P38gamma inhibitors and methods of use thereof

Abstract

The present disclosure provides, in one aspect, compounds, compositions, and methods for reducing and / or inhibiting the activity of p38gamma. In certain embodiments, the compounds, compositions, and methods of the disclosure are useful for promoting remyelination. In certain embodiments, the compounds, compositions, and methods of the disclosure are useful for treating, preventing, and / or ameliorating one or more diseases or disorders in a subject, including but not limited to multiple sclerosis (MS), inflammatory disease, and cancer.

Description

[0001] TITLE OF THE INVENTION

[0002] P38Gamma Inhibitors and Methods of Use Thereof

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 667,515. filed July 3, 2024, which is incorporated herein by reference in its entirety.

[0005] BACKGROUND

[0006] In multiple sclerosis (MS), immune cells attack the myelin sheath that envelops and insulates axons in the central nervous system. This process results in axonal dysfunction and severe neurological symptoms that recede after myelin repair. Repair is due mainly to the differentiation of adult oligodendrocyte progenitor or precursor cells (OPCs), which have the ability7to remyelinate axons. Unfortunately, disease progression, aging and primary7progressive forms of MS all result in inefficient and incomplete remyelination byoligodendrocytes, leading to neurological symptoms and disability in affected individuals. While therapies are available that target the immune system and reduce myelin destruction, no drug that promotes remyelination by oligodendrocytes has been approved for MS treatment. Efficient remyelination by oligodendrocytes remains a critical unmet need in MS therapy.

[0007] There is thus a need in the art for compounds and compositions for promoting remyelination and methods of use thereof. The present disclosure addresses this need.

[0008] BRIEF SUMMARY

[0009] In one aspect, the disclosure provides a compound of formula (I), or a salt, solvate, stereoisomer, tautomer, or isotopologue thereof, wherein A1, L1, L2, and A2are defined elsewhere herein:

[0010] A1— L1— L2— A2(i)

[0011] In another aspect, the disclosure provides a pharmaceutical composition comprising at least one compound of the disclosure and at least one pharmaceutically acceptable carrier.

[0012] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating multiple sclerosis (MS) in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0013] In another aspect, the disclosure provides a method of reducing and / or inhibiting the activity of a p38 mitogen-activated protein kinase (MAPK) family protein in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0014] In another aspect, the disclosure provides a method of promoting neuronal remyelination in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0015] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a demyelinating disease in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0016] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0017] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating epilepsy in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0018] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating anti-inflammatory disease in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0019] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a neurodegenerative disease in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0022] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "‘about 0. 1% to about 5%” or “about 0. 1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g, 1%. 2%, 3%, and 4%) and the sub-ranges (e. , 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0023] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

[0024] In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0025] Definitions

[0026] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0027] The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or. in some embodiments, from 2 to 8 carbon atoms.

[0028] Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

[0029] The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy. cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxy ethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0030] The term “alkyl” as used herein refers to straight chain and branched alky l groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl. n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alky l groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0031] The term “alkylene” or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g. , -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia). In certain embodiments, the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g, - CH2-) different (e.g, -CH2CH2-) carbon atoms.

[0032] The term “alkynyl” as used herein refers to straight and branched chain alky l groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to - C =CH. -C=CtCH3). -C =C(CH2CH3). -CH2C=CH. -CH2C=C(CH2). and -CH2OC CH2CH3) among others.

[0033] The term “amine” as used herein refers to primary, secondary7, and tertiary amines having, e g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium ions as used herein.

[0034] The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, or -NRs+, wherein each R is independently selected, and protonated forms of each, except for -NR? . which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkyl amino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.

[0035] The term “aralkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzy l and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0036] The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl. biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bomyl, camphenyl. isocamphenyl, and carenyl groups, and fused rings such as, but not limited to. decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group.

[0037] The term “cycloalkylene” or “cycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical (e.g, A , V , tZf , and '" '", inter alia). In certain embodiments, the term may be regarded as a product of removal of two hydrogen atoms from the corresponding cycloalkane (e.g., cyclobutyl) by removal of two hydrogen atoms from the same (e.g, different (e.g. U and ”^>”) carbon atoms.

[0038] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0039] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0040] A disease or disorder is “ameliorated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.

[0041] As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0042] The terms "halo." ‘‘halogen,’’ or ‘‘halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherw ise stated, a fluorine, chlorine, bromine, or iodine atom.

[0043] The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, polyhalo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1 -dichloroethyl, 1,2-di chloroethyl, l,3-dibromo-3,3- difluoropropyl. perfluorobutyl, and the like.

[0044] The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a Ce-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl. pyrazolyl, triazolyl, tetrazolyl. oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein.

[0045] Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl). N-hydroxytetrazolyl. N- hy dr oxy triazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyL 3- anthracenyl), thiophenyl (2 -thienyl, 3 -thienyl), furyl (2 -fury l, 3 -fund) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl. isoindanyl. benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyL 5-imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl. 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl). pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pynmidinyl. 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1 -isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [b] furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl. 4-benzo[b] furanyl. 5-benzo[b]furanyl. 6-benzo[b] furanyl. 7- benzo[b] furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b] furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),

[0046] 6-(2,3-dihydro-benzo[b]furanyl), 7-(2.3-dihydro-benzo[b] furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl). 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl. 2-indolyl,

[0047] 3-indolyl, 4-indolyl. 5-indolyl. 6-indolyl, 7-indolyl), indazole (1-indazolyL 3-indazolyl,

[0048] 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5 -benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl). benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5 -benzothiazolyl, 6-benzothiazolyl,

[0049] 7-benzothiazolyl), carbazolyl (1 -carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f|azepine (5H-dibenz[b,f| azepin- 1-yl, 5H-dibenz[b,f|azepine-2-yl, 5H-dibenz[b,f|azepine-3-yl, 5H-dibenz[b,f|azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),

[0050] 10,1 l-dihydro-5H-dibenz[b,f] azepine (10.1 l-dihydro-5H-dibenz[b.f|azepine-l-yl,

[0051] 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f|azepine-3-yl,

[0052] 10,1 l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f|azepine-5-yl), and the like.

[0053] The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0054] The term “heteroarylene” or “heteroarylenyl” as used herein refers to a bivalent heteroaryl radical (e.g., 2,4-pyridylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from one or more rings of a heteroaryl moiety, wherein the hydrogen atoms may be removed from the same or different rings, preferably the same ring.

[0055] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. A heterocycloalkyl can include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom can be optionally substituted. Representative heterocycloalkyl groups include, but are not limited, to the following exemplary groups: pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl. piperazinyl, oxazolidinyl, isoxazolidinyl. morpholinyl. thiazolidinyl. isothiazolidinyl, and tetrahydrofuryl. The term heterocycloalkyl group can also be a C2heterocycloalkyl, C2-C3heterocycloalkyl, C2-C4 heterocycloalkyl, C2-C5 heterocycloalky l, C2-C6 heterocycloalkyl, C2-C7 heterocycloalkyl, C2-C8heterocycloalkyl, C2-C9 heterocycloalky l, C2-C10 heterocycloalky l, C2-C11 heterocycloalkyl, and the like, up to and including a C2-14s heterocycloalky l. For example, a C2heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a Cs heterocycloalkyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to. piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl. and the like. It is understood that a heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. The heterocycloalky l group can be substituted or unsubstituted.

[0056] The term “heterocycloalkylene” or “heterocycloalkylenyl” as used herein refers to a H ! bivalent saturated cycloalkyl radical (e.g., N, inter alia). In certain embodiments, the term may be regarded as a product of removal of two hydrogen atoms from the corresponding heterocycloalkane (e.g, piperidine) by removal of two hydrogen atoms from the same (e.g., ''" I / NH) different (e.g., and " DN) carbon atom(s) and / or heteroatom(s).

[0057] The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocycly l can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl. triazolyl. tetrazolyl, oxazolyl, isoxazolyl. thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted. or disubstituted with groups such as those listed herein.

[0058] The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.

[0059] As used herein, the term “hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl. aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3). or butyl (C4), and (Co-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term “independently selected from’" as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations.

[0060] The term “linker” as used herein refers to an organic moiety that connects two parts of a compound (e.g., a first small molecule drug and a second small molecule drug). The linker can be, in non-limiting examples, a direct bond, a single atom (e.g., -O-), a peptide, or a substituted or unsubstituted alkylene or heteroalkyd ene moiety (e.g., polyethylene glycol). One skilled in the art would be apprised of the common linkers suitable for use in drug-drug conjugates and methods of preparation thereof.

[0061] The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.

[0062] The term “organic group” as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(0)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)O- 2N(R)C(0)R, (CH2)o-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)C0N(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(0)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C1oo)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety’, and wherein the carbon-based moiety can be substituted or unsubstituted.

[0063] The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0064] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non- toxic, z.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0065] As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

[0066] Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of w hich include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic. 4-hydroxybenzoic. phenylacetic, mandelic, embonic (pamoic). methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic. P-hydroxybutyric, salicylic, galactaric and galacturonic acid.

[0067] As used herein, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid fdler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in earn ing or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc: excipients, such as cocoa butter and su posi tonwaxes: oils, such as peanut oil, cottonseed oil. safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier"’ also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0068] The term “phenylene” or “phenylenyl” as used herein refers to a bivalent phenyl radical (e.g, 1.4-phenylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from a benzene moiety.

[0069] The term “solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0070] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of’ as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 \\1% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4. 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of’ can mean having a trivial amount of. such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

[0071] The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group’' or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR. 0C(0)N(R)2, CN, NO, NO2, ONO2, azido, CFy OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(0)N(R)2, 0C(0)N(R)2, C(S)N(R)2, (CH2)O-2N(R)C(O)R, (CH2)O-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)C0N(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(0)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety7; for example, R can be hydrogen, (C1- C100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl.

[0072] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0073] The terms “treat,” “treating” and “treatment.” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.

[0074] Compounds and Compositions

[0075] In one aspect, the disclosure provides a compound of formula (I), or a salt, solvate, stereoisomer, tautomer, or isotopologue thereof:

[0076] A1— L1— L2— A2(j) wherein:

[0077] A1is selected from the group consisting of:

[0078]

[0079] R1is N(RA)(RB);

[0080] R2a. R2b, and R2c, if present, are each independently selected from the group consisting of H, CN. NO2, ORA. N(RA)(RB). halogen, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl. and optionally substituted C2-C8heteroaryl;

[0081] R3is selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, and optionally substituted C2-C8heterocycloalkyl;

[0082] L1is selected from the group consisting of

[0083]

[0084] R4a. R4b, R4C, and R4d, if present, are each independently selected from the group consisting of H, CN, NO2, ORA, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, and optionally substituted C2-C8heterocycloalkyl; R5a. R5b, R5C, R5d, and R5e, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6alkyl;

[0085] R6, if present, is selected from the group consisting of H and optionally substituted C1-C6alkyl;

[0086] L2is selected from the group consisting of *-C(=O)NR7-, *-C(=O)NR7-(optionally substituted C1- C3alkylenyl)-, and *-C(=O)(optionally substituted C1-C3alkylenyl)-; each occurrence of R7. if present, is independently selected from the group consisting of H and optionally substituted C1-C6alkyl;

[0087] A2is selected from the group consisting

[0088] R8a, R8b, R8c, R8d, and R8e, if present, are each independently selected from the group consisting of H, CN, NO2, ORA, SF5, halogen, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8heteroaryl;

[0089] R9, if present, is selected from the group consisting of H, optionally substituted C1-C6alkyl, and optionally substituted C6-C1o aryl; each occurrence of RAand RB, if present, is independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C1o aryl, and optionally substituted C2-C8heteroaryl;

[0090] * indicates a bond between L1and L2.

[0091] In certain embodiments, the compound is not 5-(4-Amino-l-methyl-lH-pyrazolo[3,4- d ]pyrimidin-3-yl)-2.3-dihydro-N-[3-(trifluoromethyl)phenyl]-lH-indole-l -carboxamide.

[0092] In certain embodiments, the compound is not 5-[4-Amino-7-(l-methylethyl)-7H- pyrrolo[2,3-d ]pyrimidin-5-yl]-2,3-dihydro-N-(l-methylethyl)-lH-indole-l -carboxamide.

[0093] In certain embodiments, the compound is not 5-[4-Amino-7-(l-methylethyl)-7H- pyrrolo[2,3-d ]pyrimidin-5-yl]-N-(cyclopropylmethyl)-2,3-dihydro-lH-indole-l- carboxarmde. In certain embodiments, the compound is not 5-(4-Amino-7-methyl-7H-pyrrolo[2,3-d ]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-N-phenyl-lH-indole-l-carboxamide.

[0094] In certain embodiments, the compound is not 5-[4-Amino-7-(l-methylethyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-N-(cyclohexylmethyl)-2,3-dihydro-lH-indole-l -carboxamide.

[0095] In certain embodiments, the compound is not 5-[4-Amino-7-(l-methylethyl)-7H - pyrrolo[2,3-d]pyrimidin-5-yl]-2.3-dihydro-N -[3-(trifluoromethyl)phenyl]-lH -indole-1- carboxamide.

[0096] In certain embodiments, R1is NH2. In certain embodiments, R1is NHMe.

[0097] In certain embodiments, R2ais H. In certain embodiments, R2ais F. In certain embodiments, R2ais Cl. In certain embodiments, R2ais Br. In certain embodiments, R2ais CH3. In certain embodiments, R2ais CHF2. In certain embodiments, R2ais (CH2)CH?. In certain embodiments, R2ais C(=O)NH2. In certain embodiments, R2ais . In certain embodiments, R2ais . In certain embodiments, R2ais . In certain embodiments, R2ais In certain embodiments, R2ais CN.

[0098] In certain embodiments, R2bis H. In certain embodiments, R2bis F. In certain embodiments, R2bis Cl. In certain embodiments, R2bis Br. In certain embodiments, R2bis CH3. In certain embodiments, R2bis CHF2. In certain embodiments, R2bis (CH2)CH3. In certain embodiments, R2bis C(=O)NH2. In certain embodiments, R2bis . In certain embodiments, R2bis . In certain embodiments, R2bis . In certain embodiments, R2bis . In certain embodiments, R2bis CN.

[0099] In certain embodiments, R2cis H. In certain embodiments, R2cis F. In certain embodiments, R2cis Cl. In certain embodiments, R2cis Br. In certain embodiments, R2cis CH3. In certain embodiments, R2cis CHF2. In certain embodiments, R2cis (CH2)CH3. In certain embodiments, R2cis C(=O)NH2. In certain embodiments, R2cis incertain embodiments, R2cis . In certain embodiments, R2cis in certain embodiments, R2cis In certain embodiments, R2cis CN.

[0100] In certain embodiments, R2dis H. In certain embodiments, R2dis F. In certain embodiments, R2dis Cl. In certain embodiments, R2dis Br. In certain embodiments, R2dis CH3. In certain embodiments, R2dis CHF2. In certain embodiments, R2dis (CH2)CH3. In certain embodiments, R2dis C(=O)NH2. In certain embodiments, R2dis in certain embodiments, R2dis . In certain embodiments, R2dis incertain embodiments, R2dis In certain embodiments, R2dis CN.

[0101] In certain embodiments, R2ais . In certain embodiments, R2ais incertain embodiments, R2ais . In certain embodiments, R2ais . In certain embodiments, R2ais . In certain embodiments, R2ais . In certain embodiments, R2ais . In certain embodiments, R2ais . In certain embodiments, R2bis . In certain embodiments, R2bis V-NH in certain embodiments, R2bis In certain embodiments, R2bis . In certain embodiments, R2bis In certain embodiments, R2bis . In certain embodiments, R2bis In certain embodiments, R2bis

[0102] In certain embodiments, R3is Me. In certain embodiments, R3is z-Pr. In certain embodiments, R3is (CH2)O(CH3). In certain embodiments, R3is (CH2)NH(CH3). In certain embodiments, R3is (CH2)N(CH3)2. In certain embodiments, R3is |ncertain embodiments, R3is . In certain embodiments, R3is . In certain embodiments, R3

[0103] In certain embodiments, A1is . In certain embodiments, A1is

[0104] 1 . In certain embodiments. A1is In certain embodiments, A1is . In certain embodiments, A1is . In certain embodiments, A is . In certain embodiments, A1is . In certain embodiments, A1is . In certain embodiments, A1is . In certain embodiments, A1is . In certain embodiments, A1is In certain embodiments, A1is In certain embodiments, A1is . In certain embodiments, A1is In certain embodiments, A1is . In certain embodiments, A1is In certain embodiments, A1is . In certain embodiments, A1is In certain embodiments. A1is in certain embodiments. A1is . In certain embodiments, A1is In certain embodiments, A1is . In certain embodiments, A1is ,1is , certain embodiments, A1is , certain embodiments, A1is

[0105] certain embodiments. A1is

[0106] In certain embodiments, R4ais H. In certain embodiments, R4ilis CH3. In certain embodiments, R4ais F. In certain embodiments, R4ais Cl. In certain embodiments, R4ais OCH3. In certain embodiments, R4ais CN. In certain embodiments, R4bis H. In certain embodiments, R4bis CH3. In certain embodiments, R4bis F. In certain embodiments, R4bis Cl. In certain embodiments, R4bis OCH3. In certain embodiments, R4bis CN. In certain embodiments, R4cis H. In certain embodiments, R4cis CH3. In certain embodiments, R4cis F. In certain embodiments, R4cis Cl. In certain embodiments, R4cis OCH3. In certain embodiments, R4cis CN. In certain embodiments, R4dis H. In certain embodiments, R4dis CH3. In certain embodiments, R4dis F. In certain embodiments. R4dis Cl. In certain embodiments, R4dis OCH3. In certain embodiments, R4dis CN.

[0107] In certain embodiments, R5ais H. In certain embodiments, R5bis H. In certain embodiments, R5cis H. In certain embodiments, R5dis H. In certain embodiments, R5eis H.

[0108] In certain embodiments, R6is H.

[0109] In certain embodiments, L1is . In certain embodiments, L1is , certain embodiments, L1is certain embodiments, L1is certain embodiments, L1is In certain embodiments, L1is In certain embodiments, L is .1is , In certain embodiments, L1is . In certain embodiments, L1is In certain embodiments, L1is In certain embodiments, L1is

[0110] In certain embodiments, R7is H.

[0111] In certain embodiments, L2is In certain embodiments, L2is certain embodiments, L2is

[0112] In certain embodiments, R8ais H. In certain embodiments, R8ais Me. In certain embodiments, R8ais t-Bu. In certain embodiments, R8ais F. In certain embodiments, R8ais Cl. In certain embodiments, R8ais Br. In certain embodiments, R8ais CFs. In certain embodiments, R8ais CH2CF3. In certain embodiments, R8ais OCHF2. In certain embodiments, R8ais OCF3. In certain embodiments, R8ais SF5. In certain embodiments, R8a . In certain embodiments, R8ais . In certain embodiments, R8ais In certain embodiments, R8bis H. In certain embodiments, R8bis Me. In certain embodiments, R8bis t-Bu. In certain embodiments, R8bis F. In certain embodiments, R8bis Cl. In certain embodiments, R8bis Br. In certain embodiments, R8bis CF3. In certain embodiments, R8bis CH2CF3. In certain embodiments, R8bis OCHF2. In certain embodiments, R8bis OCFs. In certain embodiments, R8bis SFs. In certain embodiments, R8b . In certain embodiments, R8bis In certain embodiments, R8bis

[0113] . In certain embodiments, R8cis H. In certain embodiments, R8cis Me. In certain embodiments, R8cis / -Bu. In certain embodiments, R8cis F. In certain embodiments, R8cis Cl. In certain embodiments, R8cis Br. In certain embodiments, R8cis CF3. In certain embodiments, R8cis CH2CF3. In certain embodiments, R8cis OCHF2. In certain embodiments, R8cis OCF3. In certain embodiments, R8cis SF5. In certain embodiments, R8c

[0114] In certain embodiments, R8cis In certain embodiments, R8cis . certain embodiments, Rxdis H. In certain embodiments, R8dis Me. In certain embodiments, R8dis t-Bu. In certain embodiments, R8dis F. In certain embodiments, R8dis Cl. In certain embodiments, R8dis Br. In certain embodiments, R8dis CF3. In certain embodiments, R8dis SFs. In certain embodiments. R8dis CH2CF3. In certain embodiments. R8dis OCHF2. In certain embodiments, R8dis OCF3. In certain embodiments, R8dis

[0115] In certain embodiments, R8dis

[0116] In certain embodiments, R9is H. In certain embodiments, R9is In certain embodiments, A2is certain embodiments, A2is ■>' . In certain embodiments, A2is . In certain embodiments, A2is in certain embodiments, A2is certain embodiments, A2is certain embodiments, A2is certain embodiments. A2is certain embodiments.

[0117] In certain embodiments, certain embodiments, A2is In certain embodiments. A2is certain embodiments, certain embodiments, certain embodiments, A2is . In certain embodiments, certain embodiments, A2is embodiments, certain embodiments, A2is In certain embodiments, A2is

[0118] In certain embodiments, certain embodiments, certain embodiments, A2is In certain embodiments, A2is ,

[0119] N-N embodiments, A2is / In certain embodiments,

[0120] In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkylenyl, optionally substituted alkenylenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroarylenyl, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6alkyl, C3-Cs cycloalkyl, C2-C12 heterocycloalkyl, C1-C6hydroxyalkyl, halogen, CN, NO2 OR1, NiR’liR11). C1-C6haloalkoxy, Cs-Cs halocycloalkoxy, aryl, heteroaryl. (C1-C6alkydenyl)C(=O)N(RI)(Rn), (C1-C6alkylenyl)C(=O)ORI, O(C1-C3alkylenyl)C(=O)ORn, O(C1-C3alkylenyl)C(=O)N(RI)(Rn), =O)2RI, S(=O)2N(RI)(Rn), (=0)NRIRn, wherein R1and Rnare each independently selected from the group consisting of H, -C(=O)(C1-C6alkyl), C1- C6alkyl. C1-C6haloalkyl, C1-C6heteroalkyl, C3-Cs cycloalkyl, C2-C12 heterocycloalkyl, C7- C12 aralkyl, aryl, and heteroaryl.

[0121] In certain embodiments, the compound is selected from the group consisting of: 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0122] 5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0123] 5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2- fluoro-5 -(trifl uoromethyl)phenyl)indoline-l -carboxamide;

[0124] 5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(3-

[0125] ( tri fl uoromelhy I (benzyl )in doline- 1 -carboxamide;

[0126] (R)-5-(4-amino-l-(pyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0127] (S)-5-(4-amino-l-(pyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0128] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3- (trifluoromethy l)benzy l)indoline- 1 -carboxamide; 5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0129] (R)-5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0130] (S)-5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0131] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylimidazo[l,2- a]pyridine-3 -carboxamide;

[0132] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0133] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-

[0134] (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyridine-3-carboxamide;

[0135] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0136] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-3-

[0137] (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0138] 5-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-

[0139] (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0140] 5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-

[0141] (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0142] 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-

[0143] (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0144] 5-(8-aminoimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-

[0145] (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0146] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(2,2,2- trifluoroethyl)phenyl)indoline-l -carboxamide;

[0147] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(2,2,2- trifluoroethyl)phenyl)indoline-l -carboxamide;

[0148] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-

[0149] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0150] 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-

[0151] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0152] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-

[0153] (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide; 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0154] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3- chlorophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0155] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(m-tolyl)imidazo[l,2- a] pyridine-3 -carboxamide;

[0156] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- methylphenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0157] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3,5- bis(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0158] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(4-methyl-lH- imidazol-l-yl)-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0159] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0160] 7-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyndine-3-carboxamide;

[0161] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-chloro-2- fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0162] 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0163] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(4-methyl-lH- imidazol-l-yl)-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0164] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-bromo-2- fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0165] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0166] 5-(4-amino-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0167] 5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4- (trifluoromethyl)pyridin-2-yl)indoline-l -carboxamide; l-(5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)indolin-l-yl)-2-(3- (trifluoromethy l)phenyl)ethan- 1 -one;

[0168] 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(trifluoromethyl)phenyl)-lH- indole-3-carboxamide; 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0169] 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(4-fluoro-3-

[0170] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0171] 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(tert-butyl)-l-(p-tolyl)-lH- pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0172] 7-(8-amino-3-isopropylimidazo[1.5-a]pyrazin-l-yl)-N-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0173] 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(4-fluoro-3-

[0174] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0175] 7-(8-amino-3-isopropylimidazo[L5-a]pyrazin-l-yl)-N-(4-fluoro-3-

[0176] (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0177] 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-

[0178] (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0179] 6-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-

[0180] (trifluoromethyl)phenyl)benzofuran-3-carboxarmde;

[0181] 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-chloro-N-(2-fluoro-5-

[0182] (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0183] 5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-

[0184] (trifluoromethyl)phenyl)indoline- 1 -carboxamide; l-(5-(8-amino-3-methylimidazo[l ,5-a]pyrazin-l-yl)indolin-l-yl)-2-(4-(2,2,2- trifluoroethyl)phenyl)ethan- 1 -one;

[0185] 5-(8-amino-5-fluoro-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0186] 7-(8-amino-3-(methoxymethyl)imidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide; l-(5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)indolin-l-yl)-2-(3-(2,2,2- trifluoroethyl)phenyl)ethan- 1 -one;

[0187] 5-(8-amino-5-chloro-3-methylimidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0188] 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-(trifluoromethyl)pyri din-4- yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0189] 7-(8-amino-5-fluoro-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide; 6-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-

[0190] (trifluoromethyl)phenyl)benzo[b]thiophene-3-carboxamide:

[0191] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0192] 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0193] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)isoindoline-2-carboxamide;

[0194] 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(4-fluoro-3- (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0195] 5-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0196] 7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-fluoro-5-

[0197] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0198] 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(tert-butyl)-l-methyl-lH- pyrazol-5-yl)imidazo[l,2-a]pyndine-3-carboxamide;

[0199] 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(l-methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0200] 7-(8-amino-3-(l-methylpyrrolidin-3-yl)imidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0201] 7-(8-amino-3-((methylamino)methyl)imidazo[l ,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0202] 5-(8-amino-3-(l-methylpyrrolidin-3-yl)imidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0203] 6-(4-amino- 1 -methyl- 1 H-py razolo[3,4-d] pyrimi din-3 -y 1)-N -(2-fluoro-5- (trifluoromethyl)phenyl)-2-methylbenzofuran-3-carboxamide;

[0204] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-4-methy lindoline- 1 -carboxamide;

[0205] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0206] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-8-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0207] 7-(8-amino-3-((dimethylamino)methyl)imidazo[1.5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide; 7-(8-amino-5-chloro-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0208] 7-(4-aminofuro[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5-

[0209] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0210] 7-(4-aminothieno[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0211] 5-(4-aminothieno[2,3-d]pyrimidin-5-yl)-4-chloro-N-(2-fluoro-5-

[0212] (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0213] 5-(4-amino-l,6-dimethyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0214] 5-(4-aminofuro[2,3-d]pyrimidin-5-yl)-4-chloro-N-(2-fluoro-5-

[0215] (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0216] 7-(8-amino-5-ethyl-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0217] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-8-methylirmdazo[l,2-a]pyndine-3-carboxamide;

[0218] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0219] 7-(4-amino-l,6-dimethyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0220] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethy l)pheny l)-7-methy lbenzofuran-3 -carboxamide;

[0221] 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-7-methyl-lH-indole-3-carboxamide;

[0222] 8-amino-l-(3-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)imidazo[l,2-a]pyridin-

[0223] 7-yl)-3-methylimidazo[l,5-a]pyrazine-5-carboxamide;

[0224] 5-(4-amino-6-(difluoromethyl)-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4- chloro-N-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0225] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethoxy )phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0226] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(3-(tert-butyl)-l -methyl- lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0227] 7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-(tert-butyl)-l-methyl-lH- pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide; 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0228] 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)-lH-indole-3-carboxamide;

[0229] 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0230] 5-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0231] 7-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(tert-butyl)-l -methyl- lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0232] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethoxy)phenyl)-2,3,3a,7a-tetrahydro-lH-indole-l-carboxamide;

[0233] 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-

[0234] (trifluoromethyl)phenyl)-7-methylpyrazolo[l,5-a]pyridine-3-carboxamide;

[0235] 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-7-chloro-N-(2-fluoro-5-

[0236] (trifluoromethyl)phenyl)-lH-indole-3-carboxamide:

[0237] 7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0238] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(3-

[0239] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0240] 6-(8-amino-3-methylimidazo[l ,5-a]pyrazin- 1 -yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0241] 7-(8-amino-5-(azetidin-3-ylidenemethyl)-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0242] 7-(8-amino-3-methyl-5-((l-methylazetidin-3-ylidene)methyl)imidazo[l,5-a]pyrazin- l-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0243] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5-(pentafluoro- X6-sulfaneyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0244] 7-(8-amino-3-methyl-5-((l-methylazetidin-3-yl)methyl)imidazo[l,5-a]pyrazin-l-yl)- N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0245] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(3-(pentafluoro-X6- ulfaneyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0246] 7-(3-amino-lH-indazol-4-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2- a] pyridine-3 -carboxamide; 7-(3-amino-lH-pyrazolo[3,4-c]pyridin-4-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0247] 7-(8-amino-5-(azetidin-3-ylmethyl)-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0248] 7-(3-amino-l-methyl-lH-indazol-4-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0249] 7-(3-amino-l-methyl-lH-pyrazolo[3,4-c]pyridin-4-yl)-N-(2-fluoro-5-

[0250] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0251] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-methyl-5-

[0252] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0253] 7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-methyl-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0254] 7-(3-amino-l-methyl-lH-indazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)imidazo[l,2- a]pyridine-3 -carboxamide;

[0255] 7-(3-amino-l-methyl-lH-pyrazolo[3,4-c]pyridin-4-yl)-N-(3- (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0256] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-8-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0257] 7-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0258] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrirnidin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)in doline- 1 -carboxamide;

[0259] 5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0260] 5-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0261] 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(3- (trifluoromethoxy )phenyl)indoline- 1 -carboxamide;

[0262] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(tert-butyl)-l- methyl-lH-pyrazol-5-yl)-4-fluoroindoline-l-carboxamide;

[0263] 5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(tert-butyl)-l -methyl- lH-pyrazol-5-yl)-4-fluoroindoline-l-carboxamide;

[0264] 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide; 5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5-

[0265] (tri fl uoromethy I )phenyl )indoline- 1 -carboxamide;

[0266] 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-cyano-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0267] 5-(8-amino-5-fluoro-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0268] 5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (pentafluoro-X6-ulfaney l)pheny l)indoline- 1 -carboxamide;

[0269] 5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )phenyl)indoline- 1 -carboxamide;

[0270] 5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )pheny l)in doline- 1 -carboxamide;

[0271] 5-(4-amino-7-fluoro-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-4-fluoro-N-(2-fluoro- 5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0272] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (pentafl uoro-6-ul faney l)pheny l)indoline- 1 -carboxamide;

[0273] 5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (pentafl uoro-Z6-ul fancy l)pheny l)indoline- 1 -carboxamide;

[0274] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(4- (trifluoromethyl)pyridin-2-yl)indoline- 1 -carboxamide;

[0275] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2- (trifluoromethyl)pyridin-4-yl)indoline- 1 -carboxamide;

[0276] 5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(4- (trifluoromethyl)pyridin-2-yl)indoline- 1 -carboxamide;

[0277] 5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2- (trifluoromethyl)pyridin-4-yl)indoline-l -carboxamide;

[0278] 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )phenyl)indoline- 1 -carboxamide;

[0279] 5-(4-amino-7-isopropyl-7H-pyrrolo[2.3-d]pyrimidin-5-yl)-N-(3- (difluoromethoxy)phenyl)-4-fluoroindoline-l -carboxamide;

[0280] 5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (pentafl uoro- / / ’-ul faney l)pheny l)indoline- 1 -carboxamide;

[0281] 5-(4-aminofuro[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide; 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-8-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0282] 5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0283] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-

[0284] (difluoromethoxy)phenyl)-4-fluoroindoline-l -carboxamide:

[0285] 5-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0286] 7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-8-cyano-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0287] 6-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0288] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0289] 6-(4-aminofuro[2,3-d]pyrimidin-5-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxarmde;

[0290] 7-(4-amino-6-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0291] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-(difluoromethoxy)- 2-fluorophenyl)-4-fluoroindoline- 1 -carboxamide;

[0292] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )phenyl)in doline- 1 -carboxamide;

[0293] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (pentafluoro-X6-sulfaneyl)phenyl)indoline-l -carboxamide;

[0294] 5-(4-amino-6-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0295] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(5-

[0296] (difluoromethoxy)-2-fluorophenyl)indoline-l -carboxamide:

[0297] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(4-methyl-3- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;

[0298] 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5-

[0299] (pentafluoro- z / ’-sul faney I Jphen I Jindoline- 1 -carboxamide:

[0300] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethoxy)phenyl)benzofuran-3-carboxamide; 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (pentafluoro- X6-sulfaneyl)phenyl)benzofuran-3 -carboxamide;

[0301] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(4- (trifluoromethyl)pyridin-2-yl)benzofuran-3-carboxamide;

[0302] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(4-methyl-3- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0303] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(4-methyl-3- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0304] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-4-methoxy indoline- 1 -carboxamide;

[0305] 6-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-7-chloro-N-(2-fluoro-5- (pentafluoro-X6-sulfaneyl)phenyl)benzofuran-3-carboxamide;

[0306] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,4-difluoro-5- (trifluoromethyl)phenyl)-7-fluorobenzofuran-3-carboxamide;

[0307] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2.4-difluoro-5- (trifluoromethy l)phenyl)-4-fluoroindoline- 1 -carboxamide;

[0308] 6-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-7-fluoro-N-(2-fluoro-5- (pentafluoro-X6-sulfaneyl)phenyl)benzofuran-3-carboxamide;

[0309] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-(tert-butyl)-2- fluorophenyl)-7-fluorobenzofuran-3 -carboxamide;

[0310] 6-(4-amino-l-cyclobutyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0311] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(tert-butyl)pyridin- 2-yl)-4-fluoroindoline- 1 -carboxamide;

[0312] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-(tert-butyl)-2- fl uorophenyl)-4-fluoroindoline-l -carboxamide;

[0313] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-4- methyl-5-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0314] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-4- ((l-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0315] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-4- (piperidin-4-ylmethyl)-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;

[0316] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-6-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide; 6-(4-amino-l-cyclopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0317] 5-(4-amino-7-isopropylpyrrolo[2,l-f|[l,2,4]triazin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0318] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(5-methyl-4- (trifluoromethyl)pyridin-2-y l)indoline- 1 -carboxamide;

[0319] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(5-methyl-4- (trifluoromethyl)pyridin-2-yl)benzofuran-3-carboxamide;

[0320] 6-(4-amino-7-isopropylpyrrolo[2,l-f][l,2,4]triazin-5-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0321] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(tert-butyl)pyridin- 2-yl)-7-fluorobenzofuran-3 -carboxamide;

[0322] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-4- methyl-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0323] 6-(4-aminofuro[2,3-d]pyrimidin-5-yl)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-7- fluorobenzofuran-3-carboxamide;

[0324] 6-(4-aminofuro[2,3-d]pyrimidin-5-yl)-7-fluoro-N-(2-fluoro-5-

[0325] (trifluoromethoxy)phenyl)benzofuran-3-carboxamide;

[0326] 6-(4-aminothieno[2,3-d]pyrimidin-5-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0327] 5-(4-amino-7-isopropylimidazo[5,l-f|[l,2,4]triazin-5-yl)-4-fiuoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;

[0328] 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(5-fluoro-4- (trifluoromethyl)pyridin-2-y l)indoline- 1 -carboxamide;

[0329] 6-(4-amino-7-isopropylimidazo[5,l-f|[l,2,4]triazin-5-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;

[0330] 6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(5-fluoro-4- (trifluoromethyl)pyridin-2-yl)benzofuran-3-carboxamide;

[0331] 7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-6-fluoro-N-(2-fluoro-5-

[0332] (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide; and

[0333] 6-(4-aminofuro[2,3-d]pyrimidin-5-yl)-N-(4-chloro-2-fluoro-5-

[0334] (trifluoromethyl)phenyl)-7-fluorobenzofuran-3-carboxamide.

[0335] The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (7?) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0336] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form.

[0337] In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0338] In certain embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0339] In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

[0340] Compounds described herein also include isotopically -labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H, “C,13C,14C,36C1,18F,123I,125I,13N,15N,15O,170,18O,32P, and35S. In certain embodiments, isotopically -labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such asnC,18F,15O, and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0341] In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0342] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds. Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

[0343] Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0344] In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected wi th Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acety l, in the presence of amines that are blocked with acid labile groups, such as l-bulyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.

[0345] In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyd group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxydic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride labile silyl carbamates.

[0346] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxydic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.

[0347] Typically blocking / protecting groups may be selected from allyl, benzy l (Bn), benzy doxycarbonyl (Cbz), allyloxy carbonyl (Alloc), methyl, ethyl, / -buty l, t- butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxy carbonyl (Teoc). / -butyloxy carbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyd, and fluorenylmethoxycarbonyl (FMOC).

[0348] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0349] Table 1. Exemplary compounds of the present disclosure

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364] -61 -

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388] Methods

[0389] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating multiple sclerosis (MS) in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0390] In another aspect, the disclosure provides a method of reducing and / or inhibiting the activity of a p38 mitogen-activated protein kinase (MAPK) family protein in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure. In certain embodiments, the p38 MAPK family protein is p38gamma also known as MAPK12. In certain embodiments, p38gamma is selectively inhibited. In certain embodiments, p38gamma is selectively inhibited over one or more of other p38 MAPK family proteins, such as but not limited to p38alpha, p38beta, and p38delta. In certain embodiments, p38gamma is selectively inhibited over one or more of other p38 MAPK family proteins by a factor of at least 0.1, 0.2. 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2. 2.3, 2.4, 2.5, 2.6. 2.7, 2.8, 2.9, 3. 3.1, 3.2, 3.3. 3.4, 3.5, 3.6, 3.7. 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, or greater than 5 in terms of pICso.

[0391] In another aspect, the disclosure provides a method of promoting neuronal remyelination in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure. In certain embodiments, multiple sclerosis (MS) in the subject is treated, prevented, and / or ameliorated.

[0392] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a demyelinating disease in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure. In certain embodiments, the demyelinating disease is selected from the group consisting of multiple sclerosis (MS), adrenoleukodystrophy, adrenomyeloneuropathy, Charcot Marie tooth disease, motor neuron disease, polyneuropathy, intemuclear ophthalmoplegia, Parkinson’s disease, neuromyelitis optica spectrum disorder (NMOSD). transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), progressive multifocal leukoencephalopathy (PML), and central pontine myelinolysis (osmotic demyelination syndrome).

[0393] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure. In certain embodiments, the cancer is characterized by increased MAPK12 mRNA expression. In certain embodiments, the cancer is at least one selected fro the group consisting of cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), head and neck cancer (HNSC). kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and thyroid carcinoma (THCA).

[0394] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating epilepsy in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0395] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating anti-inflammatory disease in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure.

[0396] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a neurodegenerative disease in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure and / or a pharmaceutical composition of the disclosure. In certain embodiments, the neurodegenerative disease is at least one selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Lewy Body disease, and tau-related diseases. Administration / Dosage / Formulations

[0397] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of the disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0398] Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or disorder in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A nonlimiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0399] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0400] In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination w ith the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, know n in the medical arts.

[0401] A medical doctor, e.g.. physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0402] In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity7of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound.

[0403] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions descnbed herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0404] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may 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 dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or poly alcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

[0405] In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every7two, days, every7three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account.

[0406] The compound(s) described herein for administration may be in the range of from about 1 pg to about 10,000 mg, about 20 pg to about 9,500 mg, about 40 pg to about 9,000 mg, about 75 pg to about 8,500 mg, about 150 pg to about 7,500 mg, about 200 pg to about 7,000 mg, about 350 pg to about 6,000 mg, about 500 pg to about 5,000 mg, about 750 pg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0407] In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5.000 mg, or less than about 3,000 mg, or less than about 2.000 mg, or less than about 1.000 mg. or less than about 500 mg. or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg. or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0408] In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, or reduce one or more symptoms of a disease or disorder in a patient.

[0409] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0410] Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal. transmucosal (e.g.. sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g, trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapul monary. intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0411] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein.

[0412] Oral Administration

[0413] For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g, polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fdlers (e.g, cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g, magnesium stearate, talc, or silica); disintegrates (e.g, sodium starch glycollate); or wetting agents (e.g, sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY -P Type, Aqueous Enteric OY -A Type, OY -PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g, sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g, lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxy benzoates or sorbic acid).

[0414] Parenteral Administration

[0415] For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used.

[0416] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. Additional Administration Forms

[0417] Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0418] Controlled Release Formulations and Drug Delivery Systems

[0419] In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

[0420] The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may. although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

[0421] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

[0422] In some cases, the dosage forms to be used can be provided as slow- or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profde in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein.

[0423] Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.

[0424] Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

[0425] Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release component” is defined herein as a compound or compounds, including, but not limited to. polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0426] The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0427] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

[0428] The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

[0429] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

[0430] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

[0431] Dosing

[0432] The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.

[0433] A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0434] It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

[0435] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days. 4 days. 5 days. 6 days, 7 days, 10 days, 12 days. 15 days, 20 days, 28 days. 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0436] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection.

[0437] The compounds described herein can be formulated in unit dosage form. The term “unit dosage form"’ refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0438] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LDso and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0439] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g.. nitrogen atmosphere, and reducing / oxi dizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

[0440] The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein.

[0441] EXAMPLES

[0442] Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein.

[0443] Materials and Methods

[0444] General

[0445] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. All non-aqueous reactions were carried out under an atmosphere of dry nitrogen and (unless otherwise noted). Proton nuclear magnetic resonance spectra were obtained on a Bruker AVANCE 400 spectrometer at 400 MHz. Spectra are given in ppm (6) and coupling constants, J values, are reported in hertz (Hz). Tetramethylsilane was used as an internal standard for proton nuclear magnetic resonance.19F (376 MHz) were taken with 'H decoupling and chemical shifts were not corrected with an external standard. Mass spectra and LCMS analyses were obtained using a Waters Acquity UPLC-MS spectrometer using Electron spray Ionization. NMR and MS data for Examples are presented in Table 2.

[0446] Table 2. Selected characterization data for certain exemplary compounds of the disclosure

[0447] Step-1: To an ice-cold solution of (3-chloropyrazin-2-yl)methanamine (10.0 g, 69.7 mmol) in tetrahydrofuran (200 mL) was added DIPEA (36.5 mL. 209 mmol), isobutyric acid (9.20 g, 104 mmol) and then EDC (20.0 g, 104 mmol). The reaction was allowed to slowly warm to rt. After 12 h, the reaction mixture was diluted with water and extracted with EtOAc (2x100 mL). The EtOAc layer was washed with water (2xl00mL) and then brine (IxlOOmL), dried over Na2SO4, fdtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 80% EtOAc / hexanes) gave A-((3-chloropyrazin-2- yl)methyl)isobutyramide (9.00g, 60%). ESI (m / z) [CoHnCINsO+H] 214.

[0448] Step-2: To an ice-cold solution of A-((3-chloropyrazin-2-yl)methyl)isobutyramide (9.00 g, 42.1 mmol) in ethyl acetate (90 mL) and DMF (10 mL) was added phosphoryl trichloride (9.84 mL, 105 mmol) dropwise. The reaction was allowed to slowly warm to rt over 2 h. Afterwards, the reaction mixture was partitioned between satd. NaHCCh solution (100 mL) and EtOAc (100 mL). The organic layer was washed with cold water (2 xlOO mL) and brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 8- chloro-3-isopropylimidazo[l,5-a]pyrazine (7.5 g, 91%). ESI (m / z) [C9H10CIN3+HP 196.

[0449] Step-3: To an ice-cold solution of 8-chloro-3-isopropylimidazo| l .5-o|pyrazine (7.5 g, 38.3 mmol) in DCM (75 mL) was added NBS (8.19 g, 46.0 mmol) portion wise. After 30 min, the reaction mixture was diluted with DCM (100 mL). The organic solution was washed with water (100 mL x 2) and brine (100 mL x 1), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give l-bromo-8-chloro-3-isopropylimidazo[I,5- a]pyrazine (9.00 g, 86%). ESI (m / z) [C9H9BrClN3+2H]+276.

[0450] Step-4: A solution of l-bromo-8-chloro-3-isopropylimidazo[l,5-a]pyrazine (9.00 g, 32.8 mmol) in 2 M ammonia in IPA (400 mL, 32.8 mmol) was heated in an autoclave to 120 °C for 16 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was treated with ACN (30 mL), for 30 min, and the resulting solid collected by filtration and then dried to afford l-bromo-3-isopropylimidazo[l,5-a]pyrazin-8- amine (7.00 g, 84%). ESI (m'z) [C9HnBrN4+H]+255.

[0451] Step 1: To a solution of (3-chloropyrazin-2-yl)methanamine hydrochloride (5g, 27.8 mmol) in DCM (100 mL) was added DIPEA (24.2 mL, 139 mmol) and then AC2O (2.88 mL, 30.6 mmol) After 5 h, the reaction mixture was diluted with EtOAc (200 mL). The organic solution was washed with water (100 mL x 2) and then brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) gave A-((3-chloropyrazin-2- yl)methyl)acetamide (4.0 g, 78%). ESI (m / z) [CTHSCINSO+H] 186.

[0452] Step-2: To an ice-cold solution of A-((3-chloropyrazin-2-yl)methyl)acetamide (4.0 g, 21.5 mmol) in ethyl acetate (80 mL) and ACA imethvI formamide (4 mL) was added POCl3(5.02 mL, 53.9 mmol) dropwise. The reaction was allowed to slowly warm to rt. After 2 h, the reaction mixture was partitioned between EtOAc (100 mL) and cold satd. NaHCOs (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 8-chloro-3-methylimidazo[l,5-a]pyrazine (3.0 g). ESI (m / z ) [C7H6C1N3+H]+168.

[0453] Step 3: To an ice-cold solution of 8-chloro-3-methylimidazo[l,5-a]pyrazine (1 g, 5.97 mmol) in DCM (30 mL) was added NBS (1.06 g, 5.97 mmol). The reaction was allowed to slowly warm to rt. After 2 h, the reaction mixture was diluted with DCM (50 mL). The organic solution was washed with water (50 mL x 2) and then brine (20 mL). dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30% EtOAc / hexanes) gave l-bromo-8-chloro-3- methylimidazo[l,5-a]pyrazine (1.0 g, 68 %). ESI (m / z) [C?H5BrClN3+2H]+248.

[0454] Step 4: A solution of l-bromo-8-chloro-3-methylimidazo[l,5-o]pyrazine (1.00 g, 4.06 mmol) in ammonia (2 M in IPA, 50 mL, 4.06 mmol) was heated to 115 °C in an autoclave. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (100 mL). The organic solution was washed with water (50 mL) and then brine (20 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was treated with acetonitrile (5 mL) and for 1 h. The resulting solid was collected by filtration and dried under reduced pressure to afford l-bromo-3-methylimidazo[l,5- n]pyrazin-8-amine (600 mg, 65%). ESI (m / z) [C7H?BrN4+2H]+227.

[0455] Preparation of 3-iodo-lH-pyrazolo[3.4-d ]pyrimidin-4-amine

[0456] To a solution of 3-iodo-1H -pyrazolo[3,4-d|pyrimidin-4-amine (10.0 g, 38.3 mmol) in DMF (100 mL) was added K2CO3 (10.5 g, 76.7 mmol) and 2-iodopropane (7.81 g, 46.0 mmol). After 16 h, the reaction was quenched with water (200 mL) and then extracted with EtOAc (3 x 500 mL). The combined organics were washed with ice-cold brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with hexanes (100 mL) and CH2Cl2(20 mL). The resulting solid was collected by filtration and dried under vacuum to afford 3-iodo-l-isopropyl-1H-pyrazolo[3,4-cZ]pyrimidin- 4-amine (8.00 g, 68%) as a brown solid. 'H-NMR (400 MHz. CDCh): 5 8.32 (s. 1H), 5.96 (bs, 2H), 5.14-5.04 (m, 1H), 1.55 (d, J=6.80 Hz, 6H); ESI (m / z) [CsHioINs + H]+304.

[0457] To a solution of 3-iodo-1H -pyrazolo[3,4-d ]pyrimidin-4-amine (2.0 g, 7.6 mmol) in DMF (50 mL) was added K2CO3 (1.59 g, 11.5 mmol) and Mel (0.72 mL, 11.4 mmol). After 16 h, the reaction mixture was filtered through a celite pad using EtOAc. The filtrate was washed with water (200 mL), dried over Na2SO4, filtered and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) afforded 3-iodo- l -methyl- 1H-pyrazolo|3.4-d|pyrimidin-4-amine (0.80 g, 38%) as a pale yellow solid. 'H-NMR (400 MHz, CDCh): 8.31 (s, 1H), 5.95 (bs, 2H), 4.07 (s, 3H); ESI (m / z) [CsHelNs + H]+276.

[0458] P38gamma Inhibition Assay Recombinant, full-length human MAPK12 with a histidine purification tag is incubated at a concentration of 2.5 nM with 20 mM recombinant human full-length myelin basic protein containing a Histidine tag, 10 mM magnesium acetate and [y-33P]-ATP (specific activity and concentration as required). The total ATP concentration was 1 mM. Reaction was initiated by the addition of the magnesium acetate and [y-33P]-ATP. After incubation, the reaction was stopped by the addition of phosphoric acid. An aliquot of the reaction was spotted onto a filter and washed prior to drying and scintillation counting. The activity of MAPK12 was detected by the transfer of33P from ATP to the myelin basic protein substrate. Typically, activity relative to control is determined for 10 doses of inhibitor in concentrations ranging from nanomolar to high micromolar. Plots of percent acti vity as a function of the log concentration of compound are fitted to determine the IC50 (Table 1).

[0459] Example 1: Preparation of 5-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf|pyrimidin-3-yl)-

[0460] A-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 1)

[0461] Step-1: To a solution of tert-butyl 5-bromoindoline-l -carboxylate (2.00 g, 6.71 mmol) in CH2Cl2(75 mL) was added di-tert-butyl dicarbonate (2.93 mL, 12.6 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 60% EtOAc / hexanes) gave tert-butyl 5- bromoindoline-1 -carboxylate (2.00 g, 53%). ESI (m / z) [C19H2sBNO4+H-56]+243.

[0462] Step-2: To an argon sparged solution of tert-butyl 5-bromoindoline-l -carboxylate (1.00 g, 3.35 mmol) in 1,4-dioxane (30 mL) was added bis(pinacolato)diboron (1.70 g, 6.71 mmol) and potassium acetate (0.658 g, 6.71 mmol) followed by PdCh(dppf).CH2C12 (0.137 g, 0. 168 mmol). The reaction was heated to 85 °C for 6 h. Afterwards, the reaction mixture was diluted with CH2Cl2(60 mL). The organic solution was washed with water (10 mL) and then brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 2% MeOH / CH2Ch) gave tertbutyl 5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)indoline-l-carboxylate (1.50 g) as a viscous mass. ESI (m / z) [ C19H28BNO4+H]+346.

[0463] Step-3: To an argon sparged solution of 3-iodo-l-isopropyl-lL7-pyrazolo[3,4- <7|pyrimidin-4-amine (0.50 g, 1.65 mmol) in a mixture of 1 ,4-dioxane (20 mL) : water (2 mL) was added / e / 7-butyl 5-(4.4.5.5-tetramethyl- l .3.2-dioxaborolan-2-yl)indoline- l-carboxylate (854 mg, 2.47 mmol) and potassium carbonate (456 mg, 3.30 mmol) followed by XPhosPdG2 (129 mg, 0. 165 mmol). The reaction was heated to 100 °C for 6 h. Afterwards, the reaction mixture was diluted with methylene chloride (50 mL). The organic solution was washed with water (4 x 10 mL) and then brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 2% MeOH / CFLCh) gave / e / 7-butyl 5-(4-amino-l- isopropyl- 1H-pyrazolo [3, 4-d |pyrimi din-3 -yl)indoline-l -carboxy late (0.40 g, 61%). ESI (mty [C21H26N6O2+H]+395.

[0464] Step-4: A mixture of tert-butyl 5-(4-amino-l -isopropyl- 1H -pyrazolo[3.4-d ] pyrimidin-3-yl)indoline-l -carboxylate (0.40 g, 1.01 mmol) and 4 M HC1 (15 mL) was stirred for 2 h at rt. Afterwards, the reaction mixture was concentrated under reduced pressure. The residue was treated with satd. NaHCCh solution and extracted with methylene chloride (20 mL). The organic solution was washed with water (4 x 4 mL) and then brine (4 mL). dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3- (indolin-5-yl)-l-isopropyl-1H-pyrazolo[3,4-d ] pyrimidin-4-amine (0.22 g) which was used without further purification. ESI (m / z) [ C1eHisNe+H] + 295.

[0465] Step-5: To a solution of 3-(indolin-5-yl)-l-isopropyl-1H -pyrazolo[3,4--d|pyrimidin-4- amine (0.20 g, 0.67 mmol) in CH2Cl2(5 mL) was added l-fluoro-2-isocyanato-4- (trifluoromethyl)benzene (0. 139 g, 0.679 mmol). After 12 h, the solvent was concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOf I / CH2CT2) gave 5-(4-amino- l -isopropyl- 1H -pyrazolo|3.4-d|pyrimidin-3-yl)-N-(2- fluoro-5 -(trifl uoromethyl)phenyl)indoline-l -carboxamide (65 mg, 12%). ESI (m / z) [C24H21F4N7O +H]+500.

[0466] Example 2: Preparation of 5-(8-amino-3-isopropylimidazo[l,5-«]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 2) Step-1: To an ice-cold solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indoline- 1 -carboxylate (1.00 g. 2.90 mmol) in 2.2.2-trifluoroethanol (10 mL) was added TMSC1 (0.55 mL, 4.34 mmol) dropwise. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL). The organic solution was sequentially washed with satd. NaHCOs (50 mL), water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (0.70 g). The material was used without further purification. ESI (m / z) [C14H20BNO2+H]+246.

[0467] Step-2: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (0.70g, 2.8 mmol) in CH2Cl2(20 mL) was added 1 -fluoro-2-isocyanato-4- (trifluoromethyl)benzene (586 mg, 2.86 mmol). After 30 min, the reaction mixture was concentrated under reduced pressure to afford A-(2-fluoro-5-(trifluoromethyl)phenyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (1.10 g). ESI (m / z) [C22H23BF4N2O3+ H]+451.

[0468] Step-3: To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-tz]pyrazin- 8-amine (0.15 g, 0.58 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (318 mg, 0.706 mmol) in a mixture of 1,4-di oxane (3 mL) : water (0.3 mL) was added potassium carbonate (203 mg, 1.47 mmol) followed by RuPhosPdG3 (49.2 mg, 0.059 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the mixture was diluted with EtOAc (100 mL). The organic solution washed with water (2 x 50 mL) and then brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOI I / CI I2CI2) gave a residue that was treated with acetonitrile (10 mL) and the mixture was stirred at rt for 1 h. The resulting solid was collected by filtration and dried under vacuum to give 5-(8-amino-3-isopropylimidazo[L5- a]pyrazin-l-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (24 mg, 8%). ESI (m / z) [C25H22F4N6O+H]+499.

[0469] Example 3: Preparation of (5)-5-(4-amino-l-(l-methylpyrrolidin-3-yl)-LH-pyrazolo[3,4- d\ pyrimidin-3-yl)- -(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 3)

[0470] Step-1: To a solution of (<S)-5-(4-amino-l-(pyrrolidin-3-yl)-1H-pyrazolo[3,4- <7|pyrimidin-3-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide (0.10 g, 0.19 mmol) in MeOH (3 mL) was added paraformaldehyde (11.4 mg, 0.380 mmol). After 15 min, sodium cyanoborohydride (23.8 mg, 0.380 mmol) was added. After 12 h. the reaction mixture was treated with cold water (50 mL) and then extracted with EtOAc (2 x 100 mL). The combined organics were washed with water (2 x 50 mL) and then brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave a solid. The solid was stirred with w-pentane (5 mL) at rt. After 2 h, the solid was collected by filtration and then dried under vacuum to afford fS')-5-(4-amino- l -(l -methylpyrrolidin-3-yl)- 1H-pyrazolo|3.4-d |pyrimidin-3-yl)-N-(2-fluoro-5-(tririuoromethyl)phenyl)indoline- l - carboxamide (15 mg, 14%). ESI (m / z) [C26H24F4N8O+ H]+541.

[0471] Example 4: Preparation of 5-(8-amino-3-isopropylimidazo[l,5-«]pyrazin-l-yl)-N-(3-

[0472] (trifluoro methyl)benzyl)indoline-l-carboxamide (Compound 4)

[0473] Step-1: To an ice-cold, solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indoline-l -carboxylate (1.00 g, 2.90 mmol) in 2,2,2-trifluoroethanol (5.80 g, 57.9 mmol) was added TMSC1 (1.11 mL, 8.69 mmol) dropwise. The reaction was then allowed to warm to rt. After 4 h, the reaction mixture was concentrated under reduced pressure and then diluted with CH2Cl2(50 mL). The organic solution was sequentially washed with satd. NaHCCh (25 mL), water (2 x 25 mL) and then brine (2 x 10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (0.75 g). The material was used without further purification. ESI (m / z) [C14H20BNO2+H]+246. Step-2: A solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (0.50 g, 2.04 mmol) and l-(isocyanatomethyl)-3-(trifluoromethyl)benzene (1.23 g, 6.12 mmol) in THF (20 mL) was stirred for 2 h at rt. Afterwards, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 40% EtOAc / hexanes) gave 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-N-(3- (trifluoromethyl)benzyl)indoline-l -carboxamide (0.75 g, 88%). ESI (m / z) [C23H26BF3N2O3 + H]+447.

[0474] Step-3: To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-a]pyrazin- 8-amine (0.15 g, 0.588 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-A-(3- (trifluoromethy l)benzyl)indoline-l -carboxamide (0.525 g, 1.17 mmol) in a mixture of 1,4 dioxane (10 mL) : water ( 1 mL) was added potassium carbonate (0. 163 g, 1.17 mmol) followed by XPhosPdG2 (0.043 g, 0.059 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2(30 mL). The resulting organic mixture was washed with water (10 mL x 2) and then brine (10 mL x 2), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel,CH2Cl2to 4% MeOH / CH2C12) gave a solid which was washed with acetonitrile (5 mL), filtered and dried under vacuum to give 5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)- A-(3-(trifluoromethyl)benzyl)indoline-l-carboxamide (65 mg, 22%). ESI (m / z) [C25H26F3N7O+H] ' 495.

[0475] Example 5: Preparation of (7?)-5-(4-amino-l-(pyrrolidin-3-yl)-1H-pyrazolo[3,4- r / | pyrimidin-3-y I)- N-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide

[0476] (Compound 5)

[0477] Step-1: To a solution of 3-iodo-1H-pyrazolo[3,4-d |pyrimidin-4-amine (0.800 g, 3.06 mmol) and tert-butyl (S)-3-((methylsulfonyl)oxy)pyrrolidine-l -carboxylate (1.22 g, 4.60 mmol) in DMF (30 mL) was added K2CO3 (1.05 g, 7.66 mmol). The reaction was heated to 85 °C for 16 h. Afterwards, the reaction mixture was treated with water and extracted with EtOAc (2 x 100 mL). The combined organics were washed with cold brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with MTBE and hexanes to afford tert-butyl (R)-3-(4-amino-3-iodo-127-pyrazolo[3,4- c / |pyrimi din- l-yl)pyrrolidine-l -carboxy late (1.00 g, 76%) as a pale brown solid. ESI (m / z) [C14H19lN6O2+H]+431.

[0478] Step-2: To an argon sparged solution of tert-butyl (7?)-3-(4-amino-3-iodo- 1H- pyrazolo[3.4-d ]pyrimidin-l-yl) pyrrolidine- 1 -carboxylate (0.50 g, 1.16 mmol) and A-(2- fluoro-5-(trifluoromethyl)phenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l- carboxamide (0.68 g, 1.51 mmol) in a mixture of 1 ,4-dioxane (30 mL) :water (3 mL) was added K2CO3 (402 mg, 2.91 mmol) followed by RuPhosPdG3 (48.7 mg, 0.058 mmol). The resulting reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 100% EtOAc) gave tert-butyl (7?)-3-(4-amino-3-(l-((2-fluoro-5- (trifluoromethyl)phenyl)carbamoyl)indolin-5-yl)-1H-pyrazolo[3,4-d ]pyrimidin-l- yl)pyrrolidine-l -carboxylate (300 mg, 41%) a pale brown solid. ESI (m / z) LC?OH3OF4N803+H]+627.

[0479] Step-3: To an ice-cold solution of tert-butyl (7?)-3-(4-amino-3-(l-((2-fluoro-5- (trifluoromethy l)phenyl) carbamoyl)indolin-5 -y 1)- 1 H-py razol o| 3 ,4-d | py rimidin- 1 - yl)pyrrolidine-l -carboxylate (0.10 g, 0.16 mmol) in 2,2,2-trifluoroethanol (10 mL) was added TMSC1 (0.041 mL, 0.319 mmol) dropwise. The reaction was allowed to warm to rt. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue w as treated with satd. NaHCCh solution (50 mL) and extracted with 10% MeOH in CH2Cl2(2 x 100 mL). The organic solution was w ashed with water (2 x 25 mL) and then brine solution (2 x 25 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CFbCbto 15-20% MeOH / CFbCb) gave (7?)-5-(4-amino-l-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d|pyrimidin-3-yl)-A-(2-fluoro-5- (trifluoromethyl)phenyl)indoline-l -carboxamide (50 mg, 59%) as an off-white solid. ESI (m / z) [C25H22F4N8O+H]+527.

[0480] Example 6: Preparation of 5-(8-amino-3-isopropylimidazo[l,5-«]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 6)

[0481] Step-1: To a solution of ter / -butyl (7?)-3-((methylsulfonyl)oxy)pyrrolidine-l- carboxylate (457 mg, 1.72 mmol) in DMF (10 mL) was added 3-iodo-lH-pyrazolo[3,4- <7]pyrimidin-4-amine (0.300 g. 1.14 mmol) followed by potassium carbonate (397 mg. 2.87 mmol). The reaction was heated to 85 °C for 12 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The organic solution was washed with water (50 mL x 2) and then brine (50 mL x 1), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was stirred with MTBE (10 mL) for 1 h. The resulting solid was collected by filtration and then dried under vacuum to afford tert-butyl (S)-3-(4- amino-3-iodo- 1H -pyrazolo|3.4-d |pyrimidin- l -yl (pyrrolidine- 1 -carboxylate (200 mg, 40%) as an off-white solid. ESI (m / z) [C14H19IN6O2+H]+431.

[0482] Step-2: To an argon sparged solution of tert-butyl (5)-3-(4-amino-3-iodo-1H - pyrazolo| 3.4-d|pyrimidin- l-yl)pyrrolidme- l -carboxylate (287 mg, 0.666 mmol) and A-(2- fluoro-5-(trifluoromethyl)phenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l- carboxamide (250 mg, 0.555 mmol) in a mixture of 1 ,4-di oxane (7.5 mL) : water (0.75 mL) was added potassium carbonate (192 mg, 1.38 mmol) followed by RuPhosPdG3 (46.4 mg, 0.056 mmol). The reaction was heated to 100 °C for 24 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The organic solution was washed with water (50 mL x 2) and then brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave tert-butyl (S)-3-(4-amino-3-(l-((2-fluoro-5- (trifluoromethyl)phenyl)carbamoyl)indolin-5-yl)-1H-pyrazolo[3,4-d|pyri mi din-1- yl)pyrrolidine- 1 -carboxylate (150 mg, 43%). ESI (m / z) [C30H30F4N8O3+ H]+627.

[0483] Step-3: To an ice-cold, solution of tert-butyl (S)-3-(4-amino-3-(l-((2-fluoro-5- (trifluoromethyl) phenyl)carbamoyl )indolin-5-yl)- 1H -pyrazolo|3.4-d |pyrimidin- l - yl)pyrrolidine-l -carboxylate (0.10 g, 0.16 mmol) in 2,2,2-trifluoroethanol (5 mL) was added TMSC1 (0.04 mL, 0.319 mmol) dropwise. After 1 h, the reaction mixture was concentrated under reduced pressure and then diluted with EtOAc (100 mL). The organic solution was washed with satd. NaHCOs solution (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. hexanes to 50% EtOAc / hexanes) gave (S)-5-(4-amino-l-(pyrrolidin-3-yl)-1H-pyrazolo[3,4- t / |pynmidin-3-yl)-N-(2-fluoro-5-(tri fl uoromethyl)phenyl)indoline- 1 -carboxamide (25 mg, 29%). ESI (m / z ) [C25H22F4N8O+ H]+527.

[0484] Example 7: Preparation of 5-(4-amino-l-isopropyl-3«,7«-dihydro-1H-pyrazolo[3,4-r / | pyriniidin-3-yl)-A-(3-(trifluoromethyl)benzyl)indoline-l -carboxamide (Compound 7)

[0485] Step-1: To an argon sparged solution of 3-iodo-l-isopropyl-1H -pyrazolo[3,4-d|pyrimidin-4-amine (0.150 g. 0.495 mmol) and 5-(4.4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-A-(3-(trifluoromethyl)benzyl)indoline-l-carboxamide (0.331 g. 0.742 mmol) in a mixture of 1 ,4-di oxane (30 mL) : water (3 mL) was added potassium carbonate (0.137 g, 0.990 mmol) followed by XPhosPdG2 (0.036 g, 0.049 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the reaction mixture was concentrated under reduced pressure. The residue was diluted with CEI2CI2 (50 mL). The organic mixture was washed with water (10 mL x 2) and then brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 4% MeOH / CH2Cl2) gave a solid. The solid was stirred with acetonitrile (5 mL), subsequently collected by filtration and dried under vacuum to afford 5-(4-amino-l-isopropyl- 1H -pyrazolo[3,4-d|pyrimidin-3-yl)-A-(3- (trifluoromethyl)benzyl)indoline-l -carboxamide (65 mg, 26%). ESI (m / z ) [C25H26F3N7O +H]+498.

[0486] Example 8: Preparation of (7?)-5-(4-amino-l-(l-methylpyrrolidin-3-yl)-LH-pyrazolo[3,4- d pyrimidin-3-yl)- / V-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 8)

[0487]

[0488] Step-1: To a solution of (7?)-5-(4-amino-l-(pyrrolidin-3-yl)-l#-pyrazolo[3,4- <7|pyrimidin-3-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)indohne-l-carboxamide hydrochloride (0.15 g, 0.26 mmol) in MeOH (20 mL) was added paraformaldehyde (24.0 mg, 0.799 mmol) followed by sodium cyanoborohydride (33.5 mg, 0.533 mmol). After 16 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with water (10 mL). The resulting solid was collected by filtration and dried under vacuum. Purification by flash chromatography (silica gel, ChbChto 15-20% MeOH / CH2Cl2) gave a brown solid which was stirred in acetonitrile (5 mL). The solid w as collected by filtration and then dried under vacuum to afford ( / ?)-5-(4-amino- l -(l -methylpyrrolidin-3-yl)- 1H- pyrazolo|3.4-d |pyrimidin-3-yl)-N-(2-fluoro-5-(trinuoromethyl)phenyl)indolme- 1 - carboxamide (40 mg, 27%) as a white solid. ESI (m -z) [C26H24F4N8O+I P 541.

[0489] Example 9: Preparation of 5-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0490] A-phenylindoline-l -carboxamide (Compound 9)

[0491] Step-1: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (200 mg, 0.816 mmol) in dichloromethane (10 mL) w as added phenyl isocyanate (117 mg, 0.979 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure to afford N- phenyl-5-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)indoline-l-carboxamide (280 mg). The material w as used without further purification. ESI (m / z) [C21H25BN2O3+ H]+365.

[0492] Step-2: To an argon sparged solution of A-phenyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indoline-l -carboxamide (350 mg, 0.961 mmol) and 3-iodo-l-isopropyl- 1H -pyrazolo|3.4-d|pynmidin-4-amine (233 mg. 0.769 mmol) in 1.4-dioxane (15 mL) : water (1.5 mL) was added potassium carbonate (332 mg, 2.40 mmol) followed by XPhosPdG2 (70.7 mg, 0.096 mmol). The reaction was heated to 90 °C for 16 h. Afterwards, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 100% EtOAc) gave a solid which was stirred with acetonitrile (4 mL) for Ih. The solid was collected by filtration, dried and lyophilized from acetonitrile / water to afford 5-(4-amino-l -isopropyl- 1H-pyrazolo[3.4-cf]pyrimi din-3-yl)-A- phenylindoline-1 -carboxamide (60 mg, 15%). ESI (m / z) [C23H23N7O+ H]+414.

[0493] Example 10: Preparation of 6-(4-amino-l-isopropyl-LH-pyrazolo[3,4-t / ]pyrimidin-3-yl)-

[0494] 7V-(2-fluoro-5-(trifluoromethyl)phenyl)benzo [rf] isoxazole-3-carboxamide (Compound

[0495] 10)

[0496] Step-1: To an ice-cold solution of 6-bromobenzo[< ]isoxazole-3-carboxyhc acid (2.00 g, 8.26 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (1.406 g, 7.85 mmol) in CH2Cl2(20 mL) was added pyridine (13.3 mL, 165 mmol) followed by POCl3(0.847 mL, 9.09 mmol). The reaction was allowed to slowly warm to room temperature. After 2 hr, the reaction was quenched with saturated NaHCCh solution (40 mL). The resulting mixture was extracted with EtOAc ( 2 x 20 mL). The combined organics were washed with brine, dried over Na2SOr, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 50% EtOAc / hexanes) gave 6-bromo-A-(2-fluoro-5-(trifluoromethyl) phenyl)benzo[<7]isoxazole-3-carboxamide (2.00 g, 60%). ESI (m / z) [C15H7BrF4N2O2+H]+404.

[0497] Step-2: To a solution of 6-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)benzo[<7]isoxazole-3-carboxamide (2.00 g, 4.96 mmol) in 1,4- dioxane (20 mL) was added bis(pinacolato)diboron (1.63 g, 6.45 mmol). The resulting mixture was sparged with argon for 5 min. followed by addition of potassium acetate (0.974 g, 9.92 mmol) and PdC12(dppf) (0.182 g, 0.248 mmol). The reaction was heated to 80 °C for 12 h. Afterwards, the mixture was filtered through a celite bed using 1,4-di oxane and then concentrated. The residue was triturated with methyl / c / V-butyl ether (20 mL) and hexanes (20 mL). A dark solid was removed by filtration. The filtrate was concentrated under reduced pressure to afford a viscous mass which was triturated with hexane (50 mL). The resulting solid was collected by filtration and dried under vacuum to afford A-(2-fluoro-5- (trifluoromethyl)phenyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[<7| isoxazole- 3-carboxamide (2.00 g) as brown solid. The material was used as is without further purification.

[0498] Step-3: A solution of 3-iodo-l-isopropyl-1H-pyrazolo[3,4-d|pyrimidin-4-amine (0.15 g, 0.49 mmol) in 1,4-dioxane (20 mL) : water (2 mL) was sparged with argon then N-(2- fluoro-5-(trifluoromethyl)phenyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzo[<f|isoxazole-3-carboxamide (0.446 g, 0.99 mmol) and potassium phosphate (0.21 g, 0.99 mmol) were added followed by XPhos-Pd-G2 (0.039 g, 0.049 mmol). The reaction was heated to 60 °C for 3 h. Afterwards, the reaction mixture was diluted with dichloromethane (50 mL). The mixture was washed with water (2 x 10 mL) and then brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 4% MeOH / CH2Cl2) gave 6-(4-amino-l- isopropyl-I77-pyrazolo[3,4--d|pyrimidin-3-yl)-A-(2-fluoro-5- (trifluoromethyl)phenyl)benzo[<T]isoxazole-3-carboxamide (32 mg, 12%). ESI (m / z ) [C23H17F4N7O2 +H]+500.

[0499] Example 11 : Preparation of 5-(4-amino-l-isopropyl-1H -pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0500] A (2-fluoro-5-(trifluoromethyl)phenyl)-2,3-dihydro-l / / -pyrrolo[3,2-A]pyridine-l- carboxamide (Compound 11)

[0501] Step-1: To a solution of l / / -pyrrolo[3.2-i5]pyridine (7.00 g. 59.3 mmol) in tetrahydrofuran (140 mL) was added a solution of di-tert-butyl dicarbonate (14.4 mL, 62.2 mmol) dissolved in CH2Cl2(70 mL). After 12 h, the reaction mixture was concentrated under reduced pressure to afford tert-butyl- 1H-pyrrolo[3,2-Z?]pyridine- 1 -carboxylate (12.0 g). The material was used without any further purification. ESI (m / z) [C12H14N2O2+H]+219.

[0502] Step-2: To a solution of tert-butyl-1H -pyrrolo[3,2-7']pyridine-l-carboxylate (12.0 g, 55.0 mmol) in ethanol (350 mL) was added 20% Pd(0H)2 / C (6.00 g, 42.7 mmol). The reaction mixture was stirred under a hydrogen atmosphere (200 psi) in an autoclave for 48 h at rt. Afterwards, reaction mixture was carefully filtered through a celite bed using EtOAc (200 mL). The resulting filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 10% EtOAc / hexane) gave tert-butyl 2,3- dihydro-1H -pyrrolo[3,2-6]pyridine-l-carboxylate (9.00 g). ESI (m / z) [C12H16N2O2+H ]+221.

[0503] Step-3: To an ice-cold, solution of tert-butyl 2,3-dihydro-1H-pyrrolo[3,2-h]pyridine- 1-carboxylate (9.00 g, 40.9 mmol) in 2,2,2-trifluoroethanol (200 mL) was added TMSC1 (10.4 mL, 82 mmol) dropwise. The reaction was allowed slowly warm to rt. After 12 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with satd. NaHCCh solution (100 mL) and the resulting mixture extracted with 10% MeOH in CH2Cl2(5 x 100 mL). The combined organics were washed with water (100 mL) and then brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (4.00 g) ESI m / z) [C7H8N2+ H]+121.

[0504] Step-4: To an ice-cold solution of 2.3-dihydro-1H-pyrrolo[3,2-h]pyridine (1.50 g, 12.4 mmol) in acetonitrile (30 mL) was added a solution of l-bromopyrrolidine-2,5-dione (1.55 g, 8.74 mmol) in acetonitrile (10 mL) over 20 min. After 1 h, reaction mixture was diluted with EtOAc (50 mL). The organic solution was washed with water (50 mL x 2) and then brine (20 mL x 2), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. hexanes to 30% EtOAc / hexanes) gave 5-bromo-2,3-dihydro- 1 H-pyrrolo|3.2-A| pyridine (800 mg, 25 % over 2 steps). ESI (m / z) [C7H7BrN2+H]+200.

[0505] Step-5: To a solution of 5-bromo-2,3-dihydro-1H-pyrrolo[3,2-d]pyridine (800 mg, 4.02 mmol) in di chloromethane (24 mL) was added l-fluoro-2-isocyanato-4-(trifluoromethyl) benzene (989 mg, 4.82 mmol). After 1 h, the reaction mixture was diluted with dichloromethane (50 mL). The organic solution was washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30% EtOAc / hexanes) gave 5-bromo-N-(2-fluoro-5-(trifluoromethyl )phenyl)-2.3-dihydro- 1H- pyrrolo[3,2- / ?]pyridine-l -carboxamide (1.20 g, 73%). ESI (m z) [C15lTioBrF4N30+2E[]+406.

[0506] Step-6: To an argon sparged solution of 5-bromo-A-(2-fluoro-5-(trifluoromethyl) phenyl)-2,3-dihydro-1H-pyrrolo[3,2- / >]pyridine-l-carboxamide (1.20 g, 2.97 mmol) in 1,4- dioxane (36 mL) was added bis(tributyltin) (2.066 g, 3.56 mmol) followed by Pd(PPhs)4 (0.343 g, 0.297 mmol). The reaction was heated to 100 °C for 48 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The organic mixture was washed with water (50 mL x 2) and then brine (50 mL x 2). dried over anhydrous Na2S(X filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30% EtOAc / hexanes) gave A-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(tributylstannyl)-2,3- dihydro- 1 H-pyrrolo| 3.2-6 Ipyridinc- 1 -carboxamide (600 mg, 32%). ESI (m / z) [C27H37F4N3OSn+H]+615.

[0507] Step-7: To an argon sparged solution of A-(2-fluoro-5-(trifluoromethyl)phenyl)-5- (tributylstannyl)-2,3-dihydro-1H-pyrrolo[3,2-6]pyridine-l-carboxamide (300 mg, 0.488 mmol) and 3-iodo-l-isopropyl-1H-pyrazolo[3,4--d|pyrimidin-4-amine (148 mg, 0.488 mmol) in 1,4-dioxane (9 mL) was added XPhosPdG2 (38.4 mg, 0.049 mmol) and the resulting mixture heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL x 2) and then brine (50 mL x 2), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CH2Cl2) gave a residue which was stirred in MeOH (1 mL) at rt for 1 h. The resulting solid was collected by filtration to give 5-(4- amino-l-isopropyl-1H-pyrazolo[3,4-d ]pyrimidin-3-yl)-A-(2-fluoro-5- (trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrolo[3,2-6]pyridine-l -carboxamide (25 mg, 10%) after lyophilization from acetonitrile / water. ESI (m / z) [C23H20F4N8O+H]+501.

[0508] Example 12: Preparation of l-(5-(4-amino-l-isopropyl-1H-pyrazolo|3,4- / |pyrimidin-3- yl) indoIin-l-yl)-2-phenylethan-l-one (Compound 12)

[0509] Step-1: To an ice-cold solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indoline hydrochloride (400 mg, 1.42 mmol) in CH2Cl2(10 mL) was added ElsN (0.495 mL, 3.55 mmol) followed by dropwise addition of 2-phenylacetyl chloride (264 mg, 1.70 mmol). The reaction was allowed to slowly warm to rt. After 4 h, the reaction mixture was treated with satd. NaHCOs (50 mL), then extracted with CH2Cl2(50 mL x 2). The combined organics were washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 2-phenyl-l-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-l-yl)ethan-l-one (500 mg, 97 %) as yellow solid. ESI (m / z) [C22H26BNO3+H]+364.

[0510] Step-2: To an argon sparged solution of 3-iodo-l -isopropyl- 1H -pyrazolo[3, 4- -d|pyrimidin-4-amine (200 mg, 0.66 mmol) and 2-phenyl-l-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-l-yl)ethan-l-one (312 mg, 0.858 mmol) in a mixture of 1,4- di oxane (20 mL): water (4 mL) was added K2CO3 (228 mg, 1.65 mmol) followed by XPhosPdG2 (26.0 mg, 0.033 mmol). The reaction was heated to 100 °C for 6 h. Afterward, the reaction mixture was filtered through celite using with EtOAc (50 mL). The organic filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 100% EtOAc) gave a residue that was triturated with acetonitrile (10 mL). The resulting solid was collected by filtration and dried under vacuum to afford l -(5-(4-amino- l-isopropvl- 1H-pyrazolo|3.4-d|pyrimidin-3- yl)indolin-l-yl)-2-phenylethan-l-one (120 mg, 44%) as an off-white solid. ESI (m / z) [C24H24N6O+H]+413.

[0511] Example 13: Preparation of 7-(4-amino-l-isopropyl-Lff-pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0512] A-phenylimidazo[l,2-a]pyridine-3-carboxamide (Compound 13)

[0513] Step-1: To a solution of methyl 7-bromoimidazo[l,2-a]pyridine-3 -carboxy late (2.00 g, 7.84 mmol) in THF (30 mL) : water (10 mL), was added LiOHH2O (0.987 g, 23.5 mmol). After 12 h, the mixture was concentrated under reduced pressure. The residue was treated with water (15 mL) and then acidified with 6 N hydrochloric acid. The resulting solid was collected by filtration, w ashed with water (20 mL) and dried under vacuum to afford 7- bromoimidazo[l,2-a]pyridine-3-carboxylic acid (1.5 g, 79 %). ESI (m / z) [CsHsBrlShCh +H]+242.

[0514] Step-2: To a solution of 6-bromopyrazolo[l,5-a]pyridine-3-carboxylic acid (0.35 g, 1.45 mmol) in DMF (30 mL) was sequentially added aniline (0.20 g, 2. 17 mmol), A-ethyl-A- isopropylpropan-2-amine (0.938 g, 7.26 mmol) and HATU (0.828 g, 2.178 mmol). After 12 h, the reaction mixture was diluted with methylene chloride (10 mL). The organic solution was washed with water (2 x 10 mL) and then brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Chto 10% MeOH / CEECh) gave 7-bromo-A / - phenylimidazo[l,2-tf]pyridine-3-carboxamide (0.45 g, 98 %) as a solid. ESI (m / z) [CuHioBrNsO + H]+317.

[0515] Step-3: To an argon sparged solution of 7-bromo-A-phenylimidazo[l,2-a]pyridine-3- carboxamide) (0.45 g, 1.42 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (0.47 g, 1.85 mmol) and potassium acetate (0.279 g, 2.85 mmol) followed by PdCh(dppf) (0. 104 g, 0. 142 mmol). The reaction was heated to 100 °C for 12 h. After cooling to room temperature, the reaction mixture was passed through a celite bed using CH2Cl2(2 x 30 mL). The filtrate w as washed with water (10 mL) and then brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford JV-phenyl-7-(4, 4,5, 5-tetramethyl- L3,2-dioxaborolan-2-yl)imidazo[l,2-tf]pyridine-3-carboxamide (0.65 g). ESI (m z) [C20H22BN3O3 + H]+364. The material was used as is without further purification.

[0516] Step-4: To an argon sparged solution of 3-iodo- 1 -isopropyl- 1H-pyrazolo[3, 4- ri|pyrimidin-4-amine (0.20 g, 0.66 mmol) in a mixture of 1.4-dioxane (30 mL) : water (3 mL) was added / V-pheny 1-7-14.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-yl)imidazo| 1.2-1 / Ipyndine- 3-carboxamide (0.36 g, 0.99 mmol) and potassium carbonate (0.182 g, 1.32 mmol) followed by XPhosPd-G2 (0.049 g, 0.066 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the reaction mixture was cooled and then diluted with methylene chloride (100 mL). The mixture was washed ith water (2 x 10 mL) and then brine (10 mL). dried over anhydrous sodium sulphate, filtered and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, CEbChto 10% MeOH / CFLCh) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave a solid which washed with water (10 mL) and lyophilized from acetonitrile / water to give 4-amino-l-isopropyl-1H-pyrazolo[3,4-ri]pyrimidin-3-yl)-A- phenylimidazo[l,2-a]pyridine-3-carboxamide (65 mg, 23%) as a white solid after lyophilization. ESI (m / z) [C22H20N8O+ H]+413.

[0517] Example 14: Preparation of 5-(4-amino-l-isopropyl-1H-pyrazolo|3,4-r / |pyrimidin-3-yl)- 7V-(2-fluorophenyl)indoline-l-carboxamide (Compound 14)

[0518] Step-1: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (200 mg, 0.710 mmol) in tetrahydrofuran (6 mL) was added Et?N (0.198 mL, 1.42 mmol) followed by l-fluoro-2-isocyanatobenzene (107 mg, 0.781 mmol). After 12, the reaction mixture was diluted with EtOAc (50 mL). The organic solution was washed with and brine (50 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexane) gave N-(2- fluorophenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (230 mg, 85%). ESI (m / z ) [C21H24BFN2O3+H]+383.

[0519] Step-2: To an argon sparged solution of A-(2-fluorophenyl)-5-(4.4.5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)indoline-l -carboxamide (227 mg, 0.594 mmol) and 3-iodo-l- isopropyl-lL7-pyrazolo[3,4--d|pyrimidin-4-amine (150 mg, 0.495 mmol) in a mixture of 1,4- dioxane (4.5 mL) : water (0.45 mL) was added potassium carbonate (137 mg, 0.990 mmol) followed by XPhosPdG2 (38.9 mg, 0.049 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with water (20 mL x 2) and then brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 95% EtOAc / hexanes) afforded 5-(4-amino-l-isopropyl-1H-pyrazolo[3,4- t / |pynmidin-3-yl)-N-(2-fluorophenyl)indoline- 1 -carboxamide (35 mg, 16%) after lyophilization from acetonitrile / water. ESI (m z) [C23H22FN7O+H]+432.

[0520] Example 15: Preparation of 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0521] \-(3-nuoroplienyl)iii(loline- 1-carboxainide (Compound 15)

[0522] Step-1: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (200 mg, 0.71 mmol) in tetrahydrofuran (6 mL) was added EtsN (0.198 mL, 1.42 mmol) and l-isocyanato-3-(trifluoromethyl)benzene (146 mg, 0.781 mmol). After 12 h. the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with and brine (50 mL), dried over Na2SOr, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-A-(3-(trifluoromethyl) phenyl)indoline- 1 - carboxamide (250 mg. 81%). ESI (m / z) [C22H24BF3N2O3+H]+433.

[0523] Step-2: To an argon sparged solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-A-(3-(trifluoromethyl)phenyl)indoline-l -carboxamide (257 mg, 0.594 mmol) and 3-iodo- l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.495 mmol) in a mixture of 1,4- dioxane (4.5 mL) : water (0.45 mL) was added potassium carbonate (137 mg, 0.990 mmol) followed by XPhosPdG2 (38.9 mg, 0.049 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with water (50 mL x 2) and then brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 100% EtOAc) afforded 5-(4-amino-l-isopropyl-1H-pyrazolo[3,4-d ] pyrimidin-3- yl)-A-(3-(trifluoromethyl)phenyl)indoline-l-carboxamide (40 mg, 16%) after lyophilization from acetonitrile / water. ESI (m / z) [C24H22F3N7O+H]+482.

[0524] Example 16: Preparation of 6-(4-amino-l-isopropyl-1H-pyrazolo[3,4-d|pyrimidin-3-yl)-

[0525] 7V-(2-fluoro-5-(trifluoromethyl)phenyl)pyrazoIo [ 1 ,5-«] pyridine-3-carboxamide

[0526] (Compound 16)

[0527] Step-1: To an ice-cold suspension of 6-bromopyrazolo[l,5-a]pyridine-3-carboxylic acid (1.50 g, 6.22 mmol) and pyridine (11 mL, 12.4 mmol) in CH2Cl2(15 mL) was added 2- fluoro-5-(trifluoromethyl)aniline (1.23 g, 6.85 mmol) followed by POCl3(0.89 mL, 9.3 mmol). The reaction was allowed to warm to rt. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCOs (30 mL) and then extracted with EtOAc (2 x 200 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 40% EtOAc / hexanes) gave 6- bromo-A-(2-fluoro-5-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide (1.30 g, 52%) as an off-white solid. ESI (m / z ) [C15HgBrF4N3O+H]+402.

[0528] Step-2: To an argon sparged solution of 6-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide (0.80 g, 1.99 mmol) in 1,4- dioxane (20 mL) was added bis(pinacolato)diboron (758 mg, 2.99 mmol) and potassium acetate (488 mg, 4.98 mmol) followed by addition of PdCE(dppf) (145 mg, 0.199). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was cooled and then filtered through a celite pad using 9:1 MeOH / CEECE. The filtrate was concentrated under reduced pressure. The residue was treated with hexanes, sonicated and the resulting solid collected by filtration to afford A-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl) pyrazolof 1 ,5-a]pyridine-3-carboxamide (1.0 g) as a dark solid. ESI (m / z) [C2iH2oBF4N303-82]+328 (boronic acid mass). The material was used as is without further purification.

[0529] Step-3: A solution of 3-iodo- 1 -isopropyl- 1H-pyrazolo| 3.4- / |pyrimidin-4-amine (0.20g, 0.66 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (889 mg, 1.979 mmol) in 1,4- dioxane (30 mL): water (6.00 mL) was sparged with argon for 5 min., followed by the addition of CszCCE (537 mg, 1.65 mmol) and XphosPd-G2 (25.9 mg. 0.033 mmol). The reaction was heated to 100 °C for 6 h. Afterwards, the reaction mixture was cooled and then filtered through a celite pad using 9:1 MeOH / CEECE. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) gave a light brown solid (150 mg). The solid was stirred with acetonitrile (10 mL) at rt. After 30 min, the solid was collected by filtration and then dried under vacuum to afford 6-(4-amino- l-isopropyl-1H-pyrazolo[3,4-d|pyrimidin-3-yl)-A-(2-fluoro-5- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide (125 mg, 38 % yield) as an off-white solid. ESI (m / z) [C23H18F4NsO +H]+499.

[0530] Example 17: Preparation of 7-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)- 7V-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-«]pyridine-3-carboxamide (Compound 17)

[0531] Step-1: To a room temperature solution of ethyl 7-bromoimidazo[ 1 ,2-t?]pyridine-3- carboxylate (1 g. 3.72 mmol) in mixture of THF (10 mL) : water (3 mL) was added LiOH H2O (0.46 g, 11.1 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with water (15 mL) and then neutralized with 2 N hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried under vacuum to afford 7-bromo imidazo| 1 ,2-o|pyndine-3 -carboxy lie acid (0.75 g, 84 %). ESI (m / z) [C8H5BrN2O2+ H]+243.

[0532] Step-2: To an ice-cold solution of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (0.75 g, 3.11 mmol) in dichloromethane (30 mL) was added pyridine (2.52 mL, 31.1 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (1.11 g, 6.22 mmol) followed by POCl3(0.319 mL, 3.42 mmol). The reaction was allowed to warm to rt. After 30 min, the reaction mixture was concentrated under reduced pressure. The residue was treated with satd. NaHCO? and then extracted with CH2Cl2(50 mL). The organic layer was washed with water (40 mL x 2) and then brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 60% EtOAc / hexanes) gave 7- bromo-A-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a,]pyridine-3-carboxamide (0.75 g, 60%). ESI (m / z) [C15H8BrF4N3O + H]+403.

[0533] Step-3: To an argon sparged solution of 7-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-G]pyridine-3-carboxamide (0.65 g, 1.61 mmol) in 1,4- dioxane (30 mL) was added bis(pinacolato)diboron (0.49 g, 1.94 mmol) and potassium acetate (0.317 g, 3.23 mmol) followed by PdC12(dppf (0.118 g, 0.162 mmol). The reaction was heated to 90 °C for 16 h. Afterwards, the reaction mixture was cooled and then diluted with methylene chloride (100 mL). The mixture was washed with water (4 x 10 mL) and then brine (10 mL). dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give A-(2-fluoro-5-(trifluoromethyl)phenyl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (0.85 g). ESI (m / z) [C21H20BF4N3O3 + H]+368 (boronic acid mass). The residue was used as is without further purification.

[0534] Step-4: To an argon sparged solution of 3-iodo-l -isopropyl- 1H -pyrazolo[3,4- < |pyrimidin-4-amine (0.25 g, 0.82 mmol) in 1,4-dioxane (20 mL) : water (2 mL) was added A-(2-fluoro-5-(trifluoromethyl)phenyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l,2-a]pyridine-3-carboxamide (0.556 g, 1.23 mmol) and potassium carbonate (0.228 g, 1.650 mmol) followed by XPhosPd-G2 (0.065 g, 0.082 mmol). The reaction was heated to 100 °C for 6 h. Afterwards, the reaction mixture was cooled, filtered and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CH2Ch) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave 7-(4-amino-l-isopropyl-1H- pyrazolo[3,4-d|pyrimidin-3-yl)-JV-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2- a]pyridine-3-carboxamide (0.027 g, 6%) after lyophilization from acetonitrile / water. ESI (m / z ) [C23H18F4N8O+H]+499.

[0535] Example 18: Preparation of 5-(4-amino-l-isopropyl-1H-pyrazolo|3,4-r / |pyrimidin-3-yl)-

[0536] A-(2-fluoro-3-(trifluoromethyl) phenyl)indoline-l-carboxamide (Compound 18)

[0537] Step-1: To an ice-cold solution of 2-fluoro-3-(trifluoromethyl)aniline (1.00 g, 5.58 mmol) in CH2Cl2(20 mL) was added pyridine (0.903 mL, 11.1 mmol) followed by dropwise addition of phenyl chloroformate (0.840 mL, 6.70 mmol). The reaction was allowed to warm to rt. After 2 h. the reaction mixture was treated with water (20 mL) and then extracted with CFLCb (2 x 50 mL). The combined organics were washed with IN HC1 solution (20 mL) and then brine solution (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 10% EtOAc / hexanes) gave phenyl (2-fluoro-3-(trifluoromethyl)phenyl)carbamate (LOO g, 59%) as an off-white solid.

[0538] Step-2: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (300 mg, 1.06 mmol) in CH2Cl2(20 mL) was added EtaN (0.371 mL, 2.66 mmol) followed by phenyl (2-fluoro-3-(trifluoromethyl)phenyl)carbamate (383 mg, 1.278 mmol). After 2 h, the reaction mixture was treated with water (20 mL) and extracted with CH2Cl2(2 x 25 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 10% EtOAc / hexanes) gave A-(2-fluoro-3- (trifluoromethyl) phenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l- carboxamide (450 mg) as an off-white solid. ESI (m / z ) [C22H23BF4N2Ch]+451.

[0539] Step-3: To an argon sparged solution of 3-iodo-l-isopropyl-1H-pyrazolo[3,4- 6 / |pyrimidin-4-amine (150 mg. 0.495 mmol) and JV-(2-fluoro-3-(trifluoromethyl)phenyl)-5- (4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)indoline-l-carboxamide (267 mg. 0.594 mmol) in a mixture of 1 ,4-dioxane (20 mL) : water (4 mL) was added potassium carbonate (171 mg, 1.237 mmol) followed by XPhosPdG2 (19.47 mg, 0.025 mmol). The reaction was heated to 90 °C for 12 h. Afterwards, the reaction mixture was filtered through a celite pad using EtOAc (30 mL). The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 90% EtOAc / hexanes) gave a light brown solid. The solid was stirred in acetonitrile (5 mL) then collected by filtration and dried under vacuum to afford 5-(4-amino-l-isopropyl-1H-pyrazolo[3,4- <7|pyrimidin-3-yl)-A-(2-fluoro-3-(trifluoromethyl)phenyl)indoline-l -carboxamide (60 mg, 24%) as an off-white solid. ESI (m / z) [C24H2iF4N?0]+500.

[0540] Example 19: Preparation of 5-(4-amino-l-isopropyl-1H-pyrazolo|3,4-r / |pyrimidin-3-yl)- 7V-(2-fluoro-4-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 19)

[0541] Step-1: To a solution of 2-fluoro-4-(trifluoromethyl)aniline (500 mg, 2.79 mmol) in THF (15 mL) was added pyridine (442 mg, 5.58 mmol) followed by phenyl chloroformate (656 mg, 4.19 mmol). After 5 h, the reaction mixture was diluted with EtOAc (10 mL). The organic solution was washed with water (10 mL x 2) and then brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave phenyl (2-fluoro-4- (trifluoromethyl)phenyl)carbamate (500 mg, 59%).

[0542] Step-2: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (200 mg, 0.71 mmol) in THF (6 mL) was added Et?N (4.89 mL, 3.55 mmol) followed by portionwise addition of phenyl (2-fluoro-4-(trifluoromethyl)phenyl)carbamate (319 mg, 1.06 mmol). After 24 h, the reaction mixture was diluted with EtOAc (20 mL). The organic mixture was washed with water (10 mL x 2) and then brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 70% EtOAc / hexanes) gave 7V-(2-fluoro-4- (trifluoromethyl)phenyl)-5-(4,4,5,5-tetramethyl-L3.2-dioxaborolan-2-yl)indoline-l- carboxamide (250 mg. 78%). ESI (m / z) [C22H23BF4N2O3+H]+451.

[0543] Step-3: To an argon sparged solution of A-(2-fluoro-4-(trifluoromethyl)phenyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (214 mg, 0.475 mmol) and 3-iodo-l-isopropyl-1H-pyrazolo[3,4-6f]pyrimidin-4-amine (120 mg, 0.396 mmol) in a mixture of 1.4-dioxane (4.5 mL) : water (0.45 mL) was added potassium carbonate (109 mg. 0.792 mmol) followed by XPhosPdG2 (31.1 mg, 0.040 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (20 mL). The organic mixture was washed with water (5 mL x 2) and then brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 100% EtOAc / hexanes) afforded a solid. The solid was stirred in 2 mL of ACN for 1 h, collected by filtration and dried to give 5-(4-amino-l- isopropyl-l#-pyrazolo[3,4-d|pyrimidin-3-yl)-A-(2-fluoro-4- (trifluoromethyl)phenyl)indoline-l -carboxamide (23 mg, 11%) after lyophilization from acetonitrile / water. ESI (m / z) [C24H21F4N7O+H] 500.

[0544] Example 20: Preparation of 5-(4-amino-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)-A-(2-fluoro- 5-(trifhioromethyl)phenyl)indoline-l-carboxamide (Compound 20)

[0545] Step-1: To a solution of 3-iodo-1H -pyrazolo[3,4--d|pyrimidin-4-amine (500 mg, 1.91 mmol) in DMF (20 mL) was added cesium carbonate (1.56 g, 4.79 mmol) and trityl chloride (641 mg, 2.29 mmol). The reaction was heated to 70 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with water (10 mL x 2) and then brine (10 mL). dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 100% EtOAc) gave 3- iodo-l-trityl-1H-pyrazolo[3,4-( ]pyrimidin-4-amine (600 mg, 62%). ESI (m / z) [C24H18IN5+H]+504.

[0546] Step-2: To an argon sparged solution of 3-iodo-l-trityl-1H-pyrazolo[3,4- ]pyrimidin- 4-amine (300 mg, 0.596 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (349 mg, 0.775 mmol) in a mixture of 1.4-dioxane (9 mL) : water (0.9 mL) was added potassium phosphate tribasic (253 mg, 1.19 mmol) followed by RuPhosPdG3 (24.9 mg, 0.030 mmol). The reaction was heated to 75 °C for 4 h. Afterward, the reaction mixture was diluted with EtOAc (10 mL). The organic solution was washed with water (10 mL x 2) and then brine (10 mL). dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30% EtOAc / hexanes) afforded 5-(4-amino- l -trityl- lff-pyrazolo[3,4-d ]pyrimidin-3-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l- carboxamide (100 mg, 23%). ESI (m / z) [C40H29F4N7O+H]+700.

[0547] Step-3: To a solution of 5-(4-amino-l-trityl-1H-pyrazolo[3.4-d ]pyrimidin-3-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (100 mg, 0.143 mmol) in di chloromethane (5 mL) was added trifluoroacetic acid (0.110 mL, 1.42 mmol). After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with satd. NaHCCE solution (20 mL) and then extracted with 10% MeOH in CH2Cl2(2 x 10 mL). The organic solution was washed with water (10 mL x 2) and then brine (20 mL). dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 15% MeOH / CH2Cl2) gave 5-(4-amino-1H - pyrazolo[3.4-d ]pyrimidin-3-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)indohne-l- carboxamide (23 mg, 35%) after lyophilization from acetonitrile / water. ESI (m z) [C21H15F4N7O+H]+458.

[0548] Example 21: Preparation of 5-(4-amino-l-methyl-1H -pyrazolo[3,4-« / |pyrimidin-3-yl)-A- (2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 21)

[0549]

[0550] To an argon sparged solution of 3-iodo- l -methyl- 1H-pyrazolo|3.4-d|pyrimidin-4- amine (200 mg, 0.727 mmol) and 7V-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (393 mg, 0.873 mmol) in a mixture of 1,4-dioxane (4.5 mL) : water (0.45 mL) was added K2CO3 (201 mg, 1 .454 mmol) followed by XPhosPdG2 (28.6 mg, 0.036 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was fdtered through a celite pad using EtOAc (300 mL). The resulting filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 5-10%MeOH / CH2Ch) gave a solid which was triturated with acetonitrile (10 mL). The solid was collected by filtration and dried to afford 5-(4-amino-l-methyl-1H-pyrazolo[3,4-d|pyrimidin-3-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (65 mg, 18%) as off white solid. ESI (m / z ) [C22Hi7F4N7O]+472.

[0551] Example 22: Preparation of 2-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf]pyriinidin-3-yl)- 7V-(2-fhioro-5-(trifluoromethyl)phenyl)imidazo[5,l-A]thiazole-7-carboxamide

[0552] (Compound 22)

[0553] Step-1: To an ice-cold solution of ethyl 2-isocyanoacetate (2.32 g, 20.5 mmol) in DMF (6 mL) was added NaH (60%; 0.823 g, 20.5 mmol). After Ih, the reaction mixture was added to a solution of 2,5 -dibromothiazole (2.5 g, 10.2 mmol) in THF (6 mL) at -20 °C. The mixture was allowed to warm to rt. After 2 h, the reaction was quenched with saturated NH4CI solution (25 mL). The mixture was extracted with methylene chloride (200 mL). The organic layer was washed with water (4 x 25 mL) and then brine (50 mL), dried over anhydrous sodium sulphate, filtered and then concentrated under reduced pressure. Purification by column chromatography (silica gel, hexanes to 30% ethyl acetate / hexanes) afforded ethyl 2-bromo imidazo[5,l-6]thiazole-7-carboxylate (1.95 g, 68%). ESI (m / z) [CsH7BrN2O2S+H]+276.

[0554] Step-2: To a solution of ethyl 2-bromoimidazo[5,l-6]thiazole-7-carboxylate (1.95 g, 7.09 mmol) in a mixture of THF (30 rnL) : water (30 mL) was added NaOH (0.709 g, 17.7 mmol). After heating to 80 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with water and acidified with 2 N hydrochloric acid. The resulting solid was collected by filtration, rinsed with water (10 mL) and dried under vacuum to afford the 2-bromoimidazo[5,l-Zi]thiazole-7-carboxylic acid (1.65 g). ESI (m / z) [C6H3BrN2O2S+H]+248. The material was used as is without further purification.

[0555] Step-3: To an ice-cold solution of 2-bromoimidazo[5,l-i5]thiazole-7-carboxylic acid (1.00 g, 4.05 mmol) in CH2Cl2(15 mL) was sequentially added 2-fluoro-5- (trifluoromethyl)aniline (0.725 g, 4.05 mmol), pyridine (10 mL, 124 mmol) and POCl3(0.566 mL, 6.07 mmol). The reaction was allowed to warm to it. After 1 h, the reaction mixture was concentrated under reduced pressure. The resulting solid was treated with satd. NaHCCh and then extracted with CH2Cl2(20 mL). The combined organics were washed with water (10 mL x 2) and then brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 40% EtOAc in hexanes) gave 2-bromo-A-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[5, 1 -b ] thiazole-7- carboxamide (0.65 g). ESI (m / z) [C HeB^lSfiOS + H]+408 and 410.

[0556] Step-4: To an argon sparged solution of 2-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[5,l- / >]thiazole-7-carboxamide (0.65 g, 1.59 mmol) in 1.4- di oxane (10 mL) was added w-hexabutyldilin (0.805 mL, 1.59 mmol) followed by Pd(PPh?)4 (0.184 g, 0.159 mmol). The reaction was heated to 100 °C for 16. Afterwards, the reaction mixture was diluted with methylene chloride (20 mL). The organic mixture was washed with water (4 x 10 mL) and then brine (10 mL), dried over anhydrous sodium sulphate, filtered and then concentrated under reduced pressure. Purification by flash chromatography (silica gel. hexanes to 20% ethyl acetate / hexanes) gave A-(2-fluoro-5-(trifluoromethyl)phenyl)-2- (tributylstannyl)imidazo[5,l- / >]thiazole-7-carboxamide (0.2 g). ESI (m / z) [C25H33F4NsOSSn+ H]+619.

[0557] Step-5: To an argon sparged solution of 3-iodo- 1 -isopropyl- 1H-pyrazolo[3, 4- <7]pyrimidin-4-amine (0.10 g, 0.33 mmol) in 1,4-dioxane (5 mL) was added / V-(2-fluoro-5- (trifluoromethyl)phenyl)-2-(tributylstannyl)imidazo[5,l-Zi]thiazole-7-carboxamide (0.20 g, 0.33 mmol) followed by Pd(PPli3)4 (0.038 g, 0.033 mmol). Th reaction was heated to 100 °C for 16 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2C12to 2% MeOH / CELCE) followed by trituration with acetonitrile gave 2-(4-amino- 1 -isopropyl- 1H-pyrazolo[3,4-d|pyrimidin-3- yl)-A-(2-fluoro-5-(trifliioromethyl )phenyl)imidazo| 5. l-6]thiazole-7-carboxamide (0.026 g, 15%). ESI (m / z) [ C21H16F4N8OS+ H] 499.

[0558] Example 23: Preparation of 5-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 23)

[0559] Step-1: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (300 mg, 1.32 mmol) and fert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indoline-l-carboxylate (547 mg, 1.58 mmol) in a mixture of 1.4-dioxane (7 mL) : water (2 mL) was added cesium carbonate (861 mg, 2.64 mmol) followed by RuPhosPdG3 (55.2 mg, 0.066 mmol). The reaction was heated to 90 °C for 16 h. Afterward, the reaction mixture was diluted with EtOAc (20 mL). The organic mixture was washed with water (10 mL x 2) and then brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CEbChto 10% MeOH / CEhCh) afforded tert-butyl 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)indoline-l-carboxylate (250 mg, 51%). ESI (m / z) [C20H23N5O2+H]+366.

[0560] Step-2: To an ice-cold solution of tert-butyl 5-(8-amino-3-methylimidazo[l,5- a|pyrazin-l-yl)indoline-l-carboxylate (250 mg. 0.684 mmol) in 2,2,2-trifluoroethanol (7.50 mL) was added TMSC1 (0.437 mL, 3.42 mmol) dropwise. The reaction was allowed to slowly warm to rt. After 5 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with satd. Nal ICO? solution (20 mL) then extracted with 10% MeOH in CH2Cl2(2 x 50 mL). The combined organics were washed with water (25 mL) and then brine solution (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford l-(indolin-5-yl)-3-methylimidazo[l,5-a]pyrazin-8-amine (70 mg, 38%). ESI (m / z) [C15H15N5+H]+266. Step-3: To an ice-cold solution of l-(indolin-5-yl)-3-methylimidazo[l,5-a]pyrazin-8- amine (70 mg, 0.26 mmol) in CH2Cl2(3 mL) was added l-fluoro-2-isocyanato-4- (trifluoromethyl)benzene (43.3 mg, 0.21 1 mmol). After 30 min, the reaction mixture was concentrated under reduced pressure. Purification by reverse phase chromatography (Cl 8, 10% acetonitrile / water to 30% acetonitrile / water) followed by lyophilization from acetonitrile / water afforded 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-A-(2-fluoro-5- (trifluoromethyl)phenyl)indoline-l -carboxamide (30 mg, 24%). ESI (m / z) [C23H18F4N6O +H]+471.

[0561] Example 24: Preparation of 5-(8-aminoimidazo[l,5-«]pyrazin-l-yl)-N-(2-fluoro-5-

[0562] (trifluoro methyl)phenyl)indoline-l-carboxamide (Compound 24)

[0563] Step-1: A solution of (3-chloropyrazin-2-yl)methanamine hydrochloride (6.00 g, 33.3 mmol) in trimethyl orthoformate (73.7 mL, 667 mmol) was heated to 120 °C for 1 h in a microwave. The reaction mixture was filtered through a celite pad using EtOAc (100 mL). The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30% EtOAc / hexanes) gave a residue which was stirred in hexanes (20 mL). The resulting solid was collected by filtration and dried to afford A-((3-chloropyrazin-2-yl)methyl)formamide (3.50 g, 61%) as a brown solid. ESI (m / z) [CsHeClNsOf 172.

[0564] Step-2: To an ice-cold solution of A-((3-chloropyrazin-2-yl)methyl)formamide (3.50 g, 20.4 mmol) in acetonitrile (50 mL) was added POCl3(2.28 mL, 24.4 mmol) followed by dropwise addition of DMF (0.079 mL, 1.02 mmol). The reaction was allowed to warm to rt. After 16 h, the reaction mixture was treated with saturated NaHCOs (50 mL) and then extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (30 mL) and then concentrated under reduced pressure. The reside was triturated with hexane (10 mL). The resulting solid was collected by filtration and dried to afford 8-chloroimidazo[l,5- < 1 pyrazine (2.00 g, 63%) as light brown solid. ESI (m / z [C6FLClNs] 154.

[0565] Step-3: To an ice-cold solution of 8-chloroimidazo[1.5-a]pyrazine (1.00 g, 6.51 mmol) in DMF (30 mL) was added NBS (0.927 g, 5.21 mmol) portion-wise. The reaction was allowed to warm to rt. After 1 h, the reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 30 mL). The organic mixture was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30% EtOAc / hexanes) removed the minor 3 -bromo isomer and gave l-bromo-8-chloroimidazo[l,5-a]pyrazine (0.65 g, 42.9 %) as off-white solid. ESI (m / z ) [C6H3BrClN3]+232.

[0566] Step-4: To a solution of l-bromo-8-chloroimidazo[l,5-n]pyrazine (800 mg, 3.44 mmol) in isopropyl alcohol (5 mL) was added ammonia (1.0 M in IPA, 34.4 mL, 34.4 mmol). The reaction was heated to 100 °C for 16 h in a steel bomb. Afterwards, the reaction mixture was concentrated. The residue was treated with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organics were dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was treated with acetonitrile (5 mL). The resulting solid was collected by filtration and dried to afford l-bromoimidazo[l,5-n]pyrazin-8-amine (650 mg, 89%) as an off-white solid. ESI (m / z) [C6H5BrN4]+215.

[0567] Step-5: To an argon sparged solution of l-bromoimidazo[l,5-a]pyrazin-8-amine (200 mg, 0.939 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(4,4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indoline-l -carboxamide (507 mg, 1.12 mmol) in a mixture of 1 ,4-dioxane (5 mL) : water (1 mL) was added K2CO3 (259 mg, 1.878 mmol) followed by RuPhosPdG3 (39.3 mg, 0.047 mmol). The reaction was heated to 100 °C for 1 h in a microwave. Afterwards, the reaction mixture was filtered through a celite pad using EtOAc (20 mL). The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 5% MeOEI / CH2Cl2) gave 5-(8- aminoimidazo[l,5-a]pyrazin-l-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l- carboxamide as a light yellow solid which was stirred in acetonitrile (10 mL). The solid was collected by filtration and dried to afford 5-(8-aminoimidazo[L5-a]pyrazin-l-yl)-A-(2-fluoro- 5-(trifluoromethyl)phenyl) indoline-l-carboxamide (110 mg, 25%) as an off-white solid. ESI ( / n / z) [C22Hi6F N6O]+457

[0568] Example 25: Preparation of 5-(4-amino-l-isopropyl-l / / -pyrazolo[3,4-rf]pyi'imidin-3-yl)- 7V-(3-(2,2,2-trifluoroethyl)phenyl)indoline-l-carboxamide (Compound 25)

[0569] Step-1: To an ice-cold solution of 3-(2,2,2-trifluoroethyl)aniline (500 mg, 2.85 mmol) in tetrahydrofuran (1 mL) was added pyridine (0.462 mL, 5.71 mmol) followed by phenyl chloroformate (670 mg, 4.28 mmol). The reaction was allowed to warm to rt. After 2 h, the reaction mixture was diluted with EtOAc (10 mL). The organic solution was washed with water (5 mL x 2) and then brine (5 mL), dried over NazSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave phenyl (3-(2,2,2-trifluoroethyl)phenyl) carbamate (600 mg, 71%). ESI (m / z ) [C15H12F3NO2 +H]+296.

[0570] Step-2: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (500 mg, 1.77 mmol) in tetrahydrofuran (15 mL) was added EtsN (1.23 mL, 8.88 mmol) followed by phenyl (3-(2,2,2-trifluoroethyl)phenyl)carbamate (629 mg, 2.13 mmol). The reaction was heated to 75 °C for 12 h. Afterwards, the reaction mixture was diluted with EtOAc (20 mL). The organic mixture was washed with water (25 mL x 2) and then brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane to 20% EtOAc / hexane) gave 5- (4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)-A-(3-(2,2,2-trifluoroethyl) phenyl)indoline-l- carboxamide (500 mg, 63%). ESI (w ) [C23H26BF3N2O3 +H]+447.

[0571] Step-3: To an argon sparged solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-A-(3-(2,2,2-trifluoroethyl)phenyl)indoline-l-carboxamide (530 mg, 1.18 mmol) and 3- iodo-l-isopropyl-l / / -pyrazolo[3,4-d|pyrimidin-4-amine (300 mg, 0.990 mmol) in 1,4- dioxane (6 mL) : water (2 mL) was added potassium carbonate (274 mg, 1.97 mmol) followed by RuPhosPdG3 (83 mg, 0.099 mmol). The reaction was heated to 85 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic solution was washed with water (25 mL x 2) and then brine (25 mL). dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. 90% EtOAc / hexanes) followed by reverse phase chromatography (10% ACN / water to 60% ACN / water gave 5-(4-amino-l-isopropyl-1H-pyrazolo[3,4-d|pyrimidin-3-yl)-A-(3-(2,2,2- trifluoro ethyl)phenyl)indoline-l -carboxamide (65 mg, 13%). ESI (zn / z) [C25H24F3N7O +H]+496. Example 26: Preparation of 5-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)- 7V-(4-(2,2,2-trifluoroethyl)phenyl)indoline-l-carboxamide (Compound 26)

[0572] Step-1: To an argon sparged solution of (4-aminophenyl)boronic acid hydrochloride (4.00 g, 23.0 mmol) and 1.1.1 -trifl uoro-2-iodoethane (14.5 g. 69.2 mmol) in a mixture of 1,4- dioxane (70 mL) : water (10 mL) was added cesium carbonate (30.1 g, 92 mmol) and XantPhos (2.67 g, 4.61 mmol) followed by Pd2(dba)s CHCh (2.38 g, 2.30 mmol). The reaction was heated to 75 °C for 16 h. Afterward, the reaction mixture was diluted with EtOAc (100 mL). The organic mixture was washed with water (50 mL x 2) and then brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave 4-(2,2,2- trifluoroethyl) aniline (1.20 g, 29%). ESI (m / z ) [CsHsFsN +H]+176.

[0573] Step-2: To an ice-cold solution of 4-(2,2,2-trifluoroethyl) aniline (500 mg, 2.85 mmol) in tetrahydrofuran (1 mL) was added pyridine (0.462 mL, 5.71 mmol) followed by phenyl chloroformate (670 mg, 4.28 mmol). The reaction was allowed to warm to rt. After 2 h, the reaction mixture was diluted with EtOAc (10 mL). The organic solution was washed with water (5 mL x 2) and then brine (5 mL), dried over NazSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave phenyl (4-(2,2,2-trifluoroethyl)phenyl) carbamate (600 mg, 71%). ESI (m / z ) [C15H12F3NO2 +H]+196.

[0574] Step-3: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (400 mg, 1.42 mmol) in tetrahydrofuran (12 mL) was added EtsN (0.990 mL, 7.10 mmol) followed by phenyl(4-(2,2,2-trifluoroethyl)phenyl)carbamate (503 mg, 1.70 mmol). The reaction w as heated to 75 °C for 12 h. Afterward, the reaction mixture w as diluted with EtOAc (20 mL). The organic solution w as washed with water (25 mL x 2) and then brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave phenyl 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-A^-(4-(2,2,2- trifl uoroethyl)phenyl)indoline-l -carboxamide (400 mg, 63%). ESI (m / z) [C23H26BF3N2O3+H]+447.

[0575] Step-4: To an argon sparged solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-A-(4-(2,2,2-trifluoroethyl)phenyl)indoline-l-carboxamide (353 mg, 0.792 mmol) and 3- iodo-l-isopropyl-1H-pyrazolo[3,4-ri|pyrimidin-4-amine (200 mg, 0.660 mmol) in 1,4- dioxane (6 mL) : water (2 mL) was added potassium carbonate (182 mg, 1.32 mmol) followed by RuPhosPdG3 (55.2 mg. 0.066 mmol). The reaction was heated to 85 °C for 12 h. Afterwards, the reaction mixture was diluted with EtOAc (20 mL). The organic mixture was washed with water (25 mL x 2) and then brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CH2Cl2) followed by reverse phase chromatography (Cl 8, 10% acetonitrile / water to 60% acetonitrile / water) gave 5-(4-amino- 1 -isopropyl- 1 H-pyrazolo| 3.4- t / |pynmi din-3 -yl)-N-(4-(2.2, 2-trifluoroethyl)phenyl)indoline-l -carboxamide (30 mg, 9%) after lyophilization from acetonitrile / water. ESI (m / z) [C25H24F3N7O +H]+496.

[0576] Example 27: Preparation of 7-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf]pyi’imidin-3-yl)-

[0577] Ar-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 27)

[0578] Step-1: To an argon sparged solution of ethyl 7-bromoimidazo[L2-a]pyridine-3- carboxylate (5.00 g, 18.5 mmol) in 1,4-dioxane (150 mL) was added bis(pinacolato)diboron (7.08 g, 27.9 mmol) and potassium acetate (5.47 g, 55.7 mmol) followed by PdC12(dppf (1.36 g, 1.85 mmol). The reaction was heated to 85 °C for 12 h. Afterwards, the reaction mixture was diluted with methylene chloride (20 mL). The organic mixture was washed with water (4 x mL) and then brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain ethyl 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxylate (6.78 g) which was used for next step without further purification. ESI (m / z) [C16H21BN2O4+ H]+234 (boronic acid mass).

[0579] Step-2: To an argon sparged solution of 3-iodo-l -isopropyl- 1H-pyrazolo[3, 4- <7|pyrimidin-4-amine (4.5 g, 14.8 mmol) in a mixture of 1,4-dioxane (150 mL) : water (15 mL) was added K2CO3 (4.10 g, 29.7 mmol) and 3-(ethoxycarbonyl)imidazo[l,2-«]pyridin-7- yl)boronic ester (5.21 g, 22.2 mmol) followed by XPhosPd-G2 (1.16 g. 1.48 mmol). The reaction was heated to 90 °C for 12 h. Afterwards, the reaction mixture was diluted with methylene chloride (100 mL). The organic mixture was washed with water (2 x 20 mL) and then brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel CEbChto 10% MeOH / CH2Cl2) to afford ethyl 7-(4-amino-l-isopropyl-1H-pyrazolo[3,4-d ]pyrimidin-3- yl)imidazole[l,2-a ]pyridine-3-carboxylate (3.7 g, 68%) as a brown solid. ESI m / z) [C1sHi9N7O2+H]+366.

[0580] Step-3: To a solution of ethyl 7-(4-amino- l -isopropyl- IT / -pyrazolo|3.4-d |pyrimidin- 3-yl)imidazo[l,2-a]pyridine-3-carboxylate (3.70 g, 10. 1 mmol) in a mixture of THF (30 mL) : water (30 mL), was added LiOHEhO (1.06 g, 25.3 mmol). After 6 h, the reaction mixture was concentrated under reduced pressure. The residue was acidified with 6 N HC1. The resulting solid was collected by filtration and rinsed with water (50 mL) and then dried under vacuum to afford 7-(4-amino-l-isopropyl- 1H -pyrazolo[3.4-d ]pyrimidin-3-yl)imidazo[l,2- o|pyridine-3 -carboxylic acid (2.0 g). The material was used as is without any further purification. ESI (m / z) [C16EI15N7O2+I P 338.

[0581] Step-4: To a solution of 7-(4-amino- l -isopropyl- 1H -pyrazolo|3.4-d |pyrimidin-3- yl)imidazo[l,2-a]pyridine-3-carboxylic acid (0.20 g, 0.59 mmol) in DMF (6 mL) was added 3-(trifluoromethyl)aniline (0.191 g, 1.18 mmol) and DIPEA (0.311 mL, 1.77 mmol) followed by HATU (0.271 g, 0.71 1 mmol). After 12 h, the reaction mixture was diluted with water (10 mL). The resulting solid was collected by filtration and then dried under vacuum. Purification by reverse phase preparative HPLC (C18, acetonitrile / w ater with 10 mM ammonium bicarbonate) gave a solid that was washed with water (10 mL) and lyophilized from acetonitrile / water to give 7-(4-amino- l -isopropyl-1H-pyrazolo|3.4-d|pynmidin-3-yl)-N-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (0.094 g, 33%). ESI (m / z) [C23Hi9F3N8O+H]+481.

[0582] Example 28: Preparation of 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 28)

[0583] Step-1: To a solution of ethyl 7-bromoimidazo[l,2-a]pyridine-3-carboxylate (0.50 g. 1.85 mmol) in a mixture of THF (20 mL) : water (5 mL) was added LiOH FhO (234 mg, 5.57 mmol). After 5 h, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with 2 M HC1. The resulting solid was collected by filtration and dried under vacuum to give 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (0.30 g, 89%). ESI (m'z) [C8H5BrN2O2+H]+243.

[0584] Step-2: To an ice-cold solution of 7-bromoimidazo[l,2-r7]pyridine-3-carboxylic acid (0.40 g, 1.65 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (892 mg, 4.98 mmol) in pyridine (6 mL) was added POCl3(0.155 mL, 1.65 mmol). The resulting solution was allowed to warm to rt. After 1 h, the reaction was quenched with a solution of satd. NaHCOs (20 mL). The mixture was extracted with EtOAc (50 mL). The organic was washed with water (50 mL) and then brine solution (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 7-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo| 1.2- o|pyridine-3 -carboxamide (250 mg. 37 %). ESI (m / z) [C15H8BrF4N3O+2H]+404.

[0585] Step-3: To an argon sparged solution of 7-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (200 mg, 0.497 mmol) in 1,4- dioxane (6 mL) was added bis(pinacolato)diboron (189 mg. 0.746 mmol) and potassium acetate (98 mg, 0.995 mmol) followed by PdCh(dppf) (36.4 mg, 0.050 mmol). The reaction was heated to 85 °C for 12 h. Afterwards, the reaction mixture was concentrated under reduced pressure to afford A-(2-fluoro-5-(trifluoro methyl)phenyl)-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (0.40 g). The material was used as is without further purification. ESI (m / z) [C2IH2OBF4N303+H]+368 (boronic acid).

[0586] Step-4: To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-a]pyrazin- 8-amine (150 mg, 0.588 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (396 mg, 0.882 mmol) in a mixture of 1,4-dioxane (10 mL) : water (0.12 mL) was added potassium carbonate (163 mg. 1.17 mmol) followed by XPhosPd-G2 (46.3 mg, 0.059 mmol). The reaction was heated to 90 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 20% MeOH / CH2Cl2) followed by preparative reverse phase HPLC (C18, acetonitrile / water with 0.05% TFA ) gave a solid which was dissolved with 10% MeOH in di chloromethane (100 mL). The mixture was washed with sat NaHCOs (20 mL x 2) and then brine (20 mL). dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure to afford 7-(8-amino-3-isopropylimidazo[1,5-a ]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (30 mg, 10%) after lyophilization from acetonitrile / water. ESI (m / z ) [C24Hi9F4N?O+H]+498.

[0587] Example 29: Preparation of 7-(4-amino-l-isopropyl-1H-pyrazolo[3,4-r / |pyriinidin-3-yl)-

[0588] A-(3-(trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 29)

[0589] To a solution of 7-(4-amino-l-isopropyl-17Apyrazolo[3,4-t / ]pyrimidin-3- yl)imidazo[l,2-a]pyridine-3-carboxylic acid (0.20 g, 0.59 mmol) and HATU (338 mg, 0.889 mmol) in DMF (6 mL) was added 3 -(trifluoromethoxy )aniline (158 mg, 0.889 mmol) followed by DIPEA (0.518 mL, 2.96 mmol). After 12 h, the reaction mixture was diluted with water (20 mL). The resulting solid was collected by filtration and dried under vacuum. Purification by preparative reverse phase HPLC (C18, acetonitrile / water with 0.05% TFA ) gave a solid which was dissolved in 10% MeOH in dichloromethane (100 mL). The resulting solution was washed with sat NaHCOs solution (20 mL x 2) and then brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 7-(4- amino-l-isopropyl-1H-pyrazolo[3,4-t / ]pyrimidin-3-yl)-jV-(3- (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (45 mg, 15 %) after lyophilization from acetonitrile / water. ESI (m z) [C24Hi8F6NsO+H]+497.

[0590] Example 30: Preparation of 7-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)- -(4-fluoro-3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 30)

[0591] To a solution of 7-(4-amino-l-isopropyl-1H -pyrazolo[3,4-tZ]pyrimidin-3- yl)imidazo|T,2-a|pyridine-3-carboxylic acid (0.250 g. 0.741 mmol) in DMF (5 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (0.159 g, 0.889 mmol) and DIPEA (0.388 mL, 2.22 mmol) followed by HATU (0.338 g, 0.889 mmol). After 12 h, the reaction mixture was diluted with water (10 mL). The resulting solid was collected by filtration and then purified by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) ) to afford a solid which was washed with water (10 mL) and after lyophilization, gave 7-(4-amino-l-isopropyl-l#-pyrazolo[3,4-<f]pyrimidin-3-yl)- / V-(4-fluoro- 3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (0.12 g, 32%). ESI (m / z) [C23H18F4N8O+H]+499.

[0592] Example 31 : Preparation of 7-(4-amino-l-isopropyl-1H -pyrazolo[3,4-r / ]pyrimidin-3-yl)-

[0593] A-(3-chlorophenyl)imidazo [ 1,2-a] pyridine-3-carboxamide (Compound 31)

[0594] To a room temperature solution of 7-(4-amino-l-isopropyl-1H -pyrazolo[3,4- -d|pyrimidin-3-yl)imidazo[L2-a]pyridine-3-carboxylic acid (0.20 g. 0.59 mmol) and 3- chloroaniline (151 mg, 1.18 mmol) in DMF (20 mL) was added DIPEA (192 mg, 1.48 mmol) and then HATU (338 mg, 0.889 mmol). After 16 h, the reaction was treated with water. The resulting solid was collected by filtration and purified by reverse phase preparative HPLC (Cl 8, acetonitrile / water with 0.05% TFA) to give a solid. The solid was partitioned between saturated NaHCO? and 5% MeOH / CEECh. The organic layer was dried (Na2SO4), filtered and concentrated to give 7-(4-amino-l-isopropyl-1H-pyrazolo[3,4--d|pyrimidin-3-yl)-Ar-(3- chlorophenyl)imidazo[l,2-a]pyridine-3-carboxamide (40 mg, 15 %) as an off-white solid after lyophilization from acetonitrile / water. ESI (m / z [C22Hi9ClNsO+H]+447. Example 32: Preparation of 7-(4-auiino-l-isopropyl-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0595] V-( / »-tolyl)iinidazo| 1.2-( / ]pyridine-3-carboxaniide (Compound 32)

[0596] To a solution of 7-(4-amino-l-isopropyl-lE / -pyrazolo[3,4-d ]pyrimidin-3- yl)imidazo|T,2-a|pyridine-3-carboxylic acid (0.20 g, 0.59 mmol) and m-toluidine (76 mg, 0.71 mmol) in DMF (10 mL) was added DIPEA (192 mg, 1.48 mmol) and then HATU (338 mg, 0.889 mmol). After 16 h, the reaction was treated with water. The resulting solid was collected by filtration and dried. Purification by reverse phase preparative HPLC (acetonitrile / water with 0.05% TFA) gave a solid which was treated with satd. NaHCCL and then extracted with 5% MeOH in CH2Cl2to remove residual TFA. After concentration, 7-(4- amino-1 -isopropyl- 1H-pyrazolo|3.4-d |pyrimidin-3-yl)-;V-( / w-lolyl)imidazo| 1 ,2-a]pyridine-3- carboxamide was obtained as an off-white solid (55 mg, 21%). ESI (mz) [C23H22NsO+H]+427.

[0597] Example 33: Preparation of 7-(4-amino-l-isopropyl-l / / -pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0598] A-(2-fluoro-5-methylpheny l)imidazo [ 1,2-a] pyridine-3-carboxamide (Compound 33)

[0599] To a solution of 7-(4-amino-l-isopropyl-1H-pyrazolo[3,4-d|pyrimidin-3- yl)imidazo[l,2-a]pyridine-3-carboxylic acid (200 mg. 0.59 mmol) and 2-fluoro-5- methylaniline (148 mg, 1.18 mmol) in DMF (15 mL) was added DIPEA (192 mg, 1.48 mmol) followed by HATU (338 mg, 0.889 mmol). After 16 h, the reaction was treated with water. The resulting solid was collected by filtration and dried. Purification by reverse phase preparative HPLC (acetonitrile / water with lOmM ammonium bicarbonate) gave 7-(4-amino- l -isopropyl- 1H -pyrazolo|3.4-r / |pyrimidin-3-yl)-A-(2-fluoro-5-methylphenyl)imidazo| 1,2- a]pyridine-3-carboxamide as an off-white solid (40 mg, 15%). ESI (m / z) [C23H22N8O+H 445.

[0600] Example 34: Preparation of 7-(4-amino-l-isopropyl-1H -pyrazolo|3,4-r / |pyrimidin-3-yl)-

[0601] N-(3,5-bis(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carbo amide (Compound

[0602] 34)

[0603] Step-1: To an ice-cold solution of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (700 mg. 2.90 mmol) and 3,5-bis(trifluoromethyl)aniline (1.99 g, 8.71 mmol) in pyridine (21 mL) was added POCl3(0.812 mL, 8.71 mmol) dropwise. The reaction was allowed to warm to rt. After 1 h, the reaction mixture was treated with satd. NaHCOs (40 mL) and EtOAc (200 mL). The organic layer was washed with water (100 mL) and then brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave A-(3,5- bis(trifluoromethyl)phenyl)-7-bromoimidazo[l,2-a] pyridine-3 -carboxamide (500 mg, 38%). ESI (m / z [C16H8BrF6N3O+H]+452.

[0604] Step-2: To an argon sparged solution of A-(3,5-bis(trifluoromethyl)phenyl)-7- bromoimidazo[I,2-a]pyridine-3-carboxamide (500 mg, 1.10 mmol) in 1,4-dioxane (15 mL) was added potassium acetate (217 mg, 2.21 mmol) and bis(pinacolato)diboron (421 mg, 1.65 mmol) followed by PdCh(dppl) (81 mg, 0.111 mmol). The reaction was heated to 90 °C for 1 h. Afterwards, the reaction mixture was concentrated under reduced pressure to afford N- (3,5-bis(trifluoromethyl)phenyl)-7-(4,4,5,5-tetramethyl-L3.2-dioxaborolan-2-yl)imidazo[l,2- a] pyridine-3 -carboxamide (600 mg). ESI (m / z) [C22H2oBFeN 03+H]+418 (boronic acid). The material was used as is without further purification.

[0605] Step-3: To an argon sparged solution of A-(3,5-bis(trifluoromethyl)phenyl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (593 mg, 1.18 mmol) and 3-iodo-l -isopropyl- 1H -pyrazolo|3.4-d|pynmidin-4-amine (300 mg. 0.99 mmol) in 1 ,4-dioxane (6 mL) : water (2 mL) was added potassium carbonate (274 mg, 1 .97 mmol) followed by XPhosPd-G2 (78 mg, 0.099 mmol). The reaction was heated to 90 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The organic mixture was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CFLCh) and then by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate ) gave a solid. The solid was rinsed with water(5 ml), dried and subsequently lyophilized from acetonitrile / water to afford 7-(4-amino-l-isopropyl-1H-pyrazolo[3,4-d|pyrimidin-3-yl)-A-(3,5- bis(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (105 mg, 19%). ESI (m / z) [C24HI8F6NSO+H]+549.

[0606] Example 35: Preparation of 5-(4-amino-l-isopropyl-LH-pyrazolo[3,4--d]pyi’iinidin-3-yl)-

[0607] A-(3-(4-methyl- LH-imidazol- l-yl)-5-(trifluoromethyl)phenyl)indoline- 1-carboxamide

[0608] (Com

[0609] Step-1: To a solution of 3-(4-methyl-1H-imidazol-l-yl)-5-(trifluoromethyl)aniline (600 mg. 2.48 mmol) in tetrahydrofuran (18 mL) was added pyridine (0.402 mL. 4.97 mmol) followed by phenyl chloroformate (584 mg, 3.73 mmol). After 2 h, the reaction mixture was diluted with EtOAc (25 mL). The organic mixture was washed with water (10 mL x 2) and then brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave phenyl (3-(4-methyl- 1H-imidazol- l -yl)-5-(tnfluoro methyl)phenyl)carbamate (600 mg, 66%). ESI m / z) [C18H14F3N3O2 +H]+362.

[0610] Step-2: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (500 mg, 1.77 mmol) in tetrahydrofuran (15 mL) was added EtsN (2.47 mL. 17.7 mmol) followed by phenyl (3-(4-methyl-1H-imidazol-l-yl)-5- (trifluoromethyl)phenyl)carbamate (642 mg, 1.77 mmol). The reaction was heated to 80 °C for 5 h. Afterwards, the reaction mixture was diluted with EtOAc (20 mL). The organic mixture was washed with water (25 mL x 2) and then brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes 50% EtOAc / hexanes) gave / V-(3-(4-methyl- 1H-irnidazol- l -yl)-5- (trifluoromethyl)phenyl)-5-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)indoline-l- carboxamide (650 mg, 71%). ESI (m / z ) [C26H28BF3N4O3 +H]+513.

[0611] Step-3: To an argon sparged solution of 3-iodo- 1 -isopropyl- 1H-pyrazolo[3, 4- <7|pyrimidin-4-amine (300 mg, 0.990 mmol) and A-(3-(4-methyl-1H-imidazol-l-yl)-5- (trifluoromethyl)phenyl)-5-(4,4,5,5-tetramethyl-L3.2-dioxaborolan-2-yl)indoline-l- carboxamide (609 mg. 1.18 mmol) in a mixture of 1,4-di oxane (9 mL) : water (0.9 mL) was added potassium carbonate (274 mg, 1.97 mmol) followed by XPhosPdG2 (78 mg, 0.099 mmol). The reaction was heated to 90 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with water (25 mL x 2) and then brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 90% EtOAc / hexanes) gave a residue which was treated with acetonitrile (3 mL) and stirred for 1 h at rt. The resulting solid was collected by filtration and dried under reduced pressure to afford 5-(4-amino-l- isopropyl-1H-pyrazolo[3,4--d|pyrimidin-3-yl)-A-(3-(4-methyl-l / / -imidazol-l-yl)-5- (trifluoromethyl)phenyl)indoline-l -carboxamide (60 mg, 10%) after lyophilization from acetonitrile / water. ESI (m / z) [C26H28BF3N4O3 +H]+563.

[0612] Example 36: Preparation of 7-(4-amino-l-isopropyl-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0613] A-(3-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0614] (Compound 36)

[0615] To an argon sparged solution of 3-iodo-l -isopropyl- 1H -pyrazolo[3,4-d ]pyrimidin-4- amine (0.250 g, 0.825 mmol) in 1,4-dioxane (10 mL) : water (1 mL) and A-(3-fluoro-5- (trifluoromethyl)phenyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- a]pyridine-3-carboxamide (0.556 g, 1.23 mmol) was added potassium carbonate (0.228 g, 1.65 mmol) followed by XPhosPd-G2 (0.065 g. 0.082 mmol). The reaction was heated to 90 °C for 12 h. Afterwards, the reaction mixture was concentrated and then diluted with methylene chloride (10 mL). The organic mixture was washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CFbCbto 10% MeOH / CEhCh)) and then by preparative HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave a solid. The solid w as rinsed with water (10 mL) then dried. Lyophilization from acetonitrile / water gave 7-(4-amino-l-isopropyl-1H -pyrazolo[3,4- r / |pyrimidin-3-yl)-A-(3-fluoro-5-(trifluoromethyl) phenyl)imidazo[ L2-a]pyridine-3- carboxamide (62 mg, 15%). ESI (m / z) [C23H18F4N8O +H]+499.

[0616] Example 37: Preparation of 7-(4-amino-l-methyl-1H-pyrazolo[3,4-r / |pyrimidin-3-yl)- / V- (2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound

[0617] 37)

[0618] Step-1: To a solution of ethyl 7-bromoimidazo[l,2-a]pyridine-3-carboxylate (10.0 g. 37.1 mmol) in a mixture of THF (150 mL) and water (50 mL) was added LiOHEbO (4.68 g. 111 mmol). After 6 h, 6 N HC1 (aq) was added to adjust the mixture to pH~2-4. The resulting solid w as collected by filtration and dried to afford 7-bromoimidazo[ 1 ,2-rz]pyridine- 3-carboxylic acid as an off-white solid (8.00 g, 89%). ESI (m / z) [CsFEBrlShCh+H]4240.

[0619] Step-2. To an ice-cold suspension of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (1.00 g, 4. 15 mmol) in pyridine (20 mL) was added 2-fluoro-5-(trifluoromethyl)aniline (1.11 g, 6.22 mmol) followed by POCl3(0.58 mL, 6.22 mmol). The reaction was allowed to warm to rt. After 2 h, the reaction mixture was concentrated to dry ness. The residue was treated with saturated NaHCOs solution (30 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were washed with bnne (50 mL). dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 60% EtOAc / hexanes) gave 7-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide as an off- white solid (0.60 g, 36%). ESI (m / z) [C15H8BrF4N3O+H]+401.

[0620] Step-3. To a nitrogen sparged solution of 7-bromo- / V-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[I,2-a]pyridine-3-carboxamide (0.60 g, 1.49 mmol) and bis(pinacolato)diboron ( 569 mg, 2.24 mmol) in 1,4-di oxane (20 mL) was added potassium acetate (366 mg, 3.73 mmol) followed by Pd(dppf)Ch (109 mg, 0. 149). The reaction was heated to 100 °C for 16 h. Upon completion, the mixture filtered through a celite pad using 9: 1 MeOH / CH2Cl2. The filtrate was concentrated to dryness. The dark residue was treated with hexanes, briefly sonicated, and then filtered to afford A-(2-fluoro-5- (trifluoromethyl)phenyl)-7-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)imidazo[l,2- a]pyridine-3-carboxamide as dark solid (0.90 g). ESI (m / z) [C2iH2oBF4N303+H]+450. The material was used without further purification.

[0621] Step-4. To an argons sparged solution of 3-iodo-l-methyl-1H-pyrazolo[3,4- c / |pynmidin-4-amine (300 mg, 1.09 mmol) and X-(2-fluoro-5-(trifluoromethyl)phenyl)-7- (4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (735 mg, 1.63 mmol) in a mixture of 1,4-dioxane (20 mL) : water (4 mL) was added K2CO (377 mg, 2.73 mmol) followed by XPhosPd-G2 (86 mg, 0. 109 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the reaction mixture was filtered through a celite pad using 9:1 MeOH / CH2Cl2. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CFLCb) followed by preparative HPLC (C18, acetonitrile / water with 10 mM ammonium bicarbonate) gave 7-(4-amino-l-methyl-1H- pyrazolo| 3.4-d |pynmidin-3-yl )-N-(2-fluoro-5-(tri fluoromethyl) phenyl)imidazo[ 1 ,2- a]pyridine-3-carboxamide (15 mg) as off-white solid. ESI (m / z [C21H14F4N8O+I P 471.

[0622] Example 38: Preparation of 7-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d |pyrimidin-3-yl)-

[0623] A (5-chloro-2-fluorophenyl)imidazo [ 1,2-a] pyridine-3-carboxamide (Compound 38)

[0624] Step-1: To an ice-cold suspension of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (1.00 g, 4.15 mmol) and 5-chloro-2-fluoroaniline (0.906 g. 6.22 mmol) in pyridine (10 mL) was added POCl3(0.580 mL, 6.22 mmol). The reaction was allowed to warm to rt. After 2 h, the reaction mixture was treated with saturated NaHCO3solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 40% EtOAc / hexanes) gave 7-bromo-A-(5-chloro-2-fluorophenyl)imidazo[1.2-a]pyridine-3-carboxamide (700 mg, 45%) as an off-white solid. ESI (m / z) [CuHsBrCIFNsO+H]* 369.

[0625] Step-2: To an argon sparged solution of 7-bromo-A-(5-chloro-2- fluorophenyl)imidazo[I,2-a]pyridine-3-carboxamide (0.6 g, 1.62 mmol) and bis(pinacolato)diboron (0.62 g, 2.44 mmol) in 1,4-dioxane (60 mL) was added potassium acetate (320 mg, 3.26 mmol) followed by Pd(dppf)Ch (119 mg, 0.163 mmol). The reaction was heated to 100 °C for 6 h. Afterwards, the reaction mixture was filtered through celite using 10% MeOH in CH2Cl2. The filtrate was concentrated under reduced pressure to afford A-(5-chloro-2-fluorophenyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- a] pyridine-3 -carboxamide (600 mg) as a brown solid which was used without any further purification. ESI (m / z) [C2OH2OBC1FN303-82]+334.

[0626] Step-3: To and argon sparged solution of 3-iodo-l -isopropyl- 1H-pyrazolo[3, 4- <7|pyrimidin-4-amine (0.3 g, 0.99 mmol) and A-(5-chloro-2-fluorophenyl)-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[I,2-a]pyridine-3-carboxamide (617 mg, 1.48 mmol) in a mixture of 1,4-dioxane (20 mL) : water (4 mL) was added potassium carbonate (342 mg. 2.47 mmol) . XPhosPd-G2 (38.9 mg, 0.049 mmol). The reaction was heated to 100 °C for 4 h. Afterwards, the reaction was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) followed by preparative reverse phase HPLC (C18, acetonitrile / water with lOrnM ammonium bicarbonate) afforded 7-(4-amino-l- isopropyl- 1H -pyrazolo[3,4-d|pyrimidin-3-yl)-A-(5-chloro-2-fluorophenyl)imidazo[ 1 ,2- tf]pyridine-3-carboxamide (90 mg, 19%) as an off-white solid. ESI (m / z) [C22H18C1FN8O+H]+465

[0627] Example 39: Preparation of 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound

[0628] 39)

[0629] Step-1: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (0.20 g, 0.8 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-7-(4.4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[I,2-«]pyridine-3-carboxamide (475 mg, 1.05 mmol) in a mixture of 1,4-dioxane (6 mL): water (0.6 mL) was added potassium carbonate (243 mg. 1.762 mmol) followed by XPhosPd-G2 (69 mg, 0.088 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave a solid. The solid was washed with water and subsequently lyophilized from acetonitri e / water to afford 7-(8- amino-3-methylimidazo[L5-a]pyrazin-l-yl)-iV-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (60 mg, 14 %). ESI (m / z) [C22H15F4N7O+H]+497.

[0630] Example 40: Preparation of 7-(4-amino-l-isopropyl-1H -pyrazolo|3,4-r / |pyrimidin-3-yl)- A (3-(4-methyl-LH-imidazol-l-yl)-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3- carboxamide (Compound 40)

[0631] Step-1: To an ice-cold solution of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (0.5 g, 2.07 mmol) and 3-(4-methyl-1H-imidazol-l-yl)-5-(trifluoromethyl)aniline (751 mg, 3.11 mmol) in a mixture of pyridine (10 mL) : CH2Cl2(10 mL) was added POCl3(0.58 mL, 6.22 mmol). The reaction was allowed to warm to rt. After 1 h, the reaction was treated with satd. NaHCCh (40 mL) and extracted with EtOAc (200 mL). The organic extract was washed with water (100 mL) and then brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 7-bromo-A-(3-(4-methyl-1H-imidazol-l-yl)-5- (trifluoromethyl)phenyl)imidazo[l,2-n]pyridine-3-carboxamide (0.3 g, 31%) as a solid. ESI (m,z) [C19Hi3BrF3N5O+H]+464.

[0632] Step-2: To an argon sparged solution of 7-bromo-N-(3-(4-methyl-1H -imidazol-l-yl)- 5-(trifluoromethyl) phenyl)imidazo[1.2-a]pyridine-3 -carboxamide (0.30 g. 0.64 mmol) and bis(pinacolato)diboron (246 mg, 0.969 mmol) in 1,4-dioxane (12 mL) was added potassium acetate (127 mg, 1.29 mmol) followed by Pd(dppt)Ch (47.3 mg, 0.065 mmol). The reaction was heated to 95 °C for 12 h. Afterwards, the reaction mixture was concentrated under reduced pressure to afford A-(3-(4-methyl-1H-imidazol-l-yl)-5-(trifluoromethyl)phenyl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (430 mg) which was used without further purification. ESI (m / z) [C25H25BF3NsO3+H]+430 (boronic acid).

[0633] Step-3: To an argon sparged solution of 3-iodo-l -isopropyl- 1H-pyrazolo[3, 4- <7|pyrimidin-4-amine (0. 3 g, 0.99 mmol) and A-(3-(4-methyl-1H -imidazol-l-yl)-5- (trifluoromethyl)phenyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- a]pyridine-3-carboxamide (759 mg, 1.48 mmol) in a mixture of 1,4-dioxane (4.5 mL) : water (0.45 mL) was added potassium carbonate (274 mg. 1.97 mmol) followed by XPhosPd-G2 (78 mg, 0.099 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) followed by reverse phase column chromatography (Cl 8, water to 60% acetonitrile in water) gave 7-(4-amino-l-isopropyl-1H -pyrazolo[3,4--d|pyrimidin-3-yl)-A-(3-(4-methyl-lEf- imidazol-l-yl)-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (25 mg, 4%) after lyophilization from acetonitrile / water. ESI (m / z) [C27H23F3N10O+H 561.

[0634] Example 41 : Preparation of 7-(4-amino-l-isopropyl-1H -pyrazolo[3,4-rf]pyrimidin-3-yl)-

[0635] A (5-bromo-2-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 41)

[0636] To an ice-cold solution of 7-(4-amino-l-isopropyl-1H -pyrazolo[3,4-d ]pyrimidin-3- yl)imidazo[l,2-a]pyridine-3-carboxylic acid (150 mg, 0.445 mmol) and 5-bromo-2- fluoroaniline (169 mg, 0.889 mmol) in pyridine (2 mL) was added DMAP (5.43 mg, 0.044 mmol) followed by POCl3(0.083 mL. 0.889 mmol). The reaction was allowed to warm to room temperature. After 1 h, the reaction mixture was treated with satd. NaHCCL solution. The aqueous mixture was extracted wi th EtOAc (2 x 20 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave 7-(4-amino-l-isopropyl-1H-pyrazolo[3,4--d|pyrimidin-3-yl)-A^-(5-bromo-2- fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide (18 mg, 7%) as an off-white solid. ESI (mz) [C22HisBrFNsO+H]+509.

[0637] Example 42: Preparation of 6-(4-amino-l-isopropyl-1H-pyrazolo|3,4-r / |pyrimidin-3-yl)- 7V-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide (Compound 42)

[0638] Step-1: To a solution of ethyl 6-bromobenzofuran-3-carboxylate (1.00 g, 3.72 mmol) in mixture of THF (20 mL): water (20 rnL), was added LiOHELO (0.312 g, 7.43 mmol). After 12 h, the reaction mixture was concentrated. The residue was acidified with 6 N HC1. The resulting solid was collected by filtration, rinsed with water and dried under vacuum to afford 6-bromobenzofuran-3-carboxylic acid (0.80 g, 89 %,). ESI (m / z) [CgHsBrCh-H]' 239 and 241.

[0639] Step-2: To an ice-cold solution of 6-bromobenzofuran-3-carboxylic acid(0.80 g, 3.29 mmol) in dichloromethane (10 mL) and pyridine (20 mL) was added 2-fluoro-5- (trifluoromethyl)aniline (0.707 g, 3.95 mmol) followed by POCl3(0.307 mL, 3.29 mmol). The reaction was allowed to warm to rt. After 2 h. the reaction mixture was diluted with CH2Cl2(60 mL). The organic mixture was washed sequentially with saturated NaHCOs solution, water (10 mL x 2) and brine (20 mL x 2) then dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) gave 6-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3- carboxamide (0.70 g, 52 %) as a solid. ESI (m / z) [C16H8BrF4NO2+H]+. 402.

[0640] Step-3: To an argon sparged solution of 6-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide (0.60 g, 1.42 mmol) and bis(pinacolato)diboron (0.568 g, 2.23 mmol) in 1,4-dioxane (20 rnL) was added potassium acetate (0.293 g, 2.98 mmol) followed by Pd(dppl)Ch (0.109 g, 0.149 mmol). The reaction was heated to 90 °C for 16 h. Afterwards, the reaction mixture was diluted with CH2Cl2(30 mL). The organic mixture was washed with water (15 mL x 2) and then brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CFbCbto 10% MeOH / CFhCh) gave -(2-fluoro-5- (trifluoromethyl)phenyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ben / ofuran-3- carboxamide (0.55 g, 82%). ESI (mz) [C22H20BF4NO4+ H]+450.

[0641] Step-4: To an argon sparged solution of 3-iodo- 1 -isopropyl- 1H -pyrazolo[3, 4- <7|pyrimidin-4-amine (0.25 g, 0.82 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-dihydrobenzofuran-3-carboxamide (0.447 g, 0.990 mmol) in 1,4-dioxane (15 mL) : water (1.5 mL) was added potassium carbonate (0.228 g, 1.65 mmol) followed by XPhosPd-G2 (64 mg, 0.082 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with CH2Cl2(100 mL). The organic mixture was w ashed with water (20 mL x 2) and then brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CEECbto 10% MeOH / CH2Cb)gave 6-(4-amino- 1 -isopropyl- 1H- pyrazolo[3,4-d|pyrimidin-3-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3- carboxamide (0.09 g, 21 %) as a solid. ESI (m / z) [C24H18F4N6O2 + H]+499.

[0642] Example 43: Preparation of 5-(4-amino-2-methyl-2 / / -pyrazolo[3,4-r / |pyrimidin-3-yl)-A- (2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 43)

[0643] Step-1: To an argon sparged solution of 3-bromo-2-methyl-2 / f-pyrazolo[3,4- r / |pyrimidin-4-amine (0.350 g, 1.53 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indoline-l -carboxylate (0.795 g, 2.30 mmol) in a mixture of 1,4-dioxane (10 mL) : water (1 mL) was added cesium carbonate (1.00 g, 3.07 mmol) followed by RuPhosPdG3 (0. 128 g, 0. 153 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the reaction mixture was diluted with CH2Cl2(20 mL). The organic mixture was washed with water (20 mL) and then brine (10 mL), dried overNa2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2C12to2% MeOH / CEECb) gave tert-butyl 5-(4-amino-2-methyl-2H-pyrazolo|3.4-d|pynmidin-3- yl)indoline-l -carboxylate (0.17 g, 30%). ESI (m / z) [ C19H22N6O2+H]+367. Step-2: To an ice-cold solution of tert-butyl 5-(4-amino-2-methyl-277-pyrazolo[3,4- <7]pyrimidin-3-yl)indoline-l-carboxylate (0.190 g. 0.519 mmol) in 2,2,2-trifluoroethanol (4 mL) was added TMSC1 (0.066 mL, 0.519 mmol) dropwise. The reaction was allowed to warm to rt. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with satd. NaHCCh (25 mL) and then extracted with CH2Cl2(2 x 50 mL). The combined organics were washed with water (2 x 25 mL) and then brine (2 x 10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 3-(indolin-5-yl)-2-methyl-277-pyrazolo[3,4-<2r|pyrimidin-4-amine (0.130 g, 94%). ESI (m / z ) [C14H14N6 +H]+267.

[0644] Step-3: To a solution of 3-(indolin-5-yl)-2-methyl-277-pyrazolo[3,4-J]pyrimidin-4- amine (0.130 g, 0.488 mmol) in methylene chloride (1 mL) was added 1 -fluoro-2-isocyanato- 4-(trifluoromethyl) benzene (0.080 g, 0.391 mmol). After 1 h, the reaction mixture was concentrated. Purification by flash chromatography (silica gel, CH2Cl2to 4% MeOH / CH2Cl2) followed by preparative HPLC (Cl 8, acetonitrile / water) gave 5-(4-amino-2-methyl-277- pyrazolo|3.4-d|pyrimidin-3-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)indoline- l - carboxamide (13 mg, 5%) after lyophilization from acetonitrile / water. ESI (m / z) [ C22H17F4N7O+H]+472.

[0645] Example 44: Preparation of 5-(4-amino-l-methyl-LH-pyrazolo[3,4-rf]pyrimidin-3-yl)-N- (4-(trifluoromethyl)pyridin-2-yl)indoline-l-carboxamide (Compound 44)

[0646] Step-1: To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indoline-l -carboxylate (2.00 g, 5.79 mmol) in trifluroethanol (20 mL) was added TMSC1 (2.22 mL, 17.3 mmol). After 2 hr at rt, the reaction mixture was concentrated under reduced pressure. The residue was triturated with hexanes to afford 5-(4, 4,5, 5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)indoline hydrochloride (1.90 g, crude) as off white solid. ESI (m / z ) [C14H2iBClNO2]+246.

[0647] Step-2: To a solution of 4-(trifluoromethyl)pyridin-2-amine (1.00 g, 6.17 mmol) in CH2Cl2(20 mL) was added pyridine (0.998 mL, 12.3 mmol) followed by phenyl chloroformate (1.15 g, 7.40 mmol). The reaction was stirred at rt for 4 hr. Upon completion. the reaction mixture was treated with water and extracted with CH2Cl2(50 mL). The organic was concentrated under reduced pressure. Purification by flash chromatography (silica gel. 30-40% EtOAc in hexanes) gave phenyl (4-(trifluoromethyl)pyridin-2-yl)carbamate as an off-white solid. (1.2 g, 68%). ESI (m / z ) [C13H9F3N2O2]+283.

[0648] Step-3: To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (500 mg, 1.77 mmol) in CH2Cl2(5 mL) was added TEA (0.619 mL, 4.44 mmol) followed by phenyl (4-(trifluoromethyl)pyridin-2-yl)carbamate (601 mg, 2.13 mmol). After 16 hr at rt, the reaction was treated with water and then extracted with CH2Cl2(100 mL). The organic was concentrated under reduced pressure. Purification by flash chromatography (silica gel, 30-40% EtOAc in hexanes) gave 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-A-(4-(trifluoromethyl)pyridin-2-yl)indoline- 1 -carboxamide (700 mg. 91%) as an off-white solid. ESI (m / z ) [C2iH23BF3N3O3]+434.

[0649] Step-4: To an argon purged solution of 3-iodo-l-methyl-1H -pyrazolo[3,4- <7|pyrimidin-4-amine (200 mg, 0.727 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-A-(4-(trifluoromethyl)pyridin-2-yl)indoline-l -carboxamide (378 mg, 0.873 mmol) in a mixture of L4-dioxane (15 mL) and water (1.5 mL) was added K.2CO3 (201 mg, 1.45 mmol) followed by RuPhosPdG3 (30.4 mg, 0.036 mmol). The reaction was heated to 80 °C for 6 hr. Afterward, the reaction mixture was filtered through celite using EtOAc (300 mL). The organic filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5% MeOH in CH2Cl2) and then by preparative HPLC (Cl 8, ACN / water with 0.05% ammonium bicarbonate in water) gave 5-(4-amino-l -methyl- l / Y- pyrazolo[3,4-d ]pyrimidin-3-yl)-A-(4-(trifluoromethyl)pyridin-2-yl)indoline-l -carboxamide (85 mg, 25%) as a tan solid. ESI (m / z ) [C2iHi7F3NsO]+455.

[0650] Example 45: Preparation of l-(5-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yl)indolin- l-yl)-2-(3-(trifluoromethyl)phenyl)ethan- 1-one (Compound 45)

[0651] Step-1: To a solution of 2-(3-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.44 mmol) in DMF (15 mL) was added DIPEA (2.13 mL, 12.2 mmol) and HATU (1397 mg, 3.67 mmol) followed by 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline hydrochloride (828 mg, 2.94 mmol). After 12 h, the reaction mixture was diluted with EtOAc (25 mL). The organic mixture was washed with water (15 mL x 2) and then brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30% EtOAc / hexanes) gave l-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)indolin-l-yl)-2-(3-(trifluoromethyl)phenyl)ethan-l-one (500 mg, 47% yield). ESI (m / z ) [C23H25BF3NO3 +H]+432.

[0652] Step-2: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-<7]pyrazin-8- amine (200 mg, 0.881 mmol) and l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin- l-yl)-2-(3-(trifluoromethyl) phenyl)ethan-l-one (456 mg, 1.05 mmol) in 1,4-dioxane (6 mL) : water (0.6 mL) was added potassium carbonate (243 mg, 1.762 mmol) followed by XPhosPdG2 (69.2 mg, 0.088 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (10 mL). The organic solution was washed with water (10 mL) and then brine (10 mL), dried overNa2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CELCL) gave a residue that was stirred in ACN (5 mL) for 1 h. The resulting solid was collected by filtration to give l-(5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l- yl)indolin-l-yl)-2-(3-(trifluoromethyl)phenyl)ethan-l-one (130 mg, 32%) after lyophilization. ESI (m / z) [C24H20F3N5O +H]+452.

[0653] Example 46: Preparation of 6-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yI)-A-(3-

[0654] (trifluoromethyl)phenyl)-1H-indole-3-carboxamide (Compound 46)

[0655] Step-1: To an ice-cold solution of 6-bromo-1H-indole-3-carboxylic acid (1.00 g, 4.17 mmol) and 3-(trifluoromethyl)aniline (1.34 g, 8.33 mmol) in pyridine (20 mL) was added POCl3(1.1 mL, 12.5 mmol) dropwise. The reaction was allowed to slowly warm to rt. After 3 h, the reaction mixture was diluted with EtOAc (100 mL). The organic solution was sequentially washed with satd. NaHCOs solution (100 mL), water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) gave 6-bromo-A-(3- (trifluoromethyl)phenyl)-1H-indole-3 -carboxamide (0.3 g, 18 %). ESI (m / z) [C16HioBrF3N20+H]+.

[0656] Step-2: To an argon sparged solution of 6-bromo-A-(3-(trifluoromethyl) phenyl)-1H- indole-3-carboxamide (0.25 g, 0.65 mmol) and bis(pinacolato)diboron (249 mg, 0.979 mmol) in 1,4-dioxane (7.5 mL) was added potassium acetate (128 mg, 1.305 mmol) followed by PdCh(dppf) (47.7 mg, 0.065 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The mixture was washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) gave 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-A-(3-(trifluoromethyl)phenyl)-1H- indole-3 -carboxamide (0.25 g. 89%) as a brown solid. ESI (m / z) [C22H22BF3N2O3+H 431.

[0657] Step-3: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-6']pyrazin-8- amine (100 mg, 0.440 mmol) and 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3- (trifluoromethyl)phenyl)-1H-indole-3 -carboxamide (227 mg, 0.528 mmol) in a mixture of 1,4-dioxane (3 mL) : water (0.3 mL) was added potassium carbonate (122 mg, 0.881 mmol) followed by XPhosPd-G2 (34.7 mg. 0.044 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (100 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to EtOAc) gave a solid which was stirred in ACN (1 mL) for 1 h at rt. The solid was collected by filtration to give 6-(8-amino-3-methylimidazo[l ,5-r7]pyrazin-l -yl)-iV- (3 -(trifluoromethyl)phenyl)-1H-indole-3 -carboxamide (15 mg, 0.033 mmol, 7%) after lyophilization from acetonitrile / water. ESI (m / z) | C23I I IVEVNGO 1 111 451.

[0658] Example 47: Preparation of 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-A-(3- (trifluoro methyl)phenyl)imidazo[l,2-a]pyridine-3-carboxainide (Compound 47)

[0659] Step-1: To an ice-cold solution of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (1.50 g, 6.22 mmol) and 3-(trifluoromethyl)aniline (1.50 g, 9.33 mmol) in pyridine (20 mL) was added POCl3(0.870 mL, 9.33 mmol) dropwise. The reaction was allowed to warm to rt. After 6 h, the reaction mixture was concentrated then treated with water (50 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 80% EtOAc / hexanes) gave 7- bromo-A-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (500 mg, 20%) as a tan solid. ESI (m / z) [C1sEl9BrF3N3O+H]+384.

[0660] Step-2: To an argon sparged solution of 7-bromo-A-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (500 mg, 1.30 mmol) and bis(pinacolato)diborane (496 mg, 1.95 mmol) in 1,4-di oxane (30 mL) was added potassium acetate (319 mg, 3.25 mmol) followed by Pd(dppt)Ch (95 mg, 0.130 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was filtered through a celite pad using EtOAc (300 mL). The filtrate dried over Na2SO4, filtered and concentrated under reduced pressure to afford 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-A-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (600 mg). The material was used as is without further purification. ESI (m / z) [C21H21BF3N3O3-82+ILP 350.

[0661] Step-3: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (200 mg, 0.881 mmol) and 7-(4.4.5.5-tetramethyl- l .3.2-dioxaborolan-2-yl)-.V-(3- (trifluoromethyl)phenyl)imidazo[l,2-u] pyridine-3-carboxamide (570 mg, 1.32 mmol) in a mixture of 1,4-dioxane (20 mL) : water (4 mL) was added K2CO3 (304 mg, 2.20 mmol) followed by XPhosPdG2 (69.3 mg, 0.088 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOf I / CH2CT2) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave a solid residue that was triturated with acetonitrile / water (1 :5, 2 mL). The resulting solid was collected by filtration and dried under vacuum to afford 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-JV-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (50 mg, 12%) as a pale yellow solid. ESI (m / z) [C22Hi6F3N?O+H]+452.

[0662] Example 48: Preparation of 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-A / -(4- fluoro-3-(trifluoromethyl)phenyl)imidazo[l,2-«]pyridine-3-carboxamide (Compound 48)

[0663] Step-1: To a solution of 7-bromoimidazo[1.2-a]pyridine-3-carboxylic acid (1.5 g, 6.22 mmol) in DMF (30 mL) was added DIPEA (3.26 mL, 18.6 mmol) and HATU (3.55 g, 9.33 mmol) followed by 4-fluoro-3-(trifluoromethyl)aniline (2.22 g, 12.4 mmol). After 12 h, reaction mixture was treated with water (50 mL). After 1 h, the resulting solid was collected by fdtration and dried under reduced pressure to give 7-bromo-.'V-(4-fluoro-3- (trifluoromethyl)phenyl)imidazo[l,2-< ]pyridme-3-carboxamide (1.5 g, 59%). ESI (m / z) [C15H8BrF4N3O-H]- 400.

[0664] Step-2: To an argon sparged solution of 7-bromo- / V-(4-fluoro-3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (1.5 g, 3.7 mmol) and bis(pinacolato)diborane (1.42 g, 5.59 mmol) in 1,4-dioxane (45 mL) was added potassium acetate (0.732 g, 7.46 mmol) followed by Pd(dppf)Ch (0.273 g, 0.373 mmol). The reaction was heated to 85 °C for 12 h. Afterward, the reaction mixture was concentrated under reduced pressure to afford / V-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(4.4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (1.8 g). The material was used without further purification. ESI (m / z) IC21H20BF4N3O3+HI 368 (boronic acid).

[0665] Step-3: To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-rz]pyrazin- 8-amine (150 mg, 0.588 mmol) and A-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl) imidazo[l,2-a]pyridine-3-carboxamide (396 mg, 0.882 mmol) in a mixture of 1.4-dioxane (4.5 mL) : water (0.45 mL) was added K2CO3 (163 mg. 1.17 mmol) followed by XPhosPdG2 (46.3 mg, 0.059 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. CH2Cl2to 10% MeOH / CELCE) followed by preparative HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave 7-(8-amino-3-isopropylimidazo[ 1 ,5-a]pyrazin- l-yl)- / V- (4-fluoro-3-(trifluoromethyl)phenyl)imidazo[l,2-<7]pyridine-3-carboxamide (30 mg, 10%) after lyophilization from acetonitrile / water. ESI (m / z) [C24Hi9F4N?O+H]+498.

[0666] Example 49: Preparation of 7-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yl)-A-(3-(ter / - butyl)-l-( / ;-tolyl)-1H-pyrazol-5-yl)imidazo[l,2-«|pyridine-3-carboxamide (Compound

[0667] 49)

[0668] Step-1: To an ice-cold solution of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (800 mg. 3.32 mmol) and 3-(fert-butyl)-l-(p-tolyl)-1H-pyrazol-5-amine (114 mg, 4.98 mmol) in pyridine (16 mL) and CH2Cl2(16 mL) was added POCk (1527 mg, 9.96 mmol) dropwise. The reaction was allowed to warm to rt. After 2 h, the reaction mixture was treated with saturated NaHCOs (20 mL) and EtOAc (100 mL). The organic layer was washed with water (100 mL) and then brine (50 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 7-bromo-jV-(3-(tert-butyl)-l-(p-tolyl)-1H -pyrazol-5-yl)imidazo[l,2- a]pyridine-3 -carboxamide (420 mg, 28%). ESI (m / z ) [C22H22BrNsO+H]4452.

[0669] Step-2: To an argon sparged solution of 7-bromo-A-(3-( / ert-butyl)-l-(p-tolyl)-1H - pyrazol-5-yl)imidazo [1.2-a]pyridine-3-carboxamide (420 mg, 0.928 mmol) and bis(pinacolato)diborane (354 mg, 1.39 mmol) in 1,4-dioxane (12 mL) was added potassium acetate (182 mg, 1.85 mmol) followed by Pd(dppt)Ch (67.9 mg, 0.093 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was concentrated under reduced pressure to afford A-(3-(tert-butyl)-l-(jO-tolyl)-1H-pyrazol-5-yl)-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[L2-a]pyridine-3-carboxamide (380 mg). The material was used without further purification. ESI (m / z) IC2XH34BN5O3+H-82I 418 (boronic acid).

[0670] Step-3: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (120 mg, 0.528 mmol) and 7V-(3-(tert-butyl)-l-( / ?-tolyl)-1H -pyrazol-5-yl)-7-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl) imidazo[l,2-a]pyridine-3-carboxamide (264 mg, 0.528 mmol)) in a mixture of 1,4-dioxane (3.6 mL) : water (0.36 mL) was added potassium carbonate (146 mg, 1.05 mmol) followed by XPhosPdG2 (41.5 mg. 0.053 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with

[0671] EtOAc (50 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 20% MeOI I / CI I2CI2) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave 7-(8-amino-3-methylimidazo[l ,5-a]pyrazm-l-yl)-N-(3-(tert-butyl)~l -(p- toiyl)-1H"pyrazol-5-yl)imidazo[ l,2"a]pyndine-3-carboxamide (50 mg, 18%) after lyophilization from acetonitrile / water. ESI (m / z) [C29H29N9O+H]+520.

[0672] Example 50: Preparation of 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-A-(3- (trifluoro methyl)phenyl)imidazo[ l,2-a]pyridine-3-carboxamide (Compound 50)

[0673] To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-cz]pyrazin-8-amine (200 mg. 0.784 mmol) and 7-(4.4,5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)-A-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (507 mg, 1.17 mmol) in a mixture of 1,4-dioxane (20 rnL) : water (4 mL) was added K2CO3 (271 mg, 1.96 mmol) followed by XPhosPdG2 (61.7 mg, 0.078 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CELCkto 10% MeOH / CH2Cl2) and then by reverse phase preparative HPLC (Cl 8, acetonitrile / water with 0.05% TFA) gave a residue that was treated with NaHCO3 solution (10 mL). The resulting solid was collected by filtration, washed with water (10 mL) and then dried under reduced pressure to afford 7-(8-amino-3-isopropylimidazo[l,5-α7]pyrazin-l-yl)-A- (3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (110 mg, 29%) as a pale yellow solid. ESI (m / z) IC24H20F3N7O+H] 480.

[0674] Example 51: Preparation of 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-A-(4- fluoro-3-(trifluoromethyl)phenyl)imidazo[l,2-«]pyridine-3-carboxamide (Compound 51)

[0675] To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8-amine (100 mg, 0.440 mmol) and A-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (198 mg, 0.440 mmol) in a mixture of 1.4-dioxane (3 mL) : water (0.3 mL) was added potassium carbonate (122 mg, 0.881 mmol) followed by XPhosPdG2 (0.044 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture washed with water (50 mL) and then brine (50 mL). dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. CH2Cl2to 20% MeOH / CH2Cl2) followed by reverse phase preparative HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave 7-(8-amino-3- methylimidazo| l .5-c / |pyrazin- l -yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)imidazo| 1.2- a]pyridine-3-carboxamide (12 mg, 5%) as a solid after lyophilization from acetonitrile / water. ESI (m z) tC22Hi5F4N7O+HJ+470.

[0676] Example 52: Preparation of 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(4- fluoro-3-(trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound

[0677] Step-1: To an ice-cold solution of 7-bromoimidazo[1.2-a]pyridine-3-carboxylic acid (1.5 g, 6.22 mmol) and 4-fluoro-3-(trifluoromethoxy)aniline (2.42 g, 12.4 mmol) in CH2Cl2(20 mL) and pyridine (20 mL) was added POCl3(1.740 rnL, 18.67 mmol) dropwise. The reaction was allowed to warm at rt. After 2 h, the reaction mixture was diluted with EtOAc (100 mL). The organic solution was sequentially washed with satd. NaHCCh (100 mL), water (50 mL x 2) and then brine (50 mL x 2). dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 7-bromo-A-(4-fluoro-3-(trifluoromethoxy)phenyl)imidazo[ 1,2- tf]pyridine-3-carboxamide (1.00 g, 38%). ESI (m / z) [C1sEhB^NsCh+EfT 418.

[0678] Step-2: To an argon sparged solution of 7-bromo-A-(4-fluoro-3- (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (1.00 g, 2.39 mmol) and bis(pinacolato)diborane (0.729 g, 2.87 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (0.469 g, 4.78 mmol) followed by Pd(dppf)C12 (0. 175 g. 0.239 mmol). The reaction was heated to 100 °C for 1 h. Afterwards, the reaction mixture was concentrated under reduced pressure to afford A-(4-fluoro-3-(trifluoromethoxy)phenyl)-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (1.00 g). The material was used without further purification. ESI (m / z) [C2iH2oBF4N304+H-82]+384 (boronic acid).

[0679] Step-3: To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-u]pyrazin- 8-amine (99 mg, 0.387 mmol) and A-(4-fluoro-3-(trifluoromethoxy)phenyl)-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (150 mg, 0.322 mmol) in a mixture of 1 ,4-di oxane (3.6 mL) : water (0.36 mL) was added potassium carbonate (89 mg, 0.645 mmol) followed by XPhosPdG2 (0.032 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL). The organic mixture washed with water (50 mL) and then brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CEbChto 10% MeOH / CFLCb) followed by preparative reverse phase HPLC (acetonitrile / water with 10 mM ammonium bicarbonate) afforded 7-(8-amino-3- isopropylimidazo[l,5-rz]pyrazin-l-yl)-A-(4-fluoro-3-(trifluoromethoxy)phenyl)imidazo[l,2- a] pyridine-3 -carboxamide (35 mg, 21%) after lyophilization from acetonitrile / water. ESI (m / z) [C24H19F4N7O2+H]+514.

[0680] Example 53: Preparation of 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide (Compound 53)

[0681] Step-1: To a solution of ethyl 6-bromobenzofuran-3 -carboxylate (2.00 g, 7.43 mmol) in THF (60 mL) : water (5 mL) was added LiOH hydrate (0.936 g, 22.3 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure. The residue was acidified with 2 M HC1 solution. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to afford 6-bromobenzofuran-3 -carboxy lie acid (1.57 g, 88%). ESI (m / z ) [C9H5BrO3-H] - 239.

[0682] Step-2: To an ice-cold solution of 6-bromobenzofuran-3-carboxylic acid (1.5 g, 6.1 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (1.10 g, 6. 17 mmol) in pyridine (20 mL) and CH2Cl2(20 mL) was added POCl3(0.863 mL, 9.26 mmol) dropwise. The reaction was allowed to warm to rt. After 2 h, the reaction mixture was treated with a satd. NaHCOs (20 mL) then extracted with CH2Cl2(50 mL). The organic layer was washed with water (50 mL) and then brine solution (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 6-bromo-A-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide (0.95 g, 38%). ESI (m / z ) [C16HsBrF4NO2+H]+402.

[0683] Step-3: To an argon sparged solution of 6-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide (0.95 g, 2.36 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (0.464 g, 4.72 mmol) and bis(pinacolato)diboron (0.900 g, 3.54 mmol) followed by PdC12(dppf (0.173 g, 0.236 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the reaction mixture was diluted with CFLCh QOO mL). The organic mixture was washed with water (50 mL) and then brine (50 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. 50% EtOAc / hexanes) gave A-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (0.85 g, 80%). ESI (m,z) [C22H2OBF N04+H]+450.

[0684] Step-4: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (0. 15 g, 0.66 mmol) in a mixture of 1 ,4-dioxane (10 mL) : water (1 mL) was added N- (2-fluoro-5-(trifluoromethyl)phenyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3-carboxamide (0.356 g, 0.793 mmol) , potassium carbonate (0.183 g, 1.32 mmol) followed by XPhosPdG2 (0.052 g, 0.066 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the mixture was diluted with di chloromethane (50 mL). The organic mixture washed with water (2 x 10 mL) and then brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CFLChto 10% MeOH / CFLCh) gave 6-(8-amino-3- methylimidazo[I,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3- carboxamide (48 mg, 48%). ESI (m / z) [ C23H15F4N5O2+H 470. Example 54: Preparation of 6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide (Compound 54)

[0685] Step-1: To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-tz]pyrazin- 8-amine (0.15 g, 0.58 mmol) in a mixture of 1,4-dioxane (10 mL) : water (1 mL) was added X-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3 -carboxamide (0.264 g, 0.588 mmol) and potassium carbonate (0.163 g, 1.176 mmol) followed by XPhosPdG2 (0.046 g. 0.059 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the reaction mixture was diluted with di chloromethane (50 mL). The organic mixture washed with water (2 x 10 mL) and then brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CLbChto 4% MeOH / CH2Cl2) gave 6-(8-amino-3- isopropylimidazof l,5-a]pyrazin-l-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3- carboxamide (87 mg, 29%). ESI (m / z) [C25Hi9F4N5O2+H]+498.

[0686] Example 55: Preparation of 5-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yl)-4-chloro-

[0687] A,-(2-fluoro-5-(trifluoromethyl)phenyl)indoline- 1 -carboxamide (Compound 55)

[0688] Step-1: To a solution of 4-chloroindoline (5.0 g, 32.6 mmol) in CH2Cl2(50 mL) was added DIPEA (11.3 mL, 65.1 mmol) followed by (Boc)2O (7.56 mL, 32.6 mmol). After 12 h, the reaction mixture was diluted with dichloromethane (50 mL). The organic solution was washed with water (2 x 20 mL) and then brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. CEbChto 3-4% MeOI I / CI I2CI2) gave tert-butyl 4-chloroindoline-l -carboxylate (5.10 g, 61%). ESI (m / z) [(C13HI6C1N02+H)-100]+154.

[0689] Step-2: To a solution of tert-butyl 4-chloroindoline-l -carboxylate (5.10 g, 20.1 mmol) in CH2Cl2(100 mL) was added NBS (3.58 g, 20. 1 mmol). After 16 h, the reaction mixture was diluted with CH2Cl2(100 mL). The organic solution was washed with water (50 mL) and then brine (50 mL). dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave tert-butyl 5-bromo-4-chloroindoline-l -carboxylate (3.75 g, 56%). ESI (m / z ) |C13Hl 5BrCINO2+H-56| 276.

[0690] Step-3: To an argon sparged solution of tert-butyl 5-bromo-4-chloroindoline-l- carboxylate (2.0 g. 6.0 mmol) in 1,4-dioxane (30 mL) and bis(pinacolato)diboron (2.29 g, 9.02 mmol) was added potassium acetate (1.18 g, 12.0 mmol) followed by PdCh(dppl) (0.440 g, 0.601 mmol). The reaction was heated to 100 °C for 12 h. Afterwards, the reaction mixture was diluted with di chloromethane (100 mL). The organic mixture was washed with water (2 x 10 mL) and then brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 4% MeOH / CELCL) gave / er / -but l 4-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indoline-l -carboxylate (1.2 g). ESI (m / z) [C19EI27BCINO4 +H-56 325.

[0691] Step-4: To an ice-cold solution of / ert-butyl 4-chloro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indoline- 1 -carboxylate (1.2 g, 3.1 mmol) in 2,2,2-trifluoroethanol (60 mL) was added TMSC1 (1 .21 mL, 9.48 mmol) dropwise. The reaction was allowed to warm to rt. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted satd. NaHCCh solution (40 mL) then extracted with CH2Cl2(2 x 50 mL). The combined organics were washed with water (2 x 25 mL) and then brine (2 x 10 mL). dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 4- chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (0.75 g). The material was used without further purification. ESI (m / z [C14Hi9BClNO2 +H]+280.

[0692] Step-5: To a solution of 4-chloro-5-(4,4,5.5-tetramethyl-l,3,2-dioxaborolan-2- yl)indoline (0.75 g, 2.68 mmol) in CH2Cl2(30 mL) was added l-fluoro-2-isocyanato-4- (trifluoromethyl)benzene (0.550 g, 2.68 mmol) . After 16 h, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 4-chloro- / V-(2-fluoro-5-(trifluoromethyl)phenyl)-5- (4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)indoline-l-carboxamide (0.65 g, 22 % over 3- steps). ESI (m / z ) [C22H22BC1F4N2O3+H]+485. Step-6: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (0.150 g, 0.661 mmol) and 4-chloro-A-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(4, 4,5,5- tetramethyl-I,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (0.384 g, 0.793 mmol) in a mixture of 1,4-dioxane (30 rnL) : water (3 mL) was added potassium carbonate (0.183 g, 1.32 mmol) followed by XPhosPdG2 (0.052 g, 0.066 mmol). The reaction was heated to 100 °C for 16 h. Afterwards, the mixture was diluted with di chloromethane (50 mL). The organic mixture was washed with water (2 x 10 mL) and then brine (20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CFbCbto 4% MeOH / CIbCh) gave 5-(8-amino-3-methylimidazo[l,5-a] pyrazin- l-yl)-4-chloro-A-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide (35 mg, 10 % yield). ESI (m / z) [C23Hi7ClF4N6O+H]+505.

[0693] Example 56: Preparation of 5-(8-amino-3,5-dimethyliinidazo[l,5-a]pyrazin-l-yl)-A-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 56)

[0694] Step-1: A solution of l-bromo-3,5-dimethylimidazo[l,5-a]pyrazin-8-amine (150 mg, 0.622 mmol) in 1,4-dioxane (20 mL):water (4 mL) was sparged with argon then ,V-(2-fluoro- 5-(lrifluoromethyl)phenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l- carboxamide (336 mg. 0.747 mmol) and K2CO3 (215 mg. 1.555 mmol) were added followed by XPhosPdG2 (49 mg, 0.062 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was filtered through a celite pad using 1 :9 MeOH / CH2Cl2. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica gel. EtOAc to 2-5% MeOH / EtOAc) gave 5-(8-amino-3,5-dimethylimidazo[1.5-a]pyrazin-l-yl)-A- (2-fluoro-5-(trifluoromethyl)phenyl) indoline- 1 -carboxamide (73 mg, 23.23%) as an off- white solid. ESI (m / z) [C24H2OF4N60+H]+485.

[0695] Example 57: Preparation of l-(5-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yl)indolin- l-yl)-2-(4-(2,2,2-trifluoroethyl)phenyl)ethan-l-one (Compound 57)

[0696] Step-1: To an argon sparged solution of l-bromo-4-(2,2,2-trifluoroethyl)benzene (2.00 g, 8.37 mmol) and diethyl malonate (1.40 g, 8.79 mmol) in toluene (40 mL) was added potassium phosphate tribasic (5.32 g, 25. 1 mmol) followed by JohnPhos (0.25 g. 0.83 mmol) and Pd(OAc)2 (0.094 g, 0.418 mmol) The reaction was heated to 120 °C for 3 h. Afterward, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (20 mL x 1) and brine (20 mL x 1). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane to 20% EtOAc / hexane) gave diethyl 2-(4-(2,2,2-trifluoroethyl)phenyl)malonate (2.00 g, 75%) as a pale-yellow liquid. ESI (m / z) [C15H17F3O4+H 319.

[0697] Step-2: To a solution of diethyl 2-(4-(2,2,2-trifluoroethyl)phenyl)malonate (1.20 g, 3.77 mmol) in toluene (4 mL) was added 32% NaOH solution (1.5 mL. 3.77 mmol). The reaction was sequentially heated to 100 °C for 2 h, cooled to room temperature, cone HC1 (3.14 mL, 37.7 mmol) was added and the reaction was heated to 100 °C for 2 h. Afterward, the reaction mixture was diluted with EtOAc (100 mL) and then washed with brine (20 mL). The organic layer was dried over anhydrous Na2SO4and then concentrated under reduced pressure to give 2-(4-(2,2,2-trifluoroethyl)phenyl)acetic acid (400 mg). ESI (m / z) [C10H9F3O2-H]- 217.

[0698] Step-3: To a solution of crude 2-(4-(2,2,2-trifluoroethyl)phenyl)acetic acid (400 mg, 1.83 mmol) in DMF (12 mL) was added DIPEA (1.28 mL, 7.33 mmol), HATU (1.04 g, 2.75 mmol) followed by 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (449 mg, 1.83 mmol). The reaction was stirred for 12 h at ft. Afterward, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave l-(5- (4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)indolin-l-yl)-2-(4-(2,2,2- trifluoroethyl)phenyl)ethan-l-one (200 mg, 24 %) as brown solid. ESI (m / z) [C24H27BF3NO3+H]+446.

[0699] Step-4: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (100 mg, 0.44 mmol) and l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l- yl)-2-(4-(2,2,2-trifluoroethyl)phenyl)ethan-l-one (196 mg, 0.44 mmol) in mixture of 1,4- di oxane (3 mL) and water(0.3 mL) was added potassium carbonate (122 mg, 0.881 mmol) followed by XphosPdG2 (34.6 mg, 0.044 mmol) the resulting mixture was heated to 100 °C for 16 h in a sealed tube. Afterw ard, the reaction mixture w as diluted with EtOAc (50 mL), washed with water (20 mL x 2) and brine (20 mL). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) followed by reverse phase chromatography (C18, 10% acetonitrile / water to 50% acetonitrile / water) gave l-(5-(8-amino- 3-methylimidazo| 1 ,5-o | yrazin- 1 -y I Jindolin- 1 -yl)-2-(4-(2,2,2-trifluoroethy l)phenyl)ethan-l - one (46 mg, 22%) as an off-white solid after lyophilization. ESI (m / z) [C25H22F3N5O+H ]+466.

[0700] Example 58: Preparation of 5-(8-amino-5-fluoro-3-methylimidazo[l,5-a]pyrazin-l-yl)-

[0701] A-(2-fliioro-5-(trifluoromethyl)phenyl)iiidoline- 1-carboxamide (Compound 58)

[0702] Step-1: To a solution of l-bromo-3-methylimidazo[l,5-o]pyrazin-8-amine (500 mg, 2.20 mmol) in MeOH (5 mL) and acetonitrile (5 mL) was added Selectfluor (936 mg, 2.64 mmol). The reaction w as stirred for 12 h at it Afterward, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% CH3OH / CH2Cl2) gave l-bromo-5-fluoro-6-methoxy-3-methyl-5,6- dihydroimidazo[l,5-a]pyrazin-8-amine (400 mg, 65%) as a brown solid. ESI (m / z) [CsHioBrFN40+H]+278.

[0703] Step-2: To a solution of l-bromo-5-fluoro-6-methoxy-3-methyl-5,6- dihydroimidazo[l,5-a]pyrazin-8-amine (400 mg, 1.44 mmol) in acetonitrile (ImL) was added cesium carbonate (4.70 g, 14.4 mmol). The reaction was heated to 90 °C for 30 min by microwave. Afterwards the reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc in hexanes) gave l-bromo-5-fluoro-3-methylimidazo[l,5-a]pyrazin- 8-amine (50 mg, 14 %) as a brown solid. ESI (m / z) [CrHeBrEN-i+H]4246.

[0704] Step-3: To an argon sparged solution of l-bromo-5-fluoro-3-methylimidazo[l,5- a]pyrazin-8-amine (50 mg, 0.20 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (138 mg, 0.306 mmol) in 1,4-dioxane (1.5 mL): water (0.2 mL) was added potassium carbonate (56.4 mg, 0.408 mmol) followed by XPhosPdG2 (16 mg, 0.020 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was diluted with EtOAc (50 mL), washed with water (20 mL) followed by brine (20 mL ). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 90% EtOAc in hexanes) followed by reverse phase chromatography (Cl 8, 10% acetonitrile / water to 50% acetonitrile / water) gave 5-(8-amino-5- fluoro-3 -methyl imidazof 1 ,5-a]pyrazin-l -yl)-JV-(2-fluoro-5-(trifluoromethyl)phenyl)indohne- 1-carboxamide (12 mg, 12%) as pale-yellow solid after lyophilization. ESI (m / z) [C23Hi7F5N6O+H]+489.

[0705] Example 59: Preparation of 7-(8-amino-3-(methoxymethyl)imidazo[l,5-«]pyrazin-l-yl)-

[0706] A-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0707] (Compound 59)

[0708] Step-1: To an ice-cold solution of (3-chloropyrazin-2-yl)methanamine (5.00 g, 34.8 mmol) in CH2Cl2(100 mL) were added DIPEA (30.4 mL, 174 mmol) followed by w-propyl phosphonic acid anhydride (50 % T3P in EtOAc) (41 mL, 83 mmol). The reaction was allowed to slowly warm to rt. After 16 h, all volatiles were removed under vacuo. The residue was diluted with NaHCCh solution and extracted with EtOAc (2x100 mL). The organics were washed with water (100 mL), brine (50 mL) and then dried over Na2SO4, filtered and concentrated under reduced pressure to give A-((3-chloropyrazin-2-yl)methyl)-2- methoxyacetamide (5.00 g, 66%) as an off-white solid. ESI (m / z) [C8HIOC1N302+H]+216.

[0709] Step-2: To an ice-cold solution of A-((3-chloropyrazin-2-yl)methyl)-2- methoxyacetamide (5.00 g, 23.1 mmol) in acetonitrile (100 mL) was added pyridine (18.7 mL, 232 mmol) and DMF (1.79 mL. 23.1 mmol) followed by dropwise addition of POCl3(5.40 mL, 58.0 mmol). The reaction was allowed to slowly warm to rt over 16 h. Afterward, the reaction mixture was reduced under vacuo. The residue was partitioned between satd. NaHCCh solution (100 mL) and EtOAc (100 mL). The organic layer was washed with cold water (2 xlOO mL) and brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 30-40% EtOAc / hexanes) gave 8-chloro-3-(methoxymethyl)imidazo[ 1 .5-01 pyrazine (2.00 g. 10.1 mmol, 43%) as a pale-yellow solid. ESI (m / z) [CsHsCINsO+H]’ 198.

[0710] Step-3: To an ice-cold solution of 8-chloro-3-(methoxymethyl) imidazo[l,5- pyrazine (2.00 g. 10.1 mmol) in DMF (20 mL) was added A-bromosuccinimide( 1.98 g, 11.1 mmol) portionwise. The reaction was allowed to warm to rt. After 2 h, the reaction was quenched with water (30 mL). The resulting precipitate was collected by filtration and dried to give l-bromo-8-chloro-3-(methoxymethyl) imidazo[l,5-«]pyrazine (2.00 g, 71 % yield) as pale-yellow solid. ESI (m / z [CsHrBrCINsO+H]* 276.

[0711] Step-4: A solution of l-bromo-8-chloro-3-(methoxymethyl)imidazo[l,5-«]pyrazine (1.00 g, 3.62 mmol) in excess 2 M ammonia in z-PrOH (100 mL) was heated in an autoclave to 100 °C for 16 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was treated with ACN (30 mL). After 30 min, the resulting solid collected by filtration and then dried to afford l-bromo-3-(methoxymethyl)imidazo[l,5- o|pyrazin-8-amine (0.800 g, 3. 11 mmol. 86% yield) as a brown solid. ESI (m / z) [CsH9BrN4O+H]+257.

[0712] Step-5: A solution of l-bromo-3-(methoxymethyl)imidazo[l,5-n]pyrazin-8-amine (150 mg, 0.583 mmol) in mixture of 1,4-dioxane (20 mL):water (2 mL) was sparged with argon then A-(2-fluoro-5-(trifluoromethyl)phenyl)-7-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan- 2-yl) imidazo[l,2-«]pyridine-3-carboxamide (262 mg, 0.583 mmol) and K2CO3 (202 mg, 1.45 mmol) were added followed by XPhosPdG2 (45 mg, 0.058 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was filtered through a celite pad using 1:9 MeOH / CFLCh. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica gel. CH2Cl2to 10% MeOH / CH2Cl2) followed by preparative HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave 7-(8-amino-3- (methoxymethyl)imidazo[l,5-«]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (88.5 mg, 30%) as an off- white solid. ESI (m / z) [C23H17F4N7O2+H 500. Example 60: Preparation of 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-7-chloro-

[0713] A,-(2-fluoro-5-(trifluoi’omethyl)phenyl)in<loliiie- 1 -carboxamide (Compound 60)

[0714] Step-1: To an ice-cold solution of 5 -bromoindoline (10.0 g, 50.5 mmol) in CH2Cl2(200 mL) was added triethylamine (14.0 mL, 101 mmol) and acetyl chloride (4.31 mL, 60.6 mmol). The reaction was allowed to warm to rt for 4 hr. The reaction mixture was treated with water and extracted with CH2Cl2(2x 200 mL). The organic solution was washed with water (50 mL x 2) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) followed by trituration of the residue with CH2Cl2: hexanes (1:5) (50 mL) gave l-(5-bromoindolin-l-yl)ethan-l-one (10 g, 82 %) as a brown solid. ESI (m / z) [C1oHioBrNO+H]+240.

[0715] Step-2: To a solution of l-(5-bromoindolin-l-yl)ethan-l-one (8.00 g, 33.3 mmol) in acetonitrile (150 mL) was added A-chlorosuccinimide (6.67 g, 50.0 mmol). The resulting reaction mixture was heated to 80 °C for 24 h. Afterward, the reaction mixture was cooled, and then concentrated under reduced pressure. Purification by column chromatography (silica gel, hexanes to 30-35% EtOAc / hexanes) gave l-(5-bromo-7-chloroindolin-l-yl)ethan-l-one (3.29 g, 36%) as a dark brown solid. ESI (m z) [C1oH9BrClNO+H]+274.

[0716] Step-3: To a solution of l-(5-bromo-7-chloroindolin-l-yl)ethan-l-one (3.50 g, 12.7 mmol) in mixture of MeOH (60 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.611 g, 25.5 mmol). The resulting reaction mixture was heated to 80 °C for 4 h. Afterward, all volatiles were removed under vacuo and the residue treated with EtOAc (150 mL). The organic solution was washed with water (25 mL x 2), followed by brine (25 mL), dried over Na?SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 5-10% EtOAc / hexanes) gave 5-bromo-7- chloroindoline (2.50 g. 84%) as an off-white solid. ESI (m / z) [C8H7BrClN+H]+233.

[0717] Step-4: A solution of 5-bromo-7-chloroindoline (3.00 g, 12.9 mmol). bis(pinacolato)diboron (4.91 g, 19.3 mmol) and potassium acetate (2.53 g, 25.8 mmol) in 1 ,4- dioxane (60 mL) was sparged with argon for 5 min. To this mixture PdCh(dppf) (0.944 g, 1.290 mmol) was added. The resulting reaction was heated to 100 °C for 6 h. After cooling to ft, the reaction mixture was filtered through a celite pad using EtOAc (200 mL) and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indoline (2.20 g, 61%) as an off-white solid. ESI (m / z) [CuEIigBClNCh+EI]4280.

[0718] Step-5: To a solution of l-bromo-8-chloro-3-methylimidazo[1.5-a]pyrazine (1.50 g, 6.09 mmol) in 1,4-dioxane (30 mL) was added DIPEA (2.66 mL, 15.2 mmol) followed by (2,4-dimethoxyphenyl)methanamine (1.11 g, 6.69 mmol). The reaction was heated to 80 °C for 16 h. Afterward, all volatiles were concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 1 -bromo-A-(2,4- dimethoxybenzyl)-3-methylimidazo[L5-6']pyrazin-8-amine (1.27 g, 55%) as a brown solid. ESI (m / z ) [C16Hi7BrN4O2+H]+377.

[0719] Step-6: A solution of l-bromo-A-(2,4-dimethoxybenzyl)-3-methylimidazo[l,5- a]pyrazin-8-amine (0.90 g, 2.38 mmol) and 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indoline (0.800 g, 2.86 mmol) in a mixture of 1.4-dioxane (30 mL) and water (6 mL) was sparged with argon for 5 min. To this solution was sequentially added K2CO3 (0.824 g, 5.96 mmol) and XPhosPdG2 (0.188 g, 0.239 mmol). The reaction was heated to 100 °C for 12 h under argon. Afterward, the reaction mixture was cooled, then concentrated under reduced pressure. Purification by column chromatography (silica gel, 5- 10% methanol / methylene chloride) followed by trituration with acetonitrile gave l -(7- chloroindolin-5-yl)-A-(2,4-dimethoxybenzyl)-3-methylimidazo[l,5-a]pyrazin-8-amine (0.61 g, 51%) as a brown solid. ESI (m / z) [C24H24CIN5O2+I P 450.

[0720] Step-7: To a solution of l-(7-chloroindolin-5-yl)-N-(2,4-dimethoxybenzyl)-3- methylirnidazo[L5-tf]pyrazin-8-amine (600 mg, 1.33 mmol) in CH2Cl2(10 mL) was added 1- fluoro-2-isocyanato-4-(trifluoromethyl)benzene (274 mg, 1.33 mmol). The reaction was stirred at rt. After 1 h, the reaction mixture w as concentrated under reduced pressure to afford 7-chloro-5-(8-((2,4-dimethoxybenzyl)amino)-3-methyl imidazo[l,5-a]pyrazin-l-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (820 mg. 94%) as a brown solid. ESI (m / z ) [C32H27C1F4N6O3+H]+655. The material was used without further purification.

[0721] Step-8: To a -10 °C stirred solution of 7-chloro-5-(8-((2,4-dimethoxybenzyl)amino)- 3-methyl imidazof 1 ,5-a]pyrazin- 1 -yl )-A-(2-fl uoro-5-(tri fl uoromethyl)phenyl)indoline- 1 - carboxamide (150 mg. 0.229 mmol) in TFA (2 mL, 26.0 mmol) was added triflic acid (0.5 mL, 5.63 mmol). The reaction was allowed to warm to rt. After 6 h, the reaction mixture was purged with argon and residue was diluted with EtOAc (100 mL) and neutralized with saturated NaHCCh solution. The organic layer was washed with brine (30 mL). dried over Na2SO4and then concentrated. Purification by flash column chromatography (silica gel, 5- 10% EtOAc in MeOH) followed by trituration with ACN (5 mL) gave 5-(8-amino-3- methylimidazo[l,5-a]pyrazin-l-yl)-7-chloro-A-(2-fluoro-5-(trifluoromethyl)phenyl)indoline- 1-carboxamide (45 mg, 0.086 mmol, 37% yield) as an off-white solid. ESI (m / z) [C23H17CIF4N6O +H]+505.

[0722] Example 61: Preparation of l-(5-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yl)indolin- l-yl)-2-(3-(2,2,2-trifluoroethyl)phenyl)ethan-l-one (Compound 61)

[0723] Step-1: To an argon sparged solution of l-bromo-3-(2,2,2-trifluoroethyl)benzene (2.00 g, 8.37 mmol), diethyl malonate (1.40 g, 8.79 mmol) in toluene (40 mL) was added potassium phosphate, tribasic (5.32 g, 25.1 mmol) and JohnPhos (0.250 g, 0.837 mmol) followed by Pd(OAc)2 (0.094 g, 0.41 mmol). The reaction was heated to 120 °C for 3 h. Afterward, the reaction mixture was diluted with EtOAc (50 mL). The organic solution was washed with water (20 mL) followed by brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane to 30% EtOAc / hexane) gave diethyl 2-(3-(2,2,2-trifluoroethyl)phenyl)malonate (1.50 g, 56%). ESI m / z) [C15H17F3O4+H 319.

[0724] Step-2: To a solution of diethyl 2-(3-(2,2,2-trifluoroethyl)phenyl)malonate (1.40 g, 4.40 mmol) in toluene (7 mL) added 32% NaOH solution (1.68 mL, 4.40 mmol). The reaction was heated to 100 °C for 2 h then cooled to rt. The organic layer was separated and then concentrated under reduced pressure. The residue was treated with water (1 mL) and cone. HC1 (3.67 mL, 44.0 mmol). The reaction was heated to 100 °C for 2 h. Afterward, the reaction mixture was diluted with EtOAc (100 mL ) and washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude 2-(3-(2,2,2-trifluoroethyl) phenyl) acetic acid (500 mg ) as a brown solid.

[0725] Step-3: To a solution of 2-(3-(2,2,2-trifluoroethyl) phenyl)acetic acid (450 mg, 2.06 mmol) in DMF (15 mL) was added DIPEA (1.08 mL, 6.19 mmol) and HATU (1.17 g, 3.09 mmol) followed by 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline (506 mg, 2.06 mmol). The reaction was stirred for 12 h at it. Afterward, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL x 4) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave l-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l-yl)-2-(3-(2,2,2-trifluoroethyl) phenyl)ethan-l-one (200 mg, 21%) as a light brown solid. ESI (m / z) [C24H27BF3NO?+H]+446.

[0726] Step-4: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (100 mg, 0.440 mmol) and l-(5-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)indolin- l-yl)-2-(3-(2,2.2-trifluoroethyl)phenyl)ethan-l-one (196 mg, 0.440 mmol) in a mixture of 1,4-dioxane (3 mL): water (0.3 mL) was added potassium carbonate (122 mg, 0.881 mmol) followed by XphosPdG2 (34 mg, 0.044 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was diluted with EtOAc (50 mL), washed with w ater (20 mL) and then brine (20 mL). The organic layer was dried over anhydrous Na2SO4and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 100% EtOAc / hexanes) followed by reverse phase chromatography (Cl 8, 10% acetonitrile / water to 50% acetonitrile / water) gave l-(5-(8-amino-3-methylimidazo[l,5- a]pyrazin-l-yl)indolin-l-yl)-2-(3-(2.2.2-trifluoroethyl)phenyl)ethan-l-one (60 mg, 29%) as an off-white solid after lyophilization. ESI (m / z) [C25H22F3N5O+H]1466.

[0727] Example 62: Preparation of 5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-chloro-

[0728] 7V-(2-fluoro-5-(trifluoromethyl)phenyl)indoline- 1-carboxamide (Compound 62)

[0729] Step-1: To a to -78 °C solution of 8-chloro-3-methylimidazo[ L5-a]pyrazine (1.00 g.

[0730] 5.97 mmol) in THF (30 mL) was slowdy added zi-butyllithium (2.5 M in THF) (3.10 mL, 7.76 mmol). After 30 minutes, a solution of hexachloroethane (2.119 g, 8.95 mmol) in THF (10 mL) was added slowly. After 30 minutes at -78 °C, the reaction was allowed to slowly warm to rt over a period of 2 h. The reaction mixture was treated with saturated NH4CI solution (25 mL) and then extracted with CH2Cl2(50 mL). The organic layer was washed with water (20 mL) followed by brine (30 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2C12to 10% MeOH / CH2C12) gave 5,8-dichloro-3-methylimidazo[l,5-u]pyrazine (0.75 g, 62%). ESI (m z) [C7H5CI2N3 + H]+202.

[0731] Step-2: To a solution of 5,8-dichloro-3-methylimidazo[l,5-a]pyrazine (0.750 g, 3.71 mmol) in DMF (15 mL) was added / V-bromosuccinimide (0.661 g, 3.71 mmol). The reaction was stirred at RT for 2 h. Afterward, the reaction mixture was poured into water. The resulting solid was collected by filtration and washed with water (10 mL). Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CFLCh) gave l-bromo-5,8-dichloro- 3-methylimidazo[l,5-a] pyrazine (0.550 g, 52%). ESI (zn / z) [C7H4BrChN3+ H]+281.

[0732] Step-3: To a solution of l-bromo-5,8-dichloro-3-methylimidazo[l,5-a]pyrazine (0.550 g, 1.95 mmol) in 1,4-dioxane (10 mL), was added (2,4- dimethoxyphenyl)methanamine (0.818 g, 4.89 mmol). After 48 h, the reaction mixture was diluted with methylene chloride (50 mL), washed with water (2 x 10 mL) and then brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel. hexanes to 70% EtOAc / hexanes) gave l-bromo-5-chloro-A-(2,4-dimethoxybenzyl)-3-methylimidazo[l,5- a]pyrazin-8-amine (0.75g, 93%). ESI (m / z ) [C16HieBrClN4O2+H]+413.

[0733] Step-4: A solution of l-bromo-5-chloro-A-(2,4-dimethoxybenzyl)-3-methyl imidazo[l,5-a]pyrazin-8-amine (0.750 g, 1.82 mmol) in TFA (25 mL) was heated to 80 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting solid was treated with CH2Cl2and neutralized with sat. Nal ICOs solution. The mixture was further extracted with CH2Cl2(20 mL). The combined organics were washed with water (10 mL x 2) and then brine (25 mL x 2), dried over Na2SO4and the volatiles removed under reduced pressure. Purification by flash column chromatography (silica gel, 2% methanol / methylene chloride) gave l-bromo-5-chloro-3- methylimidazo[l,5-a]pyrazin-8-amine (0.45 g, 94%). ESI (m / z) [C?H6BrClN4 + H]+261.

[0734] Step-5: To an argon sparged solution of l-bromo-5-chloro-3-methylimidazo[1.5- a]pyrazin-8-amine (0.150 g. 0.574 mmol) in a mixture of 1.4-dioxane (30 mL):water (3 mL) was added A-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)indoline-l -carboxamide (0.310 g, 0.688 mmol) and potassium carbonate (0.159 g, 1.14 mmol) followed by XPhosPdG2 (0.045 g, 0.057 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was filtered through a celite pad using methylene chloride. The filtrate was washed with water (4 x 10 mL) and then brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CH2Cl2) followed by preparative HPLC (Cl 8, acetonitrile / water with 0.05% TFA) gave a residue. The residue was treated with CH2Cl2(50 mL) and the solution washed with saturated NaHCOs (20 rnL) and then with water (10 mL). The organic layer was dried over Na2SO4, concentrated to afford 5-(8-amino- 5-chloro-3-methylimidazo[l,5-a]pyrazin-l-yl)-JV-(2-fluoro-5- (trifluoromethyl)phenyl)indoline-l -carboxamide (10 mg, 3%) after lyophilization from acetonitrile / water. ESI (m / z) [C23H17CIF4N6O + H]+505.

[0735] Example 63: Preparation of 7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-A-(2- (trifhioromethyl)pyridin-4-yl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 63)

[0736] Step-1: To an ice-cold solution of 7-bromoimidazo[L2-a]pyridine-3-carboxylic acid (1.00 g, 4.15 mmol) in CELCL QO rnL), pyridine (20 mL) and 2-(trifluoromethyl)pyridin-4- amine (0.673 g, 4.15 mmol) was added POCl3(0.773 mL, 8.30 mmol). The reaction stirred was allowed to warm to rt. Upon completion, the reaction mixture was treated with satd NaHCOs (40 mL) and CH2Cl2(100 mL). The organic layer was washed with water (50 mL) followed by brine (30 mL), dried over NasSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 7-bromo-A-(2-(trifluoromethyl) pyridin-4-yl)imidazo[l,2-a]pyridine-3-carboxamide (0.68 g, 42%). ESI (m / z) [C14HsBrF3N4O+H]+386.

[0737] Step-2: To an argon sparged solution of 7-bromo- / V-(2-(trifluoromethyl)pyridin-4- yl)imidazo[l,2-a]pyridine-3-carboxamide (0.680 g, 1.76 mmol) in 1,4-dioxane (30 mL) was added bis(pinacolato)diboron (0.538 g, 2.11 mmol) and potassium acetate (0.347 g, 3.53 mmol) followed by PdC12(dppl (0.129 g, 0.177 mmol). The reaction was heated to 100 °C for 12 h. Afterward, the reaction mixture was diluted with methylene chloride (100 mL). The resulting solution was washed with water (4 x 10 mL) and then brine (10 rnL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-A-(2-(trifluoromethyl)pyridin-4- yl)imidazo[l,2-a]pyridine-3-carboxamide (0.75 g). ESI (m / z [C2oH2oBF3N403+H]+433.

[0738] Step-3: To an argon sparged solution of l-bromo-3-isopropylimidazo[l,5-«]pyrazin- 8-amine (0.250 g, 0.980 mmol) in 1,4-dioxane (30 mL):water (3 mL) was added 7 -(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-JV-(2-(trifluoromethyl)pyridin-4-yl)imidazo[I,2- n]pyridine-3 -carboxamide (0.635 g, 1.47 mmol) and potassium carbonate (0.271 g. 1.96 mmol) followed by XPhosPdG2 (0.098 mmol). The reaction was heated to 100 °C for 15 h. Afterward, the reaction mixture was filtered through a celite pad using CH2C12(80 mL). The filtrate was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, CFLChto 10% MeOH / CFLCh) followed by preparative HPLC (Cl 8. acetonitrile / water with 10 mM ammonium bicarbonate) gave a solid which washed with water (10 mL) to give 7-(8- amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-(trifluoro methyl)pyridin-4- yl)imidazo[l,2-a]pyridine-3-carboxamide (0.07 g. 14%) after lyophilization from acetonitrile / water. ESI (m / z) [C23H19F3N8O+ H]+481.

[0739] Example 64: Preparation of 7-(8-amino-5-fluoro-3-methylimidazo[l,5-«]pyrazin-l-yl)-

[0740] A (2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0741] (Comp

[0742] Step-1: To a solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8-amine (500 mg, 2.20 mmol) in MeOH (5 mL) and acetonitrile (5 mL) was added Selectfluor (936 mg, 2.64 mmol). After 12 h. the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% CH3OH / CH2Cl2) gave 1- bromo-5-fluoro-6-methoxy-3-methyl-5,6-dihydroimidazo[l,5-a]pyrazin-8-amine (400 mg, 65%) as a brown solid. ESI (m / z ) [CsHioBrFJSUO+IT]4278.

[0743] Step-2: To a solution of l-bromo-5-fluoro-6-methoxy-3-methyl-5,6- dihydroimidazo[1.5-n]pyrazin-8-amine (500 mg, 1.80 mmol) in 1,4-dioxane (15 mL) was added potassium carbonate (499 mg, 3.61 mmol). The reaction was heated to 150 °C for 30 min by microwave. Afterward, the reaction mixture was diluted with EtOAc (50 mL) and then washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4and then concentrated under reduced pressure to afford crude l-bromo-5-fluoro-3- methylimidazo[l,5-a]pyrazin-8-amine (150 mg) as a brown solid. ESI ( / « z) [C7HeBrFN4+H]+246.

[0744] Step-3: To an argon sparged solution of l-bromo-5-fluoro-3-methyhmidazo[1.5- r7]pyrazin-8-amine (150 mg, 0.612 mmol) and X-(2-fluoro-5-(trifluoromethyl)phenyl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (412 mg, 0.918 mmol) in a mixture of 1,4-dioxane (10 mL):water (1 mL) was added potassium carbonate (169 mg, 1.22 mmol) followed by XPhosPdG2 (48 mg, 0.061 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was diluted with 10% MeOH / CELCL (100 mL). The organic mixture was washed with brine (50 mL), dried over anhydrous NazSCL. filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CHzCL) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 mM ammonium bicarbonate) gave a solid. The solid was rinsed with water (5 mL), dried and subsequently lyophilized from acetonitrile / water to afford 7-(8-amino-5-fluoro-3-methylimidazo[ l,5-u]pyrazin-l -yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (12 mg. 4%). ESI (m / z ) [C22H14F5N7O+H] ' 488.

[0745] Example 65: Preparation of 6-(4-amino-l-methyl-1H -pyrazolo[3,4-r / |pyrimidin-3-yl)- / V- (2-fluoro-5-(trifluoromethyl)phenyl)benzo[Z>]thiophene-3-carboxamide (Compound 65)

[0746] Step-1: To a solution of ethyl 6-bromobenzo[b]thiophene-3-carboxylate (1.50 g, 5.26 mmol) in a mixture of THF (30 mL):water (10 mL) was added LiOHFhO (0.292 mL, 10.5 mmol). After 12 h, the mixture was concentrated under reduced pressure. The residue was treated with water (15 mL) and then with 6 N hydrochloric acid to pH~2-3. The resulting solid w as collected by filtration, w ashed with water (20 mL) and dried under vacuum to afford 6-bromobenzo[Z>]thiophene-3-carboxylic acid (1.10 g, 82 %) as an off-white solid. ESI (m / z) [C9H5BrO2S +H]+257.

[0747] Step-2: To an ice-cold solution of 6-bromo-A-(2-fluoro-5-(trifluoromethyl)phenyl) benzo[b]thiophene-3-carboxamide (1.25 g, 2.99 mmol) and 2-fluoro-5- (trifluoromethyl)aniline (0.766 g, 4.28 mmol) in CH2Cl2(20 mL) was added pyridine (3.15 mL, 38.9 mmol) followed by POCl3(0.544 mL, 5.83 mmol). The resulting reaction mixture was allowed to warm to rt. After 1 h, the reaction was treated with a solution of saturated NaHCCh (20 mL). The mixture was extracted with CH2Cl2(2 x 150 mL). The combined organics were washed with water (50 mL) and then brine (30 mL), dried over NaiSOi and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 50% EtOAc / hexanes) gave 6-bromo-A-(2-fluoro-5- (trifluoromethyl)phenyl)benzo[i>]thiophene-3-carboxamide (1.25 g, 2.99 mmol, 77%) as an off-white solid. ESI (m / z) [C16H8BrF4NOS+H]+418.

[0748] Step-3: To an argon sparged solution of 6-bromo- / V-(2-fluoro-5- (trifluoromethyl)phenyl)benzo[Z>]thiophene-3-carboxamide (0.90 g. 2.15 mmol) and bis(pinacolato)diboron (0.820 g. 3.23 mmol) in L4-dioxane (50 mL) was added potassium acetate (0.528 g, 5.38 mmol) and PdC12(dppl (0.157 g, 0.215 mmol). The resulting reaction mixture was heated to 100 °C for 16 h. After cooling to rt, reaction mixture was filtered through a celite pad using EtOAc (100 mL) and the filtrate concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexanes to 20% EtOAc / hexanes) gave A-(2-fluoro-5-(trifluoromethyl) phenyl)-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)benzo[6]thiophene-3-carboxamide (0.72 g, 61%) as a pale-yellow gum. ESI (m / z) [C22H2OBF4N03S+H]+466.

[0749] Step-4: To an argon sparged solution of 3-bromo-l -methyl- 1H -pyrazolo|3.4- r / |pyrimidin-4-amine (300 mg, 1.31 mmol) and A-(2-fluoro-5-(trifluoromethyl)phenyl)-6- (4,4,5,5-tetra methyl-l,3,2-dioxaborolan-2-yl)benzo[ / ?]thiophene-3-carboxamide (918 mg, 1.97 mmol) in a mixture of 1,4-dioxane (20 mL):water (4 mL) was added cesium carbonate (1.07 g, 3.29 mmol) followed by XPhosPdG2 (104 mg, 0.132 mmol). The reaction was heated to 90 °C for 16 h. Afterward, the reaction mixture was filtered through a celite pad using EtOAc (200 mL) and the resulting filtrate concentrated under reduced pressure. Purification by flash chromatography (silica gel, EtOAc to 5-10% MeOH / EtOAc) gave a residue which was triturated with acetonitrile (5 mL). The resulting solid was collected by filtration and dried under vacuum to afford 6-(4-amino-l-methyl-1H-pyrazolo[3.4- <f|pyrimidin-3-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)benzo[6]thiophene-3-carboxamide (120 mg, 18.5%) as an off-white solid. ESI (m / z) [C22Hi4F4N6OS+H]+487.

[0750] Example 66: Preparation of 7-(4-amino-7-methyl-7H-pyrrolo[2,3-r / |pyrimidin-5-yl)- / V- (2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 66)

[0751] Step-1: To an argon sparged solution of 5-iodo-7-methyl-7H-pyrrolo[2,3- (TJpyrimidin-d-amine (200 mg, 0.730 mmol) and 7V-(2-fluoro-5-(trifluoromethyl)phenyl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3-carboxamide (492 mg, 1.09 mmol) in a mixture of 1,4-di oxane (5 mL): water (1 mL) was added K2CO3 (202 mg, 1.46 mmol) followed by XPhosPdG2 (57 mg, 0.073 mmol). The resulting reaction mixture was heated to 100 °C for 16 h. Afterward, the reaction mixture was cooled, filtered, and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, 10% methanol / methylene chloride) followed by preparative reverse phase HPLC (10 mM ammonium bicarbonate in waterACN) gave 7-(4-amino-7-rnethyl-7H-pyrrolo|2.3- r / ]pyrimidin-5-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)imidaz[1.2-a]pyridine-3- carboxamide (15 mg, 4%) as an off-white solid after lyophilization. ESI (m / z [C22HI5F4N7O+H]+470.

[0752] Example 67: Preparation of 5-(4-amino-7-methyl-H / -pyrrolo[2,3-r / |pyrimidin-5-yl)-A- (2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (Compound 67)

[0753]

[0754] Step-1: To an argon sparged solution of 5-iodo-7-methyl-7H-pyrrolo[2,3- t / |pyrimidin-4-amine (200 mg, 0.730 mmol) and JV-(2-fluoro-5-(trifluoromethyl)phenyl)-5- (4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)indoline-l-carboxamide (394 mg. 0.876 mmol) in a mixture of 1,4-di oxane (4.5 mL) water (0.45 mL) was added potassium phosphate tribasic (309 mg, 1.46 mmol)) followed by XPhosPdG2 (57 mg, 0.073 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was filtered through a celite bed using 10% CH3OH / CH2Cl2(50 mL). The filtrate was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% MeOH / CfhCL) followed by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 10 rnM ammonium bicarbonate) gave a solid. The solid was rinsed with water (5 mL). dried and subsequently lyophilized from acetonitrile / water to afford 5-(4-amiiio-7-methyl-7H-pvrrolo|2.3-6 / |pvrimidin-5-yl)-A,'-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (10 mg, 3%) as an off-white solid. ESI (m / z ) [C23Hi8F4N6O+H]+471.

[0755] Example 68: Preparation of 7-(8-amino-3-methylimidazo[l,5-«]pyrazin-l-yl)-N-(4- fluoro-3-(trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound

[0756] 70)

[0757] Step-1: To an argon sparged solution of ethyl 7-bromoimidazo[l,2-a]pyridine-3- carboxylate (2.00 g, 7.43 mmol) in 1,4-dioxane (6 mL) was added bis(pinacolato)diboron (2.83 g, 11.1 mmol) and potassium acetate (1.45 g, 14.8 mmol) followed by Pd(dppf)C12 (0.544 g, 0.743 mmol). The reaction mixture was heated to 100 °C for 16 h. Afterward, the reaction mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was separated, dried over Na2SO4. and then concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane to 50% EtOAc / hexane) gave ethyl 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine-3- carboxylate (2 g, 85%) as a brown liquid. ESI (mz) IC16H21BN2O4+H I 235 (boronic acid).

[0758] Step-2: To an argon sparged solution of l-bromo-3-methylimidazo[l,5-a]pyrazin-8- amine (0.5 g. 2.202 mmol) and ethyl 7-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l,2-a ]pyridine-3-carboxylate (0.905 g, 2.86 mmol) in 1,4-dioxane (15 mL) water (1.5 mL) was added potassium carbonate (0.609 g, 4.40 mmol) followed by XPhosPdG2 (0.173 g, 0.220 mmol). The reaction mixture was heated to 100 °C for 16 h. Afterw ard, the reaction mixture was diluted with EtOAc (100 mL). washed with water (50 mL) and brine (20 mL ). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane to 50% EtOAc / hexane) gave ethyl 7-(8-amino-3 -methyl imidazo[ 1 ,5-a]pyrazin- l-yl)imidazo[ 1 ,2- a]pyridine-3-carboxylate (300 mg. 40%) as a yellow solid. ESI m / z [CuFIieNsCh+I p 337.

[0759] Step-3: To a solution of ethyl 7-(8-amino-3-methylimidazo[1,5-a ]pyrazin-l- yl)imidazo[l,2-rz]pyridine-3-carboxylate (150 mg, 0.446 mmol) in mixture of TEIF (2 mL): water (1 mL) w as added L1OH.H2O (56.1 mg, 1.33 mmol) and the reaction w as stirred for 12 h at rt. Afterward, the reaction mixture was concentrated, and neutralized with 2M HC1 solution which resulted in a solid. The solid was collected by filtration and dried under reduced pressure to afford 7-(8-amino-3-methylimidazo[l,5-u]pyrazin-l-yl)imidazo[l ,2- a]pyridine-3-carboxylic acid (100 mg, 72%) as a yellow solid. ESI (m / z ) [C15H12N6O2+ITP 309.

[0760] Step-4: To a solution of 7-(8-amino-3-methylimidazo[1,5-a ]pyrazin-l- yl)imidazo[l,2-a] pyridine-3-carboxylic acid (150 mg, 0.487 mmol) in DMF (4.5 mL) was added DIPEA (0.255 mL, 1.46 mmol) and HATU (277 mg, 0.730 mmol) followed by 4- fluoro-3 -(trifluoromethoxy) aniline (190 mg, 0.973 mmol). The reaction was stirred for 16 h at rt. Afterward, water (5 mL) was added to the reaction mixture water. The resulting solid was collected by filtration and dried to give a yellow solid. Purification by preparative reverse phase HPLC (Cl 8, acetonitrile / water with 0.05% TFA) gave 7-(8-amino-3- methylimidazo[l,5-a]pyrazin-l-yl)-A-(4-fluoro-3-(trifluoromethoxy) phenyl)imidazo[l,2- a]pyridine-3 -carboxamide (15 mg, 0.031 mmol, 6%) after lyophilization from acetonitrile / water. ESI (m / z) [C22HISF4N7O2+H]+486. Example 69: Preparation of 5-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-

[0761] Step-1: To a solution of 4-chloro-3-iodo-lH-pyrazolo[4,3-c]pyridine (2.00 g, 7.16 mmol) in DMF (6 mL) was added cesium carbonate (3.50 g, 10.7 mmol) followed by Mel (0.447 mL, 7. 16 mmol). The reaction was stirred for 2 h at rt. Afterward, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane to 30% EtOAc / hexane) gave impure compound. The crude was dissolved in DMF (10 mL) and added water (30 mL) was added. The resulting solid was collected by filtration and dried under vacuum to afford 4- chloro-3-iodo-l-methyl-l / / -pyrazolo[4.3-c]pyridine (1.00 g, 47%) as an off-white solid. ESI (m / z ) [CzHsClINs+H] 294.

[0762] Step-2: To a solution of 4-chloro-3-iodo-l-methyl-1H-pyrazolo[4,3-c]pyridine (900 mg, 3.07 mmol) in «-BuOH (27 mL) was added (2,4-dimethoxyphenyl)methanamine (2.05 g, 12.3 mmol) The reaction was heated to 115 °C for 16 h. Afterward, the reaction mixture was diluted with EtOAc (50 mL), washed with water (20 mL x 2) and brine (20 mL). The organic layer was dried over NazSOi and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane to 50% EtOAc / hexane) gave JV-(2,4-dimethoxybenzyl)-3- iodo-l-methyl-1H -pyrazolo[4.3-c]pyridin-4-amine (900 mg, 69%) as a yellow solid. ESI (m / z) [C16Hi7lN4O2+H]+425.

[0763] Step-3: To an argon sparged solution of A-(2,4-dimethoxybenzyl)-3-iodo-l-methyl- 1H-pyrazolo[4,3-c]pyridin-4-amine (500 mg, 1.18 mmol) and A-(2-fluoro-5-(trifluoromethyl) phenyl)-5-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxamide (690 mg, 1.53 mmol) in 1.4-di oxane (15 mL): water (1.5 mL) was added potassium phosphate tribasic (500 mg, 2.36 mmol) followed by XPhosPdG2 (93 mg, 0.1 18 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reach on mixture was filtered through a celite bed using 10% MeOH / DCM (100 mL). The filtrate was washed with water (20 mL) and brine (20 mL ). The organic layer was dried over NazSO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% CH3OH / CH2Cl2) gave 5-(4- ((2,4-dimethoxybenzyl) amino)-! -methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-A-(2-fluoro-5- (trifluoromethyl)phenyl) indoline- 1 -carboxamide (200 mg, 27%) as a light brown solid. ESI (m / z ) [C32H28F4N6O3+H]+621.

[0764] Step-4: Solid 5-(4-((2,4-dimethoxybenzyl)amino)-l -methyl- 1H-pyrazolo[4,3-c] pyridin-3-yl)-JV-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide (200 mg, 0.322 mmol) was treated with TFA (2 mL. 26.0 mmol). After 2 h at rt, the reaction mixture was concentrated under reduced pressure, Treatment with excess sat NaHCO.- solution (20 mL) resulted in a solid which was collected by filtration. Purification by reverse phase flash chromatography (C18, 10% acetonitrile / water to 50% acetonitrile / water) followed by lyophilization gave -(4-amino-l -methyl - 1H -pyrazolo|4.3- |pyridin-3-yl)- '-(2-fluoro-5- (trifluoromethyl)phenyl)indoline-l -carboxamide (30 mg, 0.064 mmol, 19%) as an off-white solid. ESI (m / z ) [C23HI8F4N6O+H]+471.

[0765] Example 70: Preparation of 7-(4-amino-l-methyl-1H -pyrazolo[4,3-c|pyridin-3-yl)- / V-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 72)

[0766] Step-1: To an argon sparged solution of A-(2,4-dimethoxybenzyl)-3-iodo-l-methyl- 1H -pyrazolo[4,3-c]pyridin-4-amine (350 mg, 0.825 mmol) and A-(2-fluoro-5- (trifluoromethyl) phenyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- a]pyridine-3-carboxamide (556 mg, 1.23 mmol) in 1,4-dioxane (10.5 mL): water (1 mL) was added potassium carbonate (228 mg, 1.65 mmol) followed by XPhosPdG2 (64.8 mg. 0.082 mmol). The reaction was heated to 100 °C for 16 h. Afterward, the reaction mixture was filtered through a celite bed using 10% MeOH / CFLCh (100 mL). The filtrate was washed with water (20 mL ) and brine (20 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2to 10% CH3OH / CH2Cl2) gave 7-(4-((2,4-dimethoxy benzyl)amino)-l -methyl- \H- pyrazolo[4,3-c]pyridin-3-yl)-A-(2-fluoro-5-(trifluoromethyl) phenyl)imidazo[l,2-o]pyridine- 3-carboxamide (200 mg, 39%) as an off-white solid. ESI (m / z) IC31H25F4N7O3+H I 620. Step-2: Solid 7-(4-((2,4-dimethoxybenzyl)amino)-l-methyl-Lff-pyrazolo[4,3-c| pyndin-3-yl)-Af-(2-fluoro-5-(tn fluoromethyl)phenyl)imidazo| 1.2-a] pyridine-3-carboxamide (200 mg, 0.323 mmol) was treated with TFA (3 mL, 38.9 mmol). After 2h at rt, the reaction mixture was concentrated under reduced pressure. The residue was treated with excess sat. NaHCCh solution (10 mL) and stirred for 1 h. The resulting solid was collected by filtration. Purification by reverse phase flash chromatography (C18. 10% acetonitrile / water to 50% acetonitrile / water) followed by lyophilization gave 7-(4-amino-l -methyl- l H-pyrazolo|4.3- c]pyridin-3-yl)-A-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-<7]pyridine-3-carboxamide (13 mg, 8%). ESI (m / z) [C22Hi5F4N7O+H]+470.

[0767] Example 71: Preparation of 7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-A-(3-(te / 7- butyl)-l-methyl-LH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide (Compound 73)

[0768] Step-1: To an ice-cold solution of 7-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (1.5 g, 6.22 mmol) and 3-(tert-butyl)-l -methyl- 1H -pyrazol-5-amine (1.43 g, 9.33 mmol) i...

Claims

1. CLAIMSWhat is claimed is:

1. A compound of formula (I), or a salt, solvate, stereoisomer, tautomer, or isotopologue thereof:A1— L1— L2-A2(J) wherein:A1is selected from the group consisting of:R1is N(RA)(RB);R2a. R2b, and R2c. if present, are each independently selected from the group consisting of H, CN, NO2, ORA, N(RA)(RB), halogen, optionally substituted C1-C6alkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted C2-C8heterocycloalkyl, and optionally substituted C2-C8heteroaryl;R3is selected from the group consisting of H, optionally substituted C1-C6alkyl,optionally substituted C3-C8cycloalkyl, and optionally substituted C2-C8heterocycloalkyl;L1is selected from the group consisting of:- 385 -R4a. R4b, R4C, and R4d, if present, are each independently selected from the group consisting of H, CN. NO2, ORAhalogen, optionally substituted C1-C6alkyl, optionally- substituted C3-C8cycloalkyl, and optionally substituted C2-C8heterocycloalkyl;R5a, R5b, R5C, R5d, and R5e, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6alkyl;R6, if present, is selected from the group consisting of H and optionally substituted C1-C6alkyl;L2is selected from the group consisting of *-C(=O)NR7-, *-C(=O)NR7-(optionally substituted C1-C3alkylenyl)-, and *-C(=O)(optionally substituted C1-C3alkylenyl)-; each occurrence of R7, if present, is independently selected from the group consisting of H and optionally substituted C1-C6alkyl;A2is selected from the group consisting of:R8a, R8b, R8C, R8d, and R8e, if present, are each independently selected from the group consisting of H, CN, NO2, ORA, SF5, halogen, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8heteroaryl;R9, if present, is selected from the group consisting of H, optionally substituted C1-C6alkyd, and optionally substituted C6-C1o aryl; each occurrence of RAand RB, if present, is independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyd, optionally substituted C6-C1o ar d, and optionally substituted C2-C8heteroary l:* indicates a bond between L1and L2; and wherein the compound is not selected from the group consisting of:5-(4-Amino-l-methyl-lH-pyrazolo[3,4-d ]pyrimidin-3-yl)-2,3-dihydro-N-[3- (trifluoromethy l)pheny 1] - 1 H-indole- 1 -carboxamide;5-[4-Amino-7-(l-methylethyl)-7H-pyrrolo[2,3-d ]pyrimidin-5-yl]-2,3-dihydro-N-(l- methylethy 1)- 1 H-indole- 1 -carboxamide;5-[4-Amino-7-(l-methylethyl)-7H-pyrrolo[2,3-d ]pyrimidin-5-yl]-N- (cyclopropylmethyl)-2,3-dihydro-lH-indole-l-carboxamide;5-(4-Amino-7-methyl-7H-pyrrolo[2,3-d ]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-N- phenyl-lH-indole-l-carboxamide;5-[4-Amino-7-(l-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-N-(cyclohexylmethyl)-2,3-dihydro-lH-indole-l-carboxamide; and5-[4-Amino-7-(l-methylethyl)-7H -pyrrolo[2,3-d]pyrimidin-5-yl]-2,3-dihydro-N -[3- (trifluoromethyl)phenyl] - 1H -indole- 1-carboxami de.

2. The compound of claim 1, wherein R1is selected from the group consisting of NH2 and NHMe.

3. The compound of claim 1 or 2, wherein R2a, R2b, R2c, and R2d, if present, are each independently selected from the group consisting of H, F, Cl, Br, CN, CH3, CHF2, (CH2)CHs,4. The compound of any one of claims 1-3, wherein R3is selected from the group consisting of:

5. The compound of any one of claims 1-4, wherein A1is selected from the group consisting of:

6. The compound of any one of claims 1-5, wherein R4a, R4b, R4c, and R4d, if present, are each independently selected from the group consisting of H, CH3, F, Cl, OCH3, and CN.

7. The compound of any one of claims 1-6. wherein R5a, R5b, R5c, R5d, and R5e, if present, are each independently H.

8. The compound of any one of claims 1-7, wherein R6, if present, is H.

9. The compound of any one of claims 1-8, wherein L1is selected from the group consisting of:

10. The compound of any one of claims 1-9. wherein each occurrence of R7, if present, isH.

11. The compound of any one of claims 1-10, wherein L2is selected from the group consisting12. The compound of any one of claims 1-11. wherein each occurrence of R8a, R8b. R8e, and R8d, if present, is independently selected from the group consisting of H, Me, / -Bu. F, Cl,13. The compound of any one of claims 1-12, wherein R9, if present, is selected from the group consisting14. The compound of any one of claims 1-13, wherein A2is selected from the group consisting of:

15. The compound of any one of claims 1-14, wherein each occurrence of optionally substituted alky l, optionally substituted alkylenyl, optionally substituted alkenylenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally7substituted heteroarylenyl, is independently' optionally substituted with at least one substituent selected from the group consisting of C1- C6alkyl, Cs-Cs cycloalkyl. C2-C12 heterocycloalkyl, C1-Cs hydroxyalky7!, halogen, CN, NO2 OR1, NtR'jtR11). C1-C6haloalkoxy, C3-C8halocycloalkoxy. aryl, heteroaryl, (C1-C6alkylenyl)C(=O)N(RI)(Rn), (C1-C6alkylenyl)C(=O)ORI, O(C1-C3alkylenyl)C(=O)ORn, O(C1-C3alky deny l)C(=O)N(RI)(Rn), C(=O)R1 C(=0)0RJ, OC(=O)R1, OC(=O)ORI, SR1, S(-O)R'. S(=O)2RI, S(=0)2N(RI)(R11), S(=O)2NRIC(=0)NHR11, N(RI)S(=0)2R11, N(RI)C(=O)Rn, and C(=0)NRIRn. wherein R1and Rnare each independently selected from the group consisting of H, - C(=O)(C1-C6alkyd), C1-C6alkyd, C1-C6haloalkyd, C1-C6heteroalkyd, C3-C8cycloalkyd, C2- C12 heterocycloalkyl, C7-C12 aralky l, aryl, and heteroaryd.

16. The compound of any one of claims 1-15, which is selected from the group consisting of:5-(4-amino-l-isopropy7l-lH-pyrazolo[3,4-d]pyrimidin-3-y7l)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(tri fl uoromethy I )phenyl )indoline- 1 -carboxamide;5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(trifluoromethy l)benzy l)indoline- 1 -carboxamide;(R)-5-(4-amino-l-(pyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-(trifluoromethy l)phenyl)indoline- 1 -carboxamide;(S)-5-(4-amino-l-(pyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-(trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3- (trifluoromethy l)benzy l)indoline- 1 -carboxamide;5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2- fluoro-5 -(trifluoromethy l)phenyl)indoline-l -carboxamide;(R)-5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3.4-d]pyrimidin-3-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l-carboxamide;(S)-5-(4-amino-l-(l-methylpyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylimidazo[l,2- a]pyridine-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-3-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(8-aminoimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(tri fl uoromethy I )phenyl )indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(2,2,2- trifluoroethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(2,2,2- trifluoroethy l)pheny l)indoline- 1 -carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3- chlorophenyl)imidazoll.2-aJpyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(m-tolyl)imidazo[l,2- a] pyridine-3 -carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- methylphenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3,5- bis(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(4-methyl-lH- imidazol- 1 -y l)-5-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-chloro-2- fluorophenyl)imidazo[ 1 ,2-a]pyridine-3-carboxamide;7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(4-methyl-lH- imidazol-l-yl)-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-bromo-2- fluorophenyl)imidazo[L2-a]pyridine-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;5-(4-amino-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethy l)pyridin-2-yl)indoline- 1 -carboxamide; l-(5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)indolin-l-yl)-2-(3-(trifluoromethy l)phenyl)ethan- 1 -one;6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(trifluoromethyl)phenyl)-lH- indole-3-carboxamide;7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyndine-3-carboxamide;7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(tert-butyl)-l-(p-tolyl)-lH- pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(4-fluoro-3-(trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide;6-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-chloro-N-(2-fluoro-5-(trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;1 -(5-(8-amino-3 -methylimidazo [ 1.5-a] pyrazin- 1 -y l)indolin- 1 -y l)-2-(4-(2.2.2- trifluoroethyl)phenyl)ethan- 1 -one;5-(8-amino-5-fluoro-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5-(tri fl uoromethy I )phenyl )indoline- 1 -carboxamide;7-(8-amino-3-(methoxymethyl)imidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide; l-(5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)indolin-l-yl)-2-(3-(2,2,2- trifluoroethyl)phenyl)ethan- 1 -one;5-(8-amino-5-chloro-3-methylimidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;7-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-N-(2-(trifluoromethyl)pyri din-4- yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-5-fluoro-3-methylimidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(2-fluoro-5- (tn fl uoromethy l)phenyl)imidazo| 1.2-a|pyridine-3-carboxamide;6-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzo[b]thiophene-3-carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyndine-3-carboxamide;5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)isoindoline-2-carboxamide;7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(4-fluoro-3- (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(3-(tert-butyl)-l-methyl-lH- pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-methylimidazo[l ,5-a]pyrazin- l-yl)-N-( 1 -methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-(l-methylpyrrolidin-3-yl)imidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-((methylamino)methyl)imidazo[1.5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(8-amino-3-(l-methylpyrrolidin-3-yl)imidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;6-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-2-methylbenzofuran-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-4-methy lindoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-8-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-((dimethylamino)methyl)imidazo[1.5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-5-chloro-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-aminofuro [2, 3-d] pyrimi din-5 -yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyndine-3-carboxamide;7-(4-aminothieno[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-aminothieno[2,3-d]pyrimidin-5-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l,6-dimethyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-aminofuro[2,3-d]pyrimidin-5-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;7-(8-amino-5-ethyl-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-8-methylimidazo[l,2-a]pyridine-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;7-(4-amino-l,6-dimethyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-7-methylbenzofuran-3-carboxamide;6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-7-methyl-lH-indole-3-carboxamide;8-amino-l-(3-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)imidazo[L2-a]pyridin- 7-yl)-3-methylimidazo[l,5-a]pyrazine-5-carboxamide;5-(4-amino-6-(difluoromethyl)-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4- chloro-N-(2-fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(3-(tert-butyl)-l -methyl- lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-(tert-butyl)-l-methyl-lH- pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-7-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-lH-indole-3-carboxamide:5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;7-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(tert-butyl)-l -methyl- lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (trifluoromethoxy)phenyl)-2,3,3a,7a-tetrahydro-lH-indole-l-carboxamide;6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)-7-methylpyrazolo[l,5-a]pyridine-3-carboxamide;6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-7-chloro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-lH-indole-3-carboxamide:7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;6-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;7-(8-arrrino-5-(azetidin-3-ylidenemethyl)-3-methylimidazo[l,5-a]pyrazin-l-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-methyl-5-((l-methylazetidin-3-ylidene)methyl)imidazo[l,5-a]pyrazin- l-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5-(pentafluoro- X6-sulfaneyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-3-methyl-5-((l-methylazetidin-3-yl)methyl)imidazo[l,5-a]pyrazin-l-yl)- N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(3-(pentafluoro-X6- ulfaneyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(3-amino-lH-indazol-4-yl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[l,2- a] pyridine-3 -carboxamide;7-(3-amino-lH-pyrazolo[3,4-c]pyridin-4-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(8-amino-5-(azetidin-3-ylmethyl)-3-methylimidazo[1.5-a]pyrazin-l-yl)-N-(2- fluoro-5-(trifluoromethyl)phenyl)imidazoll,2-a]pyridine-3-carboxamide;7-(3-amino- 1 -methyl- 1 H-indazol-4-yl)-N-(2-fluoro-5 - (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(3-amino-l-methyl-lH-pyrazolo[3,4-c]pyridin-4-yl)-N-(2-£luoro-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-methyl-5-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-methyl-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(3-amino-l-methyl-lH-indazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)imidazo[l,2- a] pyridine-3 -carboxamide;7-(3-amino-l-methyl-lH-pyrazolo[3,4-c]pyridin-4-yl)-N-(3- (trifluoromethoxy)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-8-chloro-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)in doline- 1 -carboxamide;5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(3- (trifluoromethoxy )phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(tert-butyl)-l- methyl-lH-pyrazol-5-yl)-4-fluoroindoline-l-carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-(tert-butyl)-l -methyl- lH-pyrazol-5-yl)-4-fluoroindoline-l-carboxamide;5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(8-amino-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-cyano-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(8-amino-5-fluoro-3-methylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (pentafluoro-X6-ulfaney l)pheny l)indoline- 1 -carboxamide;5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )phenyl)in doline- 1 -carboxamide;5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )phenyl)indoline- 1 -carboxamide;5-(4-amino-7-fluoro-l -methyl- lH-pyrazolo[4,3-c]pyri din-3-yl)-4-fluoro-N-(2-fluoro- 5-(trifluoromethyl)phenyl)indoline-l -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (penlafl uoro- / -ul faney l)pheny l)indoline- 1 -carboxamide;5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (pentafluoro-X6-ulfaney l)pheny l)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(4- (trifluoromethyl)pyridin-2-y l)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2- (trifluoromethy l)pyridin-4-yl)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(4- (trifluoromethyl)pyridin-2-y l)indoline- 1 -carboxamide;5-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2- (trifluoromethyl)pyridin-4-yl)indoline- 1 -carboxamide;5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )phenyl)indoline- 1 -carboxamide;5-(4-amino-7-isopropyl-7H-pyrrolo[2.3-d]pyrimidin-5-yl)-N-(3- (difluoromethoxy)phenyl)-4-fluoroindoline-l -carboxamide;5-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (pentafl uoro-fi-ul faney l)pheny l)indoline- 1 -carboxamide;5-(4-aminofuro[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-8-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(8-amino-3,5-dimethylimidazo[l,5-a]pyrazin-l-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3- (difluoromethoxy)phenyl)-4-fluoroindoline-l-carboxamide;5-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;7-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-8-cyano-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;6-(4-amino-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;6-(4-aminofuro[2,3-d]pyrimidin-5-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;7-(4-amino-6-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-(difluoromethoxy)- 2-fluorophenyl)-4-fluoroindoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethoxy )pheny l)in doline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(2-fluoro-5- (pentafl uoro-X6-sulfaney l)pheny l)indoline- 1 -carboxamide;5-(4-amino-6-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2- fluoro-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(5- (difluoromethoxy )-2-fluoropheny l)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(4-methyl-3- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-N-(2-fluoro-5- (pentafluoro-r’-s ul faneyl Jphenyl Jindoline- 1 -carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (tri fluoromethoxy )phenyl)benzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (pentafluoro- X6-sulfaneyl)phenyl)benzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(4- (trifluoromethyl)pyridin-2-yl)benzofuran-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-N-(4-methyl-3- (trifluoromethyl)phenyl)indoline- 1 -carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(4-methyl-3- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoro-5- (trifluoromethy l)pheny l)-4-methoxy indoline- 1 -carboxamide;6-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-7-chloro-N-(2-fluoro-5- (pentafluoro-X6-sulfaneyl)phenyl)benzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,4-difluoro-5- (trifluoromethyl)phenyl)-7-fluorobenzofuran-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,4-difluoro-5- (trifluoromethy l)phenyl)-4-fluoroindoline- 1 -carboxamide;6-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-7-fluoro-N-(2-fluoro-5- (pentafluoro-X6-sulfaneyl)phenyl)benzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-(tert-butyl)-2- fluorophenyl)-7-fluorobenzofuran-3-carboxamide;6-(4-amino-l-cyclobutyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(tert-butyl)pyridin- 2-yl)-4-fluoroindoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-(tert-butyl)-2- fluorophenyl)-4-fluoroindoline-l -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-4- methyl-5-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-4- ((l-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(2-fluoro-4- (piperidin-4-ylmethyl)-5-(trifluoromethyl)phenyl)indoline-l -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-6-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;6-(4-amino-l-cyclopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;5-(4-amino-7-isopropylpyrrolo[2,l-f][l,2,4]triazin-5-yl)-4-fluoro-N-(2-fluoro-5-(trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(5-methyl-4- (trifluoromethy l)pyridin-2-y l)indoline- 1 -carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(5-melhyl-4- (trifluoromethyl)pyridin-2-yl)benzofuran-3-carboxamide;6-(4-amino-7-isopropylpyrrolo[2,l-f][l,2,4]triazin-5-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(tert-butyl)pyridin- 2-yl)-7-fluorobenzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(2-fluoro-4- methyl-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide;6-(4-aminofuro[2,3-d]pyrimidin-5-yl)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-7- fluorobenzofuran-3-carboxamide;6-(4-aminofuro [2, 3-d] pyri mi din-5 -yl)-7 -fluoro-N -(2-fluoro-5 - (trifluoromethoxy )phenyl)benzofuran-3-carboxamide;6-(4-aminothieno[2,3-d]pyrimidin-5-yl)-7-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzofuran-3-carboxamide;5-(4-amino-7-isopropylimidazo[5fl-f][l,2?4]triazin-5-yl)-4-fluoro-N-(2-fluoro-5- (trifluoromethy l)phenyl)indoline- 1 -carboxamide;5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-N-(5-fluoro-4- (trifluoromethyl)pyridin-2-y l)indoline- 1 -carboxamide;6-(4-amino-7-isopropylimidazo[5,l-f|[l,2,4]triazin-5-yl)-7-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)benzofuran-3-carboxamide;6-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-7-fluoro-N-(5-fluoro-4- (trifluoromethyl)pyridin-2-yl)benzofuran-3-carboxamide;7-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-6-fluoro-N-(2-fluoro-5- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide; and6-(4-aminofuro[2,3-d]pyrimidin-5-yl)-N-(4-chloro-2-fluoro-5- (trifluoromethyl)phenyl)-7-fluorobenzofuran-3-carboxamide.

17. A pharmaceutical composition comprising at least one compound of any one of claims 1-16 and at least one pharmaceutically acceptable carrier.

18. A method of treating, preventing, and / or ameliorating multiple sclerosis (MS) in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

19. A method of reducing and / or inhibiting the activity of a p38 mitogen-activated protein kinase (MAPK) family protein in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

20. The method of claim 19, wherein the p38 MAPK family protein is p38gamma.

21. The method of claim 20, wherein p38gamma is selectively inhibited.

22. A method of promoting neuronal remyelination in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

23. The method of any one of claims 19-22, wherein multiple sclerosis (MS) in the subject is treated, prevented, and / or ameliorated.

24. A method of treating, preventing, and / or ameliorating a demyelinating disease in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

25. The method of claim 24, wherein the demyelinating disease is selected from the group consisting of multiple sclerosis (MS), adrenoleukodystrophy, adrenomyeloneuropathy, Charcot Marie tooth disease, motor neuron disease, polyneuropathy, intemuclear ophthalmoplegia, and Parkinson’s disease.

26. A method of treating, preventing, and / or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

27. A method of treating, preventing, and / or ameliorating epilepsy in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

28. A method of treating, preventing, and / or ameliorating anti-inflammatory disease in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

29. A method of treating, preventing, and / or ameliorating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject at least one compound of any one of claims 1-16 and / or the pharmaceutical composition of claim 17.

30. The method of claim 29, wherein the neurodegenerative disease is at least one selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Lewy Body disease, and tau-related diseases.

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