed with ACN (2 x 1 mL), and concentrated under reduced pressure. The residue was purified by reversephase flash chromatography with ACN in Water (0.05 % FA), 10% to 70% gradient to provide methyl 2- (difluoromethyl)-5-(4-methoxypyrimidin-2-yl) pyrazole-3-carboxylate (0.24 g, 43.07%). LCMS: (ES, m / z): [M+1]+: 285.Intermediate 11

[0096] Preparation of 2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl)pyrazole-3-carboxylic acid: Methyl 2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl) pyrazole-3-carboxylate (0.8 g, 2.82 mmol, 1 equiv), THF (8 mL) and NaOH (4M) (8 mL) was stirred for 2 h at rt under nitrogen atmosphere then concentrated under vacuum. The residue was acidified to pH 3 with 3N HCI (aq.). The precipitated solid was collected by filtration and washed with water (1 x 5 mL) to provide 2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl) pyrazole-3-carboxylic acid (0.5 g, 65.74%). LCMS: (ES, m / z): [M+1]+: 271.Intermediate 12

[0097] Preparation of tert-butyl N-[2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl)pyrazol-3-yl] carbamate: 2-(Difluoromethyl)-5-(4-methoxypyrimidin-2-yl) pyrazole-3-carboxylic acid (0.5 g, 1.85 mmol, 1 equiv), f-BuOH (10 mL), TEA (0.94 g, 9.26 mmol, 5 equiv) and DPPA (0.76 g, 2.78 mmol, 1.5 equiv) were stirred for 12 h at 80 °C under nitrogen atmosphere then cooled to rt. The resulting mixture was concentrated under vacuum and purified by reversed-phase flash chromatography with MeCN in Water (5 mmol / L NH4HCO3), 10% to 70% gradient to provide tert-butyl N-[2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl) pyrazol-3-yl] carbamate (0.25 g, 39.58%). LCMS: (ES, m / z): [M+1]+: 342.Intermediate 13

[0098] Preparation of 2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl)pyrazol-3-amine: tert-Butyl N-[2- (difluoromethyl)-5-(4-methoxypyrimidin-2-yl) pyrazol-3-yl] carbamate (0.25 g, 0.732 mmol, 1 equiv), DCM (2.5 mL) and TFA (2.5 mL) were stirred for 1 h at rt under nitrogen atmosphere then concentrated under vacuum to provide 2-(difluoromethyl)-5-(4-methoxypyrimidin-2-yl) pyrazol-3-amine (0.2 g, 96.23%) which was used in the next step directly without further purification. LCMS: (ES, m / z): [M+1]+: 242.Intermediate 14

[0099] Preparation of 2-methoxy-6-(3-methoxy-4- nitropyrazol-1 -yljpyridine : A mixture of 3-methoxy-4- nitro-1 H-pyrazole (1 g, 6.99 mmol, 1 equiv), 2-bromo-4-methoxypyrimidine (1.45 g, 7.69 mmol, 1.1 equiv), K2CO3 (0.97 g, 6.99 mmol, 1 equiv) and DIPEA (0.90 g, 6 99 mmol, 1 equiv) in DMF (10 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere then cooled to rt. The precipitated solids were collected by filtration and washed with H2O (20 mL) to provide 2-methoxy-6-(3-methoxy-4- nitropyrazol-1 -yl)pyridine (1.3 g, 74.05%). LCMS: (ES, m / z): [M+1]+: 252.0Intermediate 15

[0100] Preparation of 3-methoxy-1-(4-methoxypyrimidin-2-yl)pyrazol-4-amine: A solution of 2-methoxy-6- (3-methoxy-4-nitropyrazol-1-yl)pyridine (500 mg, 2 0 mmol, 1 equiv) and NH4CI (534 mg, 9.99 mmol, 5 equiv) in THF (6 mL), H2O (3 mL) was treated with Fe (1.12 g, 20.0 mmol, 10 equiv) and CH3COOH (600 mg, 9.99 mmol, 5 equiv) for 1 h at 60 °C under nitrogen atmosphere, then filtered, washed with EA (50 mL), washed with water, followed by brine, and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 3-methoxy-1-(4-methoxypyrimidin-2-yl)pyrazol-4-amine (150 mg, 30.8%). LCMS: (ES, m / z): [M+1]+: 222.1Int 16 Int 17Intermediate 16

[0101] Preparation of 2-(3-cyclopropyl-4-nitropyrazol-1-yl)-4-methoxypyrimidine: A solution of 2-bromo- 4-methoxypyrimidine (1.00 g, 5.29 mmol, 1 equiv), 3-cyclopropyl-4-nitro-1 H-pyrazole (0.810 g, 5.29 mmol, 1 equiv), K CO3 (0.730 g, 5.29 mmol, 1 equiv) and DIEA (0.680 g, 5.29 mmol, 1 equiv) in DMF (20 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere then cooled to rt and purified by reverse flash chromatography with MeCN in Water, 0% to 100% gradient to provide 2-(3-cyclopropyl-4-nitropyrazol-1-yl)-4-methoxypyrimidine (700 mg, yield: 50.65%). LCMS: (ES, m / z): [M+1]+: 262Intermediate 17

[0102] Preparation of 2-(3-cyclopropyl-4-nitropyrazol-1-yl)-4-methoxypyrimidine: A solution of 2-(3- cyclopropyl-4-nitropyrazol-1-yl)-4-methoxypyrimidine (300 mg, 1.15 mmol, 1 equiv), Zn (751 mg, 11.5 mmol, 10 equiv) and AcOH (345 mg, 5.74 mmol, 5 equiv) in THF (12.5 mL) and H2O (2.50 mL) was stirred for 0.5 h at 70 °C under nitrogen atmosphere. The resulting mixture was filtered; washed with THF (2 x 5 mL) and concentratedunder reduced pressure to provide 3-cyclopropyl-1-(4-methoxypyrimidin-2-yl)pyrazol-4-amine (225 mg, yield:84.72%). LCMS: (ES, m / z): [M+1]+: 262Intermediate 18

[0103] Preparation of 3-(4-methoxypyrimidin-2-yl)-3-oxopropanenitrile: A solution of methyl 4- methoxypyrimidine-2-carboxylate (12.1 g, 71.7 mmol, 1 eq.) in THF (240 mL) was treated with NaH (60% in mineral oil, 5.16 g, 215 mmol, 3 eq.). The mixture was stirred for 0.5 h at rt under nitrogen atmosphere. Then the acetonitrile (29.4 g, 717 mmol, 10 eq.) was added and the mixture was stirred for 0.5 h at 80°C. The mixture was allowed to cool to rt, and the reaction was quenched with H2O at 0 °C. The residue was neutralized to pH=7 with cone. HCI. The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 3- (4-methoxypyrimidin-2-yl)-3-oxopropanenitrile (12 g, yield: 94.52%). LCMS: (ES, m / z) [M+1] +: 178.0.Intermediate 19

[0104] Preparation of 5-(4-methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (Example 8): A mixture of 3- (4-methoxypyrimidin-2-yl)-3-oxopropanenitrile (12.0 g, 67.7 mmol, 1 eq.) in EtOH (240 mL) was treated with methyl hydrazine (15.6 g, 339 mmol, 5 eq.) at rt and the mixture was stirred for 5 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt, then concentrated under reduced pressure and purified by column chromatography, eluted with C^Ck / MeOH (50 / 1 to 30 / 1) to afford 5-(4-methoxypyrimidin-2-yl)-2- methylpyrazol-3-amine (8 g, Y = 57.55%). LCMS: (ES, m / z): [M+1] +: 206.1.

[0105] The same procedure used for Intermediates 18 and 19 was used to prepare the following intermediates.

[0106] Intermediate 1 benzoyl acetonitrile LCMS: (ES, m / z): [M+1]+: 146.

[0107] Intermediate 2 3-(3-methoxypyridin-2-yl)-3-oxopropanenitrile LCMS: (ES, m / z): [M+1]+: 177

[0108] Intermediate 3 3-(6-methoxypyridin-2-yl)-3-oxopropanenitrile LCMS: (ES, m / z): [M+1]+: 176

[0109] Intermediate 4 3-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3-oxopropanenitrile LCMS: (ES, m / z): [M+1]+: 201

[0110] Intermediate 5 3-(1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxopropanenitrile LCMS: (ES, m / z): [M+1]+: 201

[0111] Intermediate 6 2-methyl-5-{7-methylpyrrolo[2,3-d]pyrimidin-2-yl}pyrazol-3-amine (Example 9) was synthesized following the same procedure from 3-{7-methylpyrrolo[2,3-d]pyrimidin-2-yl}-3-oxopropanenitrile and methylhydrazine LCMS: (ES, m / z): [M+1]+: 228

[0112] Intermediate 7 5-(6-methoxypyridin-2-yl)-2-methylpyrazol-3-amine (Example 10) was synthesized following the same procedure from 3-(6-methoxypyridin-2-yl)-3-oxopropanenitrile and methyl hydrazine. LCMS: (ES, m / z): [M+1]+: 205

[0113] Intermediate 8 1 -methyl-3-(1 -methyl- 1 H-pyrazolo[3,4-b]pyridin-6-yl)-1 H-pyrazol-5-amine was synthesized following the same procedure from 3-(1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxopropanenitrile and methylhydrazine. LCMS: (ES, m / z): [M+1] +: 229

[0114] Intermediate 9 2-(2-methoxyethyl)-5-(4-methoxypyrimidin-2-yl)pyrazol-3-amine (Example 12) was synthesized following the same procedure from 3-(4-methoxypyrimidin-2-yl)-3-oxopropanenitrile (200 mg, 1.13 mmol, 1 equiv) and (2-methoxyethyl)hydrazine dihydrochloride. LCMS: (ES, m / z): [M+1]+:250

[0115] Intermediate 10 2-(2-methoxyethyl)-5-phenylpyrazol-3-amine ) was synthesized following the same general procedure from benzoylacetonitrile and (2-methoxyethyl)hydrazine dihydrochloride. LCMS: (ES, m / z): [M+1]+: 218.

[0116] Intermediate 11 2-cyclopropyl-5-(4-methoxypyrimidin-2-yl)pyrazol-3-amine was synthesized following the same procedure from 3-(4-methoxypyri midin-2-yl)-3-oxopropanenitrile and cyclopropylhydrazine hydrochloride LCMS: (ES, m / z): [M+1]+: 232.

[0117] Intermediate 12 3-(4-methoxypyrimidin-2-yl)-1 H-pyrazol-5-amine was synthesized following the same procedure from 3-(4-methoxypyrimidin-2-yl)-3-oxopropanenitrile and hydrazine. LCMS: (ES, m / z): [M+1]+: 192.

[0118] Intermediate 13 2-(5-amino-3-(4-methoxypyrimidin-2-yl)-1 H-pyrazol-1 -yl)ethan-1 -ol was synthesized following same procedure from 3-(4-methoxypyrimidin-2-yl)-3-oxopropanenitrile and 2-hydrazineylethan-1 -ol. LCMS: (ES, m / z): [M+1]+: 236.05.

[0119] Intermediate 14 5-phenyl-1,2-oxazol-3-amine was synthesized following same procedure from benzoylacetonitrile and NH2OH.HCI. LCMS: (ES, m / z): [M+1]+: 161.15.

[0120] Intermediate 15 3-(4-methoxypyrimidin-2-yl)isoxazol-5-amine was synthesized following the same general procedure from 3-(4-methoxypyrimidin-2-yl)-3-oxopropanenitrile and NH2OH.HCI in the presence of sodium hydroxide (3 equiv) and water. LCMS: (ES, m / z): [M+1]+: 193 10Intermediate 35

[0121] Preparation of 4-azido-6-chloro-1-methylpyrazolo[3,4-b]pyridine: 4,6-Dichloro-1 - methylpyrazolo[3,4-b]pyridine (300 mg, 1.48 mmol, 1 equiv) and NaNs (106 mg, 1.63 mmol, 1.1 equiv) in DMF (6 mL) were stirred for 1 h at 100 °C under nitrogen atmosphere then cooled to rt. The resulting mixture wasconcentrated under vacuum to yield 4-azido-6-chloro-1-methylpyrazolo[3,4-b]pyridine (300 mg) (crude). The crude product was used in the next step directly without further purification LCMS: (ES, m / z): [M+1]+:209Intermediate 36

[0122] Preparation of 6-chloro-4-(4-isopropyl-1 H-1 ,2,3-triazol-1-yl)-1-methyl-1 H-pyrazolo[3,4-b]pyridine: To a stirred solution of 4-azido-6-chloro-1 -methyl-1 H-pyrazolo[3,4-b]pyridine (200 mg, 0.95 mmol, 1 equiv.) in MeOH (4 mL) was added 3-methyl-1 -butyne (130 mg, 1.91 mmol, 2 equiv.), sodium L-ascorbate (95.4 mg, 0 47 mmol, 0 5 equiv.) and CuSO4 (76.5 mg, 0.47 mmol, 0.5 equiv ) at rt under a nitrogen atmosphere. The resulting mixture was stirred for 1 h at rt. The reaction was quenched with water at rt, extracted with EtOAc (3 x 20 mL), washed with brine (1 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 6-chloro-4-(4-isopropyl-1 H-1 ,2,3-triazol-1-yl)-1-methyl-1 H-pyrazolo[3,4-b]pyridine (150 mg, yield: 56.5%). LCMS: (ES, m / z): [M+1]+: 277

[0123] The method used to prepare Intermediates 35 and 36 was used to prepare the following intermediates from appropriate starting materials.

[0124] Intermediate 16 6-chloro-1-methyl-4-(4-methyl-1 H-1,2,3-triazol-1-yl)-1 H-pyrazolo[3,4-b]pyridine LCMS: (ES, m / z): [M+1]+:249

[0125] 6-chloro-4-(4-cyclopropyl-1 H-1,2,3-triazol-1-yl)-1-methyl-1 H-pyrazolo[3,4-b]pyridine , LCMS: (ES, m / z): [M+1]+: 275

[0126] Intermediate 17 4-(4-(tert-butyl)-1 H-1,2,3-triazol-1-yl)-6-chloro-1-methyl-1 H-pyrazolo[3,4-b]pyridine, LCMS: (ES, m / z): [M+1]+: 291

[0127] Intermediate 18 6-chloro-4-(4,5-dimethyl-1 H-1 ,2,3-triazol-1-yl)-1-methyl-1 H-pyrazolo[3,4-b]pyridine LCMS: (ES, m / z): [M+1]+: 263

[0128] Intermediate 19 6-chloro-1-methyl-4-(4-(trimethylsilyl)-1 H-1 ,2,3-triazol-1-yl)-1 H-pyrazolo[3,4- bjpyridine ; LCMS: (ES, m / z): [M+1] +: 307. The TMS group was deprotected as described below to obtain 1-{6- chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}-1,2,3-triazole,Intermediate 41

[0129] Preparation of 1-{6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}-1 ,2,3-triazole : A solution of 1-{6- chloro-1 -methylpyrazolo[3,4-b]pyridin-4-yl}-4-(trimethylsilyl)-1 ,2,3-triazole (1 g, 3.259 mmol, 1 equiv) in THF (20 mL) was treated with TBAF (1.28 g, 4.888 mmol, 1.5 equiv) for 1 h at rt under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with ACN in H2O, 20% to 100% gradient to afford 1-{6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}-1,2,3-triazole (702 mg, 90.88%) (315A-3). LCMS: (ES, m / z): [M+1]+: 235.Intermediate 42

[0130] Intermediate 42

[0131] Preparation of 6-chloro-4-(5-isopropyl-1 H-1,2,3-triazol-1-yl)-1-methyl-1 H-pyrazolo[3,4-b]pyridine:To a stirred solution of 4-azido-6-chloro-1 -methyl-1 H-pyrazolo[3,4-b]pyridine (250 mg, 1.19 mmol, 1 equiv.) in THF (2.5 mL) was added 3-methylbut-1 -yne (178 mg, 2.42 mmol, 2 equiv.) and NMI (9.84 mg, 0.12 mmol, 0.1 equiv.) at 0 °C. The mixture was stirred for 5 min and ZnEt? (222 mg, 1.79 mmol, 1 .5 equiv.) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0 °C. The reaction was quenched with sat. Na2S2C>3 (aq.) at 0 °C, extracted with EtOAc (3 x 20 mL), washed with brine (1 x 20 mL), dried over anhydrous Na2SC>4, and concentrated under reduced pressure to afford 6-chloro-4-(5-isopropyl-1 H-1 ,2,3-triazol- 1-yl)-1 -methyl-1 H-pyrazolo[3,4-b]pyridine (200 mg, yield: 61.28%). LCMS: (ES, m / z): [M+1]*: 277

[0132] The same procedure was used to prepare the following intermediates.

[0133] Intermediate 20 6-chloro-4-(5-cyclopropyl-1 H-1,2,3-triazol-1-yl)-1-methyl-1 H-pyrazolo[3,4-b]pyridine,LCMS: (ES, m / z): [M+1]+: 275

[0134] Intermediate 21 4-(5-(tert-butyl)-1 H-1,2,3-triazol-1-yl)-6-chloro-1-methyl-1 H-pyrazolo[3,4-b]pyridine ,LCMS: (ES, m / z) [M+1]+: 291Intermediate 45

[0135] Preparation of 2,2, 5-trimethyl-1,3-dioxan-5-ol: A solution of CeCh (3.79 g, 15.4 mmol, 2.0 eq.) inTHF (20 mL) was treated with methyllithium (1 .6 M in THF, 9.6 mL, 2.0 eq.) for 40 min at -78 °C under nitrogen atmosphere followed by the addition of 2,2-dimethyl-1 ,3-dioxan-5-one (1.00 g, 7.684 mmol, 1.0 eq.) dropwise at -78 °C. The resulting mixture was stirred for an additional 3 h at -78 °C and quenched by the addition of sat. NH4CI (aq.) (5 mL) at -78 °C. The resulting mixture was filtered, washed with EA (3 x 5 mL) and concentrated under reduced pressure to provide 2,2,5-trimethyl-1 ,3-dioxan-5-ol (0.62 g, crude). The crude product was used in the next step directly without further purification.Intermediate 46

[0136] Preparation of 6-chloro-1-methyl-4-[(2,2,5-trimethyl-1,3-dioxan-5-yl)oxy]pyrazolo[3,4-b]pyridine:A solution of 2,2,5-trimethyl-1 ,3-dioxan-5-ol (600 mg, 4.10 mmol, 1.0 eq.) in DMSO (6 mL) was treated with t- BuOK (461 mg, 4.10 mmol, 1.0 eq.) for 5 min at rt under nitrogen atmosphere followed by the addition of 4,6- dichloro-1-methylpyrazolo[3,4-b]pyridine (829 mg, 4.10 mmol, 1 0 eq.) in portions at rt. The resulting mixture was stirred for an additional 1 h at rt, then quenched with ice water (2 L). The resulting mixture was extracted with EA (5 x 500 mL), washed with water (2 x 300 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with ACN in Water (10 mmol / L NH4HCO3), 30% to 80% gradient to provide 6-chloro-1-methyl-4-[(2,2,5-trimethyl-1 ,3- dioxan-5- yl)oxy]pyrazolo[3,4-b]pyridine (570.00 mg, 44.54%). LCMS: (ES, m / z): [M+1]+: 312Intermediate 47

[0137] Preparation of 2-({6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}oxy)-2-methylpropane-1,3- diol: A solution of 6-chloro-1-methyl-4-[(2,2,5-trimethyl-1,3-dioxan-5-yl)oxy]pyrazolo[3,4-b]pyridine (550 mg, 1.76 mmol, 1 .0 eq.) and 2 M HCI (2.75 mL) in THF (5.5 mL) was stirred for 3 h at rt under nitrogen atmosphere then basified to pH 8 with saturated NaHCOa (aq.). The resulting mixture was extracted with EtOAc (3 x 5 mL), dried over anhydrous NazSC , and concentrated under reduced pressure to provide 2-({6-chloro-1 -methylpyrazolo[3,4- b]pyridin-4-yl}oxy)-2-methylpropane-1 ,3- diol (400 mg, 75.11%). The crude product was used in the next step directly without further purification. LCMS: (ES, m / z): [M+1]+: 272Intermediate 48

[0138] Preparation of 6-chloro-4-[(1,3-difluoro-2-methylpropan-2-yl)oxy]-1-methylpyrazolo[3,4-b]: A solution of 2-({6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}oxy)-2-methylpropane-1,3-diol (400 mg, 1.33 mmol, 1.0 eq., 90%) in DCM (6 mL) was treated with DAST (854 mg, 5.30 mmol, 4.0 eq.) at -78 °C under nitrogen atmosphere then warmed to rt and stirred overnight at rt. The reaction was quenched by the addition of NaHCOa (aq.) (3 mL) at 0 °C, then extracted with DCM (3 x 5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with MeCN in Water (0.1% FA), 20% to 60% gradient to provide 6-chloro-4-[(1 ,3-difluoro-2-methylpropan-2-yl)oxy]-1 -methylpyrazolo[3,4- b]pyridine (120 mg, 32.85%). LCMS: (ES, m / z): [M+1]+: 276.Intermediate 49

[0139] Preparation of 6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-ol: A solution of 6-chloro-4-methoxy-1- methylpyrazolo[3,4-b]pyridine (1.00 g, 5.06 mmol, 1 eq) and L-selectride (2.89 g, 15.2 mmol, 3 eq) in THF (10 mL) was stirred for 0.5 h at 90 °C under a nitrogen atmosphere then cooled to rt. The reaction was quenched with sat. NH4CI (aq.) at rt. The residue was purified by reverse flash chromatography with ACN in water (0.05% TFA), 20% to 100% gradient to provide 6-chloro-1 -methylpyrazolo[3,4-b]pyridin-4-ol (305 mg, 32.83%). LCMS: (ES, m / z): [M+1]+: 184.Intermediate 50

[0140] Preparation of 6-chloro-4-(fluoromethoxy)-1-methylpyrazolo[3,4-b]pyridine: A solution of 6-chloro- 1-methylpyrazolo[3,4-b]pyridin-4-ol (290 mg, 1.58 mmol, 1.0 eq), fluoroiodomethane (505 mg, 3.16 mmol, 2.0 eq), t-BuOK (354 mg, 3.16 mmol, 2.0 eq) and Cui (30.1 mg, 0.158 mmol, 0.1 eq) in NMP (14.5 mL) was stirred for 2 h at 100 °C under a nitrogen atmosphere then cooled to rt. The residue was purified by reverse flash chromatography with MeCN in water (0.05% TFA), 20% to 100% gradient to provide 6-chloro-4-(fluoromethoxy)- 1 -methylpyrazolo[3,4-b]pyridine (83 mg, 2437%) (219-2). LCMS: (ES, m / z): [M+1]+: 216Intermediate 51

[0141] Preparation of 6-chloro-4-(difluoromethoxy)-1-methylpyrazolo[3,4-b]pyridine: A solution of 6- chloro-1 -methylpyrazolo[3,4-b]pyridin-4-ol (500 mg, 2.72 mmol, 1 equiv), methyl 2-bromo-2,2-difluoroacetate (772 mg, 4.08 mmol, 1.5 equiv) and K2CO3 (565 mg, 4.08 mmol, 1.5 equiv) in DMF (10 mL) was stirred for 2 h at 50 °C under nitrogen atmosphere then cooled to rt. The resulting mixture was extracted with EtOAc (2 x 50 mL), washed with water (2 x 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 6-chloro-4-(difluoromethoxy)-1-methylpyrazolo[3,4-b]pyridine (130 mg, 16.4%). LCMS: (ES, m / z): [M+1] +: 234

[0142] Preparation of 4-(tert-butoxy)-2,6-dichloropyridine: A solution of 2,6-dichloro-4-nitropyridine (11 g, 57.0 mmol, 1 eq) in THF (220 mL) was treated with t-BuOK (8.00 g, 71 .2 mmol, 1 .25 eq) and stirred for 1 h at 0 °C. The resulting mixture was concentrated under reduced pressure, diluted with water (200 mL), extracted with EtOAc (3 x 100 mL), washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, and was concentrated under reduced pressure to provide 4-(tert-butoxy)-2,6-dichloropyridine (10 g, 79 7%). LCMS: (ES, m / z): [M+1]: 220Intermediate 53

[0143] Preparation of 4-(tert-butoxy)-2,6-dichloropyridine-3-carbaldehyde: A solution of 4-(tert-butoxy)-2.6-dichloropyridine (10 g, 45.4 mmol, 1 eq) in THF (200 mL) was treated with n-BuLi (4.66 g, 72.6 mmol, 1.6 eq) for 5 min at -78 °C under nitrogen atmosphere, then stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added DMF (3.65 g, 49.9 mmol, 1.1 eq) dropwise over 5 min. The resulting mixture was stirred for an additional 2 h at -78 °C, then neutralized to pH 7 with saturated NH4CI (aq.) at -78 °C, and concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-(tert-butoxy)-2,6-dichloropyridine-3- carbaldehyde (9 g, 79.8%). LCMS: (ES, m / z): [M+1]: 248Intermediate 54

[0144] Preparation of 4-(tert-butoxy)-6-chloro-1H-pyrazolo[3,4-b]pyridine: A solution of 4-(tert-butoxy)-2.6-dichloropyridine-3-carbaldehyde (9 g, 36.2 mmol, 1 eq) in THF (180 mL) was treated with NH2NH2'H2O (3.63 g, 72.5 mmol, 2 eq). The resulting mixture was stirred overnight at 80 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 4-(terf-butoxy)-6-chloro-1 H-pyrazolo[3,4-b]pyridine (6.5 g, 79.4%). LCMS: (ES, m / z): [M+1]: 226.General Procedure AIntermediate 55

[0145] Preparation of 6-chloro-1-methyl-4-((1-(oxetan-3-yl)azetidin-3-yl)oxy)-1 H-pyrazolo[3,4-b]pyridine: A solution of 1-(oxetan-3-yl)azetidin-3-ol (120 mg, 0.929 mmol, 1 eq.), 4,6-dichloro-1-methylpyrazolo[3,4- b]pyridine (188 mg, 0.929 mmol, 1 eq.) and t-BuOK (104 mg, 0.929 mmol, 1 eq.) in DMSO (1.20 mL) was stirred for 15 min at rt under nitrogen atmosphere, then poured into water (30ml). The resulting mixture was extracted with EtOAc (3 x 5 mL), washed with water (2 x 3 mL), dried over anhydrous Na2SO4 and filtered, then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with MeCN in Water (0.1 % TFA), 10% to 100% gradient to afford 6-chloro-1-methyl-4-((1-(oxetan-3-yl)azetidin-3- yl)oxy)-1 H-pyrazolo[3,4-b]pyridine (55.0 mg, 17.88%). LCMS: (ES, m / z): [M+1]+: 295

[0146] The above general procedure was followed to synthesize compounds listed in Table A.1 that are not commercially available or synthesized using a different route with the following modifications to the base and solvent. Condition A1a: t-BuOK (1 eq to 3 eq), DMSO (10 V to 50V), r.t, 5 min to 1 h; Condition A1b: DIEA (4.0 eq), DMSO (10 V), 100 °C, o / n; Condition A1c: CS2CO3 (2 eq), DMF (20 V), 100 °C, 2 h; Condition Aid: NaH (60% in mineral oil, 3.1 eq), DMSO (50 V), r.t, 30 min; Condition A1e: NaH (60% in mineral oil, 1.1 eq.), DMF (50 V), 0 °C, 1 h; Condition A1f: EtOH (20V), 80 °C, 1 h to o / n; Condition A1g: CS2CO3 (1 eq to 2 eq), DMSO (20 v), 50 °C, 12 h; Condition A1 h: DIEA (3 eq), DMSO (20 V), 60 °C, 72 h; Condition A1i: K2CO3 (2 eq), DMF (10V), 60 °C, o / n 100 °C, 0.5 h; condition A1j: K2CO3 (2 eq), NMP (10V), 100 °C, o / n.Example 1

[0147] Preparation of 2-methyl-N-(1-methyl-4-{[1-(oxetan-3-yl) azetidin-3-yl]oxy}pyrazolo[3,4-b]pyridin-6-yl)-5-phenylpyrazol-3-amine: A solution of 6-chloro-1-methyl-4-((1-(oxetan-3-yl)azetidin-3-yl)oxy)-1 H- pyrazolo[3,4-b]pyridine (20.0 mg, 0.0680 mmol, 1 eq.), 2-methyl-5-phenylpyrazol-3-amine (14.1 mg, 0.0820 mmol, 1 2 eq.), t-BuOK (15.2 mg, 0.136 mmol, 2 eq ) and RuPhos Pd-G3 (5.68 mg, 0 00700 mmol, 0 1 eq.) in dioxane (0 400 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere, then cooled to rt. The residue waspurified by reversed-phase flash chromatography with MeCN in Water (0.1% FA), 10% to 100% gradient to afford 2-methyl-N-(1 -methyl-4-{[1-(oxetan-3-yl)azetidin-3-yl]oxy}pyrazolo[3,4-b]pyridin-6-yl)-5-phenylpyrazol-3-amine (3.30 mg, 10.73%). LCMS: (ES, m / z): [M+1]+: 432,1H NMR: (400 MHz, DMSO-d6, ppm) 5 9.18 (s, 1 H), 7.84 (s, 1 H), 7.82 - 7.76 (m, 2H), 7.40 (dd, J = 8.4, 6.9 Hz, 2H), 7.33 - 7.25 (m, 1 H), 6.92 (s, 1 H), 6 07 (s, 1 H), 5.05 (p, J = 5.5 Hz, 1 H), 4.67 (d, J = 9.3 Hz, 1 H), 458 (t, J = 6.6 Hz, 2H), 437 (dd, J = 6.6, 5.1 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 1 H), 3.79 (s, 4H), 3.29 (dd, J = 8.4, 5.2 Hz, 2H).

[0148] The above general procedure was followed to synthesize compounds listed in Table A.1 with the following modifications to the base and solvent Compounds annotated in the table were separated by chiral preparative HPLC of the corresponding racemates obtained after final coupling reaction (step 2). Condition A2a: RuPhos Pd G3 (0 1 eq), t-BuOK (2.0 eq), dioxane (20 V), 80 to 100 °C, 10 min to 2 h; Condition A2b: Brettphos Pd G3 (0.1 eq ), CS2CO3 (2 eq.), dioxane (20 V), 80 to 100°C, 3 h to o / n; Condition A2c: RuPhos Pd G3 (0 1 eq), K3PO4 (3 eq), t-AmOH (20 V to 50V), 80 to 100°C, 3 h; Condition A2d: RuPhos Pd G3 (0.1 eq), CS2CO3 (2 eq), dioxane (20 V), 100°C, 2 h; Condition A2e: RuPhos Pd G3 (0.1 eq), t-BuOK (1.0 eq), t-AmOH (20 V), 80 to 100°C, 5 min to 3 h; Condition A2f: Brettphos Pd G3 (0.1 eq.), K2CO3 (2 eq.), Dioxane (20 V), 80°C, 2 h;Condition A2g: Xphos Pd G3 (0.1 eq.), CS2CO3 (2 eq.), Dioxane (20 V), 80°C, 12h; Condition A2h: Xantphos Pd G3 (0.1 eq.), K2CO3 (2 eq.), Dioxane (20 V), 100°C, 1 h; Condition A2i: t-BuBrettphos Pd G3 (0.1 eq.), t- BuBrettphos (0.2 eq.), NaOTMS (2.0 eq.), Dioxane (20 V), 100°C, 2 h, Condition A2j: RuPhos Pd G3 (0.1 eq), K3PO4 (2 eq), dioxane (20 v), 80 °C, 30 min; Condition A2k: Brettphos Pd G3 (0.1 eq.), K3PO4 (3 eq.), dioxane (20 V), 100 °C, 1 h.Table A.1Table A.2 - where step 1 intermediate is commercially availableExample 253

[0149] Preparation of N-{4-[(1,3-difluoro-2-methylpropan-2-yl)oxy]-1-methylpyrazolo[3,4-b]pyridin-6-yl}- 5-(4-methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine: To a solution of 6-chloro-4-[(1 ,3-difluoro-2- methylpropan-2-yl)oxy]-1-methylpyrazolo[3,4-b] pyridine (100 mg, 0.363 mmol, 1.0 eq.) and 5-(4- methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (74.4 mg, 0.363 mmol, 1.0 eq.) in dioxane (1 mL) were added t- BuOK (81.4 mg, 0.726 mmol, 2.0 eq.) and RuPhos Pd G3 (16.9 mg, 0.036 mmol, 0.1 eq.), and stirred for 3 h at 100 °C under nitrogen atmosphere, then cooled to rt. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography with MeCN in Water (10 mmol / L NH4HCO3), 20% to 70% gradient to provide N-{4-[(1 ,3-difluoro-2-methylpropan-2-yl)oxy]-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-5-(4- methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (28.7 mg, 17.20%). LCMS: (ES, m / z): [M+1]+: 445.20,1H NMR (300 MHz, DMSO-de, ppm) 5 9.29 (s, 1 H), 8.54 (d, J = 5.7 Hz, 1 H), 7.94 (s, 1 H), 7.21 (s, 1 H), 6.82 (d, J = 5.7 Hz, 1 H), 6.30 (s, 1 H), 4.74 (dddd, J = 46.8, 25.5, 21.4, 10.7 Hz, 2H), 4.40 (d, J = 18.4 Hz, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 1.51 (dd, J = 21.7, 2.0 Hz, 3H)„19F NMR (282 MHz, DMSO-d6, ppm) 5 -159.98, -160.02.

[0150] Table B summarizes the compounds that were synthesized using the above general procedure starting from appropriate intermediate with following modifications to the reagents. Condition B1a: RuPhos Pd G3 (0.1 eq), t-BuOK (2.0 eq), dioxane (20 V), 80 to 100 °C, 10 min to 2 h; Condition B1 b: Brettphos Pd G3 (0.1 eq.), CS2CO3 (2 eq.), Dioxane (20 V), 80 to 100°C, 3 h to o / n; Condition B1c: RuPhos Pd G3 (0.1 eq), K3PO4 (3 eq), t- AmOH (20 V to 50V), 80 to 100°C, 3 h; Condition Bid: RuPhos Pd G3 (0.1 eq), CS2CO3 (2 eq), dioxane (20 V), 100°C, 2 h; Condition B1e: Brettphos Pd G3 (0.1 eq.), K2CO3 (2 eq.), Dioxane (20 V), 80°C, 2 hTable BIntermediate 56

[0151] Preparation of 5-bromo-N-{4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-2-methylpyrazol-3- amine: A solution of 6-chloro-4-methoxy-1-methylpyrazolo[3,4-b]pyridine (3.00 g, 15.2 mmol, 1.00 eq), 5-bromo- 2-methylpyrazol-3-amine (2.81 g, 15.9 mmol, 1.05 eq), t-BuOK (3.41 g, 30.4 mmol, 2.00 eq) and XPhos Pd G3 (1.28 g, 1.52 mmol, 0.10 eq) in dioxane (150 mL) was stirred for 1 h at 100 °C under a nitrogen atmosphere, then cooled to rt and poured into ice water (3L). The resulting mixture was extracted with EtOAc (3x1 L), washed with brine (1 x 1 L), dried over anhydrous Na2SO and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with MeCN in water (0.1% TFA), 10% to 100% gradient to provide 5-bromo-N-{4-methoxy-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-2-methylpyrazol-3-amine (1.60 g, 30.4%). LCMS: (ES, m / z): [M+1]+: 337Example 660

[0152] Preparation of N-{4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-5-(3-methoxyphenyl)-2- methylpyrazol-3-amine: A solution of 5-bromo-N-{4-methoxy-1 -methyl pyrazolo[3,4-b]pyridi n-6-yl}-2- methylpyrazol-3-amine (100 mg, 0.297 mmol, 1.00 eq), CS2CO3 (290 mg, 0.891 mmol, 3.00 eq) and Pd(dppf)Cl2CH2Cl2 (24.2 mg, 0.030 mmol, 0.10 eq) in THF (3 mL) and H2O (1 mL) was stirred for 1 h at 70 °C under a nitrogen atmosphere, then cooled to rt. The residue was purified by reverse flash chromatography with AON in water (0.05% TFA), 30% to 100% gradient to provide N-{4-methoxy -1 -methylpyrazolo[3,4-b]pyridin-6-yl}- 5-(3-methoxyphenyl)-2-methylpyrazol-3-amine (24.3 mg, 22.48%). LCMS: (ES, m / z): [M+1]+: 365,1H NMR: (300 MHz, DMSO-cfc, ppm) 5 9.23 (s, 1 H), 7.85 (d, J = 1.3 Hz, 1 H), 7 34 (p, J = 7 6 Hz, 3H), 6.94 (s, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 6.25 (s, 1 H), 3.88 (d, J = 1 .3 Hz, 3H), 3.80 (dd, J = 4.7, 1 2 Hz, 6H).

[0153] The above general procedure was followed to synthesize compounds listed in Table C with the following modifications to the base and solvent. Condition C1a: XPhos-Pd-G3 (0.1 eq), t-BuOK (3 eq), dioxane (50 V), 100 °C, 1 h; Condition C1 b: XPhos-Pd-G3 (0.1eq), t-BuOK (3 eq), toluene (20 V), 90 °C, o / n; Condition C1c: RuPhos Pd G3 (0.1 eq), t-BuOK (2.0 eq), dioxane (20 V), 80 to 100°C, 10 min to 2 h; Condition C1d: RuPhos Pd G3 (0 1 eq), t-BuOK (2.0 eq), t-AmOH (20 V), 80 to 100°C, 10 min to 2 h.

[0154] Condition C2a: Pd(dppf)Cl2'CH2Cl2 (0.1 eq), Cs2CO3(3 eq), THF / H2O (3 / 1 , 40 V), 70 °C, 1 h; condition C2b: XPhos-Pd-G3 (0.1 eq), t-BuOK (3 eq), dioxane (20 V), 70 °C, 1 h; condition C2c: XPhos-Pd-G3 (0.1 eq), CS2CO3 (3 eq), dioxane (10 v), 70 °C, 30 min; condition C2d: Pd(dppf)Cl2' CH2CI2 (0.1 eq), K2CO3 (3 eq), dioxane / H2O(3 / 1 , 30v), 100 °C, 30 min; condition C2e = Pd(PPti3)4 (0.1 eq.), K3PO4 (2 eq.), dioxane / H2O (3: 1 , 40v), 80 °C, o / n; condition C2f: Pd(dppf)Cl2'CH2Cl2 (0.1 eq), CS2CO3 (3 eq), CuCI (0.1 eq), dioxane (20 V), 100 °C, 1 h; condition C2g: Pd(PPh3)2Cl2 (0.1 eq), DMSO (20 V), 100 °C, o / n; condition C2h: RuPhos-Pd-G3 (0.1 eq), K3PO4 (2 eq), dioxane (20 V), 80 °C, 30 min.Table CIntermediate 57

[0155] Preparation of 4-methoxy-1-methyl-N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-6-amine: N-(3-Bromo-1-methyl-1 H-pyrazol-5-yl)-4-methoxy-1- methyl-1 H-pyrazolo[3,4-b]pyridin-6-amine (4.0 g, 11.9 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (5.3 g, 23.8 mmol, 2.0 eq), AcOK (3.5 g, 35.7 mmol, 3.0 eq), Xphos Pd G3 (0.9 g, 1.19 mmol, 0.1 eq) in t-AmOH (80 mL) were stirred for 5 h at 90 °C under a nitrogen atmosphere then cooled to rt and quenched by the addition of water / lce (250 mL). The resulting mixture was extracted with EA (3 x 200 mL), washed with brine (2 x 100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by trituration with hexane (100 mL x 2) and dried to afford 4-methoxy-1-methyl-N-(1-methyl-3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4-b]pyridin-6-amine (1.9 g, crude). LCMS: (ES, m / z): [M+1] +: 385

[0156] The same general procedure was followed to synthesize compounds in Table D using condition D1 a: XPhos-Pd-G3 (0 1 eq), AcOK (3 eq), t-AmOH (50 V), 90 °C, 5 hExample 301

[0157] Preparation of 6-[5-({4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}amino)-1-methylpyrazol-3- yl]-N,N-dimethylpyridin-2-amine: A solution of 4-methoxy-1-methyl-N-(1-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4-b]pyridin-6-amine (100 mg, 0.260 mmol, 1 equiv) (224-1), 6- bromo-N,N-dimethylpyridin-2-amine (104.65 mg, 0.520 mmol, 2 equiv), CS2CO3 (254.38 mg, 0.780 mmol, 3 equiv) and Pd(dppf)Cl2.CH2Cl2 (21.20 mg, 0.026 mmol, 0.1 equiv) in dioxane (1.5 mL) and H2O (0.5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reversed-phase flash chromatography with MeCN in Water (0.1% TFA), 10% to 100% gradient to provide 6-[5-({4-methoxy-1- methylpyrazolo[3,4-b]pyridin-6-yl}amino)-1-methylpyrazol-3-yl]-N, N- dimethylpyridin-2-amine (35.5 mg, 35.97%). LCMS: (ES, m / z): [M+1]+: 379,1H NMR (400 MHz, DMSO-d6, ppm) 5 9.26 (s, 1 H), 7.84 (s, 1 H), 7.52 (t, J= 7.9 Hz, 1 H), 7.12 (d, J = 7.9 Hz, 2H), 6.53 (d, J= 8.4 Hz, 1 H), 6.27 (s, 1 H), 3.96 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.07 (s, 6H).

[0158] condition D2a: Pd(dppf)Cl2'CH2Cl2 (0.1 eq), CS2CO3 (3 eq), dioxane / H2O=3:1 , 80 °C, 1 h; condition D2b: Xphos Pd G3 (0.1 eq), AcOK (3 eq), dioxane (50 V), 80 °C, 5 h; condition D2c: Ruphos Pd G3 (0.1 eq), K2CO3 (2 eq), dioxane / H2O = 3 / 1 (30 V), 80 °C, 2 h; condition D2d: Ruphos Pd G3 (0.1 eq), t-BuOK (2 eq), dioxane / H2O = 3 / 1 (30 V), 80 °C, 2 h; condition D2e: Pd(dppf)Cl2 (0.1 eq), K3PO4 (2 eq), dioxane / H2O (3 :1 , 20 V), 80 °C, 3 h; condition D2f: Pd(PPh3)4(0.1 eq), K2CO3(3 eq), toluene / H2O (10 / 1, 30V), 80 °C, 12 h; condition D2g: Pd(dppf)Cl2 (0.1 eq), CS2CO3 (2 eq), dioxane / H2O=3:1 , 80°C, 1-2 h; condition D2h: Pd(dppf)Cl2 (0.1 eq), K3PO4 (2 eq), dioxane (20 V), 80 °C, 1-2 h; condition D2i: Pd(dppf)Cl2.CH2Cl2 (0.1 eq), CS2CO3 (3 eq), dioxane (50 V), 80 °C, 2 h; condition D2j: Pd(dppf)CI2.CH2CI2(0.1 eq), Cs2CO3(3 eq), THF / H2O) (3 / 1 , 50 V), 80 °C, 2 h.Intermediate 58

[0159] N-(3-(3-iodophenyl)-1-methyl-1 H-pyrazol-5-yl)-4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-amine was prepared using conditions D1a and D2f. LCMS: [M + H]+461 .Table DExample 323

[0160] Intermediate 58 was further converted to 5-[3-(azetidin-1 -yl)phenyl]-N-{4-methoxy-1 - methylpyrazolo[3,4-b]pyridin- 6-yl}-2-methylpyrazol-3-amine (Example 323) as described below.

[0161] A solution of 5-(3-iodophenyl)-N-{4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-2-methylpyrazol-3- amine (300 mg, 0.652 mmol, 1 equiv) (Intermediate 58), azetidine (74.4 mg, 1.30 mmol, 2 equiv), f-BuBrettPhos- Pd-G3 (55.7 mg, 0.065 mmol, 0.1 equiv) and f-BuOK (219 mg, 1.956 mmol, 3 equiv) in toluene (9 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere then cooled to rt. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography with water in acetonitrile, 0% to 100% gradient to provide 5-[3-(azetidin-1 -yl)phenyl]-N-{4-methoxy-1 -methylpyrazolo[3,4-b]pyridin- 6-yl}-2- methylpyrazol-3-amine (75.2 mg, 29.57%). LCMS: (ES, m / z): [M+1] +: 390,1H-NMR: (400 MHz, DMSO-cfe ppm) 5 9.22 (s, 1 H), 7.84 (d, J = 1 .7 Hz, 1 H), 7.18 (td, J = 7.8, 1.6 Hz, 1 H), 7.11 - 7.04 (m, 1 H), 6.85 (dd, J = 14.4, 1 .9 Hz, 2H), 6.34 (d, J = 8.0 Hz, 1H), 6.24 (d, J= 1.6 Hz, 1 H), 3.96 (d, J= 1.6 Hz, 3H), 3.89 - 3.75 (m, 10H), 2.32 (d, J = 14.3 Hz, 2H).

[0162] The same procedure was used to synthesize Example 324. 1 H NMR (400 MHz, DMSO-oB, ppm) 5 9.21 (s, 1 H), 7.84 (s, 1 H), 7.18 (t, J = 1.9 Hz, 1 H), 7.11 (t, J = 7.8 Hz, 1 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.84 (s, 1 H), 6.64 (ddd, J = 8.1 , 2.3, 1 .0 Hz, 1 H), 6.25 (s, 1 H), 6.17 - 6.05 (m, 1 H), 3.96 (s, 3H), 3.88 (s, 3H), 3.78 (s, 3H), 2.37 (s, 1 H), 0.70 (td, J = 6.6, 4.4 Hz, 2H), 0.46 - 0.29 (m, 2H) [M+1] +: 390.Intermediate 59

[0163] Preparation of N-{4-chloro4-methylpyrazolo[3,4-b]pyridin-6-yl}-2-methyl-5-phenylpyrazol-3- amine: A solution of 4,6-dichloro-1-methylpyrazolo[3,4-b]pyridine (500 mg, 2.48 mmol, 1 equiv), 2-methyl-5- phenylpyrazol-3-amine (472 mg, 2.72 mmol, 1.1 equiv), CS2CO3 (2.42 g, 7.43 mmol, 3 equiv), Pd(OAc)2 (55.6 mg, 0.248 mmol, 0.1 equiv) and XantPhos (286.39 mg, 0.495 mmol, 0.2 equiv) in DMF (10 mL) was stirred at 100 °C for 1 h under nitrogen atmosphere then cooled to rt. The residue was purified by reversed-phase flash chromatography with MeCN in Water (0.1 % TFA), 10% to 100% gradient to provide N-{4-chloro-1 - methylpyrazolo[3,4-b]pyridin-6-yl}-2-methyl-5-phenylpyrazol-3-amine (232 mg, 27.67% yield, 97% purity) LCMS: (ES, m / z): [M+1]+: 3392 3 q , dioxane (30 v), 100 °C, 2 hExample 325

[0164] Preparation of 1-methyl-N6-(2-methyl-5-phenylpyrazol-3-yl)-N4-(2H-pyrazol-3-yl)pyrazolo[3,4- b]pyridine-4,6-diamine: A solution of N-{4-chloro-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-2-methyl-5-phenylpyrazol- 3-amine (200 mg, 0.590 mmol, 1 equiv), 2H-pyrazol-3-amine (58.9 mg, 0.708 mmol, 1.2 equiv) and CS2CO3 (384 mg, 1.18 mmol, 2 equiv) in 1 ,4-dioxane (6 mL) was treated with RuPhos Pd G3 (49.37 mg, 0.059 mmol, 0.1 equiv) for 2 h at 100 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reversed- phase flash chromatography with MeCN in H2O, 20% to 100% gradient to provide 1 -methyl-N6-(2-methyl-5- phenylpyrazol-3-yl)-N4-(2H-pyrazol-3-yl)pyrazolo[3,4-b]pyridine-4,6-diamine (33.9 mg, LCAP: 95.3%, 14.20%). LCMS: (ES, m / z): [M+1]+: 386.1H-NMR: (300 MHz, DMSO-d6, ppm) 5 12.33 (s, 1 H), 9.25 (s, 1 H), 8.93 (s, 1 H), 8.01 (s, 1 H), 7.76 (d, J = 7.1 Hz, 2H), 7.69 (d, J = 2.3 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1 H), 6.82 (s, 2H), 6.09 (d, J = 2.3 Hz, 1 H), 3.83 (s, 3H), 3.75 (s, 3H).

[0165] The same general procedure was used to synthesize the following compounds with modification to the catalyst and solvent as described in Table E. condition E2a: RuPhos Pd G3 (0.1 eq), t-BuOK (2.0 eq), dioxane (20 V), 80 °C to 100 °C, 1 min to 2 h; condition E2b: RuPhos Pd G3 (0.1 eq), CS2CO3 (2 eq), dioxane (20 V), 100 °C, 2 h; condition E2c: RuPhos Pd G3 (0.1 eq), K3PO4 (3 eq), f-AmOH (20 V to 50 V), 80 to 100 °C, 3 h.Table EIntermediate 60

[0166] Preparation of N-{4-chloro-1-methylpyrazolo[3,4-b]pyridin-6-yl}-5-(3-methoxypyridin-2-yl)-2- methylpyrazol-3-amine: A solution of 4,6-dichloro-1-methylpyrazolo[3,4-b]pyridine (500 mg, 2.48 mmol, 1 equiv), 5-(3-methoxypyridin-2-yl)-2-methylpyrazol-3-amine (505 mg, 2.48 mmol, 1 equiv) and CS2CO3 (1.61 g, 4.95 mmol, 2 equiv) in DMF (10 mL) was treated with Pd(OAc)2 (55.6 mg, 0.248 mmol, 0.1 equiv) and XantPhos (286 mg, 0.495 mmol, 0.2 equiv) for 2 h at 80 °C under nitrogen atmosphere then purified by reversed-phase flash chromatography with H2O in ACN, 10% to 60% gradient to afford N-{4-chloro-1-methylpyrazolo[3,4- b]pyridin-6-yl}-5-(3-methoxypyridin-2-yl)-2- methylpyrazol-3-amine (230 mg, 25.13%). LCMS: (ES, m / z): [M+1]+: 370.

[0167] The same general procedure was used to synthesize the following compounds with modification to the catalyst and solvent as described in Table F condition F1 a: Pd(OAc)2 (0 1 eq), Xantphos (0 2 eq), CS2CO3 ( 2-5 eq), DMF (20 V), 80 °C to 100 °C, 1 - 4 h; condition F1b: DPPF Pd G3 (0.1 eq), K2CO3 (2.0 eq), dioxane (10 V), 100 °C, o / n80 °C, 1 hIntermediate 61

[0168] Preparation of 5-(3-methoxypyridin-2-yl)-2-methyl-N-{1-methyl-4-[2-(oxan-2-yl)-1,2,3-triazol-4- yl]pyrazolo[3,4-b]pyridin-6-yl}pyrazol-3-amine: A solution of N-{4-chloro-1 -methylpyrazolo[3,4-b]pyridin-6-yl}- 5-(3-methoxypyridin-2-yl)-2-methylpyrazol-3-amine (200 mg, 0.541 mmol, 1 equiv), 2-(oxan-2-yl)-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1 ,2,3- triazole (181 mg, 0.649 mmol, 1.2 equiv) and K2CO3 (149 mg, 1.08 mmol, 2 equiv) in dioxane / W 3 / 1 (10 mL) was treated with CatacxiumA-Pd-G3 (39.39 mg, 0.054 mmol, 0.1 equiv) for 1 h at 80 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reversed-phase flash chromatography with MeCN in H2O, 20% to 100% gradient to afford 5-(3-methoxypyridin-2-yl)-2-methyl-N- {1-methyl-4-[2-(oxan-2-yl)-1,2,3-triazol- 4-yl]pyrazolo[3,4-b]pyridin-6-yl}pyrazol-3-amine (130 mg, 49.41 %). LCMS: (ES, m / z): [M+1]+: 487.

[0169] The same general procedure was used to synthesize the following compounds from commercially available boronic acid, boronic ester or stannanes with modification to the catalyst and solvent as described in Table F. condition F2a: Pd(amphos)Cl2 (0.1 eq), Na2COs (1.5 eq), dioxane : H2O (3:1, 10 V), 100 °C, o / n; condition F2b: Pd(dppf)Cl2 (0.1 eq), CS2CO3 (2.0 eq), CuCI (1.0 eq), DMF (10-20 V), 100 °C, 1-3 h; condition F2c: cataCXium-A-Pd-G3 (0.1 eq), K2CO3 (2-3 eq), dioxane / H2O (3 / 1 , 10 - 50 V), 80-100 °C, 1-3 h; condition F2d: Pd(dppf)CI2(0.1 eq), K2CO3 (2 eq), dioxane / H2O (3:1, 30 V), 80 °C, 3 h; Condition F2e: Pd(OAc)2(0.2 eq), Xphos (0.25 eq), KOAc (2.0 eq), t-AmOH (20 V), 100 °C, o / n; Condition F2f: Pd(PPh3)2CI2(0.1 eq), DMSO (10 V), 100 °C, o / n; condition F2g: Pd(PPh3)CI2(0.1 eq), DMF(10V), 100 °C, o / n.Table F*For example 359, see discussion below re: Example 364 deprotection.Example 364

[0170] Preparation of 5-(3-methoxypyridin-2-yl)-2-methyl-N-[1 -methyl-4-(2H-1 ,2,3-triazol-4- yl)pyrazolo[3,4-b]pyridine-6-yl]pyrazol-3-amine: A solution of 5-(3-methoxypyridin-2-yl)-2-methyl-N-{1 -methyl- 4-[2-(oxan-2-yl)-1 ,2,3-triazol-4-yl]pyrazolo [3,4-b]pyridine-6-yl}pyrazol-3-amine (130 mg, 0.267 mmol, 1 equiv) in DCM (6.5 mL) was treated with HCI (g) in 1,4-dioxane (4.0 M) (0.65 mL) for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, basified to pH 7 with NaHCOs and purified by trituration with MeCN to provide 5-(3-methoxypyridin-2-yl)-2-methyl-N-[1 -methyl-4-(2H-1 ,2,3-triazol-4- yl)pyrazolo[3,4-b]pyridin-6-yl]pyrazol-3-amine (10.6 mg, 9.39%). LCMS: (ES, m / z): [M+1]+: 403,1H-NMR: (400 MHz, DMSO-d6, ppm) 5 9.19 (s, 1 H), 8.29 (s, 1 H), 8.20 (dd, J = 4.6, 1.3 Hz, 1 H), 8.05 (d, J = 3.0 Hz, 1 H), 7.53 (dd, J = 8.4, 1.3 Hz, 1 H), 7.32 (dd, J = 8.3, 4.5 Hz, 1 H), 7.17 (s, 1 H), 7.10 (s, 1 H), 3.92 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H).

[0171] The same procedure was followed to deprotect Intermediate 22, (1 -methyl-N-(1 -methyl-3-phenyl-1 H- pyrazol-5-yl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1 H-imidazol-4-yl)-1 H-pyrazolo[3,4-b]pyridin-6-amine) to afford 4- (1 H-imidazol-4-yl)-1 -methyl-N-(1-methyl-3-phenyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4-b]pyridin-6-amine, Example 359.Intermediate 63

[0172] Preparation of 1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-ol: A solution of N-{4-methoxy-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-2-methyl-5-phenylpyrazol-3-amine (10 g, 29.906 mmol, 1 equiv) in HBr (48 wt. % in H20, 100 mL) was stirred for 12 h at 100 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reversed-phase flash chromatography with ACN in Water (0.1% TFA), 10% to 100% gradient to provide 1 -methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-ol (4.5 g, 44.62%). LCMS: (ES, m / z): [M+1]+: 321,Intermediate 64

[0173] Preparation of 1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl trifluoromethanesulfonate: A solution of 1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4- b]pyridin-4-ol (4 g, 12 486 mmol, 1 equiv), TEA (3.79 g, 37.458 mmol, 3 equiv) and trifluoromethanesulfonyl trifluoromethanesulfonate (10.56 g, 37 458 mmol, 3 equiv) in DCM (29 mL) was stirred for 10 min at 0 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL), washed with water (2 x 5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with ACN in Water (0.1 % TFA), 50% to 100% gradient to provide 1 -methyl-6-[(2- methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl trifluoromethanesulfonate (1.9 g, 32.29%). LCMS: (ES, m / z): [M+1]+: 453Intermediate 65

[0174] Preparation of tert-butyl 2-((1-methyl-6-((1-methyl-3-phenyl-1 H-pyrazol-5-yl) amino)-1H- pyrazolo[3,4-b]pyridin-4-yl)amino)-1H-imidazole-1-carboxylate: 1-Methyl-6-((1-methyl-3-phenyl-1 H-pyrazol- 5-yl)amino)-1H- pyrazolo[3,4-b]pyridin-4-yl trifluoromethanesulfonate (150 mg, 0.331 mmol, 1.0 eq), tert-butyl 2- amino-1 H-imidazole-1 -carboxylate (121 mg, 0.662 mmol, 2.0 eq), K3PO4 (140 mg, 0.662 mmol, 2.0 eq), Xphos Pd G3 (27.9 mg, 0.033 mmol, 0.1 eq) in t-AmOH (3 mL) were stirred for 2 h at 80 °C under a nitrogen atmosphere then cooled to rt and purified by reverse flash chromatography with ACN in Water (0.5% TFA), 60% to 70% gradient to provide tert-butyl 2-((1-methyl-6-((1-methyl-3-phenyl-1 H-pyrazol-5-yl) amino)-1 H-pyrazolo[3,4- b]pyridin-4-yl)amino)-1 H-imidazole-1 -carboxylate (46.0 mg, 28.7%). LCMS: (ES, m / z): [M+1]+: 486

[0175] The same general procedure was used to synthesize the following compounds with modification to the catalyst and solvent as described in Table G. Condition G3a: methanamine (10 V), 80 °C, o / n; condition G3b: RuPhos Pd G3 (0.1 eq), K2CO3 (2 eq), t-AmOH (50 V), 80°C, 2 h; condition G3c: XPhos-Pd-G3 (0.1 eq.), K3PO4 (2 eq.), t-AmOH (20 V), 80 °C, 2 h; condition G3d: RuPhos Pd G3 (0.1 eq.), KOAc (3 eq) / K3PO4(2 eq.), t- AmOH (20 V), 80 °C, 3 h; condition G3e: Brettphos Pd G3 (0.1 eq.), CS2CO3 (2 eq.), dioxane (20 V), 80 °C to 100 °C; condition G3f: RuPhos Pd G3 (0.1 eq.), KOAc (2 eq.), dioxane (20 V), 100 °C, 12hTable GExample 375

[0176] Preparation of N4-(1H-imidazol-2-yl)-1-methyl-N6-(1-methyl-3-phenyl-1 H-pyrazol- 5-yl)-1 H- pyrazolo[3,4-b]pyridine-4,6-diamine: tert-Butyl 2-((1-methyl-6-((1-methyl-3-phenyl-1 H-pyrazol-5-yl) amino)-1 H- pyrazolo[3,4-b]pyridin-4-yl)amino)-1 H-imidazole-1 -carboxylate (40 mg, 0.082 mmol, 1.0 eq) in DCM (1 mL) was mixed with HCI (2.5 mol / L, 1 mL) and stirred for 12 h at rt under a nitrogen atmosphere, then purified by reverse flash chromatography with ACN in Water (0.5% TFA), 35% to 60% gradient to provide N4-(1 H-imidazol-2-yl)-1 - methyl-N6-(1 -methyl-3-phenyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4-b]pyridine-4,6-diamine (1.8 mg, 5.6%). LCMS: (ES, m / z): [M+1]+: 386,1H NMR: (300 MHz, DMSO-d6, ppm) 5 9.47 (s, 1 H), 9.06 (s, 1 H), 7.78 (d, J = 8.1 Hz, 3H), 7.40 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.9 Hz, 1 H), 6.87 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H).General Procedure HExample 376

[0177] Preparation of 2-methyl-N-[1-methyl-4-(pyridin-2-yl)pyrazolo[3,4-b]pyridin-6-yl]-5-phenylpyrazol- 3-amine: A mixture of 1 -methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl trifluoromethanesulfonate (150 mg, 0.332 mmol, 1 equiv), 2-(tributylstannyl)pyridine (244.13 mg, 0.664 mmol, 2 equiv) and Pd (PPhs)2Cl2 (23.27 mg, 0.033 mmol, 0.1 equiv) in dioxane (1 .5 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reverse flash chromatography with AON in water, 0% to 100% gradient to provide 2-methyl-N-[1-methyl-4-(pyridin-2-yl)pyrazolo[3,4-b]pyridin-6-yl]-5- phenylpyrazol-3-amine (50.3 mg, 39.69%). LCMS: (ES, m / z): [M+1] +: 382.2,1H NMR (400 MHz, DMSO-d6, ppm) 6 9.54 (s, 1 H), 8.83 (dt, J = 4.9, 1.3 Hz, 1 H), 8.36 (s, 1 H), 8.14 - 7.98 (m, 2H), 7.89 - 7.79 (m, 2H), 7.54 (ddd, J = 7.3, 4 8, 1 .3 Hz, 1 H), 7.50 - 7.36 (m, 3H), 7.34 - 7.25 (m, 1 H), 7.05 (s, 1 H), 4.00 (s, 3H), 3.85 (s, 3H).

[0178] The same general procedure was used to synthesize the following compounds from commercially available boronic acid or boronic ester or stannanes with modification to the catalyst and solvent as described in Table H. condition H1 a: Pd(dppf)Cl2 (0.1 eq), K2CO3 (3 eq), dioxane (20 V), 80 °C, 12 h; condition H1b: Pd(PPh3)4(0.1 eq), K2CO3 (2 eq), toluene / DMF (9 / 1, 50 V), 90 °C, 3 h; condition H1c: Pd(PPh3)CI2(0.1 eq), dioxane (20 V), 80 °C, 12 h; condition H1d: Pd(dppf)CI2(0.1 eq), K2CO3 (2-3 eq), dioxane (15 V), H2O (5 V), 80 °C, 1 h

[0179] Intermediate 23, 1-methyl-N-(1-methyl-3-phenyl-1 H-pyrazol-5-yl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1 H- pyrazol-3-yl)-1 H-pyrazolo[3,4-b]pyridin-6-amine, was converted to Example 382 using the procedure described for Example 364.Table H*Example 382 general procedure was used to obtain the THP protected Intermediate 66, which was deprotectec to yield final productstep 3General Procedure I100 °C, 30 minIntermediate 67

[0180] Preparation of tert-butyl 4-({4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}amino)pyrazole-1- carboxylate: A solution of tert-butyl 4-aminopyrazole-1 -carboxylate (500 mg, 2.73 mmol, 1.0 eq), 6-chloro-4- methoxy-1 -methylpyrazolo[3,4-b]pyridine (539 mg, 2.73 mmol, 1.0 eq), RuPhos Pd G3 (228 mg, 0.273 mmol, 0.1 eq) and CS2CO3 (1.78 g, 5.46 mmol, 2.0 eq) in t-AmOH (5 mL) was stirred for 30 min at 100 °C under a nitrogen atmosphere then cooled to rt. The resulting mixture was extracted with EtOAc (3 x 20 mL), washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure and purified by reverse flash chromatography with water in ACN, 90% to 100% gradient to afford tert-butyl 4-({4-methoxy-1- methylpyrazolo[3,4-b]pyridin-6-yl}amino)pyrazole-1 -carboxylate (300 mg, 25.5%). LCMS: (ES, m / z [M+1]+: 345Intermediate 68

[0181] Preparation of N-{4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-1H-pyrazol-4-amine: A solution of tert-butyl 4-({4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}amino)pyrazole-1-carboxylate (280 mg, 0.813 mmol, 1.0 eq) in DCM (4.48 mL) and TFA (1.12 mL) was stirred for 12 hours at rt under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography with water in acetonitrile, 50% to 60% gradient to afford N-{4-methoxy-1-methylpyrazolo[3,4- b]pyridin-6-yl}-1 H-pyrazol-4-amine (200 mg, 97.6%). LCMS: (ES, m / z): [M+1] +: 245Example 387

[0182] Preparation of N-{4-methoxy-1-methylpyrazolo [3,4-b]pyridin-6-yl}-1 -(6-methylpyridin-2- yl)pyrazol-4-amine: A solution of N-{4-methoxy-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-1 H-pyrazol-4-amine (50.0 mg, 0.205 mmol, 1.0 eq), 2-bromo-6-methylpyridine (70.1 mg, 0.410 mmol, 2.0 eq), (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (7.28 mg, 0.051 mmol, 0.25 eq), K2CO3 (56.6 mg, 0.410 mmol, 2.0 eq) and Cui (5.85 mg, 0.031 mmol, 0.15 eq) in DMF (0.5 mL) was stirred for 12 h at 80 °C under a nitrogen atmosphere then cooled to rt. The resulting mixture was diluted with H2O (50 mL) and extracted with EA (1 x 80 mL), then washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water in acetonitrile 0% to 100% gradient to yield N- {4-methoxy-1-methylpyrazolo [3,4-b]pyridin-6-yl}-1-(6-methylpyridin-2-yl)pyrazol-4-amine (21.9 mg, 31.65%).LCMS: (ES, m / z): [M+1]+: 336,1H NMR: (300 MHz, DMSO-d6, ppm) 9.58 (s, 1 H), 9.12 (s, 1 H), 7.97 (s, 1 H), 7.90 - 7.78 (m, 2H), 7.70 (d, J = 7.7 Hz, 1 H), 7.17 (d, J = 7.4 Hz, 1 H), 6.05 (s, 1 H),3.92 (d, 0 = 2.4 Hz, 6H), 2.54 (s, 3H).

[0183] The same general procedure was used to synthesize compounds in Table I from the common intermediate N-{4-methoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-1 H-pyrazol-4-amine with the following modifications to the reagents, condition I3a: Trans-(1R,2R)N,N'-Dimethyl-cyclohexane-1,2-diamine (0.5 to 1.5 eq), K2CO3 (3 eq), Cui (0.1 to 0.3 eq), DMF (20 to 50 V), 100 °C, 2 h to o / n; condition I3b: Trans-(1R,2R)-N,N'- Dimethyl-cyclohexane-1,2-diamine (0.5 to 1.5 eq), t-BuOK (2 eq), Cui (0.1 eq), DMF, 100 °C, 12 h.TableIntermediate 69

[0184] Preparation of N-{4-cyclopropoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-1 H-pyrazol-4-amine: To a stirred solution of 6-chloro-4-cyclopropoxy-1 -methylpyrazolo[3,4-b]pyridine (1.5 g, 6.71 mmol, 1 equiv) and 4- aminopyrazole (0.84 g, 10 1 mmol, 1.5 equiv) in t-AmOH (30 mL) were added t-BuOK (1.51 g, 13.4 mmol, 2 equiv) and RuPhos Pd G3 (0.56 g, 0.671 mmol, 0.1 equiv) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred for an additional 1.5 h at 80 °C then cooled to rt. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by reversed-phase flash chromatography with AON in Water (0.1% TFA), 30% to 60% gradient to provide N-{4-cyclopropoxy-1- methylpyrazolo[3,4-b]pyridin-6-yl}-1 H-pyrazol-4-amine (1.1 g, 60.7%). LCMS: (ES, m / z): [M+1]+: 271

[0185] The same general procedure was used to synthesize compounds in Table J with the following modifications to the reagents, condition J 1 a: RuPhos-Pd-G3 (0.1 eq), f-BuOK (2 eq), t-AmOH (20 V), 80 °C, 1.5 h; condition J1b: RuPhos Pd G3 (0.1 eq), f-BuOK (2.0 eq), dioxane (20 V), 80 °C to 100 °C, 10 min to 2 hExample 397

[0186] Preparation of N-{4-cyclopropoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-1-phenylpyrazol-4-amine:To a stirred solution of N-{4-cyclopropoxy-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-1 H-pyrazol-4-amine (120 mg, 0.444 mmol, 1.10 equiv) and iodophenyl (82 mg, 0.402 mmol, 1 equiv) in DMF (1.6 mL) were added K2CO3 (167 mg, 1 21 mmol, 3 equiv) and trans-(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (85.8 mg, 0.603 mmol, 1.5 equiv) and Cui (7.65 mg, 0.040 mmol, 0.1 equiv) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred for an additional 1 h at 100 °C then cooled to rt. The resulting mixture was purified by column chromatography, eluted with petroleum ether / EtOAc (5:1) to afford N-{4-cyclopropoxy-1-methylpyrazolo[3,4- b]pyridin-6-yl}-1-phenylpyrazol-4-amine (51.5 mg, 36.4%). LCMS: (ES, m / z): [M+1]+: 347,1H NMR (300 MHz,D MSO-cfc, ppm) 5 9.55 (s, 1 H), 8.78 (s, 1 H), 7.91 (s, 1 H), 7.87 - 7.71 (m, 3H), 7.57 - 7.46 (m, 2H), 7.28 (t, J = 7 A Hz, 1 H), 6.35 (s, 1 H), 4.08 (dt, J = 6.1 , 3.0 Hz, 1 H), 3.97 (s, 3H), 0.95 - 0.76 (m, 4H).

[0187] The same general procedure was used to synthesize compounds in Table J with the following modifications to the reagents. Condition J2a: Trans-(1R,2R)N,N'-Dimethyl-cyclohexane-1 ,2-diamine (0.5 to 1.5 eq), K2CO3 (3 eq), Cui (0.1 to 0.3 eq), DMF (20 to 50V), 100 °C, 2 h to o / n; Condition J2b: RuPhos Pd G3 (0.1 eq), f-BuOK (1.0 eq), f-AmOH (20 V), 80 to 100 °C, 5 min to 3 h Condition J2c: RuPhos Pd G3 (0.1 eq), t-BuOK (2.0 eq), dioxane (20 V), 80 to 100 °C, 10 min to 2 h.Table JExample 407

[0188] Intermediate 70: Preparation of 6-chloro-4-methoxy-1 H-pyrazolo[3,4-b]pyridine: A solution of 2,6- dichloro-4-methoxynicotinaldehyde (25.0 g, 121 mmol, 1 eq.) in EtOH (250 mL) and hydrazine hydrate (15.1 g, 242 mmol, 2 eq., 80%) was heated for 1 .5 hours at 100 °C under nitrogen atmosphere then cooled to rt. The reaction was quenched with water / ice (1 L), with EtOAc (2 x 500 mL), washed with brine (2 x 500 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by trituration with Et20 (500 mL) to afford 6-chloro-4-methoxy-1 H-pyrazolo[3,4-b]pyridine (16.2 g, 72.9%). LCMS: (ES, m / z): [M+1]+: 184

[0189] Intermediate 71 : Preparation of 6-chloro-3-iodo-4-methoxy-1H-pyrazolo[3,4-b]pyridine: To a solution of 6-chloro-4-methoxy-1 H-pyrazolo[3,4-b]pyridine (15 g, 81.6 mmol, 1 eq.) in DCE (150 mL) at 0 °C was added NIS (22.0 g, 98.0 mmol, 1.2 eq.) under nitrogen atmosphere. The resulting mixture was warmed to rt and stirred for 12 hours at rt. The reaction was quenched with water / ice (500 mL), extracted with EtOAc (3 x 300 mL), washed with brine (2 x 300 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography, eluted with PE I EA (3:1) to afford 6-chloro-3-iodo-4-methoxy-1 H- pyrazolo[3,4-b]pyridine (20 g, 79.1 %). LCMS: (ES, m / z): [M+1]+: 310

[0190] Intermediate 72: Preparation of in 6-chloro-3-iodo-4-methoxy-1-methylpyrazolo[3,4-b]pyridine: A solution of 6-chloro-3-iodo-4-methoxy-1 H-pyrazolo[3,4-b]pyridine (20 g, 646 mmol, 1 eq.) and THF (200 mL) was cooled to 0 °C and NaH (60% in mineral oil, 3.88 g, 96.9 mmol, 1.5 eq., 60%) was added in portions at 0 °C. The resulting mixture was stirred for 30 min at rt. Then, Mel (11 .0 g, 77.5 mmol, 1.2 eq.) was added dropwise at 0 °C. The resulting mixture was stirred for an additional 2 hours at rt. The reaction was quenched with water / ice (500 mL) and the resulting mixture was extracted with EtOAc (3 x 300 mL), washed with brine (2 x 500 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel (PE: EA = 3: 1 )to provide 6- chloro-3-iodo-4-methoxy- 1 -methylpyrazolo[3,4-b]pyridine (7.1 g, 34.1%). LCMS: (ES, m / z): [M+1]+: 324

[0191] Intermediate 73: Preparation of 6-chloro-4-methoxy-1,3-dimethyl-1 H-pyrazolo[3,4-b]pyridine: To a stirred solution of K2CO3 (4.3 g, 31 .1 mmol, 1 .5 equiv) in H2O (26 mL) at 0°C under nitrogen atmosphere was added a solution of 6-chloro-3-iodo-4-methoxy-1-methyl-1 H-pyrazolo[3,4-b]pyridine (6.7 g, 20.3 mmol, 1 eq.) in dioxane (108 mL). To the above mixture was added 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (5.21 g, 20.3 mmol, 1 eq.) and Pd(PPh3)2Cl2 (1.66 g, 2.03 mmol, 0.1 eq.) at rt. The resulting mixture was stirred for 12 hours at 80°C. The reaction was quenched with water / ice (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL), washed with brine (2 x 500 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: EtOAc= 2:1) to afford 6-chloro-4-methoxy-1 ,3- dimethyl-1 H-pyrazolo[3,4-b]pyridine (2.1 g, 48.8%). LCMS: (ES, m / z): [M+1]+: 212

[0192] Example 407

[0193] Preparation of N-(5-fluoro-2-methoxyphenyl)-4-methoxy-1,3-dimethylpyrazolo[3,4-b]pyridin-6- amine: A solution of 6-chloro-4-methoxy-1 ,3-dimethylpyrazolo[3,4-b]pyridine (100 mg, 0.472 mmol, 1 eq.) in dioxane (5 mL) was treated with 3-phenylisoxazol-5-amine (75.8 mg, 0.472 mmol, 1 .00 eq.) and RuPhos Pd G3 (39.9 mg, 0.0472 mmol, 0.1 eq.) and f-BuOK (106.0 mg, 0.944 mmol, 2 eq.) for 2 h at 100°C under nitrogenatmosphere. The mixture was cooled to rt and quenched with water / ice (20 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by reverse flash chromatography with MeCN in water, 70% to 90% gradient to afford N-(5-fluoro-2-methoxyphenyl)-4-methoxy-1,3- dimethylpyrazolo[3,4-b]pyridin-6-amine (7.9 mg, 4.7%). LCMS: (ES, m / z): [M+1]+: 336,1H-NMR: (300 MHz, DMSO-ds, ppm) 5 11.02 (s, 1 H), 7.94 - 7.85 (m, 2H), 7.57 - 7.49 (m, 3H), 6.95 (s, 1 H), 6.25 (s, 1 H), 3.94 (d, J = 8.5 Hz, 6H), 2.45 (s, 3H).Examples 408 and 409Intermediate 74

[0194] Preparation of rac-(3R*,4S*)-4-({6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}oxy)oxan-3-ol: To a stirred mixture of rac-(3R*,4S*)-oxane-3,4-diol (1.17 g, 9.90 mmol, 4 eq) and t-BuOK (1.11 g, 9.90 mmol, 4 eq) in DMSO (50 mL) was added 4,6-dichloro-1 -methylpyrazolo[3,4-b]pyridine (500 mg, 2.48 mmol, 1 eq) in portions.The resulting mixture was stirred for 2 h at rt, then directly purified by reversed-phase flash chromatography with ACN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient to provide rac-(3R,4S)-4-({6-chloro-1- methylpyrazolo[3,4-b]pyridin-4-yl}oxy)oxan-3-ol (180 mg, 25.64%). LCMS: (ES, m / z): [M+1]+: 284Intermediate 75

[0195] Preparation of rac-(3R*,4S*)-4-[(1-methyl-6-{[2-methyl-5-(3-methylphenyl)pyrazol-3- yl]amino}pyrazolo[3,4-b]pyridin-4-yl)oxy]oxan-3-ol: To a stirred mixture of rac-(3R,4S)-4-({6-chloro-1 - methylpyrazolo[3,4-b]pyridin-4-yl}oxy)oxan-3-ol (160 mg, 0.564 mmol, 1 eq) and 2-methyl-5-(3- methylphenyl)pyrazol-3-amine (106 mg, 0.564 mmol, 1 eq) in 1 ,4-dioxane (1.6 mL) under nitrogen atmosphere was added t-BuOK (127 mg, 1.13 mmol, 2 eq) in portions followed by RuPhos Pd G3 (47 2 mg, 0.0560 mmol, 0.1 eq) The resulting mixture was stirred for 30 min at 100 °C, cooled to rt, concentrated under reduced pressure, and purified by reversed-phase flash chromatography with ACN in Water (10 mmol / L NH4HCO3), 30% to 90% gradient to provide rac-(3R,4S)-4-[(1-methyl-6-{[2-methyl-5-(3-methylphenyl)pyrazol-3-yl]amino}pyrazolo[3,4- b]pyridin-4-yl)oxy]oxan-3-ol (160 mg, 65.30%). LCMS: (ES, m / z): [M+1]+: 435

[0196] Chiral separation of rac-(3R*,4S*)-4-[(1-methyl-6-{[2-methyl-5-(3-methylphenyl)pyrazol-3- yl]amino}pyrazolo[3,4-b]pyridin-4-yl)oxy]oxan-3-ol: The racemate (160 mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALCellulose-SB4.6*100 mm, 3 urn; Mobile Phase A: Hex (0.1 % DEA): EtOH=50: 50; Gradient: isocratic; Injection Volume: 2.0 mL) to afford Example 790, re / -(3R*,4S*)-4-[(1-methyl-6-{[2-methyl-5-(3-methylphenyl)pyrazol-3-yl]amino}pyrazolo[3,4-b]pyridin-4-yl)oxy]oxan-3-ol (34.9 mg, 21.66%) as an off-white solid and Example 791, re / -(3S*,4R*)-4-[(1-methyl-6-{[2-methyl-5-(3-methylphenyl)pyrazol-3- yl]amino}pyrazolo[3,4-b]pyridin-4-yl)oxy]oxan-3-ol (32.1 mg, 19.96%) as an off-white solid.

[0197] Example 408: LCMS: (ES, m / z): [M+1]+: 435.20,1H NMR (400 MHz, DMSO-d6, ppm) 5 9.11 (s, 1 H), 7.89 (s, 1 H), 7.63 (s, 1 H), 7.57 (d, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.15 - 7.06 (m, 1 H), 6.88 (s, 1 H), 6.30 (s, 1 H), 5.08 (d, J = 5.3 Hz, 1 H), 4.78 (dt, J = 7.1 , 3.2 Hz, 1 H), 3.88 (s, 4H), 3.78 (s, 5H), 3.56 (ddd, J = 15.5, 9.5, 3.4 Hz, 2H), 2.36 (s, 3H), 2.16 - 2.01 (m, 1 H), 1 92 - 1.80 (m, 1 H).

[0198] Example 409: LCMS: (ES, m / z): [M+1]+: 435.20,1H NMR (400 MHz, DMSO-d6, ppm) 5 9.11 (s, 1 H), 7.89 (s, 1 H), 7.63 (s, 1 H), 7.57 (d, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.15 - 7.06 (m, 1 H), 6.88 (s, 1 H), 6.30 (s, 1 H), 5.08 (d, J = 5.3 Hz, 1 H), 4.78 (dt, J = 7.1 , 3.2 Hz, 1 H), 3.88 (s, 4H), 3.78 (s, 5H), 3.56 (ddd, J = 15.5, 9.5, 3.4 Hz, 2H), 2.36 (s, 3H), 2.16 - 2.01 (m, 1 H), 1.92 - 1.80 (m, 1 H).Examples 410 and 411Intermediate 76

[0199] Preparation of 6-chloro-1-methyl-4-[(1,1,1-trifluoropropan-2-yl)oxy]pyrazolo[3,4-b]pyridine: 4,6- Dichloro-1 -methylpyrazolo[3,4-b]pyridine (1 g, 4.95 mmol, 1 equiv), 1, 1 ,1 -trifl uoro-2-propanol (1.13 g, 9.90 mmol, 2 equiv), f-BuOK (0.61 g, 5.45 mmol, 1.1 equiv) and DMSO (10 mL) were stirred at rt for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of water / ice (2 mL), and the crude reaction mixture was purified by reversed-phase flash chromatography with AON in Water (0.05% NH4HCO3), 10% to 80% gradient to provide 6-chloro-1-methyl-4-[(1 ,1 ,1-trifluoropropan-2-yl)oxy]pyrazolo[3,4-b]pyridine (800 mg, 57.22%). LCMS: (ES, m / z): [M+1]+: 280.Intermediate 77

[0200] Preparation of in 5-(4-methoxypyrimidin-2-yl)-2-methyl-N-{1-methyl-4-[(1,1,1-trifluoropropan-2- yl)oxy]pyrazolo[3,4-b]pyridin-6-yl}pyrazol-3-amine: 6-Chloro-1-methyl-4-[(1 ,1, 1 -trifluoropropan-2- yl)oxy]pyrazolo[3,4-b]pyridine (800 mg, 2.86 mmol, 1 equiv), 5-(4-methoxypyrimidin-2-yl)-2-methylpyrazol-3- amine (587 mg, 2.86 mmol, 1 equiv), CS2CO3 (1.86 g, 5.72 mmol, 2 equiv), BrettPhos Pd G3 (259 mg, 0.286 mmol, 0.1 equiv) and dioxane (16 mL) were stirred at 100 °C for 1 h under nitrogen atmosphere, then cooled to rt, concentrated under vacuum, and purified by reversed-phase flash chromatography with MeCN in Water (0.05% NH4HCO3), 10% to 80% gradient to provide 5-(4-methoxypyrimidin-2-yl)-2-methyl-N-{1-methyl-4-[(1 , 1 ,1 -trifluoropropan-2-yl)oxy]pyrazolo[3,4-b]pyridin-6-yl)pyrazol-3-amine (560 mg, 43.44%). LCMS: (ES, m / z): [M+1 ]+: 449.

[0201] Chiral separation of 5-(4-methoxypyrimidin-2-yl)-2-methyl-N-{1-niethyl-4-[(1,1,1-trifluoropropan- 2-yl)oxy]pyrazolo[3,4-b]pyridin-6-yl}pyrazol-3-amine: The racemic product (560 mg) was purified by Prep- HPLC with the following conditions (Column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 pm; Mobile Phase A: HEX (0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 30; wavelength: 220 / 254 nm; RT1 (min): 8.453; RT2(min): 10.469; Sample Solvent: EtOH; Injection Volume: 0.6 mL; Number Of Runs: 12) to afford Example 410, re / -5-(4-methoxypyrimidin-2-yl)-2-methyl-N-(1-methyl-4-{[(2S*)-1,1,1- trifluoropropan-2-yl]oxy}pyrazolo[3,4-b]pyridin-6-yl)pyrazol-3-amine (208.6 mg, 36 91 %) and Example 411, re / -5- (4-methoxypyrimidin-2-yl)-2-methyl-N-(1-methyl-4-{[(2R*)-1, 1,1-trifluoropropan-2-yl]oxy}pyrazolo[3,4-b]pyridin-6- yl)pyrazol-3-amine (1930 mg, 34.15%).

[0202] Example 792: LCMS: (ES, m / z): [M+1]+: 449,1H NMR (400 MHz, DMSO-d6, ppm) 5 9.35 (s, 1 H), 8.54 (d, J = 5.7 Hz, 1 H), 7.88 (s, 1 H), 7.17 (s, 1 H), 6.82 (d, J = 5.7 Hz, 1 H), 6 41 (s, 1 H), 5.48 (p, J = 6.4 Hz, 1 H), 3.99 (s, 3H), 387 (m, 6H), 1.56 (d, J = 6.3 Hz, 3H).

[0203] Example 793: LCMS: (ES, m / z): [M+1]+: 449,1H NMR (400 MHz, DMSO-d6, ppm) 5 9.35 (s, 1 H), 8.54 (d, J = 5.7 Hz, 1 H), 7.88 (s, 1 H), 7.17 (s, 1 H), 6.82 (d, J = 5.7 Hz, 1 H), 6.41 (s, 1 H), 5.48 (p, J = 6.4 Hz, 1 H), 3.99 (s, 3H), 3.87 (m, 6H), 1.56 (d, J = 6.3 Hz, 3H).Examples 412 and 413Intermediate 78

[0204] Preparation of rac-(1S*,3R*)-3-({6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclohexan-1- ol: A solution of c / s-cyclohexane-1 ,3-diol (500 mg, 4.3 mmol, 1 equiv) in DMSO (25 mL) was treated with NaH (60% in oil, 319 mg, 13.3 mmol, 3.1 equiv) for 5 min at rt under nitrogen atmosphere followed by the addition of 4,6-dichloro-1 -methylpyrazolo[3,4-b]pyridine (870 mg, 4.3 mmol, 1 equiv) dropwise at rt. The resulting mixture was stirred for 0.5 h at rt under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) (10 mL) at 0 °C, then extracted with EtOAc (4 x 20 mL), washed with water (1 x 10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by reversed-phase flash chromatography with ACN in Water (10 mmol / L NH4HCO3), 10% to 100% gradient to provide rac-(1 S*,3R*)-3-({6-chloro-1-methylpyrazolo[3,4- b]pyridin-4-yl}oxy)cyclohexan-1-ol (354.3 mg, 27.75%). LCMS: (ES, m / z) [M+1]+: 282Intermediate 79

[0205] Preparation of rac-(1S*,3R*)-3-({1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino] pyrazolo[3,4- b]pyridin-4-yl}oxy)cyclohexan-1-ol: A solution of rac-(1 S,3R)-3-({6-chloro-1 -methylpyrazolo[3,4-b]pyridin-4- yl}oxy)cyclohexan-1-ol (150 mg, 0.532 mmol, 1 equiv), 2-methyl-5-phenylpyrazol-3-amine (92.2 mg, 0.532 mmol, 1 equiv), RuPhos Pd G3 (44.5 mg, 0.053 mmol, 0.1 equiv) and f-BuOK (179 mg, 1.6 mmol, 3 equiv) in dioxane (1.5 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere, then cooled to rt. The resulting mixture was filtered, washed with MeOH (3 x 10 mL), concentrated under reduced pressure, dissolved in DMF (10 mL) and purified by reversed-phase flash chromatography with ACN in Water (10 mmol / L NH4HCO3), 30% to 100% gradient to provide rac-(1 S*,3R*)-3-({1 -methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4- yl}oxy)cyclohexan-1-ol (170 mg, 74.77%). LCMS: (ES, m / z): [M+1]+: 419

[0206] Chiral separation of / ■ac-(1S*,3R*)-3-({1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino] pyrazolo[3,4-b]pyridin-4-yl}oxy)cyclohexan-1-ol: The racemate rac-(1S*,3R*)-3-({1-methyl-6-[(2-methyl-5- phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl}oxy)cyclohexan-1 -ol (170 mg, 74.77%) was purified by Chiral-HPLC with the following conditions (Column: CHIRAL ART Cel lulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RT1 (min): 5.78; RT2 (min): 7.647; Sample Solvent: EtOH; Injection Volume: 0.5 mL; Number Of Runs: 10) to afford Example 412, re / -(1S,3R)-3-({1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino] pyrazolo[3,4-b]pyridin-4-yl}oxy)cyclohexan-1 -ol (56.1 mg, 44.7%) and Example 413, re / -(1 R,3S)-3-({1-methyl-6- [(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl}oxy)cyclohexan-1 -ol (51 .3 mg, 55.3%).

[0207] Example 794: LCMS: (ES, m / z): [M+1]+: 419,1H NMR (300 MHz, DMSC-06, ppm) 6 9.15 (s, 1 H), 7.84- 7.74 (m, 3H), 7.41 (dd, J = 8.4, 6.8 Hz, 2H), 7.35 - 7.24 (m, 1 H), 6.94 (s, 1 H), 6.31 (s, 1 H), 4.81 (d, J = 4.7 Hz, 1 H), 4.54 - 4.41 (m, 1 H), 3.88 (s, 3H), 3.80 (s, 3H), 3.64 - 3.50 (m, 1 H), 2.41 (d, J = 11 .6 Hz, 1 H), 2.13 (s, 1 H), 1.93 - 1.70 (m, 2H), 1.35 (q, J= 11.1, 10.7 Hz, 3H), 1.14 (d, J= 10.6 Hz, 1 H).

[0208] Example 795: LCMS: (ES, m / z): [M+1]+: 419,1H NMR (300 MHz, DMSC-06, ppm) 5 9.15 (s, 1 H), 7.86- 7.72 (m, 3H), 7.41 (t, J = 7.5 Hz, 2H), 7.34 - 7.24 (m, 1 H), 6.94 (s, 1 H), 6.31 (s, 1 H), 4.81 (d, J = 4.7 Hz, 1 H), 4.50 (d, J = 10.9 Hz, 1 H), 3.87 (s, 3H), 3.79 (s, 3H), 3.64 - 3.50 (m, 1 H), 2.41 (d, 0 = 11.6 Hz, 1 H), 2.13 (s, 1 H), 1.82 (dd, 0 = 27.1 , 9.5 Hz, 2H), 1.35 (q, 0 = 11.1, 10.7 Hz, 3H), 1.16 (t, 0 = 11.2 Hz, 1 H).Examples 414 and 415Intermediate 80

[0209] Preparation of rac-(1S*,2R*)-2-({6-chloro-1-methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1- ol: A solution of 4,6-dichloro-1-methylpyrazolo[3,4-b]pyridine (200 mg, 0.990 mmol, 1 equiv), c / s-cyclopentane- 1 ,2-diol (506 mg, 495 mmol, 5 equiv) and t-BuOK (111 mg, 0.990 mmol, 1 equiv) in DMSO (10 mL) was stirred for 5 min at rt under nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by reverse-phase flash chromatography with AON in Water, 20% to 100% gradient to provide rac-(1 S*,2R*)-2- ({6-chloro-1 -methylpyrazolo[3,4-b] pyridin-4-yl}oxy)cyclopentan-1 -ol (170 mg, 64.15%). LCMS: (ES, m / z): [M+1]+: 268Intermediate 81

[0210] Preparation of rac-(1S*,2R*)-2-({1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4- b]pyridin-4-yl}oxy)cyclopentan-1-ol: A solution of rac-(1 S*,2R*)-2-({6-chloro-1-methylpyrazolo[3,4-b]pyridin-4- yl}oxy)cyclopentan-1-ol (150 mg, 0.560 mmol, 1 equiv), 2-methyl-5-phenylpyrazol-3-amine (116 mg, 0.672 mmol, 1.2 equiv), t-BuOK (126 mg, 1.12 mmol, 2 equiv) and RuPhos Pd G3 (46.9 mg, 0.056 mmol, 0.1 equiv) in dioxane (9 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere then cooled to rt and concentrated. The residue was purified by reverse-phase flash chromatography with ACN in Water, 20% to 100% gradient to provide rac-(1 S,2R)-2-({1- methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4- yl}oxy)cyclopentan-1 -ol (150 mg, 66.19%). LCMS: (ES, m / z): [M+1]+: 405

[0211] Chiral separation of rac-(1S*,2R*)-2-({1-methyl-6-[(2-methyl-5-phenylpyrazol-3- yl)amino]pyrazolo[3,4-b]pyridin-4-yl}oxy) cyclopentan-1-ol: The racemate was purified by preparative chiral- HPLC with the following conditions (Column: CHIRALPAK IA, 5*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RT1 (min): 5.867; RT2(min): 8.198; Sample Solvent: EtOH; Injection Volume: 0.5 mL; Number Of Runs: 10) to afford Example 414, re / -(1 S*,2R*)-2-({1-methyl-6-[(2-methyl-5-phenylpyrazol-3- yl)amino]pyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1 -ol (30.7 mg, LCAP: 99.88%, 20.43%) and Example 415, re / -(1 R*,2S*)-2-({1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b] pyridin-4-yl}oxy) cyclopentan- 1-ol (40.1 mg, LCAP: 99.74%, 26.65%).

[0212] Example 796: LCMS: (ES, m / z): [M+1]+: 405,1H-NMR: (300 MHz, DMSO-ds, ppm) 6 9.12 (s, 1 H), 7.87 (s, 1 H), 7 84 - 7.74 (m, 2H), 7.47 - 7 35 (m, 2H), 7.35 - 7.23 (m, 1 H), 6.93 (s, 1 H), 6.27 (s, 1 H), 4.80 (d, J = 5.4 Hz, 1 H), 4.66 (q, J = 5.1 Hz, 1H), 4.28 - 4 15 (m, 1 H), 3.88 (s, 3H), 3.80 (s, 3H), 2.15 - 1 98 (m, 1 H), 1.92 - 1.66 (m, 4H), 1.64 - 1.51 (m, 1 H).

[0213] Example 797: LCMS: (ES, m / z) [M+1]+: 405,1H-NMR: (300 MHz, DMSO-ds, ppm) 5 9.12 (s, 1 H), 7.87 (s, 1 H), 7.84 - 7.74 (m, 2H), 7.47 - 7.35 (m, 2H), 7.35 - 7.24 (m, 1 H), 6.93 (s, 1 H), 6.27 (s, 1 H), 4.80 (d, J = 5.5 Hz, 1 H), 4.66 (q, J = 5.0 Hz, 1H), 4.28 - 4 17 (m, 1 H), 3.88 (s, 3H), 3.80 (s, 3H), 2.15 - 1 98 (m, 1 H), 1.92 - 1.66 (m, 4H), 1.64 - 1.51 (m, 1 H).Examples 416 and 417Intermediate 82

[0214] Preparation of rac-(1 R*,2S*)-2-[(6-{[5-(3-chlorophenyl)-2-methylpyrazol-3-yl]amino}-1- methylpyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1-ol: A solution of rac-(1R*,2S*)-2-({6-chloro-1- methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1-ol (500 mg, 1.868 mmol, 1 equiv) (468-1), 5-(3- chlorophenyl)-2-methylpyrazol-3-amine (465 mg, 2.24 mmol, 1.2 equiv), f-BuOK (419 mg, 3.74 mmol, 2 equiv) and RuPhos Pd G3 (156 mg, 0.187 mmol, 0.1 equiv) in f-AmOH (10 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere then cooled to rt and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with ACN in Water (10 mmol / L NH4HCO3), 10% to 100% gradient to provide the product. LCMS: (ES, m / z): [M+1]+: 439

[0215] Chiral separation of rac-(1 R*,2S*)-2-[(6-{[5-(3- chlorophenyl)-2-methylpyrazol-3-yl]amino}-1- methylpyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1-ol The crude racemate (503 mg) was purified by preparative HPLC with the following conditions (Column: CHIRALPAKIA-3; Mobile Phase A: (3:1 Hexanes:DCM) (0.1%DEA): EtOH=90: 10; flow rate: 1.0 mL / min; Gradient: isocratic; Injection Volume: 3 L) to afford Example 416, re / -(1 R*,2S*)-2-[(6-{[5-(3-chlorophenyl)-2-methylpyrazol-3-yl]amino}-1 -methylpyrazolo[3,4-b]pyridin-4- yl)oxy]cyclopentan-1-ol (119.6 mg, LCAP: 98.05%, 14.30%) and Example 417, re / -(1S*,2R*)-2-[(6-{[5-(3- chlorophenyl)-2-methylpyrazol-3-yl]amino}-1 -methylpyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1 -ol (119.6 mg, 14.30 %).

[0216] Example 798: LCMS: (ES, m / z): [M+1]+: 439,1H NMR (300 MHz, DMSO-de, ppm) 5 9.12 (s, 1 H), 7.87 (s, 1 H), 7 81 (t, J = 1.8 Hz, 1 H), 7 75 (dt, J = 7.7, 1.3 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.38 - 7.31 (m, 1 H), 6 97 (s, 1 H), 6 26 (s, 1 H), 4.78 (d, J = 5.5 Hz, 1 H), 4.66 (d, J = 5.5 Hz, 1 H), 421 (t, J = 4.9 Hz, 1 H), 387 (s, 3H), 3.79 (s, 3H), 2 13 - 1.97 (m, 1 H), 1.91 - 1 63 (m, 4H), 1.62 - 1.46 (m, 1 H).

[0217] Example 799: LCMS: (ES, m / z): [M+1]+: 439, 1 H NMR (300 MHz, DMSO-d6) 9.15 (s, 1 H), 7.88 (s, 1 H), 7.82 (t, J = 1 .8 Hz, 1 H), 7.76 (dt, J = 7.8, 1.4 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.39 - 7.30 (m, 1 H), 6.99 (s, 1 H), 6.28 (s, 1 H), 4.81 (d, J = 5.4 Hz, 1 H), 4.67 (q, J = 5.1 Hz, 1 H), 4.22 (q, J = 5.0 Hz, 1 H), 3.88 (s, 3H), 3.80 (s, 3H), 2.06 (s, 1 H), 1.93 - 1 44 (m, 5H).Example 418 and 419Intermediate 83

[0218] Preparation of rac-(1R*,2S*)-2-({6-[(2-cyclopropyl-5-phenylpyrazol-3-yl)amino]-1- methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1-ol: A solution of Example 221, rac-(1R*,2S*)-2-({1- methyl-6-[(5-phenyl-2H-pyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1 -ol (950 mg, 2.43 mmol, 1 equiv), cyclopropylboronic acid (418 mg, 4.87 mmol, 2 equiv), 2-(pyridin-2-yl)pyridine (380 mg, 2.43 mmol, 1 equiv), Na2CO3 (516 mg, 4.87 mmol, 2 equiv) and Cu(AcO)2 (442 mg, 2.43 mmol, 1 equiv) in DCE (47.5 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reverse flash chromatography with Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Gradient: 5% B to 5% B in 2 min, 5% B to 45% B in 2.5 min, 45% B to 55% B in 12 min; to provide rac-(1R*,2S*)-2-({6-[(2- cyclopropyl-5-phenylpyrazol-3-yl)amino]-1 -methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1 -ol (270 mg, 25.78%). LCMS: (ES, m / z): [M+1]+: 431

[0219] Chiral separation of rac-(1 R*,2S*)-2-({6-[(2-cyclopropyl-5-phenylpyrazol-3-yl)amino]-1- methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1-ol: The racemate (270 mg, 0.627 mmol, 1 equiv) was purified by preparative chiral HPLC with the following conditions (Column: CHIRALPAK SB 2*25 cm, 5 pm;Mobile Phase A: HEX (0.5% 2M NHa-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RT1 (min): 8.162; RT2 (min): 10.814; Sample Solvent: EtOH; Injection Volume: 0.5 mL; Number Of Runs: 15) to afford Example 418, re / -(1R*,2S*)-2-({6-[(2-cyclopropyl-5-phenylpyrazol-3- yl)amino]-1-methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan-1-ol (101.6 mg, 37.37%) and Example 419, rel-(1 S*,2R*)-2-({6-[(2-cyclopropyl-5-phenylpyrazol-3-yl)amino]-1 -methylpyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan- 1-ol (98.3 mg, 35.97%).

[0220] Example 800: LCMS: (ES, m / z): [M+1]+: 431 ,1H-NMR: (400 MHz, DMSO-cfc, ppm) 6 9.12 (s, 1 H), 7.87 (s, 1 H), 7.82 - 7.74 (m, 2H), 7.40 (dd, J = 8.3, 7.0 Hz, 2H), 7.33 - 7.25 (m, 1 H), 6.97 (s, 1 H), 6.35 (s, 1 H), 4.81 (d, J = 5.4 Hz, 1 H), 4.67 (q, J = 5.1 Hz, 1 H), 4.23 (q, J = 5.0 Hz, 1 H), 3.89 (s, 3H), 3.59 (tt, J = 7.3, 3.8 Hz, 1 H), 2.08 (s, 1H), 1.84 (s, 2H), 1.81 (dd, J = 7.5, 3.4 Hz, 1 H), 1.75 - 1.67 (m, 1 H), 1.57 (s, 1 H), 1.17 - 1.06 (m, 2H), 1.09 - 0 98 (m, 2H).

[0221] Example 801 : LCMS: (ES, m / z): [M+1]+: 431 , 'H-NMR: (400 MHz, DMSO-d6, ppm) 5 9.12 (s, 1 H), 7.87 (s, 1 H), 7.82 - 7.74 (m, 2H), 7.40 (dd, J = 8.3, 7.0 Hz, 2H), 7.33 - 7.25 (m, 1 H), 6.97 (s, 1 H), 6.35 (s, 1 H), 4.81 (d, J = 5.4 Hz, 1 H), 4.67 (q, J = 5.2 Hz, 1 H), 4.22 (p, J = 5.2 Hz, 1 H), 3.89 (s, 3H), 3.59 (tt, J = 7.3, 3.8 Hz, 1 H), 2.09 (s, 1H), 2.15 - 2.03 (m, OH), 1.89 - 1.78 (m, 1 H), 1.83 (s, 3H), 1.76 - 1.69 (m, 1 H), 1.57 (td, J = 12.1 , 10.7, 7.6 Hz, 1 H), 1.13 (dq, J = 5.6, 3.8 Hz, 2H), 1.03 (tdd, 3 = 8.2, 4.8, 2.9 Hz, 2H).Examples 420, 421, 422, & 423Intermediate 84

[0222] Preparation of rac-2-[(1-methyl-6-{[2-(oxan-2-yl)-5-phenylpyrazol-3-yl]amino}pyrazolo[3,4- b]pyridin-4-yl)oxy] cyclopentan-1-ol: A solution of rac-2-chlorooxane (400 mg, 3.32 mmol, 2 equiv), Example 221, rac-(1R*,2S*)-2-({1-methyl-6-[(5-phenyl-2H-pyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl}oxy)cyclopentan- 1-ol (648 mg, 1.66 mmol, 1 equiv) and TEA (1.00 g, 9.95 mmol, 3 equiv) in DCM (20 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by chromatography Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 5% B to 40% B in 2.5 min, 40% B to 70% B in 10 min to provide rac-2-[(1-methyl-6-{[2-(oxan-2-yl)-5-phenylpyrazol-3- yl]amino}pyrazolo[3,4-b]pyridin-4-yl)oxy] cyclopentan-1 -ol (110 mg, 7%). LCMS: (ES, m / z): [M+1]+: 475,1H- NMR: (400 MHz, DMSO-cfe, ppm) 5 9.06 (d, J = 1.6 Hz, 1 H), 7.89 (s, 1 H), 7.86 - 7.77 (m, 2H), 7.43 (dd, J = 8.3, 6.9 Hz, 2H), 7.36 - 7.29 (m, 1 H), 7 04 (d, J = 3 5 Hz, 1 H), 6.34 (s, 1 H), 5.57 (ddd, J = 9.6, 4.3, 2.7 Hz, 1 H), 4.82 (dd, J = 5.4, 3.1 Hz, 1 H), 4.68 (q, J = 5.1 Hz, 1 H), 4.23 (tq, J = 5.4, 3.7, 2.7 Hz, 1 H), 3.90 (d, J = 1.4 Hz, 4H), 3.66 (td, J = 11.1, 3.6 Hz, 1 H), 2.47 - 2.38 (m, 1 H), 2.09 (tq, J = 12.5, 3.9 Hz, 2H), 1.93 (dd, J = 13.2, 3.2 Hz, 1 H), 1.89 - 1.78 (m, 3H), 1 .77 - 1.50 (m, 5H).

[0223] Chiral separation of rac-(1 R*,2S*)-2-[(1-methyl-6-{[2-(oxan-2-yl)-5-phenylpyrazol-3- yl]amino}pyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1-ol: The racemate (110 mg, 0 232 mmol) was purified by preparative chiral HPLC with the following conditions (Column: CHIRALPAK IA, 5*25 cm, 5 pm; Mobile Phase A: Hex: DCM=3: 1 (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Gradient: isocratic; wavelength: 220 / 254 nm; RT1 (min): 4.696; RT2 (min): 9.047; Sample Solvent: EtOH-HPLC) to afford Example 420, re / - (1 R*,2S*)-2-{[1 -methyl-6-({2-[(2S*)-oxan-2-yl]-5-phenylpyrazol-3-yl}amino)pyrazolo[3,4-b]pyridin-4- yl]oxy}cyclopentan-1-ol (13.6 mg, 12.09%) and Example 421 , re / -(1S*,2R*)-2-{[1-methyl-6-({2-[(2S*)-oxan-2-yl]-5- phenylpyrazol-3-yl}amino)pyrazolo[3,4-b]pyridin-4-yl]oxy}cyclopentan-1-ol (15.7 mg, 14.13%) and Example 422, re / -(1 R*,2S*)-2-{[1-methyl-6-({2-[(2R*)-oxan-2-yl]-5-phenylpyrazol-3-yl}amino)pyrazolo[3,4-b]pyridin-4- yl]oxy}cyclopentan-1-ol (14.6 mg, 12.97%) and Example 423, re / -(1 S* 2R*)-2-{[1-methyl-6-({2-[(2R*)-oxan-2-yl]-5- phenylpyrazol-3-yl}amino)pyrazolo[3,4-b]pyridin-4-yl]oxy}cyclopentan-1-ol (16.1 mg, 14.40%). LCMS-Example 420: (ES, m / z): [M+1]+: 475

[0224] Example 802:1H-NMR (400 MHz, DMSO-ck, ppm) 5 9.06 (s, 1 H), 7.88 (s, 1 H), 7.86 - 7.79 (m, 2H),7.43 (dd, J = 8.3, 7.0 Hz, 2H), 7.37 - 7.29 (m, 1 H), 7.03 (s, 1 H), 6.33 (s, 1 H), 5.56 (dd, J = 9.5, 2.6 Hz, 1 H), 4.81 (d, J = 5.4 Hz, 1 H), 4.67 (q, J = 5.0 Hz, 1 H), 4.26 - 4.17 (m, 1 H), 3.92 (d, J = 11.6 Hz, 1 H), 3.89 (s, 3H), 3.66 (s, 1 H), 2.46 - 2.35 (m, 1 H), 2.11 - 2.03 (m, 2H), 1.93 (d, J = 12.9 Hz, 1 H), 1.83 (s, 2H), 1.89 - 1.75 (m, 3H), 1.57 (s, 3H).

[0225] Example 803:1H-NMR: (400 MHz, DMSO-d6, ppm) 5 9.06 (s, 1 H), 7.88 (s, 1 H), 7.86 - 7.79 (m, 2H), 7.47 - 7.39 (m, 2H), 7.37 - 7.28 (m, 1 H), 7.04 (s, 1 H), 6.33 (s, 1 H), 5.57 (dd, J = 9.5, 2.7 Hz, 1 H), 4.82 (d, J = 5.4 Hz, 1 H), 4.71 - 4.65 (m, 1 H), 4.22 (p, J = 5.4 Hz, 1 H), 3.89 (s, 3H), 3.72 - 3.61 (m, 1 H), 2.46 - 2.35 (m, 1 H), 2.11 - 2.03 (m, 2H), 1.93 (d, J = 13.0 Hz, 1 H), 1.82 (dd, J = 7.2, 4.6 Hz, 1 H), 1.67 - 1.54 (m, 4H), 1 .56 (s, 3H).

[0226] Example 804:1H-NMR: (400 MHz, DMSO-d6, ppm) 6 9.06 (s, 1 H), 7.88 (s, 1 H), 7.86 - 7.79 (m, 2H),7.43 (t, J = 7.6 Hz, 2H), 7.37 - 7.28 (m, 1 H), 7.03 (s, 1 H), 6.33 (s, 1 H), 5.56 (dd, J = 9.6, 2.6 Hz, 1 H), 4.81 (d, J = 5.4 Hz, 1 H), 4.67 (q, J= 5.1 Hz, 1 H), 4.27 - 4.17 (m, 1 H), 3.92 (d, J = 11.5 Hz, 1 H), 3.89 (s, 3H), 3.71 - 3.61 (m, 1 H), 2.42 (q, J = 13.1 , 11.2 Hz, 1 H), 2.14 - 2.03 (m, 2H), 1.93 (d, J = 12.8 Hz, 1 H), 1.82 (td, J = 7.6, 3.5 Hz, 5H), 1.58 (td, J = 7.7, 7.0, 3.8 Hz, 3H).

[0227] Example 805:1H-NMR: (400 MHz, DMSO-d6, ppm) 5 9.05 (s, 1 H), 7.88 (s, 1 H), 7.85 - 7.79 (m, 2H),7.43 (t, J = 7.6 Hz, 2H), 7.39 - 7 31 (m, 1 H), 7.04 (s, 1 H), 6.33 (s, 1 H), 5.57 (dd, J = 9.5, 2 7 Hz, 1 H), 4.82 (d, J = 5.4 Hz, 1 H), 4.68 (q, J = 5.3 Hz, 1 H), 4.29 - 4.17 (m, 1 H), 3.89 (s, 4H), 3.70 - 3.62 (m, 1 H), 2.45 - 2.33 (m, 1 H), 2.14 - 2.00 (m, 2H), 1.93 (d, J = 13.3 Hz, 1 H), 1.90 - 1.76 (m, 3H), 1.77 - 1.47 (m, 5H).Example 424 & 425Intermediate 85

[0228] Preparation of rac-(1R*,2S*)-2-[(6-{[2-(difluoromethyl)-5- phenylpyrazol-3-yl]amino}-1- methylpyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1-ol: A solution of Example 221, rac-(1R,2S)-2-({1- methyl-6-[(5-phenyl-2H-pyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl}oxy) cyclopentan-1 -ol (800 mg, 2.05 mmol, 1 equiv), sodium 2-chloro-2,2-difluoroacetate (625 mg, 4.10 mmol, 2 equiv) and Na2COg (434 mg, 4.10 mmol, 2 equiv) in DMF (40 mL) was stirred for 2 h at 60 °C under nitrogen atmosphere then cooled to rt. The residue was purified by chromatography Mobile Phase A: CO2, Mobile Phase B: MEOH (0.1 % 2 M NHs-MeOH); Gradient: isocratic 43% B; to provide rac-(1 R,2S)-2-[(6-{[2-(difluoromethyl)-5-phenylpyrazol-3-yl]amino}-1- methylpyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1-ol (150 mg, 16.62%). LCMS: (ES, m / z): [M+1] +: 441

[0229] Chiral separation of rac-(1 R*,2S*)-2-[(6-{[2-(difluoromethyl)-5-phenylpyrazol-3-yl]amino}-1- methylpyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1-ol: The racemate (150 mg, 0.341 mmol) was purified by preparative chiral HPLC with the following conditions (Column: CHIRALPAK IA, 5*25 cm, 5 pm; Mobile Phase A: Hex: DCM=3: 1 (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Gradient: isocratic; wavelength: 220 / 254 nm; RT1 (min): 8.329; RT2 (min): 12.989; Sample Solvent: EtOH-HPLC) to afford Example 424 re / - (1R*,2S*)-2-[(6-{[2-(difluoromethyl)-5-phenylpyrazol-3-yl]amino}-1-methylpyrazolo[3,4-b]pyridin-4- yl)oxy]cyclopentan-1-ol (48.2 mg, 31.7%) and Example 425, re / -(1S*,2R*)-2-[(6-{[2-(difluoromethyl)-5- phenylpyrazol-3-yl]amino}-1-methylpyrazolo[3,4-b]pyridin-4-yl)oxy]cyclopentan-1 -ol (47.4 mg, 31.0%).

[0230] Example 806:1H-NMR (400 MHz, DMSO-d6, ppm) 6 9.56 (s, 1 H), 7.95 - 7.86 (m, 3H), 7.77 (s, 1 H), 7.48 (t, J = 7.3 Hz, 2H), 7.45 - 7.37 (m, 1 H), 7.09 (s, 1 H), 6.32 (s, 1 H), 4.84 (d, J = 5.5 Hz, 1 H), 4.73 - 4.64 (m , 1 H), 4.28 - 4.18 (m, 1 H), 3.89 (s, 3H), 2.10 (ddt, J = 12.4, 8.9, 5.2 Hz, 1 H), 1 90 - 1.79 (m, 1 H), 1.83 (s, 2H), 1.73 (s, 1 H), 1.64 - 1.54 (m, 1H).

[0231] Example 807:1H-NMR (400 MHz, DMSO-d6, ppm) 6 9.56 (s, 1 H), 7.95 - 7.86 (m, 3H), 7.77 (s, 1 H), 7.48 (t, J = 7.3 Hz, 2H), 7.45 - 7.37 (m, 1 H), 7.09 (s, 1 H), 6.32 (s, 1 H), 4.84 (d, J = 5.5 Hz, 1 H), 4.73 - 4.64 (m , 1 H), 4.28 - 4.18 (m, 1 H), 3.89 (s, 3H), 2.10 (ddt, J = 12.4, 8.9, 5.2 Hz, 1 H), 1.90 - 1.79 (m, 1 H), 1.83 (s, 2H), 1.73 (s, 1H), 1.64 - 1.54 (m, 1H).Example 426Intermediate 86

[0232] Preparation of 4-(tert-butoxy)-6-chloro-1-methylpyrazolo[3,4-b]pyridine: A solution of 4,6- dichloro-1 -methylpyrazolo[3,4-b]pyridine (200 mg, 0.990 mmol, 1 equiv), 2-methyl-2-propanol (73.4 mg, 0.990 mmol, 1 equiv) and t-BuOK (111 mg, 0.990 mmol, 1 equiv) in DMSO (10 mL) was stirred for 5 min at rt under nitrogen atmosphere, concentrated and purified by reverse-phase flash chromatography with MeCN in Water, 20% to 100% gradient to provide 4-(tert-butoxy)-6-chloro-1 -methylpyrazolo[3,4-b]pyridine (135 mg, 57 %). LCMS: (ES, m / z): [M+1]+: 240

[0233] Preparation of N-[4-(tert-butoxy)-1-methylpyrazolo[3,4-b]pyridin-6-yl]-5-(4-methoxypyrimidin-2- yl)-2-methylpyrazol-3-amine: A solution of 4-(tert-butoxy)-6-chloro-1 -methylpyrazolo[3,4-b]pyridine (120 mg, 0.501 mmol, 1 equiv), 5-(4-methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (123 mg, 0.601 mmol, 1.2 equiv), t- BuOK (112 mg, 1.00 mmol, 2 equiv) and RuPhos Pd G3 (41.9 mg, 0.0500 mmol, 0.1 equiv) in dioxane (6 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere then cooled to rt. The reaction mixture was concentrated and purified by reverse-phase flash chromatography with MeCN in Water, 20% to 100% gradient to provide N-[4- (tert-butoxy)-l -methylpyrazolo[3,4-b]pyridin-6-yl]-5-(4-methoxypyrimidin-2-yl)- 2-methylpyrazol-3-amine (57.3 mg, LCAP: 97.97%, 27.43%). LCMS: (ES, m / z): [M+1]+: 409,1H-NMR: (400 MHz, DMSO-d6, ppm) 5 9.19 (s, 1 H), 8.54 (d, J = 5.7 Hz, 1 H), 7.75 (s, 1 H), 7.25 (s, 1 H), 6.82 (d, J = 5.7 Hz, 1 H), 6.51 (s, 1 H), 4.00 (s, 3H), 3.87 (d, J =2.1 Hz, 6H), 1.57 (s, 9H).Example 427Intermediate 87

[0234] Preparation of 2-(5-{[4-(tert-butoxy)-1-methylpyrazolo [3,4-b]pyridin-6-yl]amino}-1- methylpyrazol-3-yl)pyrimidin-4-ol: A solution of N-[4-(tert-butoxy)-1 -methylpyrazolo[3,4-b]pyridin-6-yl]-5-(4- methoxypyrimidin-2- yl)-2-methylpyrazol-3-amine (240 mg, 0.588 mmol, 1.0 eq) and NaOH (4 M aq., 1.2 mL) in MeOH (1 .2 mL) was stirred for 4 h at 100 °C under nitrogen atmosphere then cooled to rt. The mixture wasacidified to pH 6 with AcOH. The resulting mixture was concentrated under reduced pressure to provide 2-(5-{[4- (tert-butoxy)-l -methylpyrazolo [3,4-b]pyridin-6-yl]amino}-1-methylpyrazol-3-yl)pyrimidin-4-ol (220 mg, crude). The crude product was used in the next step directly without further purification LCMS: (ES, m / z): [M+1]+: 395

[0235] Preparation of N-[4-(tert-butoxy)-1-methylpyrazolo[3,4-b]pyridin-6-yl]-5-[4- (difluoromethoxy)pyrimidin-2-yl]-2-methylpyrazol-3-amine: A solution of 2-(5-{[4-(tert-butoxy)-1 - methylpyrazolo[3,4-b]pyridin-6-yl]amino}-1-methylpyrazol-3-yl) pyrimidin-4-ol (200 mg, 0.507 mmol, 1.0 eq), KF (118 mg, 2.03 mmol, 4 0 eq) and diethyl bromodifluoromethylphosphonate (203 mg, 0.760 mmol, 1.5 eq) in ACN (2 mL) was stirred for 4 h at 40 °C under nitrogen atmosphere. The resulting mixture was filtered, washed with ACN (5 mL), concentrated under reduced pressure, and purified by reversed-phase flash chromatography with MeCN in Water (10 mmol / L NH4HCO3), 20% to 90% gradient to provide N-[4-(tert-butoxy)-1-methylpyrazolo[3,4- b]pyridin-6-yl]-5-[4-(difluoromethoxy)pyrimidin-2-yl]-2-methylpyrazol-3-amine (91.6 mg, 2 steps: 35.10%). LCMS: (ES, m / z): [M+1]+: 418.15,1H NMR (400 MHz, DMSO-de, ppm) 5 9.22 (s, 1 H), 8.82 (d, J = 5.5 Hz, 1 H), 8.12 - 7.70 (m, 2H), 7.32 (s, 1 H), 7.11 (d, J = 5.6 Hz, 1 H), 6.53 (s, 1 H), 3.89 (s, 3H), 3.88 (s, 3H), 1.57 (s, 9H),19F NMR (376 MHz, DMSO-de, ppm) 5 -88.46.Example 428

[0236] Preparation of N-{4-cyclopropoxy-1-methylpyrazolo[3,4-b]pyridin-6-yl}-5-(4-methoxypyrimidin- 2-yl)-2-methylpyrazol-3-amine: A solution of 5-(4-methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (0.5 g, 2.44 mmol, 1 00 equiv), 6-chloro-4-cyclopropoxy-1 -methylpyrazolo[3,4-b]pyridine (0.60 g, 2.68 mmol, 1.1 equiv) and K3PO4 (1 .04 g, 4 872 mmol, 2 equiv) in t-AmOH (25 mL) was treated with RuPhos Pd G3 (0.20 g, 0.244 mmol, 0.1 equiv) at rt and stirred for 1 h at 80 °C under nitrogen atmosphere, then cooled to rt and diluted with water (300 mL). The resulting mixture was extracted with EA (2 X 400 mL), concentrated under reduced pressure, and purified by column chromatography, eluted with DCM / MeOH (100 / 1-20 / 1) to afford crude product. The crude product was purified by trituration with ether to afford N-{4-cyclopropoxy-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-5- (4-methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (4.54 g, LCAP: 97.2%, 38.5%). LCMS: (ES, m / z): [M+1]+: 393.1 ,1H-NMR: (400 MHz, DMSO-cfe, ppm) 6 9.36 (s, 1 H), 8.54 (d, J= 5.7 Hz, 1 H), 7.83 (s, 1 H), 7.20 (s, 1 H), 6.82 (d, J= 5.7 Hz, 1 H), 6.55 (s, 1 H), 4.11 (dp, J = 6.3, 3.0 Hz, 1 H), 4.00 (s, 3H), 3.87 (d, J= 2.0 Hz, 6H), 0.88 (dd, J= 6.6, 3.9 Hz, 2H), 0.85 (t, J= 3.6 Hz, 2H).Example 429Intermediate 89

[0237] Preparation of 6-chloro-4-(3,3-difluorocyclobutoxy)-1-methylpyrazolo [3,4-b]pyridine: 4,6- Dichloro-1 -methylpyrazolo[3,4-b]pyridine (500 mg, 2.47 mmol, 1 equiv) in DMSO (5 mL) were added with a solution of 3,3-difl uorocyclobutan-1 -ol (802 mg, 7.42 mmol, 3 equiv) and f-BuOK (833 mg, 7.42 mmol, 3 equiv) and stirred for 6 hours at 80 °C under nitrogen atmosphere, then cooled to rt and quenched with 10 mL water. The resulting mixture was extracted with EtOAc (2 x 10 mL), washed with brine (1 x 15 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure., and purified by reversed-phase flash chromatography with MeCN in Water (5 mmol / L TFA), 50% to 60% gradient to provide 6-chloro-4-(3,3- difluorocyclobutoxy)-1-methylpyrazolo [3,4-b]pyridine (201 mg, yield: 29.6%). LCMS: (ES, m / z): [M+1]+: 274

[0238] Preparation of N-[4-(3,3-difluorocyclobutoxy)-1-methylpyrazolo[3,4-b]pyridin-6-yl]-5-(4- methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine: A solution of 6-chloro-4-(3,3-difl uorocyclobutoxy)- 1 - methylpyrazolo[3,4-b]pyridine (181 mg, 0.661 mmol, 1 equiv) in t-AmOH (3.6 mL) was treated with 5-(4- methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (149 mg, 0.727 mmol, 1.1 equiv), K3PO4 (421 mg, 1.98 mmol, 3 equiv) and RuPhos Pd G3 (55.3 mg, 0.066 mmol, 0.1 equiv) at rt under nitrogen atmosphere, and stirred for 3 hours at 80 °C under nitrogen atmosphere, then cooled to rt and quenched with Water / lce at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by reverse flash chromatography with MeCN in water, 70% to 80% gradient to provide N-[4-(3,3- difluorocyclobutoxy)- 1 -methylpyrazolo[3,4-b]pyridin-6-yl]-5-(4- methoxypyrimidin-2-yl)-2-methylpyrazol-3-amine (98.1 mg, yield: 33.1 %). LCMS: (ES, m / z): [M+1]+: 443,1H NMR: (300 MHz, DMSO-cfe ppm) 6 9.25 (s, 1 H), 8.52 (d, J = 5.8 Hz, 1 H), 7.84 (s, 1 H), 7.18 (s, 1 H), 6.80 (d, J = 5.7 Hz, 1 H), 6.17 (s, 1 H), 4.97 (s, 1 H), 3.98 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.23 (q, J = 9.3, 8.1 Hz, 2H), 2.89 (td, J = 14.4, 9.7 Hz, 2H).dioxane (20 V) 100 °C, 2 hExample 430

[0239] 6-Chloro-4-methoxy-1 -methylpyrazolo[3,4-b]pyridine (100 mg, 0.506 mmol, 1 equiv) and 1 -methyl-3- phenyl-1 H-pyrazol-5-amine (87.8 mg, 0.506 mmol, 1 equiv) in dioxane (2 mL) were stirred with t-BuOK (114 mg, 1.01 mmol, 2 equiv) and RuPhos Pd G3 (42.3 mg, 0.0506 mmol, 0.1 equiv) at rt, then stirred for 2 h at 100 °C,then cooled to rt and quenched with Water / lce. The resulting mixture was extracted with EtOAc (3 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by reverse flash chromatography with ACN in water, 70% to 80% gradient to provide 4-methoxy-1-methyl-N-(1- methyl-3-phenyl-1 H-pyrazol-5-yl)-1 H-pyrazolo[3,4-b]pyridin-6-amine (40 7 mg, yield: 35.5%). LCMS: (ES, m / z): [M+1]+: 335,1H NMR: (300 MHz, DMSO-c / 6ppm) 6 9.23 (s, 1 H), 7.88 - 7.76 (m, 3H), 7.41 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1 H), 6.95 (s, 1 H), 6.26 (s, 1 H), 3.97 (s, 3H), 3.89 (s, 3H), 3.80 (s, 3H).Example 431

[0240] A solution of 2-(5-{[4-(tert-butoxy)-1 -methylpyrazolo[3,4-b]pyridin-6-yl]amino}-3-(4-methoxypyrimidin-2- yl)pyrazol-1 -yl)ethanol, Example 41 (160 mg, 0.365 mmol, 1 equiv), sodium chlorodifluoroacetate (83.5 mg, 0.547 mmol, 1.5 equiv), CS2CO3 (357 mg, 1.10 mmol, 3 equiv) and DMF (2.4 mL) was stirred at 90 °C for 2 h under nitrogen atmosphere then cooled to rt. The resulting mixture was filtered, washed with ACN (3 x 5 mL), concentrated under reduced pressure, and purified by reversed-phase flash chromatography with MeCN in Water (0.05% NH4HCO3), 10% to 50% gradient to provide 2-(5-{[4-(tert-butoxy)-1 -methylpyrazolo[3,4-b]pyridin-6- yl](difluoromethyl)amino}-3-(4-methoxypyrimidin-2-yl)pyrazol-1 -yl)ethanol (2 4 mg, 1.24%). LCMS: (ES, m / z): [M+1]+: 489,1H NMR (400 MHz, DMSO-de) 5 8.58 (d, J = 5.8 Hz, 1 H), 8.21 (t, J = 61.4 Hz, 1 H), 7.90 (s, 1 H), 7.03 (s, 1 H), 6 88 (d, J = 5 8 Hz, 1 H), 5.81 (s, 1 H), 4.90 (t, J = 5.4 Hz, 1 H), 4.10 (t, J = 6.1 Hz, 2H), 3.97 (d, J = 14.1 Hz, 6H), 3.81 (q, J = 5.9 Hz, 2H), 1.35 (s, 9H)Example 432Intermediate 90

[0241] Preparation of N-{4-azido-1-methylpyrazolo [3,4-b]pyridin-6-yl}-2-methyl-5-phenylpyrazol-3- amine: A solution of N-{4-chloro-1 -methylpyrazolo[3,4-b]pyridin-6-yl}-2-methyl-5-phenylpyrazol-3-amine (600 mg, 1.77 mmol, 1 equiv) in DMF (12 mL) was treated with sodium azide (230 mg, 3.54 mmol, 2 equiv) overnight at 100 °C under nitrogen atmosphere, then cooled to rt. The residue was purified by reversed-phase flashchromatography with MeCN in H20, 10% to 100% gradient to provide N-{4-azido-1-methylpyrazolo [3,4-b]pyridin- 6-yl}-2-methyl-5-phenylpyrazol-3-amine (220 mg, 26.98%). LCMS: (ES, m / z): [M+1]+: 346.

[0242] Preparation of 2-methyl-N-[1-methyl-4-(5-methyl-1,2,3-triazol-1-yl)pyrazolo[3,4-b]pyridin-6-yl]-5- phenylpyrazol-3-amine: A solution of N-{4-azido-1 -methylpyrazolo[3,4-b]py ridin-6-yl}-2-methyl-5-phenylpyrazol- 3-amine (100 mg, 0.290 mmol, 1 equiv), and 1 , 1 ,3,3-tetramethylguanidine (100.05 mg, 0.870 mmol, 3 equiv) in MeCN (2 mL) was treated with dimethyl 2-oxopropylphosphonate (48.10 mg, 0.290 mmol, 1 equiv) for 1h at 80 °C under nitrogen atmosphere then cooled to rt. The residue was purified by reversed-phase flash chromatography with MeCN in H2O, 20% to 100% gradient to provide 2-methyl-N-[1 -methyl-4-(5-methyl-1 ,2,3- triazol-1 -yl)pyrazolo[3,4-b]pyridin-6-yl]-5-phenylpyrazol-3-amine (6.3 mg, LCAP: 989%, 5.58%). LCMS: (ES, m / z): [M+1]+: 386,1H NMR (400 MHz, Chloroform-d) 5 8.02 (s, 1 H), 7.87 - 7.76 (m, 2H), 7 65 (d, J = 1 0 Hz, 1 H), 7.44 (dd, J = 8.3, 6 8 Hz, 2H), 7.39 - 7.31 (m, 1 H), 6.60 (s, 1 H), 6.52 (s, 1 H), 6.48 (s, 1 H), 4.09 (s, 3H), 3.90 (s, 3H), 2.42 (d, J = 0.9 Hz, 3H).Examples 433 and 434Intermediate 91

[0243] Preparation of methyl 1-{1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b] pyridin-4-yl}-1,2,3-triazole-4-carboxylate and methyl-3-{1-methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino] pyrazolo[3,4-b]pyridin-4-yl}-1,2,3-triazole-4-carboxylate: A solution of N-{4-azido-1 -methylpyrazolo[3,4- b]pyridin-6-yl}-2-methyl-5-phenylpyrazol-3-amine (200 mg, 0.579 mmol, 1 equiv) and methyl propiolate (97.4 mg, 1.16 mmol, 2 equiv) in toluene (4 mL) was treated with Cp*RuCI(PPh3)2 (46.1 mg, 0.058 mmol, 0.1 equiv) for 2 h at 80 °C under nitrogen atmosphere, then cooled to rt. The residue was purified by reversed-phase flash chromatography with MeCN in H20, 10% to 100% gradient to provide a mixture of methyl 1 -{1 -methyl-6-[(2- methyl-5-phenyl pyrazol-3-yl)ami no]pyrazolo[3,4-b] pyridin-4-yl}- 1 ,2,3-triazole-4-carboxylate and methyl-3-{1 - methyl -6-[(2-methyl -5-pheny I pyrazol-3-y l)ami no] py razolo[3, 4-b]py ridi n-4-y l}-1 , 2, 3-tri azole-4-carboxy I ate (62 mg, 95% purity). LCMS: (ES, m / z): [M+1]+: 430.

[0244] Preparation of (1 -{1-methyl-6-[(2-methyl-5- phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4- yl}-1,2,3-triazol-4-yl)methanol and (3-{1-methyl-6-[(2-methyl- 5-phenylpyrazol-3-yl)amino]pyrazolo[3,4- b]pyridin-4-yl}-1,2,3-triazol-4-yl)methanol: A solution of methyl 1 -{1 -methyl-6-[(2-methyl-5-phenylpyrazol-3- yl)amino]pyrazolo[3,4-b]pyridin-4-yl}-1 ,2,3-triazole-4-carboxylate and methyl3-{1 -methyl-6-[(2-methyl-5- phenylpyrazol-3-yl)amino]pyrazolo[3,4-b] pyridin-4-yl}-1,2,3-triazole-4-carboxylate (55 mg, 0.128 mmol, 1 equiv)in THF (5 mL) was treated with Li Al H4 (1 .0 M in THF) (0.26 mL, 0.256 mmol, 2 equiv) for 1 h at 0 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with MeCN in H2O, 20% to 100% gradient to provide a mixture of (1 -{1 -methyl-6-[(2-methyl-5- phenylpyrazol-3-yl)amino]pyrazolo[3,4- b]pyridin-4-yl}-1,2,3-triazol-4-yl)methanol and (3-{1-methyl-6-[(2-methyl- 5-phenylpyrazol-3-yl)amino]pyrazolo[3,4- b]pyridin-4-yl}-1 ,2,3-triazol-4-yl)methanol (41 mg, 96% purity) LCMS: (ES, m / z): [M+1]+: 402.

[0245] Separation of regioisomers: The mixture of (1 -{1 -methyl-6-[(2-methyl-5-phenylpyrazol-3- yl)amino]pyrazolo[3,4-b]pyridin-4-yl}-1 ,2,3-triazol-4-yl) methanol and (3-{1-methyl-6-[(2-methyl-5-phenylpyrazol-3- yl)amino]pyrazolo[3,4-b]pyridin-4-yl}-1 ,2,3-triazol-4-yl) methanol (41 mg, 0.102 mmol, 1 equiv) was purified by preparative HPLC (Column: GreenSep Basic 3*15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NHs-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 33% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wave Length: 254 nm; RT1(min): 3.87; RT2(min): 4.77; Sample Solvent: MeOH-HPLC; Injection Volume: 2 mL; Number Of Runs: 4.0) to afford (3-{1-methyl-6-[(2-methyl-5-phenylpyrazol-3- yl)amino]pyrazolo[3,4-b]pyridin-4-yl}-1 ,2,3-triazol-4-yl)methanol (3.1 mg, yield: 7.34%) and (1-{1-methyl-6-[(2- methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-yl}-1,2,3-triazol-4-yl)methanol (10.6 mg, yield: 25.85%).

[0246] Example 433: LCMS: (ES, m / z): [M+1]+: 402.1H-NMR: (400 MHz, DMSO-d6, ppm) 59.73 (s, 1 H), 7.98 (d, J = 4.4 Hz, 2H), 7.88 - 7.78 (m, 2H), 7.42 (dd, J = 8.3, 6.9 Hz, 2H), 7.36 - 7.26 (m, 1 H), 7.14 (s, 1 H), 7.00 (s, 1 H), 5.80 (s, 1 H), 4.77 (s, 2H), 3.99 (s, 3H), 3.84 (s, 3H).

[0247] Example 434: LCMS: (ES, m / z): [M+1]+: 402.1H NMR (400 MHz, DMSO-d6, ppm) 5 9 66 (s, 1 H), 8.85 (s, 1 H), 827 (s, 1 H), 7.87 - 7.79 (m, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.36 - 7.25 (m, 2H), 7.01 (s, 1 H), 5.41 (s, 1 H), 4.67 (d, J = 3.0 Hz, 2H), 3.99 (s, 3H), 3.84 (s, 3H).Example 435

[0248] A solution of 1 -methyl-6-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyrazolo[3,4-b]pyridin-4-ol (300 mg, 0.936 mmol, 1 equiv), difluoromethyl trifluoromethanesulfonate (374.73 mg, 1.872 mmol, 2 equiv) and KOH (157.62 mg, 2.808 mmol, 3 equiv) in AON (4.5 mL) and H2O (1.5 mL) was stirred overnight at rt under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with MeCN in Water (0.1% TFA), 10% to 100% gradient to afford N-[4-(difluoromethoxy)-1 -methylpyrazolo[3,4-b]pyridin-6-yl]-2-methyl-5- phenylpyrazol-3-amine (54.6 mg, 14.96%). LCMS: (ES, m / z): [M+1]+: 371 ;1H NMR (300 MHz, DMSO-d6, ppm) 5 9.51 (s, 1 H), 7.95 (s, 1 H), 7.82 (dd, J= 8.4, 6.9 Hz, 2H), 7.61 (s, 1 H), 7.42 (t, J = 7.5 Hz, 2H), 7.39 - 7.25 (m,1 H), 6.96 (s, 1 H), 6.50 (s, 1 H), 3.93 (s, 3H), 3.80 (s, 3H).Biological Assays

[0249] HEK293 cells (Promega NC1001) (7000 cells / well in 20 l) were transfected in 384-well cell culture plates with FuGENE® 6 reagent (Promega E2691) and 2 pig / ml total DNA (1 :1 kinase:carrier ratio, Promega PI KFYVE-NanoLuc® Vector, NV4041 : transfection carrier DNA, E4881) in Opti-MEM (Gibco 11058-02)+ 1% FBS, and incubated overnight at 37°C. Cells were treated for 2 hours in the presence of a 1: 166 dilution of NanoBRET™ Nano-Gio® Live Cell Solution in Opti-MEM, tracer K8 (Promega N2622), and an example of the present disclosure. After incubation, plates were brought to room temperature over 15 minutes and treated with 10 piL per well of 3X NanoBRET™ Nano-Gio® Live Cell Solution. After 3 minutes donor emission (e.g. 450 nm) and acceptor emission (e.g. 610 nm or 630 nm) using a NanoBRET™-compatible luminometer. mBret ratio values were calculated by dividing the acceptor emission value by the donor emission value for each sample and multiplying each value by 1000. For each dilution series, a nonlinear 4PL Hillcurve was fit to determine each compound’s IC50.

[0250] IC50s for the examples are reported in the Table below.Table - Biological Activity

Claims

What is Claimed:A compound of Formula (I), or a pharmaceutically acceptable salt thereof:whereinQ is a 5-membered heteroaryl comprising a ring nitrogen atom and one additional ring heteroatom selected from 0, N, and NR5, wherein the heteroaryl is optionally substituted with halo, Ci-3alkyl, Ci-shaloalkyl, Cisalkoxy, or cyclopropyl;RAis H, Cualkyl, or Ci.3haloalkyl; R1is C^alkenyl, C^alkynyl, OR8, NHR8, N(R8)2, HET, O-HET, or N(RN)-HET, wherein HET is C3-8cycloalkyl, 3- to 8-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from S, N, and 0, or 5- or 6-membered heteroaryl comprising 1-4 ring heteroatoms selected from N and 0, and HET is optionally substituted with 1-3 R6;R2is H or halo;R3is H or Ci-ealkyl;R4is Cg- aryl or 5- to 10-membered heteroaryl comprising a ring nitrogen atom and 0-2 additional ring heteroatoms selected from N and S, wherein the aryl and heteroaryl are optionally substituted with 1-3 R7;R5is H, Ci-ealkyl, Ci-ehaloalkyl, C3-6cycloalkyl, or Ca-ehalocycloalkyl, wherein the alkyl, haloalkyl, cycloalkyl, and halocycloalkyl are optionally substituted with 0RN; each R6is independently OH, oxo, CN, halo, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci^alkoxy, C3. ecycloalkyl, or 3-6-memebred heterocycle having 1-3 ring heteroatoms selected from N, 0, and S and the heterocycle is substituted with 0 or 1 Ci.3alkyl; each R7is independently halo, CN, N(RN)2, Ci^alkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, C3. ecycloalkyl, O-C3.ecycloalkyl or 3-6-memebred heterocycle having 1-2 ring heteroatoms selected from N, 0, and S, wherein the cycloalkyl and heterocycle are optionally substituted with 1 to 3 halo; each RNis independently H or Cualkyl; and each R8is independently Ci-ealkyl or Ci-ehaloalkyl.R5r salt of claim 1 , wherein Q isand is optionally further substituted halo, Ci-salkyl, Ci.3haloalkyl, Ci.3alkoxy, or cyclopropyl.The compound or salt of claim 1 , wherein Q is4. The compound or salt of any one of claims 1 to 3, wherein R5is Ci-ealkyl.

5. The compound or salt of any one of claims 1 to 4, wherein R5is methyl6. The compound or salt of any one of claims 1 to 5, wherein R2is H.

7. The compound or salt of any one of claims 1 to 6, wherein R2is halo.

8. The compound or salt of any one of claims 1 to 6, having a structure of Formula (IA):

9. The compound or salt of any one of claims 1 to 8, wherein R1is HET, O-HET, or N(RN)-HET.

10. The compound or salt of claim 9, wherein HET is 5- or 6-membered heteroaryl comprising 1-3 ring nitrogen atoms.11 . The compound or salt of claim 9, wherein HET isCi-ehaloalkyl, Ci-ealkoxy, or Ca-ecycloalkyl.

12. The compound or salt of claim 9, wherein HET is Cs-scycloalkyl.

13. The compound or salt of claim 12, wherein HET is cyclopentyl or cyclohexyl and substituted with 1 or 2 R6.

14. The compound or salt of claim 12, wherein HET is cyclobutyl or cyclopropyl.

15. The compound or salt of claim 9, wherein HET is 3- to 8-membered heterocycloalkyl comprising 1-5 ring heteroatoms atoms selected from S, N, and 0.

16. The compound or salt of claim 15, wherein HET is azetindinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrollidinyl, 2-oxaspiro[3.3]heptanyl, 4-oxaspiro[2.4]heptanyl, or oxabicyclo[3.1.1]heptanyl.

17. The compound or salt of claim 9, wherein HET is cyclopropyl, cyclopentyl, cyclohexyl, tetrahhydrofuranyl, or tetrahydropyranyl.

18. The compound or salt of any one of claims 12 to 17, wherein least 1 R6is OH.

19. The compound or salt of any one of claims 1 to 8, wherein R1is OR8.

20. The compound or salt of claim 19, wherein R1is methoxy, t-butoxy, or -O-CH(CF3)CH3.21 . The compound or salt of any one of claims 1 to 20, wherein R3is Ci-ealkyl.

22. The compound or salt of claim 21 , wherein R3is methyl.

23. The compound or salt of any one of claims 1 to 22, wherein R4is phenyl substituted with 0-2 R7.

24. The compound or salt of any one of claims 1 to 22, wherein R4is 5- to 10-membered heteroaryl.

25. The compound or salt of claim 24, wherein R4is pyridyl, pyrimidinyl, pyrrolopyridinyl, 1 H- pyrrolo[2,3-b]pyridinyl, 1 / 7-pyrrolo[3,2-c]pyridinyl, 7 / 7-pyrrolo[2,3-d]pyrimidinyl, 1 / 7-pyrazolo[3,4-d]pyrimidinyl, 1 / 7- pyrazolo[3,4-b]pyridinyl, 5H-pyrrolo[2,3-b]pyrazinyl, quinolinyl, benzo[d|[1 ,3]dioxole, or thieno[2,3-b]pyridinyl.

26. The compound or salt of claim 24 or 25, wherein R4is pyrimidinyl substituted with 1-2 R7.

27. The compound or salt of claim 26, wherein28. The compound or salt of any one of claims 1 to 22, wherein R4is phenyl, chlorophenyl, or methylphenyl.

29. A compound listed in Table A, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising the compound or salt of any one of claims 1 to 29 and a pharmaceutically acceptable excipient.31 . A method of inhibiting a PlKfyve enzyme, comprising contacting the PlKfyve enzyme with the compound or salt of any one of claims 1 to 29 or the pharmaceutical composition of claim 3032. The method of claim 31 , wherein the contacting of the compound or salt comprises administering to a subject.

33. The method of claim 32, wherein the subject is human.

34. A method of treating a disease associated with aberrant PlKfyve activity in a subject, comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of claims 1 to 29 or the pharmaceutical composition of claim 30.

35. The method of claim 34, wherein the disease is a fibro-inflammatory condition.

36. The method of claim 35, wherein the fibro-inflammatory condition is interstitial lung disease, or a liver, kidney, cardiac, or systemic fibrotic condition.

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