Her2 mutation inhibitors

Abstract

The invention relates to compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof to their use in medicine; to compositions containing them; to processes for their preparation: and to intermediates used in such processes. The compounds of Formula (I) may be useful in the treatment of abnormal cell growth, including cancer, in a subject in need thereof.

Description

[0001] HER2 MUTATION INHIBITORS

[0002] Reference to Sequence Listing

[0003] The instant application contains a Sequence Listing which has been submitted electronically in .txt format and is hereby incorporated by reference in its entirety. Said .xml copy, created on February 1 1 , 2025, is named PC073045A~Sequence_.Listing__ST26.xml and is 4 KB in size.

[0004] Background of the Invention

[0005] The present invention relates to novel pyrazolopyrimidine compounds that act as HER2 and HER2 mutation inhibitors. The invention also relates to the preparation of the compounds and intermediates used in the preparation, compositions containing the compounds, and uses of the compounds including treatment of abnormal cell growth, such as cancer, in a subject.

[0006] Human epidermal growth factor receptor 2 (ErbB2, also known as HER2) is a receptor tyrosine kinase that belongs to a family of four kinases (EGFR, ErbB2, ErbB3 and ErbB4). The role of HER2 amplification in oncology is well known, particularly breast, gastric, lung and colon cancers. HER2 amplified breast and lung cancers are also known to metastasize and develop brain metastases. HER2 inhibitors are known, such as tucatinib, lapatinib, neratinib, sapitinib, poziotinib, canertinib, TAK-285 and varlitinib, but not all those HER2 inhibitors are selective. Additionally, there are monoclonal anybodies used for HER2 positive cancers, such as trastuzumab and pertuzumab.

[0007] Activating mutations in the HER2 gene are becoming increasingly reported. One common type of HER2 mutation is an insertion mutation. A frequently occurring insertion mutation is the HER2 YVMA mutation in exon 20. HER2 mutation cancers are also known to metastasize and develop brain metastases. See Subramanian, Janakiraman, et al. "Emergence of ErbB2 Mutation as a Biomarker and an Actionable Target in Solid Cancers.” The Oncologist. 24(12) (2019): pp. e1303-e1314; and Offin, Michael, et al. “Frequency and outcomes of Brain Metastases in Patients with HER2-Mutant Lung Cancers.” Cancer. 125(24) (2019): pp. 4380-4387.

[0008] Accordingly, there remains a need for improved HER2 mutation inhibitors having novel activity profiles, such as selective HER2 mutation inhibitors, which may be useful forthe treatment of HER2 mutation cancers or other proliferative diseases or conditions. Furthermore, brain penetrant HER2 mutation inhibitors may be useful in treating brain metastases from HER2 amplified or HER2 positive cancers, including brain metastases from HER2 mutation amplified or HER2 mutation positive cancers. The compounds, combinations and methods of the present invention are believed to have one or more advantages, such as inhibiting HER2 while avoiding EGFR inhibition, which is important to decreasing target toxicity, improving patient compliance, and improving patient quality of life. Summary of the Invention

[0009] The present invention provides, in part, compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such compounds may inhibit the activity of HER2 and HER2 mutations and may be useful in the treatment of abnormal cell growth, such as cancer. In particular, such compounds show an affinity for inhibiting HER2 and HER2 mutations, which is greater than their affinity for inhibiting EGFR. Some compounds of the present invention inhibit the activity of brain metasteses from HER2 positive or HER2 amplified cancers. Furthermore, the invention provides compounds that can inhibit the activity of brain metasteses from HER2 mutation positive or HER2 mutation amplified cancers. Also provided are pharmaceutical compositions, comprising the compounds or salts of the invention, alone or in combination with additional cancer therapeutic agents. The present invention also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts and compositions of the invention, and methods of using the foregoing. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0010] According to an embodiment (E1) of the invention there is provided a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0011] X1is selected from N and CRa;

[0012] X2is selected from N and CH;

[0013] R1is selected from the group consisting of hydrogen, C1-C3alkyl, and cyclopropyl; each R2is independently selected from methyl and halogen;

[0014] R3is a 9 to 10 membered bicyclic heteroaryl containing one, two, or three heteroatoms selected from N, O and S, wherein the bicyclic heteroaryl may be optionally substituted with one or two groups selected from halogen and C1-C3alkyl, or R3is 1-methyl-2-oxo-1 ,2-dihydropyridin- 4-yl;

[0015] R4is a 5 to 8 membered heterocycloalkyl ring containing one nitrogen heteroatom, wherein the nitrogen heteroatom is substituted with Rb, and wherein R4may also optionally be substituted with one or two groups independently selected from fluorine, methyl and methoxymethyl; Rais selected from hydrogen and fluorine;

[0016] Rbis selected from acryloyl, 1 -propionyl, 2-fluoroacryloyl, but-2-ynoyl, 2-chioropropanoyl, and 4-methoxybut-2-enoyl; and n is 1 or 2.

[0017] Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) is identical to the embodiment of Formula (I) provided above.

[0018] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0019] Detailed Description of the Invention

[0020] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein, it is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0021] E1 A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

[0022] E2 A compound of embodiment E1 or a pharmaceutically acceptable salt thereof, wherein preferably X1is N.

[0023] E3 A compound of any one of embodiments E1 to E2, or a pharmaceutically acceptable salt thereof, wherein X2is N.

[0024] E4 A compound of any one of embodiments E1 to E2, or a pharmaceutically acceptable salt thereof, wherein X2is CH.

[0025] E5 A compound of any one of embodiments E1 to E4, or a pharmaceutically acceptable salt thereof, wherein preferably R1is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl.

[0026] E6 A compound of any one of embodiments E1 to E5, or a pharmaceutically acceptable salt thereof, wherein preferably R1is methyl.

[0027] E7 A compound of any one of embodiments E1 to E6, or a pharmaceutically acceptable salt thereof, wherein preferably each R2is independently selected from the group consisting of methyl, fluoro and chloro.

[0028] E8 A compound of any one of embodiments E1 to E7, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of:

[0029]

[0030] E9 A compound of any one of embodiments E1 to E8, or a pharmaceutically acceptable salt thereof, wherein preferably R3is selected from:

[0031] E10 A compound of any one of embodiments E1 to E9, or a pharmaceutically acceptable salt thereof, wherein preferably R3is:

[0032] E11 A compound of any one of embodiments E1 to E9, or a pharmaceutically acceptable salt thereof, wherein preferably R3is:

[0033] E12 A compound of any one of embodiments E1 to E11 , or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

[0034]

[0035] E13 A compound of any one of embodiments E1 to E12, or a pharmaceutically acceptable salt thereof, wherein preferably R4is selected from the group consisting of:

[0036] E14 A compound of any one of embodiments E1 to E13, or a pharmaceutically acceptable salt thereof, wherein preferably R4is:

[0037] E15 A compound of any one of embodiments E1 to E13, or a pharmaceutically acceptable salt thereof, wherein preferably R4is: E16 A compound of any one of embodiments E1 to E13, or a pharmaceutically acceptable sail thereof, wherein preferably R4is:

[0038] E17 A compound of any one of embodiments E1 to E13, or a pharmaceutically acceptable salt thereof, wherein preferably R4is:

[0039] E18 A compound of any one of embodiments E1 to E11 , or a pharmaceutically acceptable salt thereof, wherein Rbis selected from the group consisting of acryloyl (prop-2-enoyl or H2C=CH-C(=O)-), 1-propionyl (H3CH2CC(=O)-), 2-fluoroacryloyl (H2C=C(F)C(=O)-), but- 2-ynoyl (H3CC=CC(=O)-), 2-chloropropanoyl (H3CCH(CI)C(=O)-),and 4-methoxybut-2- enoyl (H3COH2CHC=CHC(=O)-).

[0040] E19 A compound of any one of embodiments E1 to E11 , or a pharmaceutically acceptable salt thereof, wherein preferably Rbis acryloyl,

[0041] E20 A compound of embodiment E1 , or a pharmaceutically acceptable salt thereof, wherein preferably the compound is selected from the group consisting of:

[0042]

[0043] E21 A compound of embodiment E1 or E2Q, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0044] E22 A compound of embodiment E1 or E20, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is: E23 A compound of embodiment E1 or E20, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0045] E24 A compound of embodiment E1 or E20, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is: E25 A compound of embodiment E1 or E20, or a pharmaceutically acceptabie salt thereof, wherein preferably the compound is:

[0046] E26 A compound of embodiment E1 or E20, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0047] E27 A compound of embodiment E1 or E20, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0048] E28 A compound of embodiment E1 , or a pharmaceutically acceptable salt thereof, wherein preferably the compound is selected from the group consisting of:

[0049] 1 -((1 R,3r,5S)-3-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-

[0050] 4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one;

[0051] 1-(4-(3-(3-chloro-5-fluoro-4-((7-fluoro-1 -methyl-1H-benzo[d]imfdazol-5-yl)oxy)phenyl)-4- methyl-1H-pyraz.olo[3,4-d]pyrimidin-1 -yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1 -one;

[0052] 1 -(1 -methyl-4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one;

[0053] 1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-1 -methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1 - one;

[0054] 1-(4-(3-(3-fluoro-5-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one;

[0055] 1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one; and

[0056] 1 -(4-(5-(3-fluoro-5-methyl-4-((1 -methyl- 1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one. E29 A compound of embodiment E1 or E28, or a pharmaceutically acceptabie salt thereof, wherein preferably the compound is:

[0057] 1 -((1 R,3r,5S)-3-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one.

[0058] E30 A compound of embodiment E1 or E28, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0059] 1-(4-(3-(3-chloro-5-fluoro-4-((7-fluoro-1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1 -one.

[0060] E31 A compound of embodiment E1 or E28, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0061] 1 -(1 -methyl-4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benz.o[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

[0062] E32 A compound of embodiment E1 or E28, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0063] 1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2-azabicycio[2.1.1]hexan-2-yl)prop-2-en-1- one.

[0064] E33 A compound of embodiment E1 or E28, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0065] 1-(4-(3-(3-fluoro-5-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

[0066] E34 A compound of embodiment E1 or E28, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0067] 1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one,

[0068] E35 A compound of embodiment E1 or E28, or a pharmaceutically acceptable salt thereof, wherein preferably the compound is:

[0069] 1 -(4-(5-(3-fluoro-5-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one. Any of the compounds described in embodiment E28, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of embodiments E1 to E35, or pharmaceutically acceptable salts thereof.

[0070] E36 A compound of embodiment E1 , E28 or E29, wherein preferably the compound is:

[0071] 1 -((1 R,3r,5S)-3-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one. E37 A compound of embodiment E1 , E28 or E30, wherein preferably the compound is: 1-(4-(3-(3-chloro-5-fluoro-4-((7-fluoro-1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1 -one.

[0072] E38 A compound of embodiment E1 , E28 or E31 , wherein preferably the compound is:

[0073] 1 -(1 -methyl-4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

[0074] E39 A compound of embodiment E1 , E28 or E32, wherein preferably the compound is:

[0075] 1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1 H-pyrazolo[3,4-d]pyrlmidin-1-yl)-1 -methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1- one.

[0076] E40 A compound of embodiment E1 , E28 or E33, wherein preferably the compound is: 1-(4-(3-(3-fluoro-5-methyl-4-((1 -methyl-1H-benzo[d]lmidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

[0077] E41 A compound of embodiment E1 , E28 or E34, wherein preferably the compound is:

[0078] 1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

[0079] E42 A compound of embodiment E1 , E28 or E35, wherein preferably the compound is:

[0080] 1 -(4-(5-(3-fluoro-5-methyl-4-((1 -methyl-1H-benzo[d]imldazol-5-yl)oxy)phenyl)-4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

[0081] E43 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E42, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0082] E44 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of any one of embodiments E1 to E43, or a pharmaceutically acceptable salt thereof.

[0083] E45 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of any one of embodiments E1 to E43, or a pharmaceutically acceptable salt thereof, as a single agent.

[0084] E46 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of any one of embodiments E1 to E43, or a pharmaceutically acceptable salt thereof, and further comprising administering a therapeutically effective amount of an additional anti-cancer therapeutic agent.

[0085] E47 A compound or composition of any one of embodiments E1 fo E43, for use as a medicament.

[0086] E48 A compound or composition of any one embodiments E1 to E43, for use in the treatment of cancer. E49 Use of a compound or composition of any one of embodiments E1 to E43 for the manufacture of a medicament for the treatment of cancer.

[0087] E50 A method for the treatment of a disorder mediated by HER2 or HER2 mutations in a subject, comprising administering to the subject in need thereof a compound or composition of any one of embodiments E1 to E43, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.

[0088] E51 A pharmaceutical combination comprising a compound or composition of any one of embodiments E1 to E43 or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof.

[0089] E52 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E51 and at least one excipient.

[0090] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiment(s) described herein.

[0091] Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein.

[0092] Definitions

[0093] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0094] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0095] “Compounds of the invention” include compounds of Formula I and the novel intermediates used in the preparation thereof. One of ordinary skill in the art will appreciate that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.gr, enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the invention include solvates, hydrates, Isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed.

[0096] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0097] As used herein, the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0098] If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

[0099] “Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

[0100] The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent Is attached via a double bond, such as an oxo (=O) substituent, the group occupies two available valences, so the total number of other substituents that are Included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different. Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art.

[0101] “Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

[0102] “Hydroxy" refers to an -OH group.

[0103] “Oxo” refers to a double bonded oxygen (=O).

[0104] “Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-C12alkyl”), 1 to 8 carbon atoms (“C1-C8alkyl”), 1 to 6 carbon atoms (“C1-C6alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4alkyl”), 1 to 3 carbon atoms (“C1-C3alkyl”), or 1 to 2 carbon atoms (“C1-C2alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-ootyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number.

[0105] “Heterocycloalkyl” refers to a fully saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups ( / .©., S(O)q, where q is 0, 1 or 2) and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. In the case of R4, the heterocycloalkyl ring is connected to the base molecule via a carbon ring atom, not the nitrogen ring atom. Heterocycloalkyl rings include rings which are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings may contain 1 to 4 heteroatoms selected from N, O, and S(O)qas ring members, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms.

[0106] Heterocycloalkyl rings may be optionally substituted, unsubstituted or substituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto.

[0107] Heterocycloalkyl rings may include, but are not limited to, 3-8 membered heterocyclyl groups, for example 4-7, 4-6 or 5-8 membered heterocycloalkyl groups, in accordance with the definition herein. In a preferred embodiment, the heterocycloalkyl ring is a 5-8 membered group.

[0108] Illustrative examples of heterocycloalkyl rings include, but are not limited to a monovalent radical of:

[0109]

[0110] Illustrative examples of bridged, fused, and spirocyclic heterocycloalkyl groups include, but are not limited to a monovalent radical of:

[0111] "Aryl" or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0112] Similarly, "heteroaryl" or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in a ring in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Bicyclic heteroaryl groups may contain, but are not limited to, 9 to 10 ring atoms (“9-10 membered bicyclic heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0113] Illustrative examples of fused ring heteroaryl groups include, but are not limited to:

[0114]

[0115] A bond drawn into a ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms. A wavy line across a bond indicates the point of attachment.

[0116] The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.

[0117] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceuticaily acceptable excipient.

[0118] “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0119] "Excipient" as used herein describes any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0120] As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaylng agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft, and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifylng agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0121] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifylng agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0122] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease. For example, treating cancer means to administer a compound of Formula (I) to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastases or tumor growth, reversing, alleviating, or inhibiting the progress of, the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, means the act of treating as "treating" is defined immediately above. The term “treating” also includes ad]uvant and neo-ad]uvant treatment of a subject.

[0123] For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroylng) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of a tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaylng the progression of the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and / or prolonging survival of patients the cancer. Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, Weber, Wolfgang A. “Assessing Tumor Response to Therapy.” J. Nucl. Med. 50 Suppl. 1 (2009): 1 S-10S).

[0124] As used herein, the term, “subject, “individual” or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0125] As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. For therapeutic use, a “therapeutically effective amount” refers to that amount of a compound being administered that will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dose of other medications required to treat the disease, and / or (6) enhancing the effect of another medication, and / or (7) delaylng the progression of the disease in a patient.

[0126] As used herein, the term “selective” describes a functionally-defined receptor ligand or enzyme inhibitor means selective for the defined receptor or enzyme subtype as compared with other receptor or enzyme subtypes in the same family. For instance, a selective HER2 inhibitor is a compound which inhibits the HER2 receptor subtype more potently than the EGFR receptor subtype. Such selectivity is, in one embodiment, at least 2 fold (as measured using conventional binding assays), or, in another embodiment, at least 10 fold, or, in a further embodiment, at least 100 fold.

[0127] Salts

[0128] Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid, to provide a salt of the compound of the invention that is suitable for administration to a subject or patient.

[0129] In addition, the compounds of Formula I may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I; 2) purifylng compounds of Formula I; 3) separating enantiomers of compounds of Formula I; or 4) separating diastereomers of compounds of Formula I.

[0130] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1 ,5- naphathalenedisulfonic acid and xinofoate salts.

[0131] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0132] For a review on suitable salts, see Paulekun, G. S. et al. “Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database.” J. Med. Chem. 50(26) 2007, pp. 6665-6672.

[0133] Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures (I) by reacting a compound of the invention with the desired acid;

[0134] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or

[0135] (iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or by means of a suitable ion exchange procedure.

[0136] These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.

[0137] Solvates

[0138] The compounds of the invention, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

[0139] In addition, the compounds of Formula I may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I; 2) purifylng compounds of Formula I; 3) separating enantiomers of compounds of Formula I; or 4) separating diastereomers of compounds of Formula I.

[0140] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0141] When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drylng conditions. In such cases, non-stoichiometry will be the norm.

[0142] Solid form

[0143] The compounds of the invention may exist in a continuum of solid states ranging from amorphous to crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

[0144] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO Na+, -COO K+, or -SO3-N a+) or non-ionic (such as -N- N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970). Stereoisomers

[0145] Compounds of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings.

[0146] The pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl- arginine).

[0147] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0148] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains a basic moiety, an acid such as tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223- 249 and references cited therein).

[0149] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

[0150] Isotopes

[0151] The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0152] Examples of isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as2H (D, deuterium) and3H (T, tritium), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0153] Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies. The radioactive isotopes, such as, tritium and14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with positron emitting isotopes, such as,11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Substitution with deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability.

[0154] In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.

[0155] In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the invention are deuterated.

[0156] Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanylng Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6- DMSO.

[0157] Pharmaceutical Compositions in another embodiment, the invention comprises pharmaceutical compositions. For pharmaceutical composition purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

[0158] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0159] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular), in another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[0160] Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more ad]uvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings. in another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise ad]uvants, such as one or more of wetting, emulsifylng, suspending, flavoring (e.g., sweetening), or perfuming agents.

[0161] In another embodiment, the invention comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents. in another embodiment, the invention comprises a topicai dosage form. "Topical administration” includes, for example, dermal and transdermai administration, such as via transderma! patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermai device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated, see for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sei., vol. 88, pp. 955-958, 1999.

[0162] Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-ad]usted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable ( / .e. , absorbable gel sponges, collagen) and non-biodegradable ( / .e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcelliilose, hydroxyethylcellulose, or methylceliulose, or a heteropolysaccharide polymer, for example, geian gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0163] For intranasal administration, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using eiectrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 , 1 ,1 ,2- tetrafluoroethane or 1 ,1 ,1 ,2,3,3, 3-heptafluoropropane. For Intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. in another embodiment, the invention comprises a rectai dosage form. Such rectai dosage form may be in the form of, for exampie, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0164] Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 201 1 ; and Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

[0165] Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn- protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[0166] For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic ad]ustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Dosing regimens may depend on the route of administration, dose scheduling, and use of flat-dose, body surface area or weight-based dosing. For example, for weight-based dosing, intravenously doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0167] Liposome containing compounds of the invention may be prepared by methods known in the art (See, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yleld liposomes with the desired diameter.

[0168] Compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0169] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0170] The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0171] Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to ad]ust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0172] For example, the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsions comprising soybean oil orthe components thereof (soybean oil, egg phospholipids, glycerol and water).

[0173] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0174] A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the invention may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer ad]acent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co- precipitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the invention and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the invention are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0175] Administration and Dosing

[0176] Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

[0177] The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the invention may be administered orally, rectally, vaginaliy, parenterally, topically, intranasally, or by inhalation.

[0178] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0179] In another embodiment, the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0180] In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginaliy. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.

[0181] The dosage regimen for the compounds of the invention or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg / kg (i.e., mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein. In another embodiment, total daily dose of the compound of the invention is from about 0.1 to about 50 mg / kg, and in another embodiment, from about 0.5 to about 30 mg / kg. It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.

[0182] Therapeutic Methods and Uses

[0183] The compounds of the invention may inhibit the activity of HER2 and HER2 mutations and may be useful in the treatment of cancer or diseases, disorders and conditions mediated by HER2 and HER2 mutations. In particular, these compounds show an affinity for HER2 and HER2 mutations, which is greater than their affinity for EGFR.

[0184] The invention further provides therapeutic methods and uses comprising administering the compounds of Formula (I), or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutic agents or palliative agents.

[0185] In one aspect, the invention provides a method for treating abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0186] In another aspect, the invention provides a method for treating abnormal cell growth comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0187] In another aspect, the invention provides a method fortreating or ameliorating the severity of abnormal cell growth in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a method for treating the severity of abnormal cell growth in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In another further embodiment, the invention provides a method for ameliorating the severity of abnormal cell growth in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0188] In a preferred aspect, the invention provides a method for treating a disorder mediated by HER2 mutations in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder, in particular cancer.

[0189] In a preferred aspect, the invention provides a method for treating a disorder mediated by brain metastases from HER2 amplified or HER2 positive cancer in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder, in particular cancer. In a further preferred aspect, the invention provides a method for treating a disorder mediated by brain metasteses from HER2 mutation amplified or HER2 mutation positive cancer in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder, in particular cancer, in a preferred embodiment, the method for treating is of a disorder mediated by brain metasteses from HER2 amplified cancer, in a preferred embodiment, the method for treating is of a disorder mediated by brain metasteses from HER2 positive cancer. In a preferred embodiment, the method fortreating is of a disorder mediated by brain metasteses from HER2 mutation amplified cancer. In a preferred embodiment, the method for treating is of a disorder mediated by brain metasteses from HER2 mutation positive cancer. in some methods of the present invention, the methods are for treating brain metasteses. These brain metasteses occur when cancer ceiis spread from their original site to the brain, in a preferred embodiment of the present invention, the brain metasteses come from HER2 positive or HER2 ampiified cancer. In another preferred embodiment of the present invention, the brain metasteses come from HER2 mutations positive or HER2 mutations amplified cancer. in another preferred aspect, the invention provides a method for treating a disease or disorder modulated by HER2 mutations, comprising administering to a mammal in need of such treatment an amount of a compound of Formula (i), or a pharmaceutically acceptable salt thereof. In another preferred aspect, the invention provides a method for treating or preventing a disease or disorder modulated by HER2 mutations, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0190] In another preferred aspect, the invention provides a method for treating or preventing a disease or disorder modulated by brain metasteses from HER2 amplified or HER2 positive cancer, comprising administering to a mammal in need of such treatment an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In a further preferred aspect, the invention provides a method for treating or preventing a disease or disorder modulated by brain metasteses from HER2 mutation amplified or HER2 mutation positive cancer, comprising administering to a mammal in need of such treatment an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In another preferred aspect, the invention provides a method for treating or preventing a disease or disorder modulated by brain metasteses from HER2 amplified or HER2 positive cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In a further preferred aspect, the invention provides a method for treating or preventing a disease or disorder modulated by brain metasteses from HER2 mutation amplified or HER2 mutation positive cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the method for treating or preventing is a disease or disorder modulated by HER2 amplified cancer. In a preferred embodiment, the method for treating or preventing is a disease or disorder modulated by HER2 positive cancer. In another preferred embodiment, the method for treating or preventing is a disease or disorder modulated by HER2 mutation amplified cancer. In another preferred embodiment, the method for treating or preventing is a disease or disorder modulated by HER2 mutation positive cancer.

[0191] In another aspect, the Invention provides a method of inhibiting cancer cell proliferation in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation. in another aspect, the invention provides a method of inhibiting cancer celi invasiveness in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell invasiveness.

[0192] In another aspect, the invention provides a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to induce apoptosis. in another aspect, the invention provides a method of inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

[0193] In another aspect, the invention provides a method of inhibiting angiogenesis in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit angiogenesis.

[0194] In one aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treatment, in a further aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal ceil growth. In another aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.

[0195] In another aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a subject in need of such treatment. In another embodiment, the treatment is for abnormal ceil growth.

[0196] In another aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. In a further aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of abnormal cell growth in a subject. in another aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy for the treatment of abnormal cell growth. In another aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy for the treatment of abnormal cell growth in a subject.

[0197] In one aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition for which an inhibitor of HER2 mutations is indicated. In another aspect, the invention provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of a subject with a disease or condition for which an inhibitor of HER2 mutations is indicated. in one preferred aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition for which a brain penetrant inhibitor of HER2 is indicated, in a further preferred aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition for which a brain penetrant inhibitor of HER2 mutations is indicated. In another preferred aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a subject with a disease or condition for which a brain penetrant inhibitor of HER2 is indicated, in a further preferred aspect, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a subject with a disease or condition for which a brain penetrant inhibitor of HER2 mutations is indicated.

[0198] In another aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a subject in need of such treatment. In a further aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, forthe treatment of a subject with abnormal cell growth.

[0199] In yet another aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment. In a further aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a subject. In another aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of abnormal cell growth in a subject.

[0200] In another preferred aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition for which an inhibitor of HER2 mutations is indicated. In another preferred aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition in a subject for which an inhibitor of HER2 mutations is indicated.

[0201] In another preferred aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition for which a brain penetrant inhibitor of HER2 is indicated. In a further preferred aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition for which a brain penetrant inhibitor of HER2 mutations is indicated. In another preferred aspect, the invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition in a subject for which a brain penetrant inhibitor of HER2 is indicated. In a further preferred aspect the invention provides the use of a compound of Formula (i), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition in a subject for which a brain penetrant inhibitor of HER2 mutations is indicated.

[0202] “Abnormal cell growth”, as used herein, unless otherwise indicated, means cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous) or malignant (cancerous).

[0203] Abnormal cell growth includes the abnormal growth of: (1) tumor cells (tumors) that show increased expression of HER2 mutation; (2) tumors that proliferate by aberrant HER2 mutation activation; (3) tumors characterized by amplification or overexpression of HER2 mutation; and (4) tumors that are resistant to HER2 therapy or HER2 inhibition.

[0204] In frequent preferred embodiments of the methods provided herein, the abnormal cell growth is cancer. “Cancer”, as used herein, means the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth. Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, orthe lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemia, lymphoma and myeloma. Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one.

[0205] In another embodiment, the methods provided result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.

[0206] “Ameliorating”, as used herein, means a lessening or improvement of one or more symptoms upon treatment with a compound described herein, as compared to not administering the compound. Ameliorating also includes shortening or reduction in duration of a symptom.

[0207] “Tumor” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors.

[0208] “Tumor burden” or “tumor load”, as used herein, means the total amount of tumorous material distributed throughout the body. Tumor burden refers to the total number of cancer cells orthe total size of tumor(s), throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g., using calipers, orwhile in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MR!) scans.

[0209] “Tumor size”, as used herein, means the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CR or MR! scans.

[0210] In another embodiment, the treatment achieved by a compound of Formula (I) or (II) is defined by reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression free survival (PFS), disease free survival (DFS) and overall survival (OS). PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancerdoes not grow and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced stable disease (SD). DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated subjects or patients. In another embodiment, response to a combination of the invention is any of PR, CR, PFS, DFS, OR or OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.

[0211] The treatment regimen for a compound of Formula (I) that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the invention may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi2-test the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat- testy and the Wilcon on-test.

[0212] The terms “treatment regimen”, “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each compound of Formula (I), alone or in combination with another therapeutic agent.

[0213] In a preferred embodiment of the compounds, compositions, methods and uses described herein, the compounds of Formula (I) are selective for inhibiting HER2 mutations over EGFR inhibition. In a preferred embodiment, the compounds of the invention are selective for HER2- YVMA (SEQ ID NO: 2) over EGFR.

[0214] In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. In another embodiment, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, coIorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer or thyroid cancer. In further embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or stomach cancer.

[0215] In a preferred embodiment, the cancer is selected from breast cancer, lung cancer, colon cancer, ovarian cancer, and gastric cancer. In a preferred embodiment, the cancer is selected from breast cancer, lung cancer, and colon cancer. In a preferred embodiment, the cancer is breast cancer. In a preferred embodiment, the cancer is lung cancer. In a preferred embodiment, the cancer is colon cancer. In a preferred embodiment, the cancer is ovarian cancer. In a preferred embodiment, the cancer is gastric cancer.

[0216] In another embodiment, the cancer is breast cancer, including, e.g., ER-positive / HR- positive, HER2- negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In a preferred embodiment, the breast cancer is endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to HER2 inhibition. In another embodiment, the breast cancer is advanced or metastatic breast cancer. In a preferred embodiment of each of the foregoing, the breast cancer is characterized by amplification or overexpression of HER2 mutations or HER2-YVMA (SEQ ID NO: 2).

[0217] In another embodiment of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including SCLC or NSCLC), esophageal cancer, liver cancer, pancreatic cancer, or stomach cancer.

[0218] In a preferred embodiment, the cancer is HER2 positive. In another preferred embodiment, the cancer is HER2 mutations positive.

[0219] In a preferred embodiment, the cancer is HER2 amplified. In another preferred embodiment, the cancer is HER2 mutations amplified.

[0220] In a preferred embodiment of the methods provided herein, the abnormal cell growth is cancer characterized by amplification or overexpression of HER2 mutations. In another preferred embodiment of the methods provided herein, the subject is identified as having a cancer characterized by amplification or overexpression of HER2 mutations.

[0221] In a preferred embodiment of the methods provided herein, the abnormal cell growth is cancer characterized by metastasis in the brain. In another preferred embodiment of the methods provided herein, the subject is identified as having a cancer characterized by metastasis in the brain.

[0222] In a preferred embodiment of the methods provided herein, the abnormal cell growth is cancer characterized by metastasis in the brain having amplification or overexpression of HER2 mutations, in another preferred embodiment of the methods provided herein, the subject is identified as having a cancer characterized by metastasis in the brain having amplification or overexpression of HER2 mutations.

[0223] In another embodiment, the cancer is selected from the group consisting of breast cancer, lung cancer, colon cancer, ovarian cancer, and gastric cancer. In a preferred such embodiment, the cancer is breast cancer, lung cancer, colon cancer, ovarian cancer or gastric cancer characterized by amplification or overexpression of HER2 mutations. In another preferred embodiment, the cancer is (a) breast cancer or ovarian cancer; (b) characterized by amplification or overexpression of HER2 mutations; or (c) both (a) and (b).

[0224] In a preferred embodiment, the cancer is metastasis in the brain caused by other cancers characterized by amplification or overexpression of HER2, In a further preferred embodiment, the cancer is metastasis in the brain caused by other cancers characterized by amplification or overexpression of HER2 mutations.

[0225] In a preferred embodiment, the cancer is metastasis in the brain characterized by amplification or overexpression of HER2 caused by other cancers characterized by amplification or overexpression of HER2. In a further preferred embodiment, the cancer is metastasis in the brain characterized by amplification or overexpression of HER2 mutations caused by other cancers characterized by amplification or overexpression of HER2 mutations.

[0226] In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as first line therapy. In another embodiment, the compound of Formula (I) is administered as second (or later) line therapy. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with trastuzumab. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with trastuzumab, pertuzumab and either paclitaxel or docetaxel. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with monoclonal antibodies (such as trastuzumab, pertuzumab or margetuximab), antibody-drug conjugates (such as ado-trastuzumab emtansine (“t- dm1”), sacituzumab or govitecan-hziy), HER2 inhibitors (such as neratinib, lapatinib or tucatinib), CDK 4 / 6 inhibitors (such as palbociclib, ribociclib or abemaciclib), mTOR inhibitors (such as everolimus), PI3K inhibitors (such as alpelisib) or PARE inhibitors (such as olaparib ortalazoparib). In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with monoclonal antibodies, such as trastuzumab, pertuzumab or margetuximab. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with antibody-drug conjugates, such as t-dm1 , sacituzumab or govitecan-hziy. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with HER2 inhibitors, such as neratinib, lapatinib or tucatinib. in another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with CDK 4 / 6 inhibitors, such as palbociclib, ribociclib or abemaciclib. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with mTOR inhibitors, such as everolimus. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with PI3K inhibitors, such as alpelisib. In another embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with PARP inhibitors, such as olaparib or talazoparib.

[0227] Co-administration

[0228] The compounds of the invention may be used alone, or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the compound of the invention, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein.

[0229] The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

[0230] A compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-flxed combination" means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

[0231] These agents and compounds of the invention may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

[0232] Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered as single agents or may be administered in combination with other anti-cancer therapeutic agents, in particular standard of care agents appropriate for the particular cancer. In another embodiment, the methods and uses comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, co-administered with at least one other anti-cancer therapeutic agent. In a further embodiment, the methods and uses comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, co-administered with at least one other anti-cancer therapeutic agent to treat or ameliorate abnormal cell growth. In another further embodiment, the methods and uses comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, co-administered with at least one other anti-cancer therapeutic agent to treat abnormal cell growth.

[0233] “Combination therapy” or “co-administration”, as used herein, means the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with at least one additional pharmaceutical or therapeutic agent (e.g., an anti-cancer agent), wherein said compound of Formula (I) and said additional pharmaceutical or therapeutic agent are part of the same or separate dosage forms and are administered via the same or different routes of administration and on the same or different schedules.

[0234] As noted above, the compounds of the invention may be used in combination with one or more additional anti-cancer agents. The efficacy of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in certain tumors may be enhanced by combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents, such as PD-1 antagonists and the like.

[0235] In one aspect, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent (e.g., an anti-cancer therapeutic agent), which amounts are together effective In treating said abnormal cell growth.

[0236] When a combination therapy is used, the one or more additional anti-cancer agents may be administered sequentially or simultaneously with the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, the additional anti-cancer agent is administered to a mammal (e.g., a human) prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, the additional anti-cancer agent is administered to the mammal after administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, the additional anti-cancer agent is administered to the mammal (e.g., a human) simultaneously with the administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0237] The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of Formula (I), including hydrates, solvates and polymorphs or pharmaceutically acceptable salts thereof, in combination with one or more (preferably one, two, or three) additional anti-cancer therapeutic agents.

[0238] “Additional anti-cancer therapeutic agent”, as used herein, means any one or more therapeutic agent, other than a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is or can be used in the treatment of cancer. In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like. In another embodiment, the additional anti-cancer therapeutic agent is a standard of care agent. In another embodiment, the additional anti-cancer therapeutic agent is discussed below in this Combination Therapy section, such as monoclonal antibodies, antibody- drug conjugates, HER2 inhibitors, CDK 4 / 6 inhibitors, mTOR inhibitors, PI3K inhibitors, PARP inhibitors, chemotherapy, anti-PD-1 monoclonal antibody, aromatase inhibitors, endocrine therapy, chemotherapeutic agents, and anti-HER2 agents.

[0239] In a preferred embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with an additional anti-cancer therapeutic agent, wherein the additional anti-cancer agent is trastuzumab deruxtecan (Enhertu®).

[0240] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with monoclonal antibodies (such as trastuzumab, pertuzumab or margetuximab), antibody-drug conjugates (such as t-dm1 , sacituzumab or govitecan-hziy), HER2 inhibitors (such as neratinib, lapatinib ortucatinib), CDK 4 / 6 inhibitors (such as palbociclib, ribociclib or abemaclclib), mTOR inhibitors (such as everollmus), PI3K inhibitors (such as alpellsib), PARP inhibitors (such as olaparib or talazoparib), and pharmaceutically acceptable salts thereof, or combinations thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with monoclonal antibodies (such as trastuzumab, pertuzumab or margetuximab), antibody-drug conjugates (such as t-dm1 , sacituzumab or govitecan-hziy), HER2 inhibitors (such as neratinib, lapatinib ortucatinib), CDK 4 / 6 inhibitors (such as palbociclib, ribociclib or abemaclclib), mTOR inhibitors (such as everollmus), PI3K inhibitors (such as alpelisib) or PARP inhibitors (such as olaparib or talazoparib), and pharmaceutically acceptable salts thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with monoclonal antibodies (such as trastuzumab, pertuzumab or margetuximab), antibody-drug conjugates (such as t-dml , sacituzumab or govitecan-hziy), HER2 inhibitors (such as neratinib, lapatinib or tucatinib), CDK 4 / 6 inhibitors (such as palbociclib, ribociclib or abemaciclib), mTOR inhibitors (such as everolimus), PI3K inhibitors (such as alpelisib), PARP inhibitors (such as olaparib or taiazoparib), and pharmaceutically acceptable salts thereof, or combinations thereof.

[0241] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered in combination with a standard of care agent.

[0242] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab. In another embodiment, a compound of Formula (I) may be administered with trastuzumab, doxorubicin, cyclophosphamide and either paclitaxel or docetaxel. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab, docetaxel and carboplatin. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab and paclitaxel. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab, cisplatin and either capecitabine or 5-fluorouracil.

[0243] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with pertuzumab. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with pertuzumab and trastuzumab. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with pertuzumab, trastuzumab and docetaxel. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with pertuzumab, trastuzumab and chemotherapy.

[0244] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with margetuximab. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with margetuximab and chemotherapy. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with margetuximab and an anti- PD-1 monoclonal antibody. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with margetuximab and an anti- PD-1 monoclonal antibody selected from the group consisting of cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab and atezolizumab.

[0245] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with t-dm1 . in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with sacltuzumab govitecan-hziy. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with neratinib, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (i), or a pharmaceutically acceptable salt thereof, may be administered with neratinib and capecitabine, or a pharmaceutically acceptable salt thereof. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with iapatinib, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with iapatinib and capecitabine, or a pharmaceutically acceptable salt thereof, in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with Iapatinib and letrozole, or a pharmaceutically acceptable salt thereof.

[0246] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with tucatinib, or a pharmaceutically acceptable salt thereof, in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with tucatinib, trastuzumab and capecitabine, or a pharmaceutically acceptable salt thereof. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with palbociclib, or a pharmaceutically acceptable sail thereof, in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with palbociclib and fuivestrant, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with palbociclib and an aromatase inhibitor, or a pharmaceutically acceptable salt thereof. In a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with palbociclib and an aromatase inhibitor selected from the group consisting of aminoglutethimide, testolactone, anastrozoie, letrozole, exemestane, vorozole, formetsane, fadrozole, 1 ,4,6-androstatrien-3, 17-dione (“ATD”) and 4-androstene- 3,6, 17-trione (“6-OXO”), or a pharmaceutically acceptable salt thereof. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with ribociciib, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with ribociciib and fuivestrant, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with ribociciib and an aromatase inhibitor, or a pharmaceutically acceptable salt thereof, in a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with ribociclib and an aromatase inhibitor selected from the group consisting of aminoglutethimide, testolactone, anastrozole, ietrozole, exemestane, vorozole, formetsane, fadrozole, ATD and 6-OXO, or a pharmaceutically acceptable salt thereof.

[0247] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with abemaciclib, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with abemaciclib and fulvestrant, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with abemaciclib and an aromatase inhibitor, or a pharmaceutically acceptable salt thereof. In a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with abemaciclib and an aromatase inhibitor selected from the group consisting of aminoglutethimide, testolactone, anastrozole, Ietrozole, exemestane, vorozole, formetsane, fadrozole, ATD and 6-0X0, or a pharmaceutically acceptable salt thereof.

[0248] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with everolimus. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with everolimus and exemestane. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with everolimus and sunitinib or sorafenib, or a pharmaceutically acceptable salt thereof. In a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with everolimus and sunitinib, or a pharmaceutically acceptable salt thereof. In a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with everolimus and sorafenib, or a pharmaceutically acceptable salt thereof.

[0249] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with alpelisib, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with alpelisib and fulvestrant, or a pharmaceutically acceptable salt thereof.

[0250] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with olaparib. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with olaparib and bevacizumab.

[0251] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with talazoparib, or a pharmaceutically acceptable salt thereof.

[0252] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with rucaparib, or a pharmaceutically acceptable salt thereof. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with paclitaxel or docetaxel. In a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with paclitaxel. In a further embodiment, a compound of Formula (I), er a pharmaceutically acceptable salt thereof, may be administered with docetaxel. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with docetaxel and carbopiatin. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with carbopiatin. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with cisplatin and either capecitabine or 5-fluorouracil. in a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with cisplatin and capecitabine. In a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with cisplatin and 5- fluorouracil.

[0253] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with cisplatin.

[0254] In another embodiment, a compound of Formula (I), er a pharmaceutically acceptable salt thereof, may be administered with 5-fluorouracil.

[0255] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with capecitabine.

[0256] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with ietrozole. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab and capecitabine.

[0257] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with chemotherapy. In another embodiment, chemotherapy is selected from the group consisting of cyclophosphamide, methotrexate, 5-fluorouracil, vinorelbine, doxorubicin, paclitaxel, docetaxel, bleomycin, vinblastine, dacarbazine, mustine, vincristine, procarbazine, prednisolone, etoposide, cisplatin, carbopiatin, epirubicin, capecitabine, folinic acid and oxaliplatin, in another embodiment, chemotherapy is selected from the group consisting of cyclophosphamide, methotrexate, 5-fluorouracil, vinorelbine, and doxorubicin. in another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab, pertuzumab, margetuximab, t-dm1 , sacituzumab govitecan-hziy, neratinib, iapatinib, tucatinib, palbociciib, ribociclib, abemaciclib, everolimus, alpelisib, oiaparib, talazoparib, chemotherapy (such as cyclophosphamide, methotrexate, 5- fluorouracil, vinorelbine, doxorubicin, paclitaxel, docetaxel, bleomycin, vinblastine, dacarbazine, mustine, vincristine, procarbazine, prednisolone, etoposide, cisplatin, carboplatin, epirubicin, capecitabine, folinic acid and oxaliplatin), anti-PD-1 monoclonal antibody (such as cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab and atezolizumab), aromatase inhibitor (such as aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formetsane, fadrozole, ATD and 6-OXO), fulvestrant, sunitinib, sorafenib, bevacizumab, and pharmaceutically acceptable salts thereof, or combinations thereof. In a further embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab, pertuzumab, margetuximab, t-dm1 , sacituzumab govitecan-hziy, neratinib, lapatinib, tucatinib, palbociciib, ribociciib, abemaciclib, everolimus, alpelisib, olaparib, taiazoparib, cyclophosphamide, methotrexate, 5-fluorouracil, vinorelbine, doxorubicin, paclitaxel, docetaxel, bleomycin, vinblastine, dacarbazine, mustine, vincristine, procarbazine, prednisolone, etoposide, cisplatin, carboplatin, epirubicin, capecitabine, folinic acid, oxaliplatin, cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab, atezolizumab, aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formetsane, fadrozole, ATD, 6-0X0, fulvestrant, sunitinib, sorafenib, bevacizumab, and pharmaceutically acceptable salts thereof, or combinations thereof. In another embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, may be administered with trastuzumab, pertuzumab, margetuximab, t-dm1 , sacituzumab govitecan-hziy, neratinib, lapatinib, tucatinib, palbociciib, ribociciib, abemaciclib, everolimus, alpelisib, olaparib, taiazoparib, cyclophosphamide, methotrexate, 5-fluorouracil, vinorelbine, doxorubicin, paclitaxel, docetaxel, bleomycin, vinblastine, dacarbazine, mustine, vincristine, procarbazine, prednisolone, etoposide, cisplatin, carboplatin, epirubicin, capecitabine, folinic acid, oxaliplatin, cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab, atezolizumab, aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formetsane, fadrozole, ATD, 6-0X0, fulvestrant, sunitinib, sorafenib and bevacizumab, and pharmaceutically acceptable salts thereof,.

[0258] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with chemotherapy (such as cyclophosphamide, methotrexate, 5- fluorouracil, vinorelbine, doxorubicin, paclitaxel, docetaxel, bleomycin, vinblastine, dacarbazine, mustine, vincristine, procarbazine, prednisolone, etoposide, cisplatin, carboplatin, epirubicin, capecitabine, folinic acid and oxaliplatin), anti-PD-1 monoclonal antibody (such as cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab and atezolizumab), aromatase inhibitor (such as aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formetsane, fadrozole, ATD and 6-0X0), fulvestrant, sunitinib, sorafenib, bevacizumab, and pharmaceutically acceptable salts thereof, or combinations thereof. In a further embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with cyclophosphamide, methotrexate, 5-fluorouracil, vinorelbine, doxorubicin, paclitaxel, docetaxel, bleomycin, vinblastine, dacarbazine, mustine, vincristine, procarbazine, prednisolone, etoposide, cisplatin, carboplatin, epirubicin, capecitabine, folinic acid, oxaliplatin, cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab, atezoiizumab, aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formetsane, fadrozole, ATD, 6-OXO, fulvestrant, sunitinib, sorafenib, bevacizumab, and pharmaceutically acceptable salts thereof, or combinations thereof. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered with cyclophosphamide, methotrexate, 5- fluorouracil, vinorelbine, doxorubicin, paclitaxel, docetaxel, bleomycin, vinblastine, dacarbazine, mustine, vincristine, procarbazine, prednisolone, etoposide, cisplatin, carboplatin, epirubicin, capecitabine, foiinic acid, oxaliplatin, cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab, atezoiizumab, aminoglutethimide, testoiactone, anastrozole, letrozoie, exemestane, vorozoie, formetsane, fadrozole, ATD, 6-0X0, fulvestrant, sunitinib, sorafenib and bevacizumab, and pharmaceutically acceptable salts thereof.

[0259] In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered in combination with endocrine therapy, e.g., agents such as letrozoie, fulvestrant, tamoxifen, exemestane, or anastrozole. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered in combination with a chemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine. In another embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered In combination with an anti-HER2 agent, e.g., trastuzumab and / or pertuzumab.

[0260] In another embodiment, the additional anti-cancer therapeutic agent is an anti- angiogenesis agent, including for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCp inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix- metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (A vastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenesis agents include vatalanib (CGP 79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdata (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi- Aventis), XL 880 (Exellxis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer). Other anti- angiogenesis agents Include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti- angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia ™). Yet further anti-angiogenesis agents include exisulind (Aptosyn™), saisalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Yet further anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Yet further anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), ciiengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MED! 522), and zoledronic acid (Zometa™).

[0261] In another embodiment, the additional anti-cancer therapeutic agent is a signal transduction inhibitor (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include for example kinase inhibitors (e.g. , tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR) inhibitors, ErbB2 inhibitors, pan-ErbB inhibitors, IGF1 R inhibitors, MEK inhibitors, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway, and multi-targeted kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in conjunction with a compound of Formula (I) and pharmaceutical compositions described herein include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), Vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene™ (TP 38). Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), tucatinib (Tukysa™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatolisib (Pfizer), canertinib (Cl 1033), pertuzumab (Omnitarg™), lapatinib (Tykerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP- 724,714 (Pfizer), panitumumab (Vectibix™), selumetinib (AstraZeneca), everolimus (Certican™), zotarolimus (Endeavor™), temsiroiimus (Torisel™), AP 23573 (ARIAD), VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), GI-4000 (Giobeimmune), binimetinib, and encorafenib. Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG 024322 (Pfizer).

[0262] In another embodiment, the additional anti-cancer therapeutic agent is a classical antineopiastic agent. Classical antineopiastic agents include, but are not limited to, hormonal modulators, such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and anti- estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor (such as, e.g., talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classical antineopiastic agents used in combination therapy with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, optionally with one or more other agents include, but are not limited to, glucocorticoids, such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progestins, such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs; such as tamoxifen, raloxifene, lasofoxlfene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, and CHF 4227 (Chiesi)), trilostane, Selective Estrogen-Receptor Downregulators (SERD's; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane, gonadotropin- releasing hormone (GnRH; also commonly referred to as luteinizing hormone-releasing hormone [LHRH]) agonists, such as buserelin (Suprefact), goserelin (Zoladex), Ieuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Niiandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801 , abarelix, goserelin, Ieuprorelin, triptorelin, bicalutamide, antiandrogen agents, such as enzalutamide, abiraterone acetate, bicalutamide (Casodex), and combinations thereof. Other examples of classical antineopiastic agents used in combination with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, include, but are not limited to, suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101 , Onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10- hydroxycamptothecin, Irinotecan HCI (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlor ambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds, such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), satraplatin, streptozocin, and combinations thereof.

[0263] In still another embodiment, the additional anti-cancer therapeutic agent is a dihydrofolate reductase inhibitors, such as methotrexate and NeuTrexin (trimetresate glucuronate), purine antagonists, such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed, pyrimidine antagonists, such as 5- fluorouracil (5-FU), Aiimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine), Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained release and liposomal forms), enocitabine, 5-azacitidine (Vidaza), decitabine, and ethynylcytidine, and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolafrexed (Thymitaq), triapine, trimetrexate, raltitrexed, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc) and combinations thereof.

[0264] Other examples of classical antineoplastic cytotoxic agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol- Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere™), Ortataxel, paclitaxel (including Taxoprexin a DHA / paclitaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Teicyta™), DMXAA (Antisoma), ibandronic acid, L- asparaginase, pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™), bexarotene (Targretin™), tesmilifene, Theratope™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™), Cotara™ (mAb), NBI-3001 (Protox Therapeutics), polyglutamate- paclitaxel (Xyotax™) and combinations thereof. Further examples of classical antineoplastic agents include, but are not limited to, Advexin (ING 201), TNFerade (GeneVec), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin, pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, niacin, amlodipine besylate and atorvastatin calcium, torcetrapib, and combinations thereof.

[0265] In another embodiment, the additional anti-cancer therapeutic agent is an epigenetic modulator, for example an inhibitor or EZH2, SMARCA4, PBRM1 , ARID1A, ARID2, ARID1 B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1 L, HKMTsanti, PRMT1-9, LSD1 , UTX, IDH1 / 2 or BCL6.

[0266] In further embodiments, the additional anti-cancer therapeutic agent is an immunomodulatory agent, such as an inhibitor of CTLA-4, PD-1 or PD-L1 (e.gr, pembrolizumab, nivolumab or avelumab), LAG-3, TIM-3, TIGIT, 4-1 BB, 0X40, GITR, CD40, or a CAR-T-cell therapy.

[0267] Kits

[0268] Another aspect of the invention provides kits comprising the compound of the invention or pharmaceutical compositions comprising the compound of the invention. A kit may include, in addition to the compound of the invention or pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes the compound or a pharmaceutical composition thereof and one or more therapeutic agents, such as those listed above in the Co-administration section.

[0269] In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the invention in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises one or more compounds of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage and a container for the dosage.

[0270] Synthetic Methods

[0271] Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature.

[0272] For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0273] In the preparation of compounds of the invention it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition.

[0274] For example, if a compound contains an amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N- t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fiuorenylmethylenoxycarbonyl (Fmoc) for amines and lower aikyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.

[0275] Abbreviations

[0276] APCI is atmospheric pressure chemical ionization; aq is aqueous;

[0277] Bn is benzyl;

[0278] Boc is ferf-butoxycarbonyl;

[0279] Boc20 is di-terf-butyl dicarbonate; br is broad;

[0280] CDCl3is deutero-chloroform; δ is chemical shift; d is doublet; dd is doublet of doublets; ddd is doublet of doublet of doublets; dt is doublet of triplets;

[0281] DCM is dichloromethane; methylene chloride; DIAD is diisopropyl azodicarboxylate;

[0282] DIPEA is N-ethyldiisopropylamine, also known as N.N-diisopropylethylamine;

[0283] DMA is N.N-dimethylacetamide;

[0284] DME is 1 ,2-dimethoxyethane;

[0285] DMF is N.N-dimethylformamide;

[0286] DMSO is dimethyl sulfoxide;

[0287] (CD3)2SO is deuterodimethylsulfoxide;

[0288] ESI is electrospray ionization;

[0289] EtOAc is ethyl acetate;

[0290] EtOH is ethanol; g is gram;

[0291] HATU is 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;

[0292] HPLC is high pressure liquid chromatography;

[0293] IPA is isopropyl alcohol;

[0294] L is liter;

[0295] LCMS is liquid chromatography mass spectrometry; m is multiplet;

[0296] M is molar;

[0297] MeCN is acetonitrile;

[0298] (CD3)OD is deuterated methanol;

[0299] MeOH is methanol; mg is milligram;

[0300] MHz is mega Hertz; mL is milliliter; mmol is millimole; mol is mole;

[0301] MS (m / z) is mass spectrum peak;

[0302] NMR is nuclear magnetic resonance;

[0303] Pd(dppf)CI2is [1 ,1 ’-bis(diphenylphophino)ferrocene]dichloropal!adium(ll); pH is power of hydrogen; q is quartet; s is singlet;

[0304] SFC is supercritical fluid chromatography; t is triplet;

[0305] T3P is propylphosphonic anhydride;

[0306] TFA is trifluoroacetic acid; THF is tetrahydrofuran; μL is microliter; μmol is micromole; and

[0307] EXAMPLES

[0308] In order that this invention may be beter understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

[0309] The compounds and intermediates described below were named using the naming convention provided with ChemDraw, Version 20.1 .1 .125 (PerkinElmer Informatics Inc.). The naming convention provided with ChemDraw, Version 20.1.1.125 is well known by those skilled in the art and it is believed that the naming convention provided with ChemDraw, Version 20.1 .1 .125 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rales. Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0310] 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1H- benzo[d]imidazole

[0311] Step A: K2CO3(13.98 g, 101.35 mmol) was added to a stirred solution of 1-methyl-1H-benzo[d]imidazol-5-ol (5.0 g, 33.78 mmol) in DMSO (35 mL), and the mixture was stirred at ambient temperature for 5 minutes. 1-Fiuoro-2-methyl-4-nitrobenzene (5.24 g, 33.78 mmol) was added to the solution, and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was then diluted with EtOAc and washed with cold water followed by brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-2% MeOH / DCM) to get 1-methyl- 5-(2-methyl-4-nitrophenoxy)-1H-benzo[d]imidazole (7.6 g, 84%) as a solid, m / z (esi) M+1 = 284.0.

[0312] Step B: 20% Pd(OH)2on carbon (1 .4 g) was added to a stirred solution of 1-methyl-5-(2- methyl-4-nitrophenoxy)-1H-benzo[d]imidazole (7 g, 24.74 mmol) in THF:MeOH (1 :6) (105 mL) at ambient temperature. The reaction mixture was then stirred for 16 hours under hydrogen atmosphere. The mixture was then filtered through Celite®, and the bed was washed with 10% MeOH / DCM (100mL X 3). The filtrate was concentrated, and the solid was washed with diethyl ether (40 mL X 2) to get 3-methyl-4-((1-methyl-1H-benzo[d]imidazole-5-yl)oxy)aniline (6.2 g, 98%) as a solid.1H NMR (400 MHz, (CD3)2SO) 6 8.10 (s, 1 H), 7.46 (d, J = 8.5 Hz, 1 H), 6.92 - 6.84 (m, 2H), 6.66 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 2.7 Hz, 1H), 6.42 (dd, J = 2.8, 8.5 Hz, 1 H), 4.91 (s, 2H), 3.80 (s, 3H), 2.00 (s, 3H). m / z (esi) M+1 = 253.9.

[0313] Step C: A slurry of 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (5.00 g, 19.7 mmol) and MeCN (100 mL) was chilled to 0 °C. Sulfuric acid (3.16 mL, 59.2 mmol) was added dropwise, then sodium nitrite (6.42 mL, 25.7 mmol, 4M aq.) was added. The mixture was stirred for 45 minutes at 0 °C. KI (9.83 g, 59.2 mmol) was then added as an aqueous solution, and the mixture was stirred for another 1 hour. The reaction mixture was diluted with EtOAc, and the mixture was washed with saturated sodium carbonate, followed by a 1 :1 saturated sodium carbonate / 1 M sodium sulfite solution. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (0 to 4% MeOH in DCM) to yleld 5-(4-iodo-2-methylphenoxy)-1-methyl-1 H-benzo[d]imidazole (4.83 g, 13.3 mmol, 67%) as a solid, m / z (APCI-pos) M+1 = 365.0.

[0314] Step D: A mixture of 5-(4-iodo-2-methylphenoxy)-1-methyl-1 H-benzo[d]imidazole (1.0 g, 2.75 mmol), PdCl2(dppf)-CH2Cl2adduct (224.2 mg, 0.275 mmol), potassium acetate (808.4 mg, 8.24 mmol), bis(pinacoiato)diboron (1 .395 g, 5.49 mmol) and 1 ,4-dioxane (30 mL) was degassed with bubbling nitrogen for 10 minutes. The reaction was heated to 95 °C where it stirred for 5 days. The reaction was concentrated under reduced pressure and purified via column chromatography eluting with 1-3% MeOH in DCM to afford 1 -methyl-5-(2-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1H-benzo[d]imidazole (548.7 mg, 54.8%). m / z (APCI-pos) M+1 = 365.2.

[0315] 4-([1 ,2,4]triazolo[1 ,5-a]pyridin-7-yloxy)-3-methylaniline

[0316] Step A: K2CO3(6,1 g, 44.44 mmol) was added to a stirred solution of [1 ,2,4]triazolo[1 ,5- a]pyridin-7-ol (3.0 g, 22.22 mmol) in DMSO (25.0 mmol), followed by 1-fluoro-2-methyl-4- nitrobenzene (3.4 g, 22,22 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was then diluted with EtOAc, washed with water followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by column chromatography (0-20% EtOAc-Hexane) to afford 7-(2-methyl-4-nitrophenoxy)- [1 ,2,4]triazolo[1 ,5-a]pyridine (5.0 g , 83% yleld) as a solid, m / z (Esi) M+1 = 271 .24.

[0317] Step B: Zn (12 g, 184.50 mmol) was added to a stirred solution of 7-(2-methyl-4- nitrophenoxy)-[1 ,2,4]triazolo[1 ,5-a]pyridine (5 g, 184.50 mmol) in THF (48 mL) at 0° C. Then NH4CI (9.9 g, 184.5 mmol) in H2O (12 mL) was added dropwise into the solution at 0° C, and the mixture stirred for 1 hour. The reaction mixture was then fiitered through a Ceiite® pad, which was washed with EtOAc. The filtrate was washed with water foiiowed by brine. The organic iayer was dried over Na2SO4and concentrated to afford the crude, which was triturated with diethyl etherto afford 4-([1 ,2,4]triazolo[1 ,5-a]pyridin-7-yloxy)-3-methylaniline (4 g, 90% yleld) as a solid.1H NMR (400 MHz, (CD3)2SO) δ 8.86 (d, J = 7.4 Hz, 1 H), 8.33 (s, 1 H), 6.94 (dd, J = 2.6, 7.4 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 6.61 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 2.3 Hz, 1 H), 6.49 (dd, J = 2.8, 8.5 Hz, 1H), 5.10 (s, 2H), 1.98 (s, 3H). m / z (Esi) M+1 = 241 .18.

[0318] Example C

[0319] 4-(4-amino-2-methylphenoxy)-1-methylpyridin-2(1 H)-one

[0320] Step A: K2CO3(579 mg, 4.19 mmol) was added to a stirred solution of 4-hydroxy-1- methylpyridin-2(1 H)-one (175 mg, 1 ,40 mmol) and 1-fluoro-2-methyl-4-nitrobenz.ene (217 mg, 1.40 mmol) in DMSO (2 mL). The reaction mixture was stirred at 80 °C for 4 hours. After completion, the reaction mixture was poured onto crushed ice and stirred for 5 minutes, then fiitered through sintered funnel. The residue was washed with hexane foiiowed by diethyl ether to get 1-methyl-4-(2-methyl-4-nitrophenoxy)pyridin-2(1H)-one (160 mg, 44% yleld) as solid, m / z (esi) M+1 = 261 .3.

[0321] Step B: Zn dust (377 mg, 5.77 mmol) and NH4CI (309 mg, 5.77 mmol) were added at 0 °C to a stirred solution of 1-methyl-4-(2-methyl-4-nitrophenoxy)pyridin-2(1H)-one (150 mg, 0.58 mmol) in THF:H2O (5:1 ; 6 mL). The reaction mixture stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with EtOAc and filtered through pad of Celite®. The filtrate was washed with brine. The organic phase was dried over Na2SO4and concentrated to get crude 4- (4-amino-2-methylphenoxy)-1-methylpyridin-2(1 H)-one (130 mg) as a sticky solid that was used directly, m / z (esi) M = 230.8.

[0322] 4-(benzo[d]thiazol-5-yloxy)-3-methyianiline

[0323] Step A: A mixture of 1-fluoro-2-methyl-4-nitrobenzene (1.71 g, 11.02 mmol),benzo[d]thiazol-5-ol (2.00 g, 13.23 mmol) and potassium carbonate (3.05 g, 22.05 mmol) in DMSO (26 mL) was stirred for 2 hours. The mixture was then diluted with 75 mL water. The mixture was extracted with EtOAc (3 X). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to a solid. The crude mixture was purified by column chromatography (0 to 8% MeOH in DCM) to yleld 5-(2-methyl-4- nitrophenoxy)benzo[d]thiazole as a solid (2.75 g, 87%). m / z (APCI-pos) M+1 = 287.10.

[0324] Step B: A mixture of 5-(2-methyl-4-nitrophenoxy)benzo[cl]thiazole (2.75 g, 9.61 mmol), ammonium chloride (1 .03 g, 19.23 mmol), THF (48 mL) and water (2.7 mL) were cooled to 0 °C. Zinc (6.28 g, 96.12 mmol) was added as a single portion. The ice bath was removed, and the mixture was stirred at ambient temperature for 24 hours. The mixture was then filtered through GF / F paper, and the solid residue was washed generously with EtOAc. The organic filtrate was washed with water, then brine, and dried over magnesium sulfate, filtered, and concentrate to an oil. The oil was purified via column chromatography (10 to 60% EtOAc in n-heptane) to provide 4-(benzo[d]thiazol-5-yloxy)-3-methylaniiine (1.71 g, 69%). m / z (APCI-pos) M+1 = 257.10.

[0325] Example E

[0326] 4-((7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)oxy)-3-methylaniline

[0327] Step A: DIPEA (1.46 mL, 8.40 mmol) was added to a stirred solution of 5-bromo-1 ,2- difluoro-3-nitrobenzene (1 g, 16.87 mmol) in THF (5 mL) in a sealed round bottom fiask, followed by methyl amine (10.50 mL, 21.00 mmol) at 0°C and stirred at 60 °C for 16 hours. After completion, the reaction mixture was concentrated to get 4-bromo-2-fluoro-N-methyl-6- nitroaniline (1 .1 g, crude), which was used for next step without further purification.

[0328] Step B: Zn powder (2.75 g, 42.16 mmol) and NH4CI (2.25 g, 42.16 mmol) were added to a stirred solution of 4-bromo-2-fluoro-N-methyl-6-nitroaniline (1.05 g, 4.21 mmol) in THF:H2O (4:1 ; 20 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion, reaction mixture filtered through Celite®bed and washed with EtOAc. The organic part was separated by separating funnel and dried over with anhydrous Na2SO4. The organic part was concentrated to get crude which was purified by silica gel column chromatography (1 % MeOH- DCM) to afford 4-bromo-6-fluoro-Afi-methylbenzene-1 ,2-diamine (850 mg, 77% yleld in two steps) as a solid, m / z (esi) M+1 = 219.1.

[0329] Step C: Ethyl orthoformate (0.91 mL, 5.47 mmol) and p-toluenesulfonic acid (“PTSA”; 4.71 mg, 0.02 mmol) were added to a mixture of 4-bromo-6-fluoro-N1-methylbenzene-1 ,2-diamine (600 mg, 2.73 mmol) in toluene (15 mL) under argon atmosphere. The resulting solution was heated at reflux for 2 hours. The cooled reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (1 % MeOH-DCM) to afford 5-bromo-7-fluoro-1- methyl-1H-benzo[d]imidazole (550 mg, 87% yleld) as a solid, m / z (esi) M+1 = 230.9.

[0330] Step D: KOAc (2.57 g, 26.19 mmol) was added to a stirred solution of 5-bromo-7-fluoro- 1-methyl-1 H-benzo[d]imidazole (3 g, 13.09 mmol) and 4,4,4',4’,5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (6.65 g, 26.19 mmol) in dioxane (60 mL) and degassed for 5 minutes under argon atmosphere. Pd(dppf)CI2DCM (1 .01 g, 1 .31 mmol) was added, degassed for another 5 minutes and heated at 90 °C for 5 hours. After completion, the reaction mixture was filtered through Celite® bed and filtrate was concentrated to get crude. The crude was diluted with EtOAc and washed with water, brine, dried over Na2SO4and concentrated under reduced pressure to get crude which was purified by silica gel column chromatography (1 % MeOH-DCM) to afford 7- fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (2.80 g, 77% yleld) as a solid, m / z (esi) M+1 = 276.9.

[0331] Step E: Sodium perborate tetrahydrate (5.42 g, 54.32 mmol) was added to a stirred solution of 7-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (3 g, 10.86 mmol) in THF / H2O(1 :1) (60 mL), and the reaction mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was filtered through Celite® bed, and the filtrate was concentrated to get crude 7-fluoro-1-methyl-1H- benzo[d]imidazol-5-oi, which was used in the next step without further purification, m / z (esi) M+1 = 166.8.

[0332] Step F: K2CO3(8.72 g, 63.19 mmol) was added to a stirred solution of 7-fluoro-1-methyl- 1 H-benzo[d]imidazol-5-ol (3.5 g, 21.06 mmol) and 1 ”fluoro-2-methyl-4-nitrobenzene (3.61 g, 23.17 mmol) in DMSO (50 mL) at 80°C for 4 hours. After completion of reaction, it was diluted with EtOAc and washed with water, brine, dried over NazSO4and concentrated under reduced pressure to get crude. The crude was washed with pentane to afford 7-fluoro-1-methyl-5-(2- methyl-4-nitrophenoxy)-1H-benzo[d]imidazole as a solid, m / z (esi) M+1 = 301.7.

[0333] Step G: Zn powder (10.63 g, 162.63 mmol) and NH4CI (8.7 g, 162.63 mmol) were added to a stirred solution of 7-fiuoro-1-methyl-5-(2-methyl-4-nitrophenoxy)-1 H-benzo[d]imidazole (4.9 g, 16.26 mmol) in THF / H2O (50 mL, 4:1). The reaction mixture was stirred at room temperature for 2 hours. After completion, reaction mixture filtered through Celite® bed and washed with EtOAc. The organic part was separated by separating funnel, dried over with anhydrous Na2SO4and concentrated to afford 4-((7-fluoro-1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)-3-methylaniline (4.0 g, 90% yleld) as a solid.1H NMR (400 MHz, (CD3)2SO) δ 8.18 (s, 1H), 6.74 (dd, J = 2.0, 12.6 Hz, 1H), 6.70 - 6.66 (m, 2H), 6.49 (d, J = 2.2 Hz, 1H), 6.43 (dd, J = 2.8, 8.5 Hz, 1H), 4.95 (s, 2H), 3.95 (s, 3H), 1 .98 (s, 3H). m / z (esi) M+1 = 272.1 .

[0334] Example F

[0335] 3-methyl-4-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)oxy)aniline Step A: K2CO3(1 .34 g, 9.68 mmol) was added to a stirred solution of 1-fluoro-2-methyl-4- nitrobenzene (500 mg, 3.22 mmol) and 3-methyl-3H-imldazo[4,5-b]pyridin-6-ol (481 mg, 3.22 mmol) in DMSO (3 mL), and the mixture was stirred at 80 °C for 4 hours. After completion of reaction, it was diluted with EtOAc and washed with water, brine, dried over Na2SO4and concentrated under reduced pressure to get crude. The crude was purified with silica gel column chromatography (0-20% EtOAc / Hexane) to get 3-methyl-6-(2-methyl-4-nitrophenoxy)-3H- imidazo[4,5-b]pyridine (750 mg, 82% yleld) as a solid, m / z (esi) M+1 = 284.9.

[0336] Step B: Zn dust (1.83 g, 28.16 mmol) and NH4CI (1.51 g, 28.16 mmol) were added at 0 °C to a stirred solution of 3-methyl-6-(2-methyl-4-nitrophenoxy)-3H-imidazo[4,5-b]pyridine (800 mg, 2.82 mmol) in THF and water (10 mL), and the reaction was stirred at room temperature for 2 hours. After completion of reaction, it was filtered through a bed of Celite®, the filtrate was washed with water and extracted using EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to get 3-methyl-4-((3-methyl-3H-imidazo[4,5-b]pyridin-6- yl)oxy)aniline (500 mg, 70% yleld) as a semi-solid, m / z (esi) M+1 ~ 254.9.

[0337] Example G

[0338] 5-(2-chloro-6-fluoro-4-(4,4,5.5-tetramethyl-1 ,3.2-dioxaborolan-2-yl)phenoxy)-1-methyl-1H- benzo[d]imidazole

[0339] Step A: K2CO3(35.7 g, 258 mmol, 2.0 eq) and 1 -chloro-2,3-difluoro-5-nitrobenzene (25.0 g, 129 mmol, 1 .0 eq) was added to a solution of 1-methyl-1 H-benzo[d]imidazol-5-ol (19.2 g, 129 mmol, 1.0 eq) in DMSO (192 mL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by addition H2O (100 mL) at 20 °C, and then diluted with EtOAc (100 mL) and extracted with EtOAc (3 X). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate=1 / 0 to 0 / 1), providing 5-(2-chloro-6-fluoro-4-nitrophenoxy)-1-methyl-1 H-benzo[d]imidazole (32 g, 99.5 mmol) as a solid.

[0340] Step B: Zn (60.9 g, 933 mmol, 10 eq) and NH4CI (49.9 g, 933 mmol, 10 eq) was added to a solution of 5-(2-chloro-6-fluoro-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (30.0 g, 93.3 mmol, 1.0 eq) in THF (240 mL) and H2O (60 mL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM: MeOH = 10:1). 3-Chloro-5-fluoro-4- ((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)aniline (18.0 g, 61 .7 mmol) was obtained as a solid. Step C: NaNO2(4.0M, 11 .31 mL, 1 .2 eq) was added at 0 °C to a solution of 3-chioro-5- fluoro-4-((1-methyl-1 H-benzo[d]]imidazo-l5-yl)oxy)aniline (11.0 g, 37.7 mmol, 1 .0 eq) in ACN (110 mL) and H2SO4(11 .1 g, 1 13 mmol, 6.03 mL, 3.0 eq). The mixture was stirred at 20 °C for 0.5 hours. KI (10M, 11 .3 mL, 3.0 eq) was added to the mixture at 20 °C and stirred for 2 hours. The reaction mixture was quenched by addition H2O (200 mL) at 20 °C, and then diluted with EtOAc (100 mL) and extracted with EtOAc (3 X). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) providing 5-(2-chloro-6-fluoro-4-iodophenoxy)-1-methyl-1H- benzo[d]imidazole (10 g) was obtained as a solid.

[0341] Step D: Pd(dppf)CI2CH2CI2(4.06 g, 4.97 mmol, 0.1 eq), bis(pinacoloato)diboron (37.8 g, 149 mmol, 3,0 eq) and KOAc (24.4 g, 249 mmol, 5.0 eq) was added to a solution of 5-(2-chloro- 6-fluoro-4-iodophenoxy)-1 -methyl-1H-benzo[d]imidazole (20 g, 49.7 mmol, 1 .0 eq) in dioxane (500 mL). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM / MeOH = 10 / 1 to 0 / 1). The residue was purified by prep-HPLC column: Welch Ultimate XB- SIOH 250*50*10 pm; mobile phase: [heptane-EtOH: ACN = 4:1]; gradient: 0%-45% B over 20.0 minutes and SFC (column: DAICEL CHIRALPAK AD (250mm*50mm, 10 pm); mobile phase: [CO2-EtOH (0.1 % NH3H2O)]; B%:40%, isocratic elution mode). The product was triturated with petroleum ether at 20 °C for 1 hour to afford 5-(2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)-1-methyl-1 H-benzo[d]imidazole (5.3 g) as a solid.1H NMR: (400 MHz, (CD3)2SO) δ 8.19 (s, 1H), 7.64 (s, 1H), 7.54 (dd, J = 5.9, 9.2 Hz, 2H), 7.06 - 6.95 (m, 2H), 3.83 (s, 3H), 1 .32 (s, 12H).

[0342] Example H

[0343] 5-(2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1-methyl-1 H- benzo[d]imidazole

[0344] Step A: K2CO3(39.9 g, 289 mmol, 2.0 eq) and 1-methyl-1H-benzo[d]imidazol-5-ol (21.4 g, 144 mmol, 1.0 eq) was added to a solution of 1 ,2-difluoro-3-methyl-5-nitrobenzene (25 g, 144 mmol, 1.0 eq) in DMSO (250 mL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by addition H2O (200 mL) at 20 °C, and then diluted with EtOAc (100 mL) and extracted with EtOAc (3 X). The combined organic layers were concentrated under reduced pressure to give a residue. 5-(2-Fluoro-6-methyl-4-nitrophenoxy)-1-methyl-1 H-benzo[d]imidazole (40 g, crude) was obtained as a solid.

[0345] Step B: Zn (86.8 g, 1 .33 moL 10 eq.) and NH4CI (71.0 g, 1.33 mol, 10 eq.) was added to a solution of 5-(2-fluoro-6-methyl-4-nitrophenoxy)-1-methyl-1 H-benzo[d]imidazole (40 g, 133 mmol, 1 .0 eq.) in THF (320 mL) and H2O (80 mL). The mixture was stirred at 20 °C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. 3- Fluoro-5-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (15 g, crude) was obtained as a solid.

[0346] Step C: NaNO2(4M, 22.1 mL, 1 .2 eq.) was added at 0 °C to a solution of 3-fluoro-5- methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (20 g, 73.7 mmol, 1.0 eq.) in ACN (200 mL) and H2SO4(221 mmol, 1 1 .8 mL, 3.0 eq.). The mixture was stirred at 20 °C for 0.5 hours. KI (10M, 22.1 mL, 3.0 eq.) was added to the mixture at 20 °C and stirred. The mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched by addition of H2O (200 mL) at 20 °C, then diluted with EtOAc (200 mL) and extracted with EtOAc (3 X). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to afford 5-(2-fluoro-4-iodo-6-methylphenoxy)-1-methyl- 1 H-benzo[d]imidazole (25 g) as a solid.

[0347] Step D: Pd(dppf)CI2CH2CI2(3.21 g, 3.92 mmol, 0.1 eq), bis(pinacolato)diboron (29.9 g, 118 mmol, 3.0 eq) and KOAc (23.1 g, 236 mmol, 6.0 eq) were added to a solution of 5-(2-fiuoro- 4-iodo-6-methylphenoxy)-1-methyl-1H-benzo[d]imidazole (15 g, 39.2 mmol, 1.0 eq) in dioxane (150 mL). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 1 / 0) and then further purified by prep-HPLC column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [heptane-EtOH: ACN = 4:1]; gradient: 0%-45% B over 20.0 minutes and SFC (column: DAICEL CHIRALPAKAD (250mm*50mm, 10 pm); mobile phase: [CO2-EtOH (0.1 % NH3H2O)]; B%:40%, isocratic elution mode). The crude product was triturated with petroleum ether at 20 °C for 1 hour. 5-(2-Fluoro-6-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)-1-methyl-1 H-benzo[d]imidazole (5.3 g, crude) was obtained as a solid.1H NMR (400 MHz, (CD3)2SO) δ 8.16 (s, 1H), 7.56 - 7.46 (m, 2H), 7.35 (d, J = 10.5 Hz, 1H), 6.99 - 6.88 (m, 2H), 3.81 (s, 3H), 2.19 (s, 3H), 1 .31 (s, 12H).

[0348] Example I 5-(3-fluoro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole

[0349] Step A: K2CO3(2.23 g, 16.19 mmol) was added to a stirred solution of 2-chloro-4-fluoro-

[0350] 3-methyl-1 -nitrobenzene (1.2 g, 8.09 mmol) and 1-methyl-1 H-benzo[d]imidazol-5-ol (1.69 g, 8.90 mmol) in DMSO (8 mL) in a sealed tube and stirred at 80 °C for 4 hours. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-1 % MeOH / DCM) to afford 5-(3-chioro-2-methyl-4-nitrophenoxy)-1-methyl-1 H-benzo[d]imidazole (2.0 g, 78% yleld) as a solid, m / z (esi) M+1 = 317.6.

[0351] Step B: CsF (3.59 g, 23.6 mmol) was added to a stirring solution of 5-(3-chioro-2-methyl-

[0352] 4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (750 mg, 2.36 mmol) in DMSO (24 mL), and the mixture was sealed under an inert atmosphere and then heated to 1 10 °C where it stirred for 16 hours. The mixture was allowed to cool to room temperature and was then partitioned between water and EtOAc. The organic layer was washed with brine (2 X), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified via column chromatography (1-4% MeOH / CH2CI2) to afford 5-(3-fluoro-2-methyl-4-nitrophenoxy)-1-methyl- 1 H-benzo[d]imldazole (524 mg, 73%). m / z (APCi-pos) M+1 = 302.2.

[0353] Example J

[0354] 5-(5-chioro-2-methyl-4-nitrophenoxy)-1-methyl-1 H-benzo[d]imidazole

[0355] CS2CO3(34.4 g, 105.485 mmol) was added to a stirred solution of 1-chloro-5-fluoro-4- methyl-2-nitrobenzene (10 g, 52.743 mmol) and 1-methyl-1 H-benzo[d]imidazol-e5-ol (7.8 g, 52.7 mmol) in DMA (500 mL), and the mixture was heated to 80 °C for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water, followed by brine, dried over Na2SO4, filtered and concentrated. The crude product was triturated with 10% EtOAc / hexanes, and the solid was dried under reduced pressure to get 5-(5-chloro-2-methyl-4- nitrophenoxy)-1-methyl-1H- benzo[d]imidazole (14g, 84% yleld) as a solid, m / z (esi) M+1 = 317.4.

[0356] Example K 5-(4-bromo-2-chioro-6-methviphenoxy)-1-methyl-1 H-benzo[d]imidazole

[0357] Cesium carbonate (586 mg, 1.80 mmol) was added to a stirred solution of 5-bromo-1- chloro-2-fluoro-3-methylbenzene (0.268 g, 1.20 mmol) and 1 -methyl-1 H-benzo[d]imidazol-5-ol (178 mg, 1.20 mmol) in DMSO (10 mL). The mixture was then heated to 100 °C in a sealed tube overnight. The reaction was partitioned between water and CH2CI2. The combined organic layers were washed with brine (3 X), dried over Na2SO4, filtered, and concentrated to afford 5-(4-bromo- 2-chloro-6-methylphenoxy)-1-methyl-1 H-benzo[d]imidazole (270 mg, 64.0%). m / z (APCI-pos) M+1 =351 .0.

[0358] Example L

[0359] 3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine

[0360] Step A: A mixture of 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (25.0 g, 162.34 mmol) and ammonium sulfate (193.0 g, 1461 mmol) in hexamethyldisilazane (“HMDS”; 128 mL) was stirred under reflux for 5 hours. The reaction mixture was then cooled to room temperature, excess ammonium sulfate was filtered off, and the filtrate was concentrated under vacuum to give 4- chloro-1-(trimethylsilyl)-1H-pyrazolo[3,4-d]pyrimidine (25 g, crude) as an oil that was immediately used in the next step.

[0361] Step B: A solution of methylmagnesium bromide (1 .4 M, 230 mL) in THF:toluene (1 :3) was added to a stirred solution of Fe(acac)3(6.9 g, 19.5 mmoi) and crude 4-chloro-1- (trimethylsilyl)-1H-pyrazolo[3,4-d]pyrimidine (25 g, 162.34 mmol) in THF (150 mL) at -78 °C under argon. After 15 minutes, the reaction mixture was allowed to warm to 0 °C via an ice / water bath, and the cooled solution was quenched via the slow addition of saturated aqueous NH4CI. After 15 minutes of stirring, the solution was warmed to ambient temperature and diluted with EtOAc. The organic and aqueous layers were separated, and the organic layer dried over Na2SO4, filtered, and concentrated. The crude material was then purified by silica gel column chromatography (0-10% MeOH / DCM) to afford 4-methyl-1H-pyrazolo[3,4-d]pyrimidine (15.0 g, 61 % yleld in 2 steps). MS(ES): m / z 134.8 [M + H]+.

[0362] Step C: n-Bromosuccinimide (“NBS”; 31.2 g, 175.4 mmol) was added at ambient temperature to a stirred solution of 4-methyl-1H-pyrazolo[3,4-d]pyrimidine (22.0 g, 159.42 mmol) in acetonitrile (200 mL) and stirred for 2 hours at 90 °C. The mixture was concentrated, and the crude material purified directly by silica gel column chromatography (0-5% MeOH-DCM) to provide 3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine (21.4 g, 63% yleld). MS(ES): m / z 213.0 [M + H]+;1H NMR (400 MHz, DMSO) δ 14.36 (s, 1H), 8.84 (s, 1H), 2.86 (s, 3H). Example M

[0363] 3-bromo-4-methyl-1 H-pyrazolo[3,4-c]pyrimidine

[0364] Step A: In a pressure release vial trimethylboroxine (2.18 mL, 15.6 mmol), 4-chloro-1H- pyrazolo[4,3-c]pyridlne (400 mg, 2.60 mmol), tetrakis(triphenylphosphine)palladium(0) (451 mg, 391 μmol), and K2CO3(1 .08 g, 7.81 mmol) were dissolved in 1 ,4-dioxane (13.0 mL), The reaction mixture was sparged with argon for 10 minutes before sealing and heating at 100 °C for 16 hours. The reaction mixture was cooled to room temperature. The solids were filtered off, concentrated, and directly loaded onto a column for separation. The crude residue was purified over 24g silica cartridge, eluting with a gradient of 0% to 10% MeOH in DCM to afford 4-methyl-1H-pyrazolo[4,3- c]pyridine (222 mg, 64%). MS(ES): m / z 134.1 [M + H]+.

[0365] Step B: A vial was charged with 4-methyl-1H-pyrazolo[4,3-c]pyridine (222 mg, 1.67 mmol), NBS (312 mg, 1 .75 mmol), and MeCN (4.2 mL). The reaction was heated to 50 °C for 1 hour before cooling to room temperature. The reaction mixture was directly concentrated under reduced pressure, and the crude material purified by silica gel chromatography (dry load, 0 to 10% MeOH in DCM) to yleld the product as a solid, 3-bromo-4-methyl-1 H-pyrazolo[4,3-c]pyridine (197.7 mg, 56%). MS(ES): m / z 21 1.9; 213.9 [M + H]+.

[0366] Example N

[0367] 3-bromo-7-fiuoro-4-methyl-1H-pyrrolo[3,2-c]pyridine

[0368] 3-Bromo-7-fluoro-4-methyl-1 H-pyrrolo[3,2-c]pyridine was synthesized following the procedure for Example M, replacing 4-chloro-1H-pyrazolo[3,4-c]pyrimidin weith 4-bromo-7-fluoro- 1H-pyrro!o[3,2-c]pyridine. MS(ES): m / z 229.0; 231.0 [M + H]+.

[0369] Example O 3-bromo-7-fluoro-4-methyl-1H-pyrazolo[4,3-c]pyridine

[0370] 3-Bromo-7-fluoro-4-methyl-1H-pyrazolo[4,3-c]pyridine was synthesized foilowing the procedure for Example M, replacing 4-chloro-1H-pyrazolo[4,3-c]pyridine with 4-chloro-7-fluoro- 1H-pyrazolo[4,3-c]pyridine. MS(ES): m / z 230.0; 232.0 [M + H]+.

[0371] Example P f / ?)-4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[dlimidazoi-5-yl)oxy)phenyl)-1-(piperidin-3-yl)- 1H-pyrazolo[3,4-d]pyrimidine

[0372] Step A: tert- Butyl (S)-3-((methylsulfonyl)oxy)piperidine-1-carboxylate (865 mg, 3.10 mmol), 3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.41 mmol), cesium carbonate (918 mg, 2.82 mmol), and DMF (7.0 mL) were charged to a 20 mL scintillation vial. The mixture was stirred at 100 °C for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc (25 mL) and washed with brine (3 X 15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-10% MeOH-DCM) to give terf-butyl (R)-3-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -carboxylate (515 mg, 92%) as a solid. MS(ES): m / z 396.1 ; 398.1 [M + H]+.

[0373] Step B: terf-Butyl (R)-3-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carboxylate (215 mg, 543 μmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenoxy)-1H-benzo[d]imidazole (237 mg, 651 μmol), PdCI2(dppf)-CH2CI2adduct (22 mg, 27,1 μmol), and aqueous K2CO3(0.3M, 1.81 mL, 543 μmol) were dissolved in 1 ,4-dioxane (5.4 mL). The reaction mixture was sparged with argon for 10 minutes before heating to 90 °C for 2 hours. The reaction was cooled to room temperature, diluted with CHCI3(10 mL) and H2O (10 mL), and extracted with CHCI3(3 X 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-10% MeOH-DCM) to afford tert- butyl (R)-3-(4-methyl-3-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidine-1 -carboxylate (202 mg, 67%). MS(ES): m / z 554.3 [M + H]+.

[0374] Step C: TFA (560 μL, 7.22 mmol) was added to a stirred solution of tert-butyl (R)-3-(4- methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -carboxylate (200 mg, 361 μmol) and DCM (3.6 mL). The reaction mixture was stirred for 30 minutes at room temperature. Upon completion, the reaction was neutralized with 2M aqueous Na2CO3and stirred for 15 minutes to freebase the resulting salt. The aqueous phase was then extracted with DCM (3 X 5 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The resulting solid, (R)-4-methyl-3-(3-methyl- 4-((1 -methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-1-(piperidln-3-yl)-1 H-pyrazolo[3,4- d]pyrlmidine (142 mg, 87%), was used in the following step without purification. MS(ES): m / z 454.2 [M + H]+.

[0375] Example Q1 and Q2

[0376] SFC peak 1 SFC peak 2 tert-butyl (R)-4-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)azepane-1 -carboxylate and tert-butyl (S)-4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)azepane-1 -carboxylate

[0377] Step A: DIPEA (504 μL, 1 eq., 2.89 mmol) was added to a solution of tert-butyl 4- hydroxyazepane-1 -carboxylate (623 mg, 1 eq., 2.89 mmol) in DCM (5.8 mL). The reaction was cooled to 0 °C before adding methanesuifonyl chloride (269 μL, 1 .2 eq., 3.47 mmol). The reaction mixture was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated NaHCO3, and the layers were separated. The organic layer was subsequently washed with saturated NaHCO3and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude tert-butyl 4-((methylsulfonyl)oxy)azepane-1 -carboxylate residue was used directly without further purification. MS(ES): m / z 194.1 [M + H - Boc]+.

[0378] Step B: tert-Butyl 4-((methylsuifonyl)oxy)azepane-1-carboxylate (275.4 mg, 2 eq., 938.8 μmol), 3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine (100.0 mg, 1 eq., 469.4 μmol), cesium carbonate (305.9 mg, 2 eq., 938.8 μmol), and A / ,N-dimethylformamide (2.347 mL, 1 eq., 469.4 μmol) were charged to a 8 mL vial. The mixture was stirred at 100 °C for 5 hours. The mixture was concentrated on a Biotage v10 and purified by column chromatography (Redisep 24g, 0- 10% MeOH / DCM) followed by ACCQ reverse phase prep-HPLC purification eluting 20-100% acetonitrile with 0.1 % TFA in water with 0.1 % TFA. Desired fractions neutralized with saturated NaHCO3, extracted with DCM, dried with magnesium sulfate, filtered, and concentrated in vacuo to furnish racemic product. Enantiomers were separated on a Diacel ChiralCel® OJ-H, 250 (L) x 4.6 (ID) mm eluting with a mobile phase of 10% MeOH with CO2to afford tert-butyl (R)-4-(3- bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)azepane-1 -carboxylate (35 mg, 85 μmol, 18%) and tert-butyl (S)-4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)azepane-1 -carboxylate (34 mg, 83 μmol, 18%). MS(ES): m / z 410.2, 412.2 [M + H]+. Example 1 (R)-1-(3-(3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3.4- d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one

[0379] Step A: tert- Butyl (S)-3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1 .7 g, 6.0 mmol), 3-bramo-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 5.0 mmol), Cs2CO3(3.3 g, 10 mmol), and DMF (25.0 mL) were charged to a 100 mL recovery flask. The mixture was stirred overnight at 100 °C. An additional equivalent of terf-butyl (S)-3-((methylsulfonyl)oxy)piperidine-1 -carboxylate was added, and the reaction stirred for 3 hours at room temperature. The mixture was diluted with EtOAc and washed with brine (10 X). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was then purified by silica gel chromatography (0-40% EtOAc / heptane) to afford tert-butyl (R)-3-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carboxylate (971 mg, 51%). MS(ES): m / z 382.1 [M + H]+.

[0380] Step B: tert-Butyl (R)-3-(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carboxylate (971 mg, 2.5 mmol), TFA (3.9 mL, 51 mmol), and DCM (13 mL) were charged to a vial. The mixture was stirred at room temperature for 2 hours before the volatiles were removed in vacuo to give (R)-3-bromo-1-(piperidin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidine (716 mg crude). The crude material was used directly in the next step without further purification. MS(ES): m / z 282.1 [M + H]+.

[0381] Step C: (R)-3-Bromo-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (716 mg, 2.5 mmol), DIPEA (4.4 mL, 25 mmol), acryloyl chloride (0.23 mL, 2.8 mmol), and DCM (13 mL) were charged to a 50 mL recovery flask. The mixture was stirred at room temperature for 10 minutes. The reaction was directly concentrated and purified by silica gel chromatography (0-10% MeOH / DCM) to afford (R)-1-(3-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (443 mg, 52% yleld in 2 steps). MS(ES): m / z 336.1 [M + H]+.

[0382] Step D: (R)-1-(3-(3-Bromo-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1- one (138 mg, 0.42 mmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)-1 H-benzo[d]imidazole (100 mg, 0.27 mmol), K3PO4(175 mg, 0.82 mmol), Pd(Ph3)4(48 mg, 0.04 mmol), 1 ,4-dioxane (2.7 mL), and H2O (0.39 mL) were charged to a vial. The mixture was sparged with argon, capped, and stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature then directly concentrated. The crude material was then purified by silica gel chromatography (0-10% MeOH / DCM) to afford (R)-1-(3-(3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin- 1 -yl)prop-2-en-1 - one (75 mg, 50%). MS(ES): m / z 548.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 9.39 (s, 1 H), 9.04 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.7, 2.2 Hz, 1H), 7.92 (s, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 8.7, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.73 - 6.50 (m, 1H), 6.36 - 6.27 (m, 1H), 5.77 - 5.63 (m, 1H), 5.00 (s, 1H), 4.86 (d, J = 12.9 Hz, 0.5H), 4.60 (d, J = 13.2 Hz, 0.5H), 4.23 (d, J = 13.3 Hz, 0.5H), 4.04 (d, J = 10.5 Hz, 0.5H), 3.93 - 3.76 (m, 3.5H), 3.51 - 3.43 (m, 0.5H), 3.29 (t, J = 12.8 Hz, 0.5H), 2.99 (s, 0.5H), 2.49 - 2.38 (m, 1H), 2.29 (dd, J = 13.3, 4.2 Hz, 1H), 2.05 (d, J = 13.7 Hz, 1H), 1 .76 (dt, J = 15.0, 7.5 Hz, 1H).

[0383] Example 2 (R)-1 -(3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

[0384] Step A: A 250 mL round bottom flask was charged with tert-butyl (S)-3- ((methylsulfonyl)oxy)piperidine-1 -carboxylate (4.4 g, 16 mmol), 3-bromo-4-methyl-1H- pyrazolo[3,4-d]pyrimidine (2.2 g, 10 mmol), CS2CO3(12 g, 38 mmol), and DMF (52 mL). The mixture was sparged with nitrogen for 10 minutes and then fitted with a Findenser. The reaction mixture was heated under nitrogen to 100 °C and stirred for 16 hours, before additional mesylate (1 eq.) was added followed by CS2CO3(1 .2 eq.). The reaction was stirred for an additional 6 hours before cooling to room temperature and quenching with water (500 mL). The aqueous phase was extracted with EtOAc (100 mL, 4 X). The combined organic layers were washed with brine (100 mL, 2 X), dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-8% MeOH / DCM) to give tert-butyl (R)-3-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -carboxylate (1 .5 g, 37%). MS(ES): m / z 396.2 [M + H]+.

[0385] Step B: TFA (6,0 mL, 78 mmol) was added to a stirred solution of tert-butyl (R)-3-(3- bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -carboxylate (1.5 g, 39 mmol) in DCM (38 mL). The reaction mixture was stirred at room temperature for 4 hours before additional TFA (0.14 mL, 1 .8 mmol) was added. The reaction was stirred for 1 hour further before quenching with 10% aqueous K2CO3(20 mL). The aqueous phase was extracted with DCM (20 mL, 2 X). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The product, (R)-3-bromo-4-methyl-1-(piperidin-3-yl)-1 H-pyrazolo[3,4-d]pyrimldine (1.1 g, 91 %), was used directly in the next reaction without further purification. MS(ES): m / z 296.1 [M + H]+.

[0386] Step C: (R)-3-Bromo-4-methyl-1-(piperidin-3-yl)-1H-pyrazolo[3,4-c]pyrimidine (1.1 g, 3.5 mmol), DIPEA (1 .9 mL, 11 mmol), and DCM (35 mL) were added to a 50 mL round bottom flask. The mixture was cooled to 0 °C before acryloyl chloride (0.29 mL, 3.5 mmol) was added. The reaction was stirred at this temperature for 20 minutes. The reaction was directly concentrated and purified by silica gel chromatography (0-16% MeOH / DCM) to yleld (R)-1-(3-(3-bromo-4- methyl-1H-pyrazoio[3,4-d]pyrimidin-1 -yl)piperidin-1-yl)prop-2-en-1-one (346 mg, 28%). MS(ES): m / z 350.1 [M + H]+.

[0387] Step D: (R)-1-(3-(3-bromo-4-methyl-1H-pyrazoio[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop- 2-en-1-one (110 mg, 0.31 mmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)-1 H-benzo[d]imidazole (172 mg, 0.47 mmol), K3PO4(200 mg, 0.94 mmol), 1 ,4-dioxane (5.0 mL), and H2O (1 .0 mL) were added to a 20 mL microwave vial. The vial was sparged with nitrogen for 5 minutes then Pd(Ph3)4(36 mg, 0.03 mmol) was added. The vial was sparged with nitrogen for an additional 5 minutes then heated to 100 °C for 2 hours. The reaction was diluted with water (20 mL) and extracted with 3:1 CHCl3 / IPA (5 X). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-10% MeOH / DCM) to give (R)-1-(3-(4-methyl-3-(3-methyl- 4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrirnidin-1-yl)piperidin-1 - yl)prop-2-en-1-one (75 mg, 47%). MS(ES): m / z 508.3 [M + H]+; HPLC purity: 97.0%;1H NMR (400 MHz, CDCl3) 6 8.87 (s, 1H), 7.88 (s, 1H), 7.53 (dd, J = 2.2, 0.9 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.72 - 6.49 (m, 1H), 6.30 (d, J = 17.5 Hz, 1 H), 5.70 (dd, J = 22.1 , 10.5 Hz, 1H), 4.96 (s, 1H), 4.77 (dd, J = 94.2, 15.0 Hz, 1H), 4.14 (dd, J = 69.6, 10.5 Hz, 1H), 3.94 - 3.35 (m, 4H), 3.30 - 2.78 (m, 1H), 2.69 (s, 3H), 2.44 - 2.39 (m, 4H), 2.27 (d, J = 12.7 Hz, 1H), 2.12 - 1.95 (m, 1H), 1.88 - 1 .69 (m, 1H).

[0388] Example 3 (R)-1 -(3-(4-ethyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

[0389] Tetrakis(triphenylphosphine)palladium(0) (3.33 mg, 2.88 μmol) was added to a stirred solution of (R)-1-(3-(3-bromo-4-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1- one (10.5 mg, 28.8 μmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)-1 H-benzo[d]imidazole (15.8 mg, 43.2 μmol) and potassium carbonate (12.0 mg, 86.5 μmol) in 1 ,4-dioxane (0.5 mL) at 100 °C under argon. The reaction mixture was concentrated, and the crude material was loaded onto Celite®. The material was purified by silica gel chromatography (0-10% MeOH-CH2CI2) to give (R)-1-(3-(4-ethyl-3-(3-methyl-4-((1-methyl-1H- benzo[d]imldazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 - one (4.3 mg, 29%). m / z 522.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.91 (s, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.36 (m, 3H), 7.1 1 (dd, J = 8.7, 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.57 (m, 1H), 6.30 (m, 1H), 5.69 (m, 1H), 4.97 - 4.65 (m, 1H), 4.23 - 3.80 (m, 1H), 3.87 (s, 3H), 3.42-3.20 (m, 1H), 2.99 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 2.01 (m, 2H), 1.27 (m, 3H).

[0390] Example 4 (R)-1-(3-(4-cyclopropyl-3-(3-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

[0391] Tetrakis(triphenylphosphine)palladium(0) (3.56 mg, 2.88 μmol) was added to a stirred solution of K2CO3(12.8 mg, 92.5 μmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)-1H-benzo[d]imldazole (16.8 mg, 46.2 μmol), and (R)-1-(3-(3-bromo- 4-cyclopropyl-1H-pyrazolo[3,4-d]pyrimldln-1-yl)plperidin-1-yl)prop-2-en-1-one (11 .6 mg, 30.8 μmol) In 1 ,4-dioxane (1 mL) at 100 °C under argon. The reaction mixture was concentrated, and the resulting crude material was loaded onto Celite®. The material was purified by silica chromatography (0-10% MeOH-DCM) to give (R)-1 -(3-(4-cyclopropyl-3-(3-methyl-4-((1 -methyl- 1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1-yl)prop-2-en- 1-one (3.6 mg, 22%). m / z 534.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.76 (s, 1H), 7.88 (s, 1H), 7.65 (m, 1H), 7.48 (m, 1H), 7.39 (m, 2H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.59 (m, 1H), 6.29 (m, 1H), 5.69 (m, 1H), 4.92-4.64 (m, 2H), 4.21 - 4.03 (m, 1H), 3.87-3.70 (m, 3H), 3.43-3.20 (m, 1H), 2.95-2.89 (m, 1H), 2.41 (s, 3H), 2.30 - 1.95 (m, 2H), 2.01 (m, 1H), 1 .75 (m, 1H), 1.42 (m, 2H), 1 .27-1.23 (m, 4H), 1.12 (m, 2H), 0.87 (m, 1H). Example 5

[0392] (R)-1 -(3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-tflpyrimidin-1 -yl)piperidin-1 -yl)propan-1 -one

[0393] HATU (63 mg, 0.17 mmo!) was added to a stirred solution of propionic acid (12 μL, 0.17 mmol), N-ethyl-N-isopropylpropan-2-amine (77 μL, 0.44 mmol), and (R)-4-methyl-3-(3-methyl-4- ((1-methy1-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.11 mmol) in DCM (2.2 mL). After 30 minutes at room temperature, the reaction was partitioned between saturated aqueous NaHCO3(10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (3 X 5 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH-DCM) to provide (R)-1 -(3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5- yl)oxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1-yl)propan-1 -one (34.3 mg, 61 %) as a solid. MS(ES): m / z 510.3 [M + H]+; HPLC purity: 98.1 %;1H NMR (400 MHz, CDCI3) δ 8.86 (d, J = 10.6 Hz, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.44 - 7.33 (m, 3H), 7.11 (dt, J = 8.8, 2.5 Hz, 1H), 6.92 (dd, J = 8.4, 3.9 Hz, 1H), 5.01 - 4.61 (m, 2H), 4.13 - 3.89 (m, 1H), 3.87 (s, 3H), 3.51 (dt, J = 148.6, 12.2 Hz, 1H), 3.22 - 2.70 (m, 1H), 2.69 (d, J = 6.9 Hz, 3H), 2.51 - 2.31 (m, 6H), 2.29 - 2.22 (m, 1H), 1 .98 (t, J = 17.0 Hz, 1H), 1 .73 (ddd, J = 13.0, 8.4, 4.2 Hz, 1H), 1.17 (q, J = 7.1 Hz, 3H).

[0394] Example 6 (R)-2-fluoro-1-(3-(4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

[0395] HATU (31.2 mg, 82.0 μmol) was added to a stirred solution of 2-fluoroacrylic acid (5.54 mg, 61 .5 μmol), (R)-4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1- (piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (18.6 mg, 41 .0 μmol) and N-ethyl-N- isopropylpropan-2-amine (14.6 μL, 82.0 μmol) in DMF (0.5 mL) at room temperature. After 30 minutes, the reaction was concentrated, and the crude material was purified by silica gel chromatography (0-10% MeOH-DCM) to afford (R)-2-ftuoro-1-(3-(4-methyl-3-(3-methyl-4-((1- methyl-1 H-benzo[d]lmidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperid!n-1- yl)prop-2-en-1-one (5.1 mg, 24%). MS(ES): m / z 526.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.88 (s, 1H), 8.45 (s, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.26 - 7.18 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.26 (dd, J = 47.5, 3.6 Hz, 1H), 5.16 - 4.97 (m, 2H), 3.98 (s, 3H), 3.83 - 3.12 (m, 1H), 2.92 (d, J = 30.9 Hz, 1H), 2.72 (s, 3H), 2.53 - 2.40 (m, 1H), 2.37 (s, 3H), 2.32 - 2.24 (m, 1H), 2.12 - 1 .98 (m, 1H), 1.81 (t, J = 12.9 Hz, 1H), 1 .56 - 1.35 (m, 3H).

[0396] Exampie 7 (R)-1 -(3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-yn-1-one

[0397] (R)-4-Methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 -

[0398] (piperidin-3-yl)-1H-pyrazoio[3,4-d]pyrimidine (10 mg, 22 μmol), 2-butynoicacid (2.9 μL, 33 μmol), and N-ethyl-N-isopropylpropan-2-amine (19 μL, 0.1 1 mmol) were dissolved in DMF (1 mL). T3P (33 μL, 50% wt, 55 μmol) was added dropwise at room temperature. After 30 minutes, the reaction was quenched by addition of H2O (1 mL) and extracted with EtOAc (3 X 5 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-8% MeOH-DCM) to yleld the product, (R)-1-(3-(4-methyl- 3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidin-1-yl)but-2-yn-1 -one (4.7 mg, 41 %). MS(ES): m / z 520.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.87 (d, J = 13.0 Hz, 1H), 7.88 (d, J = 1.5 Hz, 1H), 7.54 (ddd, J = 7.9, 2.2, 0.9 Hz, 1H), 7.44 - 7.32 (m, 3H), 7.11 (ddd, J = 8.7, 4.2, 2.3 Hz, 1H), 6.92 (dd, J = 8.3, 5.9 Hz, 1H), 4.97 (dtt, J = 20.2, 11 .2, 4.4 Hz, 1H), 4.79-4.42 (m, 2H), 3.87 (d, J = 1 .5 Hz, 3H), 3.65 (ddd, J = 167.6, 12.9, 10.8 Hz, 1H), 3.26 - 2.80 (m, 1H), 2.69 (d, J = 9.1 Hz, 3H), 2.42 (d, J = 3.0 Hz, 2H), 2.41 - 2.33 (m, 1H), 2.28 - 2.22 (m, 1H), 2.04 (s, 1H), 2.04 - 1 .96 (m, 1H), 1 .92 (s, 1H), 1 .76 (dddt, J = 26.4, 13.8, 8.4, 4.4 Hz, 1H), 1.38 - 1.18 (m, 2H).

[0399]

[0400] (S)-2-chloro-1-((R)-3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-1-one

[0401] (S)-2-Chloropropanoyl chloride (2.45 μL, 24.9 μmol) was added to a stirred solution of (R)-4-methy1-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 -(pipe ridin-3-yl)- 1H-pyrazolo[3,4-d]pyrimidine (11.3 mg, 24.9 μmol) and N-ethyl-N-isopropylpropan-2-amine (10.8 μL, 62.3 μmol) in DCM (0.25 mL) at 0 °C. The reaction was stirred for 5 minutes at 0 °C before being quenched with 10% K2CO3(1 mL). The biphasic mixture was extracted with DCM (3 X 5 mL), and the combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (1-8% MeOH-DCM) to give (S)-2-chloro- 1 -((R)-3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1 -yl)propan-1 -one (6.4 mg, 47%). m / z 544.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.87 (d, J = 6.0 Hz, 1H), 7.88 (s, 1H), 7.53 (t, J = 4.6 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.11 (d, J = 8.9 Hz, 1H), 6.92 (dd, J = 8.2, 3.4 Hz, 1H), 5.05 - 4.77 (m, 1H), 4.73 - 4.59 (m, 2H), 4.29 - 3.99 (m, 1H), 3.87 (s, 3H), 3.83 - 3.34 (m, 1H), 3.28 - 2.75 (m, 1H), 2.70 - 2.64 (m, 2H), 2.42 (d, J = 2.9 Hz, 3H), 2.27 (s, 2H), 2.05 - 1 .91 (m, 2H), 1 .70 (dd, J = 10.4, 6.5 Hz, 3H).

[0402] (R)-2-chloro-1-((R)-3-(4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-1-one (R)-2-Chloropropanoyl chloride (2.2 μL, 22 μmol) was added to a stirred solution of (R)- 4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 -(piperidin-3-yl)-1H- pyrazolo[3,4-d]pyrimidine (10 mg, 22 μmol) and N-ethyl-N-isopropylpropan-2-amine (9.6 μL, 55 μmol) in DCM (0.22 mL) at 0 °C. The reaction was stirred for 5 minutes at 0 °C before being quenched with 10% K2CO3(1 mL). The biphasic mixture was extracted with DCM (3 X 5 mL), and the combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (1-8% MeOH-DCM) to give (R)-2-chloro-1 -((R)- 3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1 -yl)piperidin-1 -yl)propan-1-one (5.8 mg, 48%). m / z 544.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.86 (d, J = 10.7 Hz, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.37 (dd, J = 15.1 , 9.9 Hz, 3H), 7.1 1 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.24 - 4.89 (m, 1H), 4.84 - 4.45 (m, 2H), 4.27 - 3.89 (m, 2H), 3.87 (s, 3H), 3.35 (m, 1H), 3.08 - 2.91 (m, 1H), 2.69 (s, 3H), 2.42 (s, 3H), 2.48 - 2.23 (m, 2H), 2.01 (m, 1H), 1.68 (dd, J = 27.6, 6.5 Hz, 3H).

[0403] ( R,E)-4-methoxy-1-(3-(4-methyl-3-(3-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3.4-cflpyrimidin-1 -yl)piperidin-1 -yl)but-2-en-1 -one

[0404] Step A: Oxalyl chloride (0.12 mL, 1 .4 mmol) was added at room temperature to a solution of (E)-4-methoxybut-2-enoic acid (139 mg, 1.2 mmol) in DCM (0.50 mL) and DMF (5 mg, 5 μL). The solution was stirred for 3 hours before using directly in the following step.

[0405] Step B: (R)-4-Methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imfdazol-5-yl)oxy)phenyl)-1 - (piperidin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidine (10.5 mg, 23.2 μmol) and N-ethyl-N- isopropylpropan-2-amine (16 μL, 92.8 μmol) were dissolved in DCM (0.5 mL) and cooled to 0 °C. A portion of the crude acid chloride solution from Step A (15 μL) was then added, and the reaction stirred for 5 minutes at 0 °C. The reaction was quenched with H2O (1 mL), and the biphasic mixture was extracted with DCM (3 X 5 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (1-8% MeOH-DCM) to give ( R,E)-4-methoxy-1-(3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)but-2-en-1 - one (5.5 mg, 43%). m / z 552.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.86 (s, 1H), 7.88 (s, 1H), 7.53 (dd, J = 2.3, 0.8 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.11 (dd, J = 8.7, 2.2 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.89 - 6.85 (m, 1H), 6.61 - 6.45 (m, 1H), 5.03 - 4.83 (m, 2H), 4.69 - 4.20 (m, 1H), 4.15 - 3.97 (m, 2H), 3.87 (s, 3H), 3.56 - 3.32 (m, 3H), 3.26 - 2.79 (m, 1H), 2.69 (s, 3H), 2.42 (s, 3H), 2.39 - 2.20 (m, 2H), 2.08 - 1 .95 (m, 1H), 1 .89 - 1 .67 (m, 2H). Example 11

[0406] (S)-1 -(3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

[0407] Step A: A microwave vial was charged with tert-butyl (R)-3- ((methylsulfonyl)oxy)piperidine-1 -carboxylate (130 mg, 0.47 mmol), 3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.23 mmol), Cs2CO3(160 mg, 0.49 mmol), and DMF (1.2 mL). The reaction mixture was heated to 90 °C and stirred for 20 hours. The reaction was then poured into water and extracted with EtOAc (3 X). The organic layers were, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-8% MeOH / DCM) to give tert-butyl (S)-3-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1-carboxylate (49 mg, 53%). MS(ES): m / z 396.1 [M + H]+.

[0408] Step B: TFA (0.19 mL, 2.5 mmol) was added to a stirred solution of tert-butyl (S)-3-(3- bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -carboxylate (49 mg, 0.12 mmol) in DCM (1.2 mL). The reaction mixture was stirred at room temperature for 45 minutes before quenching with 10% aqueous K2CO3. The aqueous phase was extracted with DCM (3 X). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product (S)-3- bromo-4-methyl-1-(piperidin-3-yl)-1 H-pyrazolo[3,4-d]pyrimidine (30 mg, 82%) was used directly in the next reaction without further purification. MS(ES): m / z 296.1 [M + H]+.

[0409] Step C: (S)-3-Bromo-4-methyl-1-(piperidin-3-yl)-1 H-pyrazoio[3,4-d]pyrimidine (30 mg, 0.10 mmol), DIPEA (0.05 mL, 0.30 mmol), and DCM (1 .0 mL) were added to a vial. The mixture was cooled to 0 °C before acryloyl chloride (0.01 mL, 0.12 mmol) was added. The reaction was stirred at this temperature for 1 hour. The reaction was directly concentrated and purified by silica gel chromatography (0-16% MeOH / DCM) to yleld (S)-1-(3-(3-bromo-4-methyl-1H-pyrazolo[3,4- d]pyrimidin-1 -yl)piperidin-1-yl)prop-2-en-1-one (17 mg, 48%). MS(ES): m / z 350.1 [M + H]+.

[0410] Step D: (S)-1-(3-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop- 2-en-1-one (12 mg, 0.03 mmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenoxy)-1H-benzo[d]imidazole (18 mg, 0.05 mmol), K3PO4(21 mg, 0.10 mmol), 1 ,4- dioxane (1 .0 mL), and H2O (0.2 mL) were added to a microwave vial. The vial was sparged with nitrogen for 5 minutes then Pd(Ph3)4(3.8 mg, 0.003 mmol) was added. The vial was sparged with nitrogen for an additional 5 minutes then heated to 100 °C for 1 hour. The reaction was directly concentrated and purified by silica gel chromatography (0-10% MeOH / DCM) to give (S)-1-(3-(4- methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (9.1 mg, 55%). MS(ES): m / z 508.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.87 (s, 1 H), 7.88 (s, 1H), 7.53 (dd, J = 2.2, 0.9 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.72 - 6.49 (m, 1H), 6.30 (d, J = 17.5 Hz, 1H), 5.70 (dd, J = 22.1 , 10.5 Hz, 1H), 4.96 (s, 1H), 4.77 (dd, J = 94.2, 15.0 Hz, 1H), 4.14 (dd, J = 69.6, 10.5 Hz, 1H), 3.94 - 3.35 (m, 4H), 3.30 - 2.78 (m, 1H), 2.69 (s, 3H), 2.44 - 2.39 (m, 4H), 2.27 (d, J = 12.7 Hz, 1H), 2.12 - 1 .95 (m, 1H), 1.88 - 1.69 (m, 1H).

[0411] Example 12

[0412] (R)-1 -(4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)azepan-1 -yl)prop-2-en-1 -one

[0413] Step A: TFA (0.13 mL, 20 eq., 1 .7 mmol) was added to a stirred solution of tert-butyl (R)- 4-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)azepane-1 -carboxylate (35 mg, 1 eq., 85 μmol) and DCM (0.43 mL, 1 eq., 85 μmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and dried on high vacuum overnight to afford (R)-1 -(azepan-4-yl)-3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidine (26 mg, 84 μmol, 98%), which was used in the next step without purification. MS(ES): m / z 310.1 , 312.1 [M + H]+.

[0414] Step B: (R)-1-(Azepan-4-yl)-3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine (26 mg, 1 eq., 85 μmol) was dissolved in DCM (2 mL), and DIEA (0.15 mL, 10 eq., 0.85 mmol) was added. The mixture was cooled to 0°C in an ice / water bath, and then acryloyl chloride (8.3 μL, 1.2 eq., 0.10 mmol) was added dropwise. The mixture was then stirred at 0 °C for 30 minutes. The crude reaction mixture was purified via column chromatography (12G RediSep, 1 to 5% MeOH / DCM) to afford (R)-1-(4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azepan-1-yl)prop-2-en-1- one (28.2 mg, 77.4 μmol, 91 %). MS(ES): m / z 364.1 , 366.1 [M + H]+.

[0415] Step C: (R)-1-(4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azepan-1-yl)prop- 2-en-1-one (10.0 mg, 1 eq., 27.5 μmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)-1H-benzo[d]imidazo!e (15.0 mg, 1 .5 eq., 41.2 μmol), palladiumtetrakis (3.17 mg, 0.1 eq., 2.75 μmol), and K2CO3as a 2M solution in H2O (41.2 μL, 3 eq., 82.4 μmol) was dissolved in 1 ,4-dioxane (410 μL, 1 eq., 27.5 μmol). The reaction mixture was sparged with nitrogen for 10 minutes before heating to 95 °C for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified over 12g silica cartridge, eluting with a gradient of 4% to 10% MeOH in DCM to afford (R)-1 -(4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)azepan-1-yl)prop-2-en-1-one (9.37 mg, 17.7 μmol, 64.5%, 98.6% purity). MS(ES): m / z 522.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.85 (d, J = 1 .5 Hz, 1H), 7.88 (s, 1H), 7.56 - 7.50 (m, 1H), 7.43 - 7.32 (m, 4H), 7.10 (dt, J = 8.7, 1 .9 Hz, 1H), 6.91 (dd, J = 8.4, 1.8 Hz, 1H), 6.62 (dd, J = 16.8, 10.4, 2.5 Hz, 1H), 6.38 (dd, J = 16.8, 7.8, 2.1 Hz, 1H), 5.72 (dt, J = 10.5, 1.6 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.10 - 3.99 (m, 1H), 3.87 (s, 3H), 3.85 - 3.54 (m, 3H), 2.69 (d, J = 1 .9 Hz, 3H), 2.61 - 2.46 (m, 1H), 2.41 (s, 3H), 2.39 - 2.24 (m, 1H), 2.20 - 2.04 (m, 2H), 2.00 - 1.81 (m, 1H).

[0416] Example 13

[0417] (S)-1 -(4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenvi)-1H- pyrazolo[3,4-d]pyrimidin-1 -yl)azepan-1 -yl)prop-2-en-1 -one

[0418] Step A: TFA (0.13 mL, 20 eq., 1.7 mmol) was added to a stirred solution of tert-butyl (S)- 4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azepane-1 -carboxylate (34 mg, 1 eq., 83 μmol) and DCM (0.41 mL, 1 eq., 83 μmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and dried on high vacuum overnight to afford (S)-1-(azepan-4-yl)-3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine (26 mg, 84 μmol, 100%), which was used in the next step without purification. MS(ES): m / z 310.1 , 312.1 [M + H]+.

[0419] Step B: (S)-1-(Azepan-4-yl)-3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidine (26 mg, 1 eq., 83 μmol) was dissolved in DCM (2 mL), and DIEA (0.14 mL, 10 eq., 0.83 mmol) was added. The mixture was cooled to 0 °C in an ice / water bath, and then acryloyl chloride (8.1 μL, 1 .2 eq., 0.10 mmol) was added dropwise. The mixture was then stirred at 0 °C for 30 minutes. The crude reaction mixture was purified via column chromatography (12G RediSep, 1 to 5% MeOH / DCM) to afford (S)-1 -(4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)azepan-1 -yl)prop-2-en-1 - one (29.4 mg, 80.7 μmol, 97%). MS(ES): m / z 364.1 , 366.0 [M + H]+.

[0420] Step C: (S)-1-(4-(3-Bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azepan-1-yl)prop- 2-en-1-one (10.0 mg, 1 eq., 27.5 μmol), 1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)-1H-benzo[d]imidazole (15.0 mg, 1 .5 eq., 41.2 μmol), palladiumtetrakls (3.17 mg, 0.1 Eq, 2.75 μmol), and K2CO3as a 2M solution in H2O (41 .2 μL, 3 eq., 82.4 μmol) was dissolved in 1 ,4-dioxane (410 μL, 27.5 μmol). The reaction mixture was sparged with nitrogen for 10 minutes before heating to 95 °C for 1 .5 hours, and then the reaction mixture was cooled to room temperature. The reaction was concentrated in vacuo, and the crude residue was purified over 12g silica cartridge, eluting with a gradient of 4% to 10% MeOH in DCM to afford (S)-1 -(4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)azepan-1-yl)prop-2-en-1-one (7.73 mg, 14.8 pmoi, 53.8%, 99.6% purity). MS(ES): m / z 522.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.85 (s, 1H), 7.88 (s, 1H), 7.56 - 7.49 (m, 1H), 7.43 - 7.30 (m, 4H), 7.10 (dt, J = 8.7, 1.9 Hz, 1H), 6.91 (dd, J = 8.4, 1.8 Hz, 1H), 6.62 (dd, J = 16.8, 10.4, 2.5 Hz, 1H), 6.38 (dd, J = 16.8, 7.8, 2.1 Hz, 1 H), 5.72 (dt, J = 10.5, 1 .7 Hz, 1H), 5.14 - 4.98 (m, 1H), 4.11 - 3.98 (m, 1H), 3.87 (s, 3H), 3.84 - 3.67 (m, 1H), 3.67 - 3.54 (m, 2H), 2.69 (d, J = 2.0 Hz, 3H), 2.60 - 2.47 (m, 1H), 2.41 (s, 3H), 2.38 - 2.22 (m, 1H), 2.19 - 2.05 (m, 2H), 1 .99 - 1 .80 (m, 1H).

[0421] Example 14 (R)-1 -(3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-

[0422] Pyrazolo[3.4-d|pyrimidin-1 -yl)pyrrolidin-1-yl)prop-2-en-1-one

[0423] Step A: A round bottom flask was charged with 3-bromo-4-methyl-1H-pyrazolo[3,4- d]pyrimidine (40 mg, 1 eq., 0,19 mmol), tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (70 mg, 2 eq., 0.38 mmol), triphenylphosphane (0.15 g, 3 eq., 0.56 mmol), and THF (2 mL), The mixture was cooled to 0 °C in an ice bath, and DIAD (0.12 mL, 3 eq., 0.56 mmol) was added dropwise. The mixture was allowed to warm to room temperature overnight. After 16 hours, the reaction was quenched with water and extracted with DCM (3 X). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0 to 16% MeOH in DCM) to yleld a mixture of alkylated product and triphenylphosphine oxide as 226.5 mg of material. This material was dissolved in DCM (1 mL), and trifiuoroacetic acid (0.29 mL, 20 eq., 3.8 mmol) was added. No reaction was observed after 20 minutes. Additional TFA (0.6 mL, 40 eq., 7.6 mmol) was added, and the reaction stirred for an additional 16 hours at room temperature. The reaction was quenched with 10% potassium carbonate aqueous solution and extracted with DCM thrice. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0 to 16% MeOH in DCM) to yleld (R)-3-bromo-4-methyl-1- (pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (9.7 mg, 34 μmol, 18%). m / z 282.1 / 284.0 [M + H]+. Step B: A scintillation via! was charged with (R)-3-bromo-4-methyl-1-(pyrrolidin-3-yl)-1H- pyrazolo[3,4-d]pyrimidine (9.7 mg, 1 eq., 34 μmol), DCM (1 mL), DIPEA (18 μL, 3 eq., 0.10 mmol), and then cooled to 0 °C. Acryloyl chloride (3.4 μL, 1 .2 eq., 41 μmol) was added as a single portion. After 20 minutes, the mixture was removed from the ice bath, and all volatiles were concentrated under reduced pressure. The crude material was purified directly by silica gel chromatography (0 to 16% MeOH in DCM) to yleld (R)-1-(3-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1 - yl)pyrrolidin-1-yl)prop-2-en-1-one (9.6 mg, 29 pmoi, 83%). m / z 336.1 [M + H]+.

[0424] Step C: A microwave vial was charged with (R)-1-(3-(3-bromo-4-methyl-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)pyrrolidin-1-yl)prop-2-en-1 -one (4.1 mg, 1 eq., 12 μmol), 1-methyl-5-(2-methyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1H-benz.o[d]imidazole (6.7 mg, 1.5 eq., 18 μmol), potassium phosphate tribasic (7.8 mg, 3 eq., 37 μmol), 1 ,4-dioxane (1 mL), and water (0.2 mL), The mixture was sparged with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (1 .4 mg, 0.1 eq., 1 .2 μmol) was added, and the mixture sparged again for 5 minutes with nitrogen. The mixture was heated to 100 °C for 1 hour. All volatiles were removed under reduced pressure, and the mixture was purified by silica gel chromatography (0 to 8% MeOH in DCM) to yleld (R)-1-(3-(4-methyl-3-(3-methyl-4-((1 -methyl- 1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)pyrrolidin-1-yl)prop-2-en- 1-one (3.6 mg, 7.3 μmol, 60%). m / z 494.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.87 (d, J = 3.1 Hz, 1H), 7.88 (s, 1H), 7.52 (ddd, J = 5.8, 2.2, 0.9 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.11 (ddd, J = 8.8, 2.2, 1 .4 Hz, 1H), 6.90 (dd, J = 8.3, 4.6 Hz, 1H), 6.63 - 6.25 (m, 2H), 5.79 - 5.60 (m, 2H), 4.22 - 3.97 (m, 3H), 3.87 (s, 3H), 3.85 - 3.68 (m, 1H) , 2.83 - 2.65 (m, 4H), 2.63 - 2.42 (m, 1H), 2.41 (d, J = 2.9 Hz, 3H).

[0425] Example 15

[0426] 1 -(4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolol[3,4- d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one

[0427] Step A: A 250 mL round-bottom flask was charged with 2-(diacetoxylodo)mesitylene (781.7 mg, 1 eq., 2.146 mmol), 2-( tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (1000 mg, 2.05 eq., 4.400 mmol), and toluene (100 mL). The flask was attached to a rotary evaporator with the water bath heated to 55 °C, and the solvent (and the generated acetic acid) was removed over 10 minutes. A second aliquot of toluene (75 mL) was added to the flask, and the evaporation step was repeated. The evaporation step was repeated for two more times with toluene (50 mL each time) to afford crude 2,2'-di-ferf-butyl 0'4,04-(mesityl-I3-iodanediyl) bis(2- azabicyclo[2.1.1]hexane-2,4-dicarboxylate) iodonium, which was carried into the next step without purification.

[0428] Step B: 1 ,4-Dioxane (27 mL) was added to a 40 mL vial containing 3-bromo-4-methyl-1 H- pyrazolo[3,4-d]pyrimidine (228.0 mg, 1 eq., 1.070 mmol), crude 2,2'-di- tert--butyl O'4,O4-(mesityl- 13-iodanediyl) bis(2-azabicyclo[2.1.1]hexane-2,4-dicarboxylate) (1.500 g, 2 eq., 2.140 mmol), lr(ppy)3(14.01 mg, 0.02 eq., 21.40 μmol), and bis[(Z)-1-methyl-3-oxo-but-1-enoxy]copper (168.0 mg, 0.6 eq, 642.0 μmol). The vial was stirred and sparged with nitrogen for 10 minutes, then sealed with parafilm, and irradiated in the integrated photoreactor (max fan speed, 700 rpm stir rate, 100% intensity, 450 nm). After 70 minutes of irradiation, the reaction was concentrated in vacuo, and the crude residue was purified over an 80 g silica cartridge, eluting with a gradient of 1 % to 4% MeOH in DCM to afford terf-butyl 4-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (429 mg, 1.00 mmol, 94%). m / z 394.1 / 396.1 [M + H]+.

[0429] Step C: TFA (1 .54 mL, 20 eq., 20.0 mmol) was added to a stirred solution of tert-butyl 4- (3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (429 mg, 1 eq., 1.00 mmol) and DCM (5.0 mL). The reaction mixture was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and dried on high vacuum overnight to afford 4-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicycfo[2.1 ,1 ]hexane, which was used in the next step without purification, m / z 294.1 / 296.0 [M + H]+.

[0430] Step D: 4-(3-Bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -y l)-2- azabicyclo[2.1.1]hexane (294 mg, 1 eq., 1 .00 mmol) was dissolved in DCM (20 mL), and DIPEA (1.74 mL, 10 eq., 10.0 mmol) was added. The mixture was cooled to 0 °C in an ice water bath, and then acryloyl chloride (97.5 μL, 1 .2 eq., 1.20 mmol) was added dropwise. The mixture was then stirred at 0 °C for 0.5 hours. The crude reaction was concentrated to 10 mL volume, and the mixture was loaded onto a 12 g silica samplet and purified via column chromatography (40 g RediSep, 1 to 6% MeOH / DCM) to afford 1-(4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1- yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one (215 mg, 617 μmol, 61.7%). m / z 348.1 / 350.1 [M + H]+.

[0431] Step E: 1 -((1r,4r)-4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2- azabicyclo[2.1.1]hexan-2-yl)prop22-en-1-one (10.0 mg, 1 eq., 28.7 μmol), 1-methyl-5-(2-methyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1 H-benzo[d]imidazole (15.7 mg, 1 .5 eq., 43.1 μmol), palladiumtetrakis (3.32 mg, 0.1 eq., 2.87 μmol), and aqueous K2CO3(43.1 μL, 2M, 3 eq., 86.2 μmol) were dissolved in 1 ,4-dioxane (429 μL). The reaction mixture was sparged with nitrogen for 10 minutes before heating to 95 °C for 3 hours. The reaction was cooled to room temperature, concentrated in vacuo, and the crude residue was purified over 12 g silica cartridge, eluting with a gradient of 4% to 10% MeOH in DCM to afford 1-(4-(4-methyl-3-(3-methyl-4-((1 - methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one (10.41 mg, 20.2 μmol, 70.3%). m / z 506.2 [M + H]+;

[0432] HPLC purity: 98.7%;1H NMR (400 MHz, CDCI3) δ 8.89 - 8.83 (m, 1H), 7.88 (s, 1 H), 7.56 - 7.50 (m, 1H), 7.42 - 7.31 (m, 3H), 7.14 - 7.07 (m, 1H), 6.95 - 6.87 (m, 1H), 6.60 - 6.38 (m, 2H), 5.79 - 5.70 (m, 1H), 5.08 - 4.62 (m, 1H), 4.27 - 4.22 (m, 2H), 3.87 (s, 3H), 2.99 - 2.88 (m, 2H), 2.68 (s, 3H), 2.42 (s, 3H), 2.37 - 2.20 (m, 2H).

[0433] Example 16

[0434] 1 -((4r,6s)-6-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1 -yl)-1 -azaspiro[3.31heptan-1 -yl)prop-2-en-1 -one

[0435] 1 -((4r,6s)-6-(4-Methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imldazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-1 -azasplro[3.3]heptan-1 -yl)prop-2-en-1 -one (8.7 mg) was synthesized using procedure of Example 2 replacing (S)-3-((methylsulfonyl)oxy)piperidine-1- carboxylate for tert-butyl (4s,6r)-6-((methylsulfonyl)oxy)-1-azaspiro[3.3]heptane-1-carboxylate. m / z 520.2 [M + H]+;1H NMR (400 MHz, CDCh) 5 8.87 - 8.81 (m, 1H), 7.87 (s, 1 H), 7.57 - 7.52 (m, 1H), 7.41 - 7.34 (m, 3H), 7.14 - 7.09 (m, 1H), 6.95 - 6.89 (m, 1H), 6.46 - 6.39 (m, 1H), 6.25 - 6.13 (m, 2H), 5.72 - 5.66 (m, 1H), 4.12 (t, J = 7.5 Hz, 2H), 3.87 (s, 3H), 3.51 - 3.41 (m, 2H), 3.07 - 2.97 (m, 2H), 2.66 (s, 3H), 2.52 (t, J = 7.5 Hz, 2H), 2.41 (s, 3H).

[0436] Example 17

[0437] 1 -((4s,6r)-6-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1 -yl)-1 -azaspiro[3.31heptan-1 -yl)prop-2-en-1 -one

[0438] 1 -((4s,6r)-6-(4-Methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imldazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-1 -azaspiro[3.3]heptan-1 -yl)prop-2-en-1 -one was synthesized using procedure of Example 14 replacing ferf-butyl (S)-3-hydroxypyrrolidine-1 -carboxylate for tert-butyl (4r,6s)-6-hydroxy-1 -azaspiro[3.3]heptane-1 -carboxylate. m / z 520.3 [M + H]+;1H NMR (400 MHz, CDCI3) 0 8.87 - 8.81 (m, 1H), 7.91 - 7.85 (m, 1 H), 7.62 - 7.55 (m, 1 H), 7.45 - 7.32 (m, 3H), 7.25 - 6.07 (m, 4H), 5.74 - 5.61 (m, 1H), 5.44 - 5.09 (m, 1H), 4.21 - 3.53 (m, 4H), 3.89 - 3.84 (m, 3H), 2.98 - 2.64 (m, 2H), 2.75 - 2.64 (m, 3H), 2.59 - 2.50 (m, 2H), 2.46 - 2.38 (m, 3H).

[0439] 1 -(4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4- dlpyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one

[0440] 1 -(4-(4-Methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one was synthesized using procedure of Example 14 replacing tert-butyl (S)-3-hydroxypyrrolidine-1 -carboxylate for tert-butyl 4- hydroxypiperidine-1 -carboxylate, m / z 508.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.86 (s, 1H), 7.88 (s, 1 H), 7.56 - 7.50 (m, 1H), 7.43 - 7.29 (m, 4H), 7.10 (dd, J = 8.7, 2.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.63 (dd, J = 16.8, 10.6 Hz, 1H), 6.31 (dd, J = 16.8, 1.9 Hz, 1H), 5.71 (dd, J = 10.6, 1.9 Hz, 1H), 5.14 (tt, J = 1 1.4, 4.2 Hz, 1H), 4.85 (d, J = 13.5 Hz, 1H), 4.21 (d, J = 13.9 Hz, 1H), 3.87 (s, 3H), 3.43 - 3.25 (m, 1H), 2.95 (t, J = 13.0 Hz, 1H), 2.70 (s, 3H), 2.43 - 2.39 (m, 5H), 2.13 (d, J = 12.9 Hz, 2H).

[0441] 1-((3S,5R)-3-fluoro-5-(4-methyl-3-(3-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1 H-pyrazolo[3,4-tf|pyrimidin-1-yl)plperidin-1-yl)prop-2-en-1-one

[0442] Step A: 1-((3R,5S)-3-(3-Bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5- fluoropiperidin-1-yl)prop-2-en-1-one was synthesized using procedure of Example 2, substituting tert-butyl (3S,5S)-3-fluoro-5-hydroxyplperidine-1-carboxylate (supplied from Enamine, CAS 2413846-81 -6) for (S)-3-((methylsulfonyl)oxy)piperidine-1 -carboxylate. Step B: A 5 mL microwave vial was charged with 1-((3R ,5S)-3-(3-bromo-4-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5-fluoropiperidin-1-yl)prop-2-en-1-one (12.7 mg, 34.5 μmol), 1- methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1 H- benzo[d]imidazole (18.8 mg, 51 .7 μmol), potassium phosphate tribasic (22.0 mg, 103 μmol), 1 ,4- dioxane (1 mL), and water (0.2 mL). The mixture was sparged with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)paliadium(0) (3.99 mg, 3.45 μmol) was added, and the mixture was sparged again with nitrogen for 5 minutes. The mixture was heated to 100 °C for 1 hour. The reaction was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluting with a gradient of 0 to 8% MeOH in DCM), followed by preparative reversed-phase HPLC (0 to 95% MeCN in water with 0.1 % TFA) to give the product, 1-((3S,5R)- 3-fluoro-5-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidaz.ol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1 -yl)prop-2-en-1 -one (3,5 mg, 19%). MS(ES): m / z = 526.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.89 (d, J = 6.1 Hz, 1H), 7.88 (s, 1H), 7.58 - 7.52 (m, 1H), 7.43 - 7.32 (m, 3H), 7.11 (td, J = 8.6, 2.2 Hz, 1H), 6.92 (t, J = 8.4 Hz, 1H), 6.45 - 6.22 (m, 2H), 5.71 - 5.50 (m, 1H), 5.46 - 5.25 (m, 1H) 5.01 - 4.68 (m, 3H), 4.10 - 3.66 (m, 5H), 2.69 (d, J = 3.4 Hz, 3H), 2.53 - 2.39 (m, 4H), 2.31 - 2.09 (m, 1H).

[0443] 1-((3 / ?,5R)-3-fiuoro-5-(4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[dfimidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1 -one

[0444] Step A: 1-((3R,5R)-3-(3-Bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5- fluoropiperidin-1-yl)prop-2-en-1-one was synthesized using the procedure of Example 2, substituting tert-butyl (3f?,5S)-3-fluoro-5-hydroxypiperidine-1 -carboxylate for (S)-3- ((methylsulfonyl)oxy)piperidine-1 -carboxylate (supplied from Enamine, CAS 2413848-18-5).

[0445] Step B: A 5 mL microwave vial was charged with 1-((3R,5R)-3-(3-bromo-4-methyl-1 H- pyrazolo[3,4-d]pyrimidin-1-yl)-5-f!uoropiperidin-1-yl)prop-2-en-1-one (10.8 mg, 29.3 μmol), 1 - methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1 H- benzo[d]imidazole (16,0 mg, 44.0 μmol), potassium phosphate tribasic (18.7 mg, 88.0 μmol), 1 ,4- dioxane (1 mL), and water (0.2 mL). The mixture was sparged with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(Q) (3.39 mg, 2.93 μmol) was added, and the mixture was sparged again with nitrogen for 5 minutes. The mixture was heated to 100 °C for 1 hour. The reaction was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluting with a gradient of 0 to 8% MeOH in DCM) to give the product, 1- ((3R,5R)-3-fluoro-5-(4-methyl-3-(3-methyl-4-((1 -methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (7.5 mg, 49%). MS(ES): m / z ~ 526.2, [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.87 (s, 1H), 7.87 (s, 1H), 7.56 - 7.51 (m, 1H), 7.48 - 7.29 (m, 3H), 7.10 (ddd, J = 14.1 , 8.7, 2.3 Hz, 1H), 6.90 (dd, J = 18.2, 8.4 Hz, 1H), 6.61 (br s,1H), 6.37 (dd, J = 16.8, 1.8 Hz, 1H), 5.78 (br s, 1H), 5.14 - 4.86 (m, 2H), 4.72 (dtt, J = 47.3, 10.4, 5.1 Hz, 1H), 4.46 - 4.12 (m, 1H), 3.91 - 3.61 (m, 4H), 3.38 - 3.15 (m, 1H), 2.80 - 2.57 (m, 5H), 2.43 (s, 3H).

[0446] 1 -((1 S,4R,6R)-6-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one

[0447] Step A: DIPEA (408 μL, 1 eq., 2.34 mmol) was added to a solution of tert-butyl (1 S,4R,6S)- 6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 1 eq., 2.34 mmol) in DCM (4.69 mL). The reaction was cooled to 0 °C before adding mesyl chloride (219 μL, 1 .2 eq., 2,81 mmol). The reaction mixture was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with NaHCO3, and the layers separated. The organic layer was subsequently washed with NaHCO3and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue, tert-butyl (1 S,4R,6S)-6-((methylsulfonyl)oxy)-2-azabicyclo[2.2.1]heptane-2- carboxylate, was used directly without further purification.1H NMR (400 MHz, CDCI3) δ 4.21 (d, J = 54.6 Hz, 1H), 3.99 (dd, J = 29.9, 7.1 Hz, 1H), 3.18 (q, J = 13.7, 11 .3 Hz, 1H), 2.98 - 2.72 (m, 1H), 2.56 (d, J = 32.9 Hz, 1H), 2.12 (dd, J = 14.4, 7.4 Hz, 1H), 1.99 - 1.79 (m, 2H), 1.65 (d, J = 17.3 Hz, 1H), 1.46 (d, J = 10.2 Hz, 12H).

[0448] Step B: tert-Butyl (1 S,4R,6S)-6-((methylsulfonyl)oxy)-2-azabicyclo[2.2.1]heptane-2- carboxylate (0.14 g, 2 eq., 0.47 mmol), 3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidine (50 mg, 1 eq., 0.23 mmol), cesium carbonate (0.15 g, 2 eq., 0.47 mmol), and N, N-dimethylformamide (1 .2 mL) were charged to a 100 mL recovery flask. The mixture was stirred at 100 °C for 2 hours. The mixture was diluted with ethyl acetate and washed with brine. Organics were dried over sodium sulfate and purified by column chromatography (Redisep 12 g, 0-40% MeOH / DCM) to furnish tert-butyl (1 S,4R,6R)-6-(3-bromo-4-rnethyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (65.8 mg, 161 μmol, 69%). MS(ES): m / z 408.1 , 410.1 [M

[0449] Step C: TFA (248 μL, 20 eq., 3.22 mmol) was added to a stirred solution of tert-butyl (1 S,4R,6R)-6-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.2.1 ]heptane- 2-carboxylate (65.8 mg, 1 eq., 161 μmol) in DCM (1.61 mL). The reaction was stirred for 1 hour at room temperature. The reaction was diluted with DCM and quenched with Na2CO3. The reaction was washed with Na2CO3, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The product, 1-((1 S,4R,6R)-2-azabicyclo[2.2.1]heptan-6-yl)-3-bromo- 4-methyl-1 H-pyrazolo[3,4-d]pyrimidine, was used directly in the next reaction without further purification. MS(ES): m / z 308.0, 310.0 [M + H]+.

[0450] Step D: Acryloyl chloride (10.8 μL, 1 eq., 132 μmol) was added to a stirred solution of 1 - ( (1 S,4R,6R)-2-azabicyclo[2.2.1]heptan-6-yl)-3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidine (40.8 mg, 1 eq., 132 μmol) and DIPEA (69.2 μL, 3 eq., 397 μmol) in DCM (1 .32 mL) at 0 °C. The reaction was stirred for 5 minutes at this temperature. The reaction was partitioned between 10% K2CO3and DCM. The aqueous phase was extracted with DCM (10 mL X 3). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified over 4 g silica cartridge, eluting with a gradient of 5% to 50% of a 20% MeOH / DCM solution in DCM to afford 1-( (1 S,4R,6R)-6-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)- 2-azabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (42.9 mg, 118 μmol, 89.5%). MS(ES): m / z 362.0, 364.0 [M + H]+.

[0451] Step E: 1 -( (1 S,4R,6R)-6-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2- azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (14.3 mg, 1 eq., 39.5 μmol), 1-methyl-5-(2-methyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1H-benzo[d]imidazole (21 .6 mg, 1 .5 eq., 59.2 μmol), tetrakis(triphenylphosphine)palladlum(0) (4.56 mg, 0.1 eq., 3.95 μmol), and K2CO3as a 2M solution in H2O (59.2 μL, 3 eq., 1 18 μmol) was dissolved in 1 ,4-dioxane (395 μL, 0.1 molar, 1 eq., 39.5 μmol). The reaction mixture was sparged with argon for 10 minutes before heating to 100 °C for 3 hours. Then the reaction mixture was cooled to room temperature. The reaction was diluted with H2O and DCM. The aqueous phase was then extracted with DCM (3 X), the extracts dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified over 4 g silica cartridge, eluting with a gradient of 0% to 10% MeOH in DCM to afford 1 -( (1 S,4R,6R)-6-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrlmidin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1 -one (10.8 mg, 20.8 μmol, 52.6%). MS(ES): m / z 520.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.93 - 8.87 (m, 1H), 7.88 (s, 1H), 7.55 - 7.49 (m, 1H), 7.43 - 7.30 (m, 3H), 7.12 (dt, J = 8.6, 2.2 Hz, 1H), 6.91 (dd, J = 8.3, 3.7 Hz, 1H), 6.80 (dd, J = 16.8, 10.3 Hz, 1H), 6.53 - 6.32 (m, 1H), 5.76 (ddd, J = 14.8, 10.3, 2.1 Hz, 1H), 5.38 - 5.14 (m, 1H), 4.98 - 4.47 (m, 1H), 3.87 (s, 3H), 3.61 - 3.44 (m, 1H), 3.38 - 3.25 (m, 1H), 2.94 - 2.86 (m, 2H), 2.72 - 2.66 (m, 3H), 2.63 - 2.27 (m, 1H), 2.42 (s, 3H), 2.26 ~ 2.11 (m, 1H), 1.78 - 1 .68 (m, 1H).

[0452] Example 22

[0453] 1-((1 / ?,3r,5S)-3-(4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

[0454] Step A: A solution of tert-butyl exo-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1.10 g, 4.84 mmol, sourced from Combi-Blocks) and CH2CI2(9.68 mL) was cooled to 0 °C. Then triethylamine (1.01 mL, 7.26 mmol) was added, followed by methanesulfonyl chloride (431 μL, 5.57 mmol). The mixture was stirred for 1 hour and then diluted with CH2CI2. The mixture was then washed with water, and the organic layer dried over Na2SO4, filtered, and concentrated to a an oil. The crude product was then purified via column chromatography (10 to 80% EtOAc / heptane) to afford the product, tert-butyl 3-exo-((methylsulfonyl)oxy)-8- azabicyclo[3.2.1]octane-8-carboxylate, as an oil that solidified under vacuum to a white solid.1H NMR (400 MHz, CDCI3) δ 4.96 (t, J = 4.8 Hz, 1H), 4.23 - 4.07 (m, 2H), 2.94 (s, 3H), 2.23 - 2.08 (m, 2H), 2.03 - 1 .90 (m, 6H), 1 .39 (s, 9H).

[0455] Step B: A vial was charged with tert-butyl 3-exo-((methylsulfonyl)oxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.70 mmol), 3-bromo-4-methyl-1H-pyrazolo[3,4- d]pyrimidine (430 mg, 1.4 mmol), Cs2CO3(459 mg, 1 ,4 mmol), and DMF (3.5 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction was then poured into water and extracted with EtOAc (3 X). The organic layers were washed with brine (2 X), dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-8% MeOH / DCM) to give tert-butyl (1 R,3s,5S)-3-(3-bromo-4-methyl-1H-pyrazolo[3,4- d]pyrimidin-1 -yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (259 mg, 87%). MS(ES): m / z 422.1 [M

[0456] Step C: TFA (0.95 mL, 12 mmol) was added to a stirred solution of tert-butyl (1 R,3s,5S)- 3-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (259 mg, 0.61 mmol) in DCM (3.1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with DCM and quenched with Na2CO3. The reaction was washed with Na2CO3(2 X), and the organic layers were dried over Na2SO4, filtered, and concentrated. The product 1-( (1 R,3s,5S)-8-azabicycio[3.2.1]octan-3-yl)-3-bromo-4-methyl-1H-pyrazolo[3,4- d]pyrimidine (196 mg, 98%) was used directly in the next reaction without further purification. MS(ES): m / z 322.0 [M + H]+. Step D: 1-((1 / ?,3s,5S)-8-Azabicyclo[3.2.1]octan-3-yl)-3-bromo-4-methyl-1 H-pyrazolo[3,4- d]pyrimidine (196 mg, 0.61 mmol), DIPEA (0.32 mL, 1.8 mmol), and DCM (3.0 mL) were added to a vial. The mixture was cooled to 0 °C, before a 1 M solution of acryloyl chloride (0.61 mL, 0.61 mmol) in DCM was added. The reaction was stirred at this temperature for 5 minutes before partitioning between 10% aqueous K2CO3and DCM. The aqueous phase was extracted with DCM (3 X). The organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-15% MeOH / DCM) to yleld 1-((1 R,3s,5S)-3- (3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one (143 mg, 62%). MS(ES): m / z 376.0 [M + H]+.

[0457] Step E: 1 -((1 f?,3s,5S)-3-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (120 mg, 0.32 mmol), 1-methyl-5-(2-methyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1H-benzo[d]imidazole (174 mg, 0.48 mmol), K2CO3(88 mg, 0.64 mmol), Pd(Ph3)4(37 mg, 0.03 mmol), 1 ,4-dioxane (3.2 mL), and H2O (0.21 mL) were charged to a vial. The mixture was sparged with argon for 10 minutes, capped, and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and DCM. The aqueous phase extracted with DCM (3 X). The organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography. The crude material was then purified by silica gel chromatography (0-10% MeOH / DCM) to afford 1 -((1 f?,3s,5S)-3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol- 5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1 ]octan-8-yl)prop-2-en-1 - one (87 mg, 51 %). MS(ES): m / z 534.2 [M + H]+; HPLC purity: 96.0%;1H NMR (400 MHz, CDCI3) δ 8.84 (s, 1H), 7.88 (s, 1H), 7.56 - 7.50 (m, 1H), 7.42 - 7.33 (m, 3H), 7.13 (dd, J = 8.6, 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.57 (dd, J = 16.8, 10.1 Hz, 1H), 6.45 (dd, J = 16.8, 2.2 Hz, 1H), 5.75 (dd, J = 10.1 , 2.2 Hz, 1H), 5.11 (ddd, J = 12.3, 7.9, 4.6 Hz, 1H), 4.89 (m, 1H), 4.44 (m, 1 H), 3.87 (s, 3H), 2.70 (s, 3H), 2.77 - 2.49 (m, 3H), 2.42 (s, 3H), 2.24 - 1 .92 (m, 5H).

[0458] Example 23

[0459] 1 -((1 R,3s,5S)-3-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo [rf|imidazol-5-yl)oxy)phenyl)-1H~ pyrazolo[3,4-d|pyrimidin-1 -yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1 -one

[0460] 1 -((1 R,3s,5S)-3-(4-Methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5- yl)oxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (7.1 mg, 49%) was synthesized using the procedure of Example 22 replacing tert-butyl 3-exo- ((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate with tert-butyl 3-endo- ((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS(ES): m / z 534.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.85 (s, 1 H), 7.87 (s, 1 H), 7.54 - 7.49 (m, 1H), 7.41 (dd, J = 2.3, 0.6 Hz, 1H), 7.37 (dd, J = 8.7, 0.6 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.10 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1 H), 6.55 (dd, J = 16.8, 10.2 Hz, 1H), 6.43 (dd, J = 16.8, 2.2 Hz, 1H), 5.73 (dd, J = 10.2, 2.2 Hz, 1H), 5.48 (tt, J = 1 1 .5, 5.5 Hz, 1H), 5.01 - 4.96 (m, 1H), 4.57 - 4.52 (m, 1H), 3.87 (s, 3H), 2.68 (s, 3H), 2.65 - 2.49 (m, 2H), 2.41 (s, 3H), 2.29 - 1 .97 (m, 6H).

[0461] Example 24

[0462] 1-((1f?.3r.5S)-3-(3-(3-chloro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1 H- pyrazolo[3,4-d]pyrimidin-1 -yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1 -one

[0463] Tetrakis(triphenylphosphine)palladium(0) (3.56 mg, 2.88 μmol) was added to a stirred solution of 5-(2-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1 -methy-1H- benzo[d]imidazole (31 mg, 80 μmol) potassium carbonate (22 mg, 0.16 mmol) and 1-((1 / ?,3s,5S)- 3-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en- 1-one (20 mg, 53 μmol) in 1 ,4-dioxane (0.5 mL) at 100 °C under argon. The reaction mixture was concentrated. The resulting crude material was loaded onto Celite®, and the material was purified by silica chromatography (0-10% MeOH-DCM) to give 1-( (1 R,3s,5S) -3-(3-(3-chloro-4-((1-methyl- 1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (5 mg, 20%). m / z 554.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.86 (s, 1H), 7.91 (s, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.49 (m, 1H), 7.42 (m, 2H), 7.18 (dd, J = 8.7, 2.3 Hz, 1H), 7.00 (m, 1H), 6.56 (dd, J = 16.8, 10.2 Hz, 1H), 6.45 (dd, J = 16.8 ,2.2 Hz, 1H), 5.75 (dd, J = 10.1 , 2.2 Hz, 1H), 5.34 (m, 1H), 5.14 (m, 1H), 4.90 (m, 1H), 4.44 (m, 1H), 3.89 (s, 3H), 2.71 (s, 3H), 2.55 (m, 3H), 2.09 (m, 4H).

[0464] Example 25

[0465] 1 -((1 R,3r,5S)-3-(3-(2-fluoro-3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[3,4-d]Pyrimidin-1-yl)-8-azabicvclo[3.2.1]octan-8-yl)prop-2-en-1-one Tetrakis(triphenylphosphlne)palladium(0) (5.2 mg, 4.5 μmol) was added to a stirred solution of 1-((1 R,3s,5S) -3-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidiri-1-yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (17 mg, 45 μmol), potassium carbonate (19 mg, 0.14 mmol) and 5-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1 - methyl-1H-benzo[d]imidazole (26 mg, 68 μmol) in 1 ,4-dioxane (0.5 mL) at 100 °C under argon. The reaction mixture was concentrated. The resulting crude material was loaded onto Celite® and purified by silica chromatography (0-10% MeOH-DCM) to give 1-((1 R,3r,5S)-3-(3-(2-fluoro- 3-methyl-4-((1-methyl-1 H-benzo[^imidazol-5-yl)oxy)phenyl)-4-methyl-1H-pyrazolo[3,4- d]pyrimidin-1 -yl)-8-azabicyclo[3.2.1 ]octan-8-yl)prop-2-en-1-one (4.2 mg, 17%). m / z 552.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.85 (s, 1H), 7.90 (s, 1H), 7.42 (m, 2H), 7.13 (dd, J = 8.6, 2.3

[0466] Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.56 (dd, J = 16.8, 10.2 Hz, 1 H), 6.44 (dd, J = 16.8, 2.2 Hz, 1H)

[0467] 5.35 (m, 1H), 5.12 (m, 1H), 4.87 (m, 1H), 4.42 (m, 1H), 3.88 (s, 3H), 2.72 (m, 1H), 2.63 (d, J =

[0468] 2.1 Hz, 1H), 2.53 (m, 4H), 2.36 (d, J = 2.1 Hz, 3H), 2.12 (m, 8H).

[0469] 1 -((1 R,3r,5S)-3-(3-(3-fiuoro-5-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

[0470] Tetrakis(triphenylphosphine)palladium(0) (3.1 mg, 2.7 μmol) was added to a stirred solution of K2CO3(11 mg, 80 μmol), 1-( (1 R,3s,5S)-3-(3-bromo-4-methyl-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)-8-azabicyclo[3,2.1 ]octan-8-yl)prop-2-en-1-one (10 mg, 27 μmol) and 5-(2-fiuoro- 6-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1 -methyl-1H- benzo[d]imidazole (12 mg, 32 μmol) in 1 ,4-dioxane (0.5 mL) at 100 °C under argon. The reaction mixture was concentrated. The resulting crude material was loaded onto Celite® and purified by silica chromatography (0-10% MeOH-DCM) to give 1-((1 R,3r,5S)-3-(3-(3-fluoro-5-methyl-4-((1- methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-8- azablcyclo[3.2.1]octan-8-yl)prop-2-en-1-one (3.2 mg, 22%). m / z 552.3 [M + H]+; HPLC purity: 98.1 %;1H NMR (400 MHz, CDCI3) δ 8.87 (s, 1H), 7.84 (s, 1H), 7.35 (m, 3H), 7.17 (m, 2H), 6.57 (dd, J = 16.8, 10.2 Hz, 1H), 6.45 (dd, J = 16.8, 2.2 Hz, 1H), 5.76 (dd, J = 10.1 , 2.2 Hz, 1H), 5.14 (m, 1H), 4.91 (m, 1H), 4.45 (m, 1H), 3.85 (s, 3H), 2.75 (s, 3H), 2.55 (m, 4H), 2.34 (s, 3H), 2.10 (m, 3H). Example 27

[0471] 1 -((1 R,3r,5S)-3-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

[0472] Tetrakis(triphenylphosphine)palladium(0) (9.98 mg, 8.6 μmol) was added to a stirred solution of 1-( (1 R,3S,5S) -3-(3-bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-8- azablcyclo[3.2.1]octan-8-yl)prop-2-en-1-one (32.5 mg, 86.4 μmol), potassium carbonate (38.2 mg, 276 μmol) and 5-(2-chloro-6-fluora-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)- 1-methyl-1 H-benz.o[d]imidaz.ole (41 .7 mg, 104 μmol) in 1 ,4-dioxane (1 mL) at 100 °C under argon. The reaction mixture was concentrated. The resulting crude material was loaded onto Ceiite® and purified by silica chromatography (0-10% MeOH-DCM) to give 1-( (1 R,3r,5S)-3-(3-(3-chloro- 5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H-pyrazolo[3,4- d]pyrimidin-1 -yl)-8-azabicyclo[3.2.1 ]octan-8-yl)prop-2-en-1-one (10.7 mg, 35%). m / z 572.3 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.89 (s, 1H), 7.85 (s, 1H), 7.60 (m, 1H), 7.43 (dd, J = 10.1 , 2.0 Hz, 1H), 7.37 (m, 1H), 7.22 (m, 2H), 6.57 (dd, J = 16.8, 10.1 Hz, 1H), 6.46 (dd, J = 16.8, 2.2 Hz, 1H), 5.76 (m, 1H), 5.15 (m, 1H), 4.91 (m, 1H), 4.46 (m, 1H), 3.86 (s, 3H), 2.77 (s, 4H), 2.54 (m, 3H), 2.08 (m, 4H).

[0473] The compounds in Table 1 were prepared using analogous processes to the above Examples as noted In Preparation Method, including modification as appropriate.

[0474] Table 1

[0475] Example 51

[0476] 1-((1 R,3r,5S)-3-(3-(3-fluoro-5-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

[0477] Step A: tert-Butyl (1 R,3r,5S)-3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (635.8 mg, 2.80 mmol), 3-bromo-4-methyl-1 H-pyrazolo[4,3-c]pyridine (197.7 mg, 932 μmol), DIAD (544 μL, 2.80 mmol), and triphenylphosphine (734 mg, 2.80 mmol) were dissolved in THF (9.3 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give a residue, which was precipitated in EtOAc and hexane. The solid was filtered out. The filtrate was concentrated and purified by column chromatography purified over 12g silica cartridge, eluting with a gradient of 0% to 10% MeOH in DCM to furnish tert-butyl (1 R,3s,5S)-3- (3-bromo-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (317 mg, 81 %). m / z 435.1 ; 437.0 [M + H]+.

[0478] Step B: TFA (1.16 mL, 15.0 mmol) was added to a stirred solution of tert-butyl (1 R,3s,5S)- 3-(3-bromo-4-methyl-1 H-pyrazoio[4,3-c]pyridin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (317 mg, 752 μmol) in DCM (3.8 mL). The reaction mixture was stirred for 30 minutes at room temperature, before partitioning between DCM and Na2CO3, and stirred for 15 minutes to freebase the resulting salt. The aqueous layer was then extracted (3 X) with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-((1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl)-3-bromo-4-methyl-1 H-pyrazolo[4,3-c]pyridine (200 mg, 83%), m / z 321.0; 323.0 [M + H]+.

[0479] Step C: Acryloyl chloride (43.0 μL, 529 μmol) was added to a stirred solution of 1- ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-3-bromo-4-methyl-1H-pyrazoio[4,3-c]pyridine (170 mg, 529 μmol) and DIPEA (277 μL, 1 .59 mmol) in DCM (5.3 mL) at 0 °C. The reaction was stirred for 5 minutes at this temperature. The crude residue was directly concentrated and purified over 12 g silica cartridge, eluting with a gradient of 0% to 10% MeOH in DCM to afford 1-((1 R,3s,5S)- 3-(3-bromo-4-methyl-1 H-pyrazolo[4,3-c]pyridin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one (135 mg, 68%). m / z 375.1 ; 377.1 [M + H]+.

[0480] Step D: 1 -( (1 R,3r,5S)-3-(3-Bromo-4-methyl-1H-pyrazolo[4,3-c]pyridin-1 -yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-eri-1-one (15 mg, 40 μmol), 5-(2-fluoro-6-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaboroian-2-yl)phenoxy)-1-methyl-1 H-benzo[d]imidazo!e (23 mg, 60 μmol), palladiumtetrakis (4.6 mg, 4.0 μmol), and K2CO3(11 mg, 80 μmol) were dissolved in 1 ,4-dioxane (0.40 mL) and H2O (0.04 mL). The reaction mixture was sparged with argon for 10 minutes before heating to 95 °C for 3 hours. The reaction mixture was cooled to room temperature before directly concentrating. The crude residue was purified over 4 g silica cartridge, eluting with a gradient of 0% to 10% MeOH in DCM to afford 1-((1 R,3r,5S)-3-(3-(3-fluoro-5-methy1-4-((1 -methyl-1 H- benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1 H-pyrazolo[4,3-c]pyridin-1-yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (8.6 mg, 39%). m / z 551.2 [M + H]+;1H NMR (400 MHz, CDCI3) δ 8.32 (d, J = 6.1 Hz, 1H), 7.83 (s, 1H), 7.35 (dd, J = 8.2, 1.1 Hz, 1H), 7.32 - 7.27 (rn, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 6.1 Hz, 1H), 6.58 (dd, J = 16.8, 10.1 Hz, 1H), 6.47 (dd, J = 16.8, 2.3 Hz, 1H), 5.78 (dd, J = 10.1 , 2.3 Hz, 1H), 4.92 - 4.84 (m, 1H), 4.72 (tt, J = 7.6, 4.8 Hz, 1H), 4.49 - 4.44 (m, 1H), 3.85 (s, 3H), 2.77 (dt, J = 14.2, 7.0 Hz, 1H), 2.69 (s, 3H), 2.62 - 2.47 (m, 2H), 2.38 - 2.22 (m, 5H), 2.19 - 1 .94 (m, 3H). 19F NMR (376 MHz, CDCI3) 5 -128.95.

[0481] 1-(4-(3-(3-fiuoro-5-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenvi)-4-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one

[0482] Step A: A 250 mL round-bottom flask was charged with mesityl-13-iodanediyl diacetate (185 mg, 507 μmol), 2- tert- butoxycarbonyl)-1-methyl-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (255 mg, 1.06 mmol), and toluene (100 mL). The flask was attached to a rotary evaporator with the water bath heated to 55 °C, and the solvent (and the generated acetic acid) was removed over a time period of about 10 minutes. A second aliquot of toluene (75 mL) was added to the flask, and the evaporation step was repeated. Repeat the evaporation step two more times with toluene (50 mL each time), lodonium was carried into the next step without purification. Crude iodonium was dissolved in 1 ,4-dioxane (10.6 mL) and added to a 20mL vial containing copper(ll) (Z)-4-oxopent-2-en-2-olate (66.3 mg, 253 μmol), lr(ppy)3(1 1.1 mg, 16.9 μmol), and 3-bromo-4- methyl-1 H-pyrazolo[3,4-d]pyrimidine (90.0 mg, 422 μmol). The mixture was stirred and sparged with Ar for 10 minutes, then sealed with parafilm and irradiated in an integrated photoreactor (max fan speed, 700 rpm stir rate, 100% intensity, 450 nm). After 1 hour, the reaction was concentrated in vacuo, the crude residue was purified by reverse phase ISCO over 30 g C18 cartridge, eluting with a gradient of 20% to 100% acetonitrile with 0.1 % TFA in water with 0.1 % TFA. Desired fractions were combined, basified with saturated NaHCO3, and extracted with DCM. The organics were dried with sodium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 4-(3-bromo- 4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-1 -methyl-2-azabicyclo[2.1 .1 ]hexane-2-carboxylate (12.0 mg, 7%). m / z (APCI-pos) M+1 = 408.1 / 410.1 .

[0483] Step B: 2,2,2-Trifluoroacetic acid (0.13 mL, 1.8 mmol) was added to a stirred solution of tert-butyl 4-(3-bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2- azabicyclo[2.1.1]hexane-2-carboxylate (24 mg, 59 μmol) in DCM (1 .2 mL) for 1 hour. DCM (5 mL) and 2M aqueous Na2CO3(5 mL) was added to the reaction and stirred for 15 minutes to freebase the resulting salt. The aqueous layer was then extracted with DCM (3 X 5 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-(3-bromo-4-methyl- 1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2-az.abicyclo[2,1 ,1]hexane (16.0 mg, 88%), which was used in the next step without further purification, m / z (APCI-pos) M+1 = 308.1 / 310.1 .

[0484] Step C: 4-(3-Bromo-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-1 -methyl-2- azabicyclo[2.1.1]hexane (16 mg, 52 μmol) was dissolved in DCM (0.52 mL), and i-Pr2EtN (27 μL, 3 equivalents, 0.16 mmol) was added. The mixture was cooled to 0 °C in an ice / water bath, and then acryloyl chloride (52 μL, 1 molar in DCM, 52 μmol) was added dropwise. The mixture was then stirred at 0 °C for 5 minutes. The reaction mixture was directly purified via column chromatography (4G RediSep, 0 to 4% MeOH / DCM) to afford 1-(4-(3-bromo-4-methyl-1 H- pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one (14.1 mg, 75%). m / z (APCI-pos) M+1 = 362.1 / 364.0.

[0485] Step D: 1 -(4-(3-Bromo-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-1 -methyl-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one (4.5 mg, 12 μmol), 5-(2-fluoro-6-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-1-methyl-1H-benzo[d]imidazole (9.5 mg, 25 μmol), palladiumtetrakis (1.4 mg, 1.2 μmol), and K2CO3(19 μL, 2 molar solution in HZO, 37 μmol) was dissolved in 1 ,4-dioxane (0.19 mL). The reaction mixture was sparged with argon for 10 minutes before heating to 100 °C for 4 hours, and then cooled to room temperature. The solids were filtered off, and the reaction was concentrated in vacuo. The crude residue was purified over a 12g silica cartridge, eluting with a gradient of 2% to 9% MeOH in DCM to provide 1-(4-(3-(3- fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1 H-pyrazolo[3,4- d]pyrimidin-1 -yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one (4.6 mg, 69%). m / z (APCI-pos) M+1 = 538.2;1H NMR (400 MHz, CDCI3) δ 8.89 (s, 1H), 7.84 (s, 1H), 7.38 - 7.27 (m, 3H), 7.19 - 7.11 (m, 2H), 6.52 (dd, J = 16.9, 10.0 Hz, 1 H), 6.40 (dd, J = 16.7, 2.2 Hz, 1 H), 5.71 (dd, J = 10.0, 2.2 Hz, 1 H), 4.28 (s, 2H), 3.85 (s, 3H), 2.73 (s, 5H), 2.40 (dd, J = 4.7, 1.9 Hz, 2H), 2.34 (s, 3H), 2.07 (s, 3H).

[0486] The compounds in Table 2 were prepared using analogous processes to the above Examples as noted in Preparation Method, including modification as appropriate.

[0487] Table 2

[0488] BIOLOGICAL EXAMPLES

[0489] Biological Example 1 : pHER2WT in BT474 Cells

[0490] Biological Example 2: pHER2YVMA in 3T3 Cells Biological Example 3: pEGFR in 3T3 Cells

[0491] Biological Example 4: MDR1 MDCKII Permeability and Efflux Ratio

[0492] Biological Example 5: BCRP MDCKII Efflux Ratio A DNA expression plasmid (pEF6 / V-HisA) encoding the amino acid sequence shown in SEQ ID NO: 1 was generated by GeneScript. in the sequence shown below, the ErbB2(676- 775)YVMAinsert(776-1255) amino sequence is underlined. The YVMA (SEQ ID NO: 2) insertion is marked with double underline.

[0493] SEQ ID NO: 1 : Amino sequence of recombinant His8x-Tb-ErbB2(676-775)YVMAinsert(776- 1255) protein

[0494] Experimental Procedures for Cellular Activities

[0495] Cell lines. BT-474 (HTB-20) and NIH 3T3 (CRL-1658) cells were obtained from ATCC. BT-474 cells were cultured in DMEM (high glucose), 10% FBS, 1 % pen / strep, 1 mM Glutamax. To create NIH 3T3 HER2YVMA and NIH 3T3 EGFRWT cell lines, the human HER2YVMA and EGFR DNA sequences were obtained from NIH NCBI database and overexpression plasmids with a blasticidin S selection marker were generated. NIH 3T3 cells were transfected using Lipofectamine 2000 following the manufacturer’s protocol and stable clones were isolated and expanded. NIH 3T3 HER2YVMA and NIH 3T3 EGFRWT cells were cultured in DMEM (high glucose), 10% FBS, 1 % pen / strep, 1 mM Glutamax, 15 ug / mL blasticidin S HCL. All cell lines tested negative for mycoplasma.

[0496] Compound dose response. Cells were plated at 2.0e4 (Biological Example 3 = NIH 3T3 EGFRWT) or 4.0e4 (Biological Example 2 = NIH 3T3 HER2YVMA or Biological Example 1 = BT- 474) cells / well in Collagen I (BT-474) or PDL (NIH 3T3) coated 96-well TC plates and allowed to adhere overnight. 10-point, 3-fold compound dilution series (ranging from 5 μM - 25 pM or 1 μM - 5 pM, final concentration) were prepared and added to the appropriate wells on the assay plates. 1 μM of afatinib (positive) or 0.25% DMSO (negative) were used as controls. Cells were incubated with compounds for 1 hour at 37 °C, 5% CO2.

[0497] In-cell Western (ICW) phospho-HER2 detection. After compound incubation, medium was removed, and cells were fixed with 2% formaldehyde solution and permeabilized using ice cold methanol. Plates were then washed with PBS with 0.05% Tween-20 (PBS-T) and blocked with Intercept PBS blocking buffer (LI-COR) for 1 hour. After blocking, primary antibody cocktail was added to the assay plates (anti-pHER2 / ERBB2 Tyr1196 clone D66B7 (Cell Signaling Technology) and anti-GAPDH clone 6C5 (Millipore)), followed by an overnight incubation at 4 °C. Plates were then washed with PBS-T and cells were incubated with secondary antibody cocktail (anti-rabbit AF680 (Life Technologies), and anti-mouse IRdye-800CW (LI-COR)) for 1 hour. Next, the plates were washed with PBS-T and analyzed on the LI-COR Odyssey CLx.

[0498] ELISA phospho-EGFR detection. After compound incubation, NIH 3T3 EGFRWT cells were stimulated with 100 ng / mL of recombinant human EGF (R&D) for 10 minutes at 37 °C, 5% CO2. Growth medium was removed and ELISA lysis butter with protease and phosphatase inhibitors was added. EGFR phosphorylation was detected using the Duo Set IC human phospho- EGFR ELISA kit (R&D Systems) following manufacturer’s protocol. ELISA plates were analyzed by optical density measurements at 450 nM using the VersaMax plate reader (Molecular Device Inc,).

[0499] Determining cellular IC50. For ICW samples, pHER2 signal was normalized to GAPDH before generating IC50curves. Percent of control (POC) was calculated for each data point using the following equation:

[0500] After POC calculation, compound IC50values were determined using a three-parameter curve fit via CambridgeSoft BioAssay 10.1 .4 software.

[0501] Experimental Procedures for ADME Properties

[0502] Ceil Lines. MDCKII canine MDR1 KO (cMDR1 KO) ceil line transfected with either human MDR1 (Biological Example 4) or human BCRP (Biological Example 5) were obtained from Signa- Aldrich. cMDR1 KO and human MDR1 transfected cells were cultured in DMEM (high glucose, L-glutamine), 10% FBS, and 5 pg / mL gentamycin. Human BCRP transfected cells were cultured in DMEM (high glucose), 10% FBS, 1 % L-glutamine, 1 % penicillin-streptomycin and 1 % non- essential amino acids. Ail cell lines were plated at a concentration of 350,000 cells / mL and grown for 6 or 7 days at 100% humidity with 5% CO2. All ceil lines tested negative for mycoplasma.

[0503] At time of assay, stock solutions for assay controls and the test article were prepared in DMSO for final test concentration of 10 and 1 μM, respectively. Final organic concentration in the assay was 1%. Ail dosing solutions contained 10 μM lucifer yellow to monitor MDCKII cell monolayer integrity. Both positive and negative controls were used to assess functionality of efflux in the assay. For the apical to basoiateral determination (A to B), 75 μL of the test article in transport buffer were added to the apical side of the individual trans wells and 250 μL of basoiateral media, without compound or lucifer yellow, were added to each well. For the basoiateral to apical determination (B to A), 250 μL of test article in transport buffer were added to each well and 75 μL transport buffer, without compound or lucifer yellow, were added to each transwell.

[0504] The plates were incubated for 2 hours on an orbital shaker at 50 rpm and 37 °C with 5% CO2. All culture plates were removed from the incubator, and 50 μL of media were removed from the apical and basolateral portion of each well and added to 150 μL of 1 μM labetalol (internal standard) in 2:1 CH3CN:H2O, v / v. The plates were read using a fluorometer to evaluate the lucifer yellow concentrations. These values were accepted when found to be below 5% for a pical to basolateral and basolateral to apical flux across the MDCKII cell monolayers. The plates were sealed, and the contents of each well analyzed by LC-MS / MS.

[0505] Table 3

[0506] It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0507] All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

CLAIMSWe claim:1 . A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X1is selected from N and CRa;X2is selected from N and CH;R1is selected from the group consisting of hydrogen, C1-C3alkyl, and cyclopropyl; each R2is independently selected from methyl and halogen;R3is a 9 to 10 membered bicyclic heteroaryl containing one, two, or three heteroatoms selected from N, O and S, wherein the bicyclic heteroaryl may be optionally substituted with one or two groups selected from halogen and C1-C3alkyl, or R3is 1-methyl-2-oxo-1 ,2-dihydropyridin- 4-yl;R4is a 5 to 8 membered heterocycloalkyl ring containing one nitrogen heteroatom, wherein the nitrogen heteroatom is substituted with Rb, and wherein R4may also optionally be substituted with one or two groups independently selected from fluorine, methyl and methoxymethyl;Rais selected from hydrogen and fluorine;Rbis selected from acryloyl, 1 -propionyl, 2-fluoroacryloyl, but-2-ynoyl, 2-chioropropanoyl, and 4-methoxybut-2-enoyl; and n is 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein preferably X1is N.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X2is N.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X2is CH,5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is methyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is independently selected from the group consisting of methyl, fluoro and chloro.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of:

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R3is selected from:

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R3is:11 . The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R3is:

12. The compound of any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4is:

15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

16. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

17. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

19. The compound of claim 1 , selected from the group consisting of:1-((1R,3r,5S)-3-(3-(3-chloro-5-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one;1 -(4-(3-(3-chloro-5-fluoro-4-((7-fluoro-1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2-azabicyclo[2.1 .1 ]hexan-2-yl)prop-2-en-1 -one;1-( 1-methyl-4-(4-methyl-3-(3-methyl-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one;1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one;1 -(4-(3-(3-fluoro-5-methyl-4-((1 -methyl-1H-benzo[d]]imidazo-l5-yl)oxy)phenyl)-4-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one;1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one; and1-(4-(5-(3-fluoro-5-methyl-4-((1 -methyl- 1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-2-azablcyclo[2.1.1]hexan-2-yl)prop-2-en-1 -one; or a pharmaceutically acceptable salt thereof.

20. The compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:21 . The compound:

22. The compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

23. The compound:

24. The compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

25. The compound:

26. The compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

27. The compound:

28. The compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

29. The compound:

30. The compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

32. The compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

33. The compound:

34. 1-((1 R,3r,5S)-3-(3-(3-Chloro-5-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

35. 1-((1R,3r,5S)-3-(3-(3-Chloro-5-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8-azablcyclo[3.2.1]octan-8-yl)prop-2-en-1-one.

36. 1-(4-(3-(3-Chloro-5-fluoro-4-((7-fluoro-1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-4- methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2"yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

37. 1-(4-(3-(3-Chloro-5-fluoro-4-((7-fluoro-1-methyl-1 H-benzo[d|imidazol-5-yl)oxy)pher!yl)-4- methyl-1 H-pyrazolo[3:4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

38. 1-(1-Methyl-4-(4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

39. 1-(1-Methyl-4-(4-methyl-3-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

40. 1-(4-(3-(3-Chloro-5-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.41 . 1-(4-(3-(3-Chloro-5-fluoro-4-((1 -methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1 H- pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

42. 1-(4-(3-(3-Fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

43. 1-(4-(3-(3-Fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

44. 1-(4-(3-(3-Chloro-5-fluoro-4-((1-methyl-1H-benzo[d]]imidazo-l5-yl)oxy)phenyl)-4-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

45. 1-(4-(3-(3-Ch!oro-5-fiuoro-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1 H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicycio[2.1.1]hexan-2-yl)prop-2-en-1-one.

46. 1-(4-(5-(3-Fluoro-5-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 7H-pyrroio[2,3-d]pyrimidin-7-yl)-1-methyl-2-azabicyclo[2.1 .1]hexan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

47. 1-(4-(5-(3-Fluoro-5-methyl-4-((1-methyl-1 H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

48. A pharmaceutically acceptable salt of 1-((1 R,3r,5S)-3-(3-(3-chloro-5-fluoro-4-((1-methyl- 1H-benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-8- azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one.

49. A pharmaceutically acceptable salt of 1-(4-(3-(3-chloro-5-fluoro-4-((7-fluoro-1 -methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

50. A pharmaceutically acceptable salt of 1-(1-methyl-4-(4-methyl-3-(3-methyl-4-((1-methyl- 1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.51 . A pharmaceutically acceptable salt of 1 -(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1 H- benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H-pyrazolo[3,4-d]pyrlmidin-1 -yl)-1 -methyl-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

52. A pharmaceutically acceptable salt of 1-(4-(3-(3-fluoro-5-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1 H-pyrazolo[3,4-dJpyrimidin-1 -yl)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

53. A pharmaceutically acceptable salt of 1-(4-(3-(3-chloro-5-fluoro-4-((1 -methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-1H-pyrazolo[3,4-d]pyrimfdin-1-yl)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one.

54. A pharmaceutically acceptable salt of 1-(4-(5-(3-fluoro-5-methyl-4-((1 -methyl- 1 H- benzo[d]imidazol-5-yl)oxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-2- azabicycio[2.1.1]hexan-2-yl)prop-2-en-1-one.

55. A pharmaceutical composition comprising the compound according to any of claims 1 to54, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

56. A method for treating cancer, comprising administering to a subject In need thereof a therapeutically effective amount of the compound of any of claims 1 to 54, or a pharmaceutically acceptable salt thereof.

57. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any of claims 1 to 54, or apharmaceutically acceptable salt thereof, and further comprising administering an amount of an additional anti-cancer therapeutic agent.

58. A compound according to any one of claims 1 to 54 for use as a medicament.

59. A compound according to any one of claims 1 to 54 for use in the treatment of cancer.

60. Use of a compound according to any one of claims 1 to 54 for the manufacture of a medicament for the treatment of cancer.

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