HETEROCYCLIC COMPOUNDS USED AS PI3K-GAMMA INHIBITORS

Abstract

This application relates to compounds of Formula (I): or pharmaceutically acceptable salts or stereoisomers thereof, which are inhibitors of PI3K-γ which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

Description

HETEROCYCLIC COMPOUNDS AS PI3K-γ INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of U.S. Ser. No.62 / 252,050, filed November 6, 2015, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTIONThe present invention provides heterocyclic compounds that modulate the activity of phosphoinositide 3-kinases-gamma (PI3Kγ) and are useful in the treatment of diseases related to the activity of PI3Kγ including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. BACKGROUNDThe phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring (Cantley, Science, 2002, 296(5573):1655-7). PI3Ks are divided into three classes (class I, II, and III) according to their structure, regulation and substrate specificity. Class I PI3Ks, which include PI3Kα, PI3K β, PI3K γ, andPI3Kδ are a family of dual specificity lipid and protein kinases that catalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate (PIP2) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP3). PIP3 functions as a second messenger that controls a number of cellular processes, including growth, survival, adhesion and migration. All four class I PI3K isoforms exist as heterodimers composed of a catalytic subunit (p110) and a tightly associated regulatory subunit that controls their expression, activation, and subcellular localization. PI3Kα, PI3K β and PI3Kδ associate with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002, 277(44):41556-62) whereas PI3K γ associates with two regulatory subunits (p101 and p84) and its activation is driven by the activation of G-protein-coupled receptors (Brock, et al., J Cell Biol., 2003, 160(1):89-99). PI3Kα and PI3K β are ubiquitously expressed. In contrast, PI3K γ andPI3Kδare predominantly expressed in leukocytes (Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).Expression of PI3K γ is mainly restricted to hematopoietic system, although it can be also detected at lower level in endothelium, heart and brain. PI3K γ knock-out or kinase dead knock in mice are normal and fertile and do not present any overt adverse phenotypes. Analysis at the cellular level indicates that PI3K γ is required for GPCR ligand-induced PtdINs (3,4,5)P3 production, chemotaxis and respiratory burst in neutrophils. PI3K γ-null macrophages and dendritic cell exhibit reduced migration towards various chemoattractants. T-cells deficient in PI3K γ show impaired cytokine production in response to anti-CD3 or Con A stimulation. PI3K γ working downstream of adenosine A3A receptor is critical for sustained degranulation of mast cells induced byFCεRI cross- linking with IgE. PI3K γ is also essential for survival of eosinophils (Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918)Given its unique expression pattern and cellular functions, the potential role of PI3K γ in various autoimmune and inflammatory disease models has been investigated with genetic and pharmacological tools. In asthma and allergy models, PI3K γ mice or mice treated with PI3K γ inhibitor showed a defective capacity to mount contact hypersensitivity and delayed-typehypersensitivity reactions. In these models, PI3K γ was shown to be important for recruitment of neutrophils and eosinopohils to airways and degranulation of mast cells (see e.g. Laffargue et al., Immunity, 2002, 16, 441-451; Prete et al., The EMBO Journal, 2004, 23, 3505-3515; Pinho et al., L. Leukocyte Biology, 2005, 77, 800-810; Thomas et al., Eur. J. Immunol.2005, 35, 1283-1291; Doukas et al., J. Pharmacol. Exp Ther.2009, 328, 758-765).In two different acute pancreatitis models, genetic ablation of PI3K γ significantly reduced the extent of acinar cell injury / necrosis and neutrophil infiltration without any impact on secretive function of isolated pancreatic acini (Lupia et al., Am. J. Pathology, 2004, 165, 2003-2011). PI3K γ mice were largely protected in four different models of rheumatoid arthritis (CIA, α-CII-IA, K / BxN serum transfer and TNF transgenic) and PI3K γ inhibition suppressed the progression of joint inflammation and damage in the CIA and α-CII-IA models (see e.g., Camps et al., Nat. Medicine, 2005, 11, 939-943; Randis et al., Eur. J. Immunol, 2008, 38, 1215-1224; Hayer et al., FASB J., 2009, 4288-4298). In the MRL-lpr mouse model of human systemic lupus erythematous, inhibition of PI3K γ reduced glomerulonephritis and prolonged life span (Barber et al., Nat. Medicine, 2005, 9, 933-935).There is evidence suggesting that chronic inflammation due to infiltration by myeloid-derived cells is a key component in the progression of neurodegeneration diseases, such as Alzheimer’s disease (AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005, 289, C264-C276; El Khoury et al., Nat. Med., 2007, 13, 432-438). In line with this suggestion, PI3K γ inhibition was shown to attenuate A β(1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus and prevent the peptide-induced congnitive deficits and synaptic dysfunction in a mouse model of AD (Passos et al., Brain Behav. Immun.2010, 24, 493-501). PI3K γ deficiency or inhibition also was shown to delay onset and alleviate symptoms in experimental autoimmune encephalomyelitis in mice, a mouse model of human multiple sclerosis, which is another form of neurodegeneration disease (see e.g., Rodrigues et al., J. Neuroimmunol.2010, 222, 90-94; Berod et al., Euro. J. Immunol.2011, 41, 833- 844; Comerford et al., PLOS one, 2012, 7, e45095; Li et al., Neuroscience, 2013, 253, 89-99). Chronic inflammation has been formally recognized as one of the hallmarks for many different types of cancers. Accordingly, selective anti-inflammatory drugs represent a novel class of anti-cancer therapies (Hanahan and Weinberg, Cell, 2011, 144, 646-674). Since PI3K γ is reported to mediate various inflammatory processes, its role as an immune oncology target has also been investigated. A recent study reported that PI3K γ deficiency suppressed tumor growth in the syngeneic models of lung cancer, pancreatic cancer and melanoma (LLC, PAN02 and B16). PI3K γ deficiency or inhibition also inhibited tumor growth in a spontaneous breast cancer model (Schmid et al., Cancer Cell, 2011, 19, 715-727). A further study reported that PI3K γ deficiency could ameliorate inflammation and tumor growth in mice having colitis-associated colon cancer, (Gonzalez-Garcia et al., Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysis indicates that tumor infiltration by CD11b+ myeloid cells can cause protumorigenic inflammation at tumor sites and PI3K γ in the myeloid cells is critical in mediating signaling of various chemoattractants in bring the cells to the tumor (Schmid et al., Cancer Cell, 2011, 19, 715-727). Other studies suggest that PI3K γ is also required for differentiation of naïve myeloid cells into M2 macrophges at tumor sites. M2 macrophages promote tumor growth and progression by secreting immunosuppressive factors such arginase 1, which depletes the tumor microenvironment of arginine, thereby promoting T-cell death and NK cell inhibition (Schmidt et al., Cancer Res.2012, 72 (Suppl 1: Abstract, 411; Kaneda et al., Cancer Res., 74 (Suppl 19: Abstact 3650)).In addition to its potential role in promoting protumorigenic microenvironment, PI3K γ may play a direct role in cancer cells. PI3K γ is reported to be required for signaling from the Kaposi’s sarcoma-associated herpevirus encoded vGPCR oncogene and tumor growth in a mouse model of sarcoma (Martin et al., Cancer Cell, 2011, 19, 805-813). PI3K γ was also suggested to be required for growth of T-ALL (Subramanjam et al., Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells (Falasca and Maffucci, Frontiers in Physiology, 2014, 5, 1-10). Moreover, in a survey of driver mutations in pancreatic cancer, PI3K γ gene was found to contain second highest scoring predicted driven mutation (R839C) among the set of genes not previously identified as a driver in pancreatic cancer (Carter et al., Cancer Biol. Ther.2010, 10, 582-587).Finally, PI3K γ deficiency also has been reported to offer protection to experimental animals in different cardiovascular disease models. For examples, lack of PI3K γ would reduce angiotension- evoked smooth muscle contraction and, therefore, protect mice from angiotension-induced hypertension (Vecchione et al., J. Exp. Med.2005, 201, 1217-1228). In rigorous animal myocardial infarction models, PI3K γ inhibition provided potent cardioprotection, reducing infarct development and preserving myocardial function (Doukas et al., Proc. Natl. Acad. Sci. USA, 2006, 103, 19866- 19871). For these reasons, there is a need to develop new PI3Kγ inhibitors that can be used for the treatment of diseases such as cancer, autoimmune disorders, and inflammatory and cardiac diseases. This application is directed to this need and others. SUMMARYThe present invention related to, inter alia, compounds of Formula (I):or pharmaceutically acceptable salts, wherein constituent members are defined herein.The present invention further provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.The present invention further provides methods of inhibiting an activity of PI3Kγ kinase comprising contacting the kinase with a compound of Formula I, or a pharmaceutically acceptable salt thereof.The present invention further provides methods of treating a disease or a disorder associated with abnormal PI3Kγ kinase expression or activity in a patient by administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.The present invention further provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.The present invention further provides use of a compound of Formula I, or apharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTIONCompoundsThe present application provides, inter alia, a compound of Formula I:or a pharmaceutically acceptable salt thereof; wherein:X1 and X2 are each independently C or N, provided X1 and X2 are not simultaneously N; X3 is N, NR3a, or CR3;X4 is N, NR4a, or CR4;X5 is N, NR5a, or CR5;W is CH or N;Y1 is N or CR10;Y2 is N or CR11;one of Z1 and Z2 is N, the other of Z1 and Z2 is C;is a single bond or a double bond to maintain ring A and ring B being aromatic;R1 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or 4-10 membered heterocycloalkyl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently seleted Rj substituents;R2 is OR13, C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein the C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents;R3, R4, R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3, R4, R5, and R6 are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R3a, R4a, and R5a are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, C(O)Ra, C(O)NRaRa, C(O)ORa, C(=NRa)Ra, C(=NRa)NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a, R4a, and R5a are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R7 is selected from H, halo, CN, -OH, -C(O)O(C1-4 alkyl), -C(O)NH2, -C(O)NH(C1-4 alkyl), - C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), - SO2N(C1-4 alkyl)2, (C1-4 alkyl)SO2NH-, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the -C(O)O(C1-4 alkyl), -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, (C1-4 alkyl)SO2NH-, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl groups of R7 are each optionally substituted with 1 or 2 independently selected Rq substituentsR8, R9, R10 and R11 are each independently H, halo, CN, -OH, -C(O)O(C1-4 alkyl), -C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, - NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, and (C1-4 alkyl)SO2NH-, wherein the -C(O)O(C1-4 alkyl), - C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, - NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2 and (C1-4 alkyl)SO2NH- groups of R8, R9, R10 and R11 are each optionally substituted with 1 or 2 independently selected Rq substituents;each R12 is an independently selected C1-6 alkyl group;R13 is H or C1-6 alkyl optionally substitued with 1, 2 or 3 independently selected Rq substituents;each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1- 4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents;or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc,NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Rb are each further optionally substituted with 1, 2, or 3 independently selected Rd substituents;each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1- 4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;each Rd is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe,NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1, 2, or 3 independently selected Rq substituents;each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg,OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg,C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 memberedheterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents;each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1- 4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Rg are each optionally substituted with 1, 2, or 3 independently selected Rp substituents; each Rh is selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4- 7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted with 1, 2, or 3 independently selected Rj substituents;or two Rh groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which they attach form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S; each Rj substituent is independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk;each Rn is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(=NRo)NRoRo, NRoC(=NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo; andeach Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, and 5 or 6-membered heteroaryl; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; andeach Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, NHR12, NR12R12, and C1-4 haloalkoxy, wherein the C1-4 alkyl, phenyl and 5-6 membered heteroaryl of Rq are each optionally substituted with OH, CN, -COOH, NH2, C1-4 alkoxy, C3-10 cycloalkyl, and 4-6 memberedheterocycloalkyl.In some embodiments:X1 and X2 are each independently C or N, provided X1 and X2 are not simultaneously N; X3 is N, NR3a, or CR3;X4 is N, NR4a, or CR4;X5 is N, NR5a, or CR5;W is CH or N;Y1 is N or CR10;Y2 is N or CR11;one of Z1 and Z2 is N, the other of Z1 and Z2 is C; is a single bond or a double bond to maintain ring A and ring B being aromatic;R1 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or 4-10 membered heterocycloalkyl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently seleted Rj substituents;R2 is OR13, C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein the C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents;R3, R4, R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3, R4, R5, and R6 are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R3a, R4a, and R5a are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, C(O)Ra, C(O)NRaRa, C(O)ORa, C(=NRa)Ra, C(=NRa)NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a, R4a, and R5a are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R7, R8, R9, R10 and R11 are each independently H, halo, CN, -OH, -C(O)O(C1-4 alkyl), - C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, - SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, and (C1-4 alkyl)SO2NH-, wherein the - C(O)O(C1-4 alkyl), -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, - SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2 and (C1-4 alkyl)SO2NH- groups of R7, R8, R9, R10 and R11 are each optionally substituted with 1 or 2 independently selected Rq substituents;each R12 is an independently selected C1-6 alkyl group;R13 is H or C1-6 alkyl optionally substitued with 1, 2 or 3 independently selected Rq substituents;each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1- 4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents;or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc,NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Rb are each further optionally substituted with 1, 2, or 3 independently selected Rd substituents;each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1- 4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents; or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;each Rd is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe,NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1, 2, or 3 independently selected Rq substituents;each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg,OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg,C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 memberedheterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents;each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1- 4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)- C1-4 alkyl- of Rg are each optionally substituted with 1, 2, or 3 independently selected Rp substituents; each Rh is selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4- 7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted with 1, 2, or 3 independently selected Rj substituents; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they attach form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S; each Rj substituent is independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk;each Rn is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro,NRoC(O)NRoRo, NRoC(O)ORo, C(=NRo)NRoRo, NRoC(=NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo; andeach Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, and 5 or 6-membered heteroaryl; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; andeach Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, NHR12, NR12R12, and C1-4 haloalkoxy, wherein the C1-4 alkyl, phenyl and 5-6 membered heteroaryl of Rq are each optionally substituted with OH, CN, -COOH, NH2, C1-4 alkoxy, C3-10 cycloalkyl, and 4-6 membered heterocycloalkyl.In some embodiments, X1 is C; and X2 is C.In some embodiments, X1 is N; and X2 is C.In some embodiments, X1 is C; and X2 is N.In some embodiments, X3 is N.In some embodiments, X3 is NR3a.In some embodiments, X3 is CR3.In some embodiments, X4 is N.In some embodiments, X4 is NR4a.In some embodiments, X4 is CR4.In some embodiments, X5 is N.In some embodiments, X5 is NR5a.In some embodiments, X5 is CR5.In some embodiments, W is CH.In some embodiments, W is N.In some embodiments, W is CH; X1 is C; X2 is N; X3 is CR3; X4 is N; and X5 is CR5. In some embodiments, W is CH; X1 is C; X2 is C; X3 is NR3a; X4 is N; and X5 is CR5. In some embodiments, W is CH; X1 is C; X2 is C; X3 is N; X4 is NR4a; and X5 is CR5. In some embodiments, Y1 is N.In some embodiments, Y2 is N.In some embodiments, Z1 is C; and Z2 is N.is .is .is In some embodiments, R1 is H, C3-6 cycloalkyl, C1-6 haloalkyl or C1-6 alkyl.In some embodiments, R1 is H or C1-6 alkyl.In some embodiments, R1 is C1-6 alkyl.In some embodiments, R1 is methyl, ethyl or 1-propyl.In some embodiments, R1 is methyl.In some embodiments, R2 is OR13, C6-10 aryl, 5-10 memberd heterocycloalkyl, or 5-10 membered heteroaryl; wherein said C6-10 aryl, 5-10 memberd heterocycloalkyl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents.In some embodiments, R2 is OR13, C6-10 aryl, or 5-10 membered heteroaryl; wherein said C6-10 aryl or 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents.In some embodiments, R2 is OR13 or C6-10 aryl; wherein said C6-10 aryl of R2 is optionally substituted with 1, 2, or 3 independently selected Rj substituents.In some embodiments, R2 is C1-6 alkoxy, phenyl, or monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl or monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3 independently selected Rj substituents.In some embodiments, R2 is C1-6 alkoxy or phenyl, wherein said phenyl of R2 is optionally substituted with 1, 2, or 3 independently selected Rj substituents.In some embodiments, R2 is C1-6 alkoxy, phenyl, 5-6 membered heterocycloalkyl, or monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl, 5-6 membered heterocycloalkyl, monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3independently selected Rj substituents.In some embodiments, R2 is 5-6 membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 independently selected Rj substituents.In some embodiments, R2 is 1,1-dioxidothiomorpholin-4-yl optionally substituted with 1 or 2 independently selected Rj substituents.In some embodiments, R2 is ethoxy, 1,1-dioxidothiomorpholino optionally substituted with 1 or 2 C1-4 independently selected alkyl substituents, or phenyl optionally substituted with halo.In some embodiments, R2 is ethoxy or phenyl optionally substituted with halo.In some embodiments, R2 is 1,1-dioxidothiomorpholino optionally substituted with 1 or 2 independently selected C1-4 alkyl substituents.In some embodiments, R2 is 2-methyl-1,1-dioxidothiomorpholino. In some embodiments, each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk.In some embodiments, each Rk is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl.In some embodiments, each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di(C1-4 alkyl)amino.In some embodiments, each Rj is independently C1-4 alkyl or halo.In some emboidmnets, each Rj is independently C1-4 alkyl.In some embodiments, each Rj is independently methyl.In some embodiments, each Rj is independently halo.In some embodiments, R2 is ethoxy, phenyl, or 3-fluorophenyl.In some embodiments, R3a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents.In some embodiments, R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents. In some embodiments, each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc. In some embodiments, each Rb is independently selected from C1-4 alkyl, OH, ORc, CN, C(O)NRcRc, and NRcRc. In some embodiments, each Rc is independently selected from H and C1-6 alkyl.In some embodiments, R3a is H, methyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, - CH2CH2OCH3, -CH2CN, -CH2CH2NH2, -CH2C(O)NH2, benzyl, cyclobutyl, -CH2-(1-methyl-1H- pyrazol-3-yl), or -CH2CH2-(morpholin-4-yl).In some embodiments, R3 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.In some embodiments, R3 is H or C1-6 alkyl.In some embodiments, R3 is H, methyl or ethyl In some embodiments, R4a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents.In some embodiments, R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-, wherein said C1-6 alkyl, C1-6 alkynyl, C3-10 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents.In some embodiments, R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl-C1-4 alkyl-, and (5-10 membered heteroaryl)-C1-4 alkyl-, wherein said C1-6 alkyl and (4-10 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents.In some embodiments, each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc. In someembodiments, each Rb is independently selected from C1-4 alkyl, OH, ORc, CN, NRcRc, andC(O)NRcRc. In some embodiments, each Rc is independently H or C1-6 alkyl; or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.In some embodiments, R4a is H, methyl, ethyl, isopropyl, isobutyl, -CH2C≡CCH3, - CH2CH2OH, -CH2CH2OCH3, -CH2CN, -CH2CH2NH2, cyclobutyl, benzyl, -CH2C(O)NH2, -CH2-(1- methyl-1H-pyrazol-3-yl), or–CH2C(O)-(morpholin-4-yl).In some embodiments, R4 is selected from H, halo, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R4 are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents. In some embodiments, R4 is selected from H, halo, CN, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-, wherein said C1-6 alkyl, C1-6 alkynyl, C3-10 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4 are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents.In some embodiments, R4 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.In some embodiments, R4 is H or C1-6 alkyl.In some embodiments, R5 is H, halo, C1-6 alkyl, or C1-6 haloalkyl.In some embodiments, R5 is H, halo, or C1-6 alkyl.In some embodiments, R5 is H, bromo, chloro, fluoro, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R5 is H, bromo, or methyl.In some embodiments, R6 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.In some embodiments, R6 is halo, CN, or C1-6 alkyl.In some embodiments, R6 is selected from chloro, CN, and methyl.In some embodiments, R7 is H, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 independently selected Rq substituents.In some embodiments, R7 is H, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected Rq substituents.In some embodiments, R7 is H, piperidinyl, or pyridyl, wherein the piperidinyl and pyridyl groups are each optionally substituted with 1 or 2 independently selected Rq substituents.In some embodiments, R7 is H, piperidinyl, or pyridyl, wherein the piperidinyl and pyridyl groups are each optionally substituted with 1 or 2 groups independently selected from C1-4 alkyl and C1-4 alkoxy, wherein the C1-4 alkyl group is optionally substituted by OH.In some embodiments, R7 is H, piperidin-1-yl, or pyridin-3-yl, wherein the piperidin-1-yl and piperidin-3-yl groups are each optionally substituted with 1 or 2 groups independently selected from C1-4 alkyl and C1-4 alkoxy, wherein the C1-4 alkyl group is optionally substituted by OH.In some embodiments, R7, R8, and R9 are each H.R1 is H or C1-6 alkyl;R2 is 5-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 independently selected Rj substituents; each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk;R3a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- 10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents;R4a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- 10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5 is H, halo, C1-6 alkyl, or C1-6 haloalkyl;R5a is H or C1-6 alkyl;R6 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; andR7 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.is ;R1 is C1-6 alkyl;R2 is 5-6 membered heterocycloalkyl, wherein said 5-6 membered heterocycloalkyl of R2 is optionally substituted with 1 or 2 independently selected Rj substituents;each Rj is independently C1-4 alkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;each Rb is independently selected from C1-4 alkyl, OH, ORc, CN, and NRcRc, and C(O)NRcRc; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.R1 is H or C1-6 alkyl;R2 is OR13, C6-10 aryl, or 5-10 membered heteroaryl; wherein said C6-10 aryl or 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk;R3a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- 10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents; R4a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- 10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5 is H, halo, C1-6 alkyl, or C1-6 haloalkyl;R5a is H or C1-6 alkyl;R6 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; andR7 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.is ;R1 is C1-6 alkyl;R2 is C1-6 alkoxy, phenyl, or monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl or monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk;each Rk is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl, C1-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.R1 is C1-6 alkyl;R2 is C1-6 alkoxy or phenyl, wherein said phenyl of R2 is optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di(C1-4 alkyl)amino;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;each Rb is independently selected from C1-4 alkyl, OH, ORc, CN, and NRcRc, and C(O)NRcRc; and each Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.R1 is C1-6 alkyl;R2 is C1-6 alkoxy or phenyl, wherein said phenyl of R2 is optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently halo;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;each Rb is independently selected from C1-4 alkyl, OH, ORc, CN, and NRcRc, and C(O)NRcRc; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.R1 is methyl;R2 is ethoxy, phenyl, or 3-fluorophenyl;each Rj is independently halo;R3a is H, methyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CN, -CH2CH2NH2, -CH2C(O)NH2, benzyl, cyclobutyl, -CH2-(1-methyl-1H-pyrazol-3-yl), or -CH2CH2- (morpholin-4-yl);R3 is H or methyl;R4a is H, methyl, ethyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2CN, -CH2CH2NH2, cyclobutyl, benzyl, -CH2C(O)NH2, -CH2-(1-methyl-1H-pyrazol-3-yl), or– CH2C(O)-(morpholin-4-yl);R5 is H, bromo, or methyl; andR6 is chloro, CN, or methyl.In som(X) (XI) (XII) or a pharmaceutically acceptable salt thereof, wherein:R1 is C1-6 alkyl;R2 is C1-6 alkoxy, phenyl, monocyclic 5-6 membered heterocycloalkyl, monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl, monocyclic 5-6 membered heterocycloalkyl, and monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk;each Rk is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;R3 is H or C1-6 alkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl, C1-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;R7, R8, R9 are each H; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.In some embodiments, the compound is a compound of Formula X, XI, or XII:(XI) (XII)or a pharmaceutically acceptable salt thereof, wherein:R1 is C1-6 alkyl;R2 is C1-6 alkoxy, phenyl, 5-6 membered monocyclic heterocycloalkyl, or monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl or monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk; each Rk is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;R3 is H or C1-6 alkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl, C1-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;R7, R8, R9 are each H; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.b di h d i d f l :o p y p ,R1 is C1-6 alkyl; R2 is C1-6 alkoxy, phenyl, or monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl or monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk;each Rk is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;R3 is H or C1-6 alkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl, C1-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;R7, R8, R9 are each H; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.In some embodiments, the compound is a compound of Formula X, XI, or XII:(XI) (XII)or a pharmaceutically acceptable salt thereof, wherein:R1 is C1-6 alkyl;R2 is C1-6 alkoxy or phenyl, wherein said phenyl of R2 is optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di(C1-4 alkyl)amino;R3 is H or C1-6 alkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;R7, R8, R9 are each H;each Rb is independently selected from C1-4 alkyl, OH, ORc, CN, and NRcRc, and C(O)NRcRc; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents. In some embodiments, the compound is a compound of Formula X, XI, or XII:(XI) (XII)or a pharmaceutically acceptable salt thereof, wherein:R1 is C1-6 alkyl;R2 is C1-6 alkoxy or phenyl, wherein said phenyl of R2 is optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently halo;R3 is H or C1-6 alkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl;R7, R8, R9 are each H;each Rb is independently selected from C1-4 alkyl, OH, ORc, CN, and NRcRc, and C(O)NRcRc; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents. In some embodiments, the compound is a compound of Formula X, XI, or XII:or a pharmaceutically acceptable salt thereof, wherein:R1 is methyl;R2 is ethoxy, phenyl, 3-fluorophenyl, or 2-methyl-1,1-dioxidothiomorpholino;each Rj is independently halo;R3 is H or methyl;R3a is H, methyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CN, -CH2CH2NH2, -CH2C(O)NH2, benzyl, cyclobutyl, -CH2-(1-methyl-1H-pyrazol-3-yl), or -CH2CH2- (morpholin-4-yl);R4a is H, methyl, ethyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2CN, -CH2CH2NH2, cyclobutyl, benzyl, -CH2C(O)NH2, -CH2-(1-methyl-1H-pyrazol-3-yl), or– CH2C(O)-(morpholin-4-yl);R5 is H, bromo, or methyl;R6 is chloro, CN, or methyl; andR7, R8, and R9 are each H.In some embodiments, the compound is a compound of Formula X, XI, or XII:(XI) (XII)or a pharmaceutically acceptable salt thereof, wherein:R1 is methyl;R2 is ethoxy, phenyl, or 3-fluorophenyl; each Rj is independently halo;R3 is H or methyl;R3a is H, methyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CN, -CH2CH2NH2, -CH2C(O)NH2, benzyl, cyclobutyl, -CH2-(1-methyl-1H-pyrazol-3-yl), or -CH2CH2- (morpholin-4-yl);R4a is H, methyl, ethyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2CN, -CH2CH2NH2, cyclobutyl, benzyl, -CH2C(O)NH2, -CH2-(1-methyl-1H-pyrazol-3-yl), or– CH2C(O)-(morpholin-4-yl);R5 is H, bromo, or methyl;R6 is chloro, CN, or methyl; andR7, R8, and R9 are each H.In some embodiments, the compound is a compound of Formula (II):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (III):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (IV):or a pharmaceutically acceptable salt or stereoisomer thereof.In some embodiments, the compound is a compound of Formula (V):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (VI):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (VII):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (VIII):or a pharmaceutically acceptable salt thereof.In some embodiments, the com ound is a com ound of Formula (IX):(IX)or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (X):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R4a is H, C1-6 alkyl, C2-6 alkynyl, benzyl, cyanomethyl, 2- methoxyethyl, 2-hydroxyethyl, cyclobutyl, cyclopentyl, 2-amino-2-oxoethyl, N,N-dimethyl-2-amino- 2-oxoethyl, (1-methyl-1H-pyrazol-3-yl)methyl, 2-morpholinoethyl, 2-morpholino-2-oxoethyl or 2- aminoethyl.In some embodiments, the compound is a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R2 is ethoxy or phenyl optionally substituted with halo.In some embodiments, the compound is a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.In some embodiments, the compound is a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R5 is H, Br or methyl.In some embodiments, the compound is a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R6 is methyl, CN or Cl.In some embodiments, the compound is a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R7, R8 and R9 are each H.In some embodiments, the compound is a compound of Formula (XI):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R4a is H, C1-6 alkyl, C2-6 alkynyl, benzyl, cyanomethyl, 2- methoxyethyl, 2-hydroxyethyl, cyclobutyl, cyclopentyl, 2-amino-2-oxoethyl, N,N-dimethyl-2-amino- 2-oxoethyl, (1-methyl-1H-pyrazol-3-yl)methyl, 2-morpholinoethyl, 2-morpholino-2-oxoethyl or 2- aminoethyl.In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R2 is ethoxy, 1,1-dioxidothiomorpholino optionally substituted with 1 or 2 independently selected C1-4 alkyl substituents, or phenyl optionally substituted with halo.In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R2 is ethoxy or phenyl optionally substituted with halo. In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R5 is H, Br or methyl.In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R6 is methyl, CN or Cl.In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R7 is H, piperidin-1-yl, or pyridin-3-yl optionally substituted by C1-4 alkyl or C1-4 alkoxy, wherein the C1-4 alkyl group is substituted by OH.In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein R7, R8 and R9 are each H.In some embodiments, the compound is a compound of Formula (XII):or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 2-amino-N-((S)-1-(8-chloro-5-((R)-2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 2-amino-N-((S)-1-(8-chloro-5-((S)-2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.The term“n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the phrase“optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term“substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.Throughout the definitions, the term“Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like.As used herein, the term“Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl- 1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.As used herein,“Cn-m alkenyl” refers to an alkyl group having one or more double carbon- carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.As used herein,“Cn-m alkynyl” refers to an alkyl group having one or more triple carbon- carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.As used herein, the term“Cn-m alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1,-diyl, propan-1,3-diyl, propan-1,2- diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.As used herein, the term“Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.As used herein, the term“Cn-m alkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.As used herein, the term“amino” refers to a group of formula–NH2.As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.As used herein, the term“di(Cn-m-alkyl)amino” refers to a group of formula -N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.As used herein,“halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein,“Cn-m haloalkoxy” refers to a group of formula–O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.As used herein, the term“Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where“s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.As used herein,“cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring- forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein,“heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl ring. A five- membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six- membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.As used herein,“heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups.Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, 1,1-dioxidothiomorpholin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,1-dioxido-1,4- thiazepan-4-yl, 1,1-dioxido-1,2,5-thiadiazepan-5-yl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen oxygen or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more ring members selected from C(O), S(O), C(S), S(O)2, and S(NH)(O). In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more ring members selected from S(O)2 and S(NH)(O).At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.As used herein, the term“oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group.The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration.Formulas (I)-(XII) herein include stereoisomers of the compounds. In some embodiments, the carbon atom to which R1 is attached is in the (R)-configuration. In some embodiments, the carbon atom to which R1 is attached is in the (S)-configuration.Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ^ camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α- methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone– enol pairs, amide - imidic acid pairs, lactam– lactim pairs, enamine– imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.Example acids can be inorganic or organic acids and include, but are not limited to, strong and weak acids. Some example acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate. Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, iso-propyl, n- butyl, tert-butyl, trimethylsilyl and cyclohexyl substituted amides. In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By“substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.The term“compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.The phrase“pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.The present application also includes pharmaceutically acceptable salts of the compounds described herein. The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein,“pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. SynthesisAs will be appreciated, the compounds provided herein, including salts and stereoisomers thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.Compounds of Formula I can be prepared from amines 1-1 as shown in Scheme 1. Amine 1- 1 can be coupled with an optionally protected (e.g., P = Boc) carboxylic acid such as 1-2 by various methods (e.g., treatment with a coupling reagent, such as N,N,N',N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate in the presence of base, such asdiisopropylethylamine). After coupling, optionally chosen protecting groups can be removed under conditions suitable for their removal, that are also compatible with the functionality present in the resulting compounds of Formula I.Amines 1-1 can be prepared from ketones 2-1 by various methods, as illustrated in Scheme 2. For example, one method (A) involves imine formation with a source of ammonia (e.g. solution of ammonia in an alcohol, or an ammonium salt such as ammonium acetate), which may be facilitated by the introduction of a Lewis acid (e.g. titanium(IV) ethoxide or titanium tetraisopropoxide). The imine can be reduced using a reducing agent (e.g. NaBH4 or NaCNBH3), to furnish amines 1-1.Alternatively, the method of Ellman (B), can be used to furnish amine 1-1 in enantiomerically enriched form. This would be performed, for example, by condensation of ketones 2-1 with a tert- butanesulfinamide (chiral, if desired) in the presence of Lewis acid (e.g., titanium tetraethoxide), followed by reduction of the tert-butanesulfinyl ketimine (e.g. using L-Selectride®), and removal of the tert-butyl sulfinyl group with acid (e.g., 4 N HCl in dioxane). As an alternative to reductive amination, a sequence of transformations (C) can be used to furnish amine 1-1, which include reduction of the ketone to the alcohol (e.g. using NaBH4), conversion of the resulting alcohol to a leaving group (e.g., reacting with MsCl in the presence of base, such as triethylamine), displacement of the leaving group with sodium azide, followed by reduction of the azide to an amine (e.g., via hydrogenation or Staudinger reduction).As shown in Scheme 3, ketones 2-1 can be prepared from esters 3-1 via sequential hydrolysis (e.g. treatment with a hydroxide base, such as NaOH), Weinreb amide formation (e.g. by coupling the acid with N,O-dimethylhydroxylamine using a coupling agent such as EDCI and HOBt in the presence of a tertiary amine base, such as triethylamine or diisopropylethylamine), and treatment of the Weinreb amide with a Grignard reagent, R1-MgX, to afford ketone 2-1.Compounds of Formula I wherein W = CH, X1 = C, X2 = C, X3 = N or NR3a, X4 = N or NR4a, X5 = CR5 can be prepared as shown in Scheme 4. Nitro-containing starting materials 4-1 can be converted to the corresponding triflate 4-2 by several methods (e.g., by treatment withtrifluoromethanesulfonic anhydride and a base, such as triethylamine). The substituent R2 can be introduced by a coupling of 4-2 with R2-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to give derivative 4-3. The nitro group of intermediate 4-3 can be converted to the primary amine by reduction (e.g. hydrogenation over a Pt or Pd catalyst, Fe / HCl, or LiAlH4). Intermediate 4-4 can then be converted to the indazole via diazotization of the amine and cyclization employing an alkyl nitrite (e.g., amyl nitrite) in warm AcOH. If desired, the halogen present in 4-5 can serve as a handle for installation of substituent R6, via coupling with R6-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give derivative 4-6. The indazole nitrogens of 4-6 can be alkylated either by treatment with a base and an electrophile, such as an alkyl halide (e.g. K2CO3 and MeI), or via Mitsunobu conditions (PPh3, DEAD) employing a suitable alcohol, to give 4-7 as a mixture of N1 and N2 substituted indazoles. The ketone in 4-7 can be converted to an amine by various methods as shown in Scheme 2 to furnish amine 4-8. Amine 4-8 can be coupled with an optionally protected carboxylic acid such as 1-2 (from Scheme 1) by various methods as shown in Scheme 1. After coupling, any chosen protecting groups can be removed under conditions suitable for their removal, that are also compatible with the functionality present in the resulting compounds of the Formula I. It will be recognized by one skilled in the art that the order of steps in Scheme 4 can be changed in consideration of compatibility of functional groups present in the intermediates.Scheme 4.Alkoxy derivatives of the compounds of Formula I, where R2 = OR13 can be prepared as shown in Scheme 5. Alkylation of the hydroxyl group in 4-1 employing a base and an electrophile such as an alkyl halide (e.g. K2CO3 and MeI) provides alkoxy intermediates 5-1, which can be converted to compounds of Formula I employing the synthetic methodologies described in Schemes 1 and 2. It will be recognized by one skilled in the art that the order of steps in Scheme 5 can be changed in consideration of the compatibility of functional groups present in the intermediates.Alternatively, compounds of Formula I wherein W = CH, X1 = C, X2 = C, X3 = N or NR3a, X4 = N or NR4a, X5 = CR5 can be synthesized by the synthetic route outlined in Scheme 6. The ketone 4-6 can be converted to an amine 6-1 by various methods as outlined in Scheme 2. Amine 6-1 can be coupled with an optionally protected carboxylic acid such as 1-2 (from Scheme 1) by various methods (e.g., treatment with a coupling reagent such as N,N,N',N'-tetramethyl-O-(7-azabenzotriazol- 1-yl)uronium hexafluorophosphate in the presence of base, such as diisopropylethylamine). The indazole nitrogens of 6-2 can be alkylated either by treatment with a base and an electrophile such as an alkyl halide (e.g. K2CO3 and MeI), or via Mitsunobu conditions (PPh3, DEAD) employing a suitable alcohol, to give 6-3 as a mixture of N1 and N2 substituted indazoles. Any chosen protecting groups can then be removed under conditions suitable for their removal that are also compatible with the functionality present in the resulting compounds of the invention. It will be recognized by one skilled in the art that the order of steps in Scheme 6 can be changed in consideration of compatibility of functional groups present in the intermediates.Compounds of Formula I wherein X1 = C, X2 = C, X3 = N or NR3a, X4 = N or NR4a, X5 = CR5 can also be prepared by the synthetic route described in Scheme 7. Halogenation of heterocycle 4-6 with reagents such as I2, Br2, N-bromosuccinimide, or N-iodosuccinimide can furnish intermediate 7-1, which can serve as a substrate for introduction of substituent R5, via coupling with R5-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yield intermediate 7-2. The ketone 7-2 can be converted to an amine 7-3 by various methods as illustrated in Scheme 2. Amine 7-3 can be coupled with an optionally protected carboxylic acid such as 1-2 (from Scheme 1) by various methods (e.g., treatment with a coupling reagent such as N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate in the presence of base, such as diisopropylethylamine) to provide 7-4. The indazole nitrogens in 7-4 can optionally be alkylated either by treatment with a base and an electrophile, such as an alkyl halide (e.g. K2CO3 and MeI), or via Mitsunobu conditions (PPh3, DEAD) employing a suitable alcohol, to give a mixture of N1 and N2 substituted indazoles. Any chosen protecting groups can then be removed under conditions known by ones skilled in the art, that are also compatible with the functionality present in the resulting compounds of the invention. It will be recognized by one skilled in the art that the order of steps in Scheme 7 can be changed in consideration of compatibility of functional groups present in the intermediates.Scheme 7.Compounds of Formula I, wherein W = CH, Z1 = C, Z2 = N, X3 = N, X4 = CR4, X5 = CR5 can be synthesized as shown in Scheme 8. Accordingly, a carboxylic acid of formula 8-1 can be reacted to form an ester by various methods, such as conversion of the carboxylic acid to the acid chloride by reaction with COCl2 and DMF in a suitable solvent such as DCM, followed by reaction of the acid chloride with a suitable alcohol. The substituent R2 can subsequently be introduced by coupling with R2-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give derivative 8-2. Compound 8-2 can then be aminated with an electrophilic amination reagent (e.g., 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene) to form a N- amino derivative of formula 8-3. Compound 8-3 could then be reacted with a suitable acetylene 8-4 to form a heterocycle of formula 8-5. Compound 8-5 could then be selectively decarboxylated (e.g., acid deprotection of R = t-buyl with trifluoroacetic acid followed by decarboxylation) to form a heterocycle of formula 8-6, which can be halogenated (e.g., X = Cl, Br, I using agents such as an N-halosuccinimide) to give compounds of formula 8-7. If desired, the halogen present in 8-7 can serve as a handle for installation of substituent R5, via coupling with R5-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give derivative 8-8. Formation of ketone 8-9 from ester 8-8 can be achieved by several methods such as those described in Scheme 3. Intermediates of the formula 8-9 can be converted to compounds of Formula I via conversion to an amine via methods outlined in Scheme 2, followed by coupling and deprotection as outlined in Scheme 1. It will be recognized by one skilled in the art that the order of steps in Scheme 8 can be changed in consideration of compatibility of functional groups present in the intermediates.Scheme 8.Compounds of Formula I, wherein W = CH, X1 = C, X2 = N, X3 = CR3, X4 = N, and X5 = CR5, can be prepared as shown in Scheme 9. Halo-containing starting materials (9-1) can be esterified by various methods (e.g., conversion of the carboxylic acid to the acid chloride by reaction with COCl2 and DMF in a suitable solvent such as DCM, followed by reaction of the acid chloride with a suitable alcohol, such as EtOH). The ester intermediate can then be treated with an oxidizing reagent (e.g., a peroxide reagent such as the combination of H2O2 / TFA) to form the heterocyclic N- oxide, and subsequently be converted to the nitrile derivative 9-2 (e.g., by heating withtrimethylsilylcyanide and base). The substituent R2 can be introduced by a coupling of 9-2 with R2-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to give derivative 9-3. The nitrile of intermediate 9-3 can be converted to an aminomethyl group by reduction (e.g. using H2 and a catalyst, such as Raney® Ni or Pd on carbon). Following reduction, the aminomethyl group can be acylated (e.g. by reacting with R3-CO-LG, wherein CO-LG is a suitable activated carbonyl group (e.g., an acid chloride (LG = Cl) or anhydride (LG = O-(CO)R), or carboxylic acid in combination with a coupling agent (e.g., BOP, HATU, or EDCI / HOBt) and a base (e.g., diisopropylethylamine)). The acylated intermediate can be cyclized to form the bicyclic intermediate 9-4 under cyclo-dehydrating conditions (e.g. by heating in POCl3 or by treatment with P2O5, SOCl2 or with acid). Formation of ketone 9-5 from ester 9-4 can proceed as illustrated in Scheme 3. If desired, the halogen present in 9-5 (i.e., group X) can serve as a handle for installation of substituent R6, via coupling with R6-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to give derivative 9-6. If desired, treatment of 9-6 with a halogenating reagent (e.g. I2, Br2, N-chlorosuccinimide N-bromosuccinimide, or N- iodosuccinimide) can furnish intermediate 9-7 (wherein X = Cl, Br, I), which can be substituted with R5, via coupling with R5-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yield intermediate ketone 9-8. Ketone 9-8 can be treated with one of the conditions of Scheme 2 to provide an amine that can be converted to compounds of the invention 9-9 according to Scheme 1. It will be recognized by one skilled in the art that the order of steps in Scheme 9 can be changed in consideration of compatibility of functional groups present in the intermediates.Scheme 9.Compounds of Formula I, wherein W = CH, X1 = C, X2 = N, X3 = CR3, X4 = N, and X5 = CR5, can also be prepared as shown in Scheme 9b. This changing of the order of steps of Scheme 9 enables R2 to be introduced at a later stage in the synthesis and can provide for introduction of R2 with sensitive functional groups. Halo-containing starting materials 9-1 can be converted to the Weinreb amide 9b-1 (e.g., by reaction with MeONHMe in the presence of a suitable coupling reagent such as EDCI and in the presence of HOBt and a suitable base, such as Hunig’s base). The amide intermediate 9b-1 can then be treated with an oxidizing reagent (e.g., a peroxide reagent such as the combination of H2O2 / TFA) to form the heterocyclic N-oxide, and subsequently be converted to the nitrile derivative 9b-1 (e.g., by heating with trimethylsilylcyanide and base). The nitrile of intermediate 9b-1 can be converted to an aminomethyl group by reduction (e.g. Raney® Ni in formic acid). Following reduction, the aminomethyl group can be acylated (e.g. by reacting with R3-CO-LG, wherein CO-LG is a suitable activated carbonyl group (e.g., an acid chloride (LG = Cl) or anhydride (LG = O-(CO)R), or carboxylic acid in combination with a coupling agent (e.g., BOP, HATU, or EDCI / HOBt) and a base (e.g., diisopropylethylamine)). The acylated intermediate can be cyclized to form the bicyclic intermediate 9b-2 under cyclo-dehydrating conditions (e.g. by heating in POCl3 or by treatment with P2O5, SOCl2 or with acid). The Weinreb amide of intermediate 9b-2 can undergo reaction with a Grignard reagent R1MgX to afford ketone 9b-3. The substituent R2 can be introduced by a coupling of 9b-3 with R2-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to give derivative 9-5. Intermediates 9-5 can be transformed to further functionalized compounds of Formula I by the methods outlined in Scheme 9.Compounds of Formula I, wherein W = CH, X1 = C, X2 = N, X3 = CR3, X4 = N, X5 = CR5, and R2 = NR10R11 can be prepared by modification of Scheme 9 shown in Scheme 9c. Intermediate 9- 2 can be heated in the presence of an amine (R10R11NH) and in the presence of a suitable base (e.g. cesium carbonate or Hunig’s base) in a suitable solvent (e.g. acetonitrile) to provide intermediates 9c- 1. The imidazole ring can be annealed to provide intermediate 9c-2, which can be elaborated to ketone 9c-3, which can be functionalized to afford 9c-4, 9c-5 and 9c-6, and finally elaborated to compounds of Formula I using methods previously outlined in Scheme 9.Scheme 9c.As an alternative to early introduction of the amine as shown in Scheme 9c, it is occasionally preferable to introduce it at a later stage as shown in Scheme 9d. Thus, compounds of Formula I, wherein W = CH, X1 = C, X2 = N, X3 = CR3, X4 = N, X5 = CR5, and R2 = NR10R11 can be prepared by heating (e.g., at temperatures ranging from 70 to 170 ^C) the intermediate 9b-3 with an amine (R10R11NH) in the presence of a suitable base (e.g. cesium carbonate or Hunig’s base) in a suitable solvent (e.g. acetonitrile) to provide intermediate 9c-3. Intermediate ketone 9c-3 can be further functionalized and elaborated to compounds of Formula I using methods already described for Scheme 9 and Scheme 9c.Scheme 9d.Amine-containing intermediates suitable for synthesis of compounds of Formula I, wherein W = CH, X1 = C, X2 = N, X3 = CR3, X4 = N, X5 = CR5, and R2 = NR10R11 can be prepared as shown in Scheme 9e. The reaction of Weinreb amide 9b-2 with an amine (R10R11NH) in the presence of a suitable base (e.g. cesium carbonate or Hunig’s base) in a suitable solvent (e.g. acetonitrile) furnishes adduct 9e-1, which is very flexible for further transformations. Intermediate Weinreb amide 9e-1 can undergo reaction with Grignard reagents R1MgX to afford ketones of type 9e-2 that can be treated according to the methods of Scheme 2 to afford amines 9e-5 which, in turn, can be converted to compounds of Formula I as outlined in Scheme 1. Alternatively, Weinreb amide 9e-1 can be reduced by a suitable reducing agent (e.g. diisobutylaluminum hydride) to afford aldehyde 9e-3. Aldehyde 9e- 3 can either be converted to amine 9e-4 by one of the methods of Scheme 2, or converted to amine 9e-5 by condensation with tert-butylsulfinamide (chiral, if desired) in the presence of lewis acid (e.g. titanium isopropoxide), followed by reaction of the tert-butanesulfinyl aldimine with a Grignard reagent R1MgX, and removal of the tert-butyl sulfinyl group with acid (e.g.4N HCl in dioxane). Amines 9e-4 and 9e-5 serve as useful intermediates for further functionalization and elaboration to compounds of Formula I according to methods outlined in Scheme 9. It will be recognized by one skilled in the art that substituents at R5 and R6 can be introduced on many of the intermediates at various stages in Scheme 9d and Scheme 9e, according to the compatibility of functional groups with the subsequent steps to be performed.Scheme 9e.Compounds of Formula I, wherein W = CH, X1 = C, X2 = N, X3 = CR3, X4 = CR4 and X5 = N, can be prepared as shown in Scheme 10. An amino heterocycle, such as 10-1, can be halogenated according to a procedure as found in US 2008-0019915, involving protection of the amino moiety with a suitable protecting group (e.g., phthalimide), formation of the N-oxide using a suitable oxidant (e.g., m-CPBA), and rearrangement to the halo-derivative by treatment of the N-oxide with a suitable reagent (e.g., POX3, RCOX, RSO2X), which upon deprotection would furnish intermediates 10-2 (wherein X = Cl, Br, I). Halo-containing intermediate 10-2 can serve as a substrate for introduction of substituent R2. Substituent R2 can be introduced, for example, via cross-coupling with R2-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yield intermediate 10-3. Alternatively, R2 can be installed via nucleophilic aromatic substitution of the halogen of 10-2 with amines, for example, to provide 10-3 where R2 is an amine. Halogenation of 10-3 using a halogenating reagent (e.g. I2, Br2, N-chlorosuccinimide N- bromosuccinimide, or N-iodosuccinimide) can furnish intermediate 10-4 (wherein X = Cl, Br, I). Formation of bicyclic intermediates 10-6 can proceed by treatment of amino heterocycles 10-4 with α-halo carbonyl intermediates 10-5 (wherein X = Cl, Br), usually with heating and in the presence of a suitable base (e.g., Na2CO3). Alternatively, the intermediate 10-5 may be in the form of the acetal or ketal, in which case reaction of such intermediate with 10-4 may include acid rather than base (e.g., p- toluenesulfonic acid). Conversion of the ester in 10-6 to the ketone 10-7 can be performed as described in Scheme 3. If desired, the halogen in 10-7 can be used as a handle for the introduction of R6 via coupling with M-R6, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yield intermediate 10-8. Ketone 10-8 can be treated with one of the conditions of Scheme 2 to provide an amine that can be converted to compounds of the invention 10- 9 according to Scheme 1. It will be recognized by one skilled in the art that the order of steps in Scheme 10 can be changed in consideration of compatibility of functional groups present in the intermediates.Scheme 10.Compounds of Formula I, wherein W = CH, X1 = C, X2 = N, X3 = CR3, X4 = N and X5 = N, can be prepared as shown in Scheme 11. Heteroaryl starting materials 11-1 can be coupled with R2- M, where M is a boronic acid, boronic ester, or an appropriately substituted metal, such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yield intermediates 11-2. Formation of the N-oxide using a suitable oxidant (e.g., m-CPBA), and rearrangement to the halo-derivative by treatment of the N-oxide with a suitable reagent (e.g., POX3, RCOX, RSO2X), can furnish intermediate 11-3 (wherein X = Cl, Br).Nucleophilic aromatic substitution of the halide (i.e., group X) in intermediate 11-3 with hydrazine can afford intermediate 11-4. Acylation of 11-4 with 11-5, wherein CO-LG is a suitable carbonyl group (e.g., an acid chloride (LG = Cl) or anhydride (LG = O-(CO)R), or carboxylic acid in combination with a coupling agent (e.g., BOP, HATU, or EDCI / HOBt) and a base (e.g.,diisopropylethylamine)) can provide an acylhydrazide intermediate 11-6. Direct conversion of halide 11-3 to acylhydrazide intermediates 11-6 is also possible by displacement of the halide of 11-3 directly with an acyl hydrazide (e.g., R3(CO)NHNH2). A palladium-catalyzed cross coupling of an acyl hydrazide (e.g., R3(CO)NHNH2) with heteroaryl halide 11-3 (e.g., as described in Org. Lett. 2010, 12(4), p.792-795; using Pd2(dba)3, Josiphos, NaHCO3 in DMF at elevated temperature) can also provide 11-6 directly from intermediate 11-3. The intermediate 11-6 can be cyclized to form bicyclic intermediate 11-7 under cyclo-dehydrating conditions (e.g. by heating in POCl3 or by treatment with P2O5, SOCl2 or with acid). Alternatively, hydrazine containing intermediate 11-4 can be heated with orthoesters (e.g., trimethylorthoformate, triethylorthoacetate, or R3C(OR)3), often under acid catalysis (e.g., p-toluenesulfonic acid) to furnish 11-7 directly. If desired, R6 can be introduced into the compound 11-7 via cross-coupling with R6-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to afford intermediate 11-8. Conversion of the ester 11-8 to the ketone 11-9 can be performed as described in Scheme 3. Ketone 11-9 can be treated with one of the conditions of Scheme 2 to provide an amine that can be converted to compounds of the invention 11-10 according to Scheme 1. It will be recognized by one skilled in the art that the order of steps in Scheme 11 can be changed in consideration of compatibility of functional groups present in the intermediates.Scheme 11.Compounds of Formula I, wherein Z1 = C, Z2 = N, X3 = N, X4 = CR4, X5 = CR5 can also be synthesized as shown in Scheme 12. Heteroaryl starting materials 12-1 can be aminated with an electrophilic amination reagent such as 2 [(aminooxy)sulfonyl] 135 trimethylbenzene, to form a N- amino heterocycle of formula 12-2. Compound 12-2 is then reacted with a suitable acetylene 12-3 to form a heterocycle of formula 12-4. Halogenation (e.g., NCS) then affords intermediates 12-5, which can undergo cross coupling with tributylstannyl vinyl ethers under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0), in addition to a base such as CsF) to furnish intermediates 12-7 after hydrolysis. Nucleophilic aromatic substitution with ammonia, followed by halogenation then affords 12-9. Sandmeyer reaction (e.g., NaNO2, HCl, AcOH) provides compounds of formula 12-10, which can be decarboxylated (e.g., hydrolysis with aq. HCl followed by decarboxylation) to give intermediates 12-11. Halogenation (e.g., NCS) or cyanation (e.g., treatment with ClSO2NCO followed by DMF) affords compounds of formula 12-12. One method for introduction of R2 is via selective cross-coupling with R2-M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yield intermediates 12-13. Ketones 12-13 can be treated with one of the conditions of Scheme 2 to provide an amine that can be converted to compounds of the invention 12- 14 according to Scheme 1. Alternatively, NR2 can be installed via nucleophilic aromatic substitution of the halogen of 12-12 with amines. Intermediates 12-15 can be treated with one of the conditions of Scheme 2 to provide an amine that can be converted to compounds of the invention 12-16 according to Scheme 1.Scheme 12Compounds of the Formula I wherein W = C-H, Z1 = C, Z2 = N, X3 = N, X4 = N, X5 = CR5 can be prepared as shown in Scheme 13. Heteroaryl starting materials 13-1 can be coupled with R2- M, where M is a boronic acid, boronic ester, or an appropriately substituted metal such as Sn(Bu)4 or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) chloride and a base (e.g., a bicarbonate or carbonate base, or CsF)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to yield intermediates 13-2. Formation of the N-oxide using a suitable oxidant (e.g., m-CPBA), and rearrangement to the halo-derivative by treatment of the N-oxide with a suitable reagent (e.g., POX3, RCOX, RSO2X), would furnish intermediate 13-3 (wherein X = Cl, Br). Cross coupling with a vinyl metal species 13-4 such as vinyltributylstannane, followed by oxidative cleavage of the olefin (e.g., OsO4, NaIO4) would afford aldehyde 13-5. Formation of the hydrazide gives 13-6, and oxidative cyclization with a suitable reagent such as MnO2 or PhI(OAc)2 then affords triazole 13-7. The halogen can optionally be cross coupled with R6-M to provide intermediates 13-8. Selective deprotonation of the triazole ring with a strong base such as LiTMP and reaction with an electrophilic halogen source (e.g., I2) would afford 13-9. The halogen can optionally be cross coupled with R5-M to give compounds 13-10. Conversion of the ester in 13-10 to the ketone 13-11 can be performed as described in Scheme 3. Ketones 13-11 can be treated with one of the conditions of Scheme 2 to provide an amine that can be converted to compounds of the invention 13-12 according to Scheme 1.Compounds of the Formula I wherein W = C-H, Z1 = C, Z2 = N, X3 = N, X4 = N, X5 = CR5 can be prepared as shown in Scheme 14. Nitro-containing starting materials 1-1 can be reduced to the aniline 1-2. Cyclization of 1-2 with a reagent such as amyl nitrite can give indazole 1-3.Demethylation of 1-3 using BBr3 or a strong acid can give the phenol 1-4. Phenol 1-4 can be converted to the triflate 1-5 under standard conditions with triflic anhydride. Protection of the indazole nitrogens can be accomplished to give 1-6 along with its regioisomer. Displacement of the triflate with an appropriate amine can give 1-7. The ketone in 1-7 can be converted to an amine by various methods as shown in Scheme 3 to furnish amine 1-8. Amine 1-8 can be coupled with an optionally protected carboxylic acid such as 1-2 (Scheme 1) by various methods as shown in Scheme 1. After coupling, any chosen protecting groups can be removed under conditions suitable for their removal, that are also compatible with the functionality present in the resulting compounds of the Formula I. It will be recognized by one skilled in the art that the order of steps in Scheme 14 can be changed in consideration of compatibility of functional groups present in the intermediates.The reactions for preparing compounds described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, (e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.The expressions,“ambient temperature” and“room temperature” or“rt” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ºC to about 30 ºC.Preparation of compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999). Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography. Methods of UseThe compounds, salts or stereoisomers thereof described herein inhibit activity of PI3Kγ kinase. Accordingly, the compounds, salts or stereoisomers described herein can be used in methods of inhibiting PI3Kγ kinase by contacting the kinase with any one or more of the compounds, salts, or compositions described herein. In some embodiments, the compounds or salts can be used in methods of inhibiting activity of PI3Kγ in an individual in need of said inhibition by administering a inhibiting amount of a compound or salt of described herein. In some embodiments, modulating is inhibiting. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is ex vivo.In some embodiments, the PI3Kγ includes a mutation. A mutation can be a replacement of one amino acid for another, or a deletion of one or more amino acids. In such embodiments, the mutation can be present in the kinase domain of the PI3Kγ.In some embodiments, the compound or salt further inhibits PI3K ^.The compounds or salts described herein can be selective. By“selective” is meant that the compound binds to or inhibits PI3Kγ with greater affinity or potency, respectively, compared to at least one other kinase. In some embodiments, the compounds of the invention are selective inhibitors of PI3Kγ over PI3Kδ, PI3Kα, and PI3Kβ. In some embodiments, the compounds of the invention are selective inhibitors of PI3Kγ over PI3Kα and PI3Kβ. In some embodiments, selectivity can be at least about 2-fold, 3-fold, 5-fold, 10-fold, at or 20-fold over PI3Kδ as measured by the assays described herein. In some embodiments, selectivity can be tested at the Km ATP concentration of each enzyme. In some embodiments, the selectivity of compounds of the invention can be determined by cellular assays associated with particular PI3K kinase activity.Another aspect of the present invention pertains to methods of treating a kinase PI3Kγ- associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of one or more compounds of the present invention or a pharmaceutical composition thereof. A PI3Kγ-associated disease or disorder can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the PI3Kγ, including overexpression and / or abnormal activity levels. In some embodiments, the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease.In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, color cancer, endometrial cancer, bladder cancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is Askin's tumor, sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletalchondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.In some embodiments, the disease or disorder is acute myeloid leukemia (e.g., acute monocytic leukemia), small lymphocyctic lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma. In some embodiments, the mature (peripheral) t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T- cell granular lymphocytic leukemia, aggressive NK-cell leukemia, mycosis fungoides / Sezary syndrome, naplastic large cell lymphoma (T-cell type), enteropathy type T-cell lymphoma, adult T- cell leukemia / lymphoma, or angioimmunoblastic T-cell lymphoma In some embodiments, the anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.In some embodiments, the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma,lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom'smacroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa- associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma.In some embodiments, the non-Hodgkin’s lymphoma (NHL) is relapsed NHL, refractory NHL, recurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL). In some embodiments, the diffuse large B cell lymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuse large B cell lymphoma.In some embodiments, the Burkitt’s lymphoma is endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like lymphomaIn some embodiments, the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, asthma, allergy, pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease (e.g., Crohn’s disease and ulcerative colitis), thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren’s syndrome, osteoarthritis, restenosis, or atherosclerosis.In some embodiments, disease or disorder is heart hypertropy, cardiac myocyte dysfunction, chronic obstructive pulmonary disease (COPD), elevated blood pressure, ischemia, ischemia- reperfusion, vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft rejection, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, or membranous nephropathy.In some embodiments, the disease or disorder is Alzheimer's disease, central nervous system trauma, or stroke.In some embodiments, the idiopathic thrombocytopenic purpura (ITP) is relapsed ITP or refractory ITP.In some embodiments, the vasculitis is Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV).The present invention further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.The present invention further provides use of a compound described herein, or apharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.As used herein, the term“contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example,“contacting” a PI3K with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a PI3K, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the PI3K.As used herein, the term“individual” or“patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.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 that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.As used herein, the term“treating” or“treatment” can refer to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease. Combination TherapiesOne or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti- inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, cKit, IGF-1R, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006 / 056399. Other agents such as therapeutic antibodies can be used in combination with the compounds of the present invention for treatment of PI3K-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.In some embodiments, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF- ^R, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF ^R, PDGF ^R, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK- 4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3,VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a Pim inhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643) and an adenosine receptor antagonist or combinations thereof.In some embodiments, the compound or salt described herein is administered with a PI3Kδ inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor, which is selective over JAK2.Example antibodies for use in combination therapy include but are not limited toTrastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A), Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g. anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) and antibodies directed to c-MET.One or more of the following agents may be used in combination with the compounds of the present invention and are presented as a non limiting list: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec™, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.- Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox Xeloda Vinorelbine Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.Additional examples of chemotherapeutics include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin,cyclophosphamide, vincristine, etoposide, carmustine, and the like.Example steroids include corticosteroids such as dexamethasone or prednisone.Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No.5,521,184, WO 04 / 005281, and U.S. Ser. No.60 / 578,491.Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03 / 037347, WO 03 / 099771, and WO 04 / 046120.Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00 / 09495 and WO 05 / 028444.Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO00 / 053595, and WO 01 / 014402.In some embodiments, the compounds of the invention can be used in combination with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.In some embodiments, the compounds of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. In some embodiments, the compounds of the invention can be used in combination with a chemotherapeutic provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. Additive or synergistic effects are desirable outcomes of combining a PI3K inhibitor of the present invention with an additional agent.In some embodiments, PI3Kγ inhibitors provided herein can be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer as described herein. In one embodiment, the combination with one or more immune checkpoint inhibitors as described herein can be used for the treatment of melanoma. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, OX40, GITR, CD137, ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4 LAG3 TIM3 VISTA PD-1, PD-L1 and PD-L2. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule PD-1 inhibitor or a small molecule PD-L1 inhibitor.In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD- 1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab.In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD- L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016.In some embodiments, the compounds of the invention can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat and NGL919.In some embodiments, the compounds of the invention can be used in combination with an inhibitor of JAK or PI3K ^.In some embodiments, the JAK inhibitor is selective for JAK1 and JAK1 over JAK3 and TYK2. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2, JAK3, and TYK2. In some embodiments, the JAK inhibitor inhibit JAK1 preferentially over JAK2 (e.g., have a JAK1 / JAK2 IC50 ratio >1). In some embodiments, the JAK inhibitor is about 10-fold more selective for JAK1 over JAK2.In some embodiments, the JAK inhibitor is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]propanenitrile. In some embodiments, the JAK inhibitor is (3R)-3-cyclopentyl- 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (ruxolitinib; also known as INCB018424). Ruxolitinib has an IC50 of less than 10 nM at 1 mM ATP (assay D) at JAK1 and JAK2. 3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile and ruxolitinib can be made by the procedure described in US 7,598,257 (Example 67), filed December 12, 2006, which is incorporated herein by reference in its entirety. In some embodiments, the inhibitor of JAK1 and / or JAK2 is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitrile phosphoric acid salt. In some embodiments, the inhibitor of JAK1 and / or JAK2 is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3- yl)acetonitrile (baricitinib; also known as INCB028050).In some embodiments, the JAK inhibitor is a compound of Table A, or a pharmaceutically acceptable salt thereof. The compounds in Table 1 are selective JAK1 inhibitors (selective over JAK2, JAK3, and TYK2). The IC50s obtained by the method of Assay D at 1 mM ATP. Table Ay aceon r eThe PI3K ^ inhibitor can be selective. By“selective” is meant that the compound binds to or inhibits a kinase with greater affinity or potency, respectively, compared to at least one other kinase. In some embodiments, the PI3K ^ inhibitor is a selective inhibitors of PI3K ^ (e.g., over PI3Kα, PI3Kβ and PI3Kγ). In some embodiments, selectivity can be at least about 2-fold, 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the Km ATP concentration of each enzyme. In some embodiments, the selectivity of compounds described herein can be determined by cellular assays associated with particular PI3K kinase activity.In some embodiments, the inhibitor of PI3K ^ is a compound shown in Table B. The compounds of Table B have been tested in Assay C and shown to be inhibitors of PI3K ^ with the IC50s in Table B.Table B+ means <50 nM++ means 50 nM to 200 nM+++ means 50 nM to 100 nMIn some embodiments, the inhibitor of PI3K ^ is selected from:(S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2- ethoxy-6-fluorophenyl)pyrrolidin-2-one;(R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2- ethoxy-6-fluorophenyl)pyrrolidin-2-one;(S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2- ethoxy-6-fluorophenyl)pyrrolidin-2-one;(R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2- ethoxy-6-fluorophenyl)pyrrolidin-2-one;N-{(1S)-1-[5-chloro-8-(3-fluorophenyl)cinnolin-7-yl]ethyl}-9H-purin-6-amine;and pharmaceutically acceptable salts of any of the aforementioned.In some embodiments, the inhibitor of PI3Kδ is selected from:4-[(R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2- hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile;4-[1(R)-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2- hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile;5-{3-[1(R)-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5- methylphenyl}-N,N-dimethylpyridine-2-carboxamide;4-[(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2- hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile;4-[1(S)-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2- hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile; 5-{3-[1(S)-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5- methylphenyl}-N,N-dimethylpyridine-2-carboxamide;and pharmaceutically acceptable salts of any of the aforementioned.In some embodiments, PI3Kγ inhibitors provided herein can be administered in combination with an inhibitor of JAK1 and / or JAK2 or an inhibitor of PI3Kδ.The agents can be combined with the present compound in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compounds of the invention where the dexamethasone is administered intermittently as opposed to continuously.In some further embodiments, combinations of the compounds of the invention with other therapeutic agents can be administered to a patient prior to, during, and / or after a bone marrow transplant or stem cell transplant. Pharmaceutical Formulations and Dosage FormsWhen employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002 / 000196.Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.In some embodiments, the compositions of the invention contain from about 5 to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient.In some embodiments, the compositions of the invention contain from about 50 to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 50 to about 100 about 100 to about 150 about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of the active ingredient.In some embodiments, the compositions of the invention contain from about 500 to about 1000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient.Similar dosages may be used of the compounds described herein in the methods and uses of the invention.The active compound can be effective over a wide dosage range and is generallyadministered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. 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 described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g. glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.The compositions administered to a patient can be in the form of pharmaceuticalcompositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. The therapeutic dosage of a compound of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 ^g / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed herein. Labeled Compounds and Assay MethodsAnother aspect of the present invention relates to labeled compounds of the invention (radio- labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PI3K in tissue samples, including human, and for identifying PI3K ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes PI3K assays that contain such labeled compounds.The present invention further includes isotopically-labeled compounds of the invention. An “isotopically” or“radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PI3K labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 125I , 131I, 35S or will generally be most useful. For radio-imaging applications 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br will generally be most useful. It is understood that a“radio-labeled” or“labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 125I , 35S and 82Br.The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.A labeled compound of the invention can be used in a screening assay to identify / evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a PI3K by monitoring its concentration variation when contacting with the PI3K, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a PI3K (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the PI3K directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained. KitsThe present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of PI3K-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples have been found to be PI3Kγ inhibitors according to at least one assay described herein. EXAMPLES Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature (see e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002);“Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific MethodOptimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity analysis under the following conditions: Instrument; Agilent 1100 series, LC / MSD, Column: Waters SunfireTM C185 µm, 2.1 x 50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 2.0 mL / minute.Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:pH = 2 purifications: Waters SunfireTM C185 µm, 19 x 100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 mL / minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see e.g. "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used with the 30 x 100 mm column was 60 mL / minute.pH = 10 purifications: Waters XBridge C185 µm, 19 x 100 mm column, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL / minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see e.g. "Preparative LCMS Purification:Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used with 30 x 100 mm column was 60 mL / minute.The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. Example 1.2-amino-N-[1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(5-chloro-2-ethoxy-4-methyl-3- eTo a solution of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone (1.0 g, 4.4 mmol, from Oakwood) in DMF (10 mL) was added potassium carbonate (1.2 g, 8.7 mmol) and iodoethane (0.52 mL, 6.5 mmol), and the reaction mixture was heated to 60 °C for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between water (30 mL) and EtOAc (30 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-20% EtOAc / hexanes) to afford the title compound (1.07 g, 95%) as a colorless oil. LCMS calculated for C11H13ClNO4 (M+H)+: m / z = 258.0; found: 258.0. Step 2.1-(3-amino-5-chloro-2-ethoxy-4-methylphenyl)ethanoneTo a solution of 1-(5-chloro-2-ethoxy-4-methyl-3-nitrophenyl)ethanone (1.0 g, 3.9 mmol) in MeOH (10 mL) was added Pt / C (5 wt%, 200 mg, 0.04 mmol). The atmosphere was replaced with hydrogen and the reaction mixture was stirred under balloon pressure of hydrogen overnight. The reaction mixture was filtered through a pad of celite, which was washed with additional MeOH (20 mL), and the volatiles were evaporated. The residue was purified by flash chromatography on silica gel (0-20% EtOAc / hexanes) to afford the product as a white solid (630 mg, 71%). LCMS calculated for C11H15ClNO2 (M+H)+: m / z = 228.1; found: 228.1. Step 3.1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanoneTo a solution of 1-(3-amino-5-chloro-2-ethoxy-4-methylphenyl)ethanone (630 mg, 2.8 mmol) in AcOH (17 mL) was added amyl nitrite (0.41 mL, 3.0 mmol) dropwise at room temperature. After stirring for 0.5 h, a precipitate was observed, and the reaction mixture was heated to 110 °C for 1 h. The solution was cooled to room temperature and the volatiles were evaporated. The residue was azeotroped with toluene (50 mL) to remove any remaining AcOH. The resulting orange solid (630 mg, 95%) was dried under high vacuum overnight and used without purification. LCMS calculated for C11H12ClN2O2 (M+H)+: m / z = 239.1; found: 239.1. Step 4.1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanoneTo a solution of 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (30.0 mg, 0.126 mmol) in dry EtOAc (1 mL) was added trimethyloxonium tetrafluoroborate (24 mg, 0.16 mmol) at room temperature. The suspension was heated to 40 °C until complete dissolution, and the resulting solution was stirred at room temperature for 3 h. The solution was diluted with EtOAc (10 mL) and washed with saturated NaHCO3 (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated, and the resulting solid was purified by flash chromatography (0-30% EtOAc / hexanes) to afford the title compound as a white solid (27.1 mg, 85%). LCMS calculated for C12H14ClN2O2 (M+H)+: m / z = 253.1; found: 253.1. Step 5.1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanamineA solution of 1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanone (27.1 mg, 0.107 mmol) and ammonium acetate (120 mg, 1.6 mmol) in MeCN (1 mL) and MeOH (1 mL) was heated at 65 °C for 0.5 h. The solution was cooled to room temperature, and sodium cyanoborohydride (17 mg, 0.27 mmol) was added. The reaction mixture was heated to 65 °C overnight. The solution was cooled to room temperature, diluted with EtOAc (10 mL), and quenched with sat. NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated, and the product was used without purification (theoretical yield assumed). LCMS calculated for C12H14ClN2O (M-NH2)+: m / z = 237.1; found: 237.1. Step 6. tert-butyl 3-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5- a]pyrimidin-2-ylcarbamateTo a vial containing 1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanamine (27.2 mg, 0.107 mmol, from Example 1, Step 5), 2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (39 mg, 0.14 mmol, from J&W Pharmlab), and N,N,N',N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate (53 mg, 0.14 mmol) was added DMF (2 mL), followed by dropwise addition of N,N-diisopropylethylamine (0.037 mL, 0.21 mmol) at room temperature. After stirring for 1 h, the reaction mixture was diluted with EtOAc (10 mL) and quenched with water (5 mL). The layers were separated, and the organic layer was dried over MgSO4, filtered, and concentrated. The product was used without purification (theoretical yield assumed). LCMS calculated for C24H29ClN7O4 (M+H)+: m / z = 514.2; found: 514.2. Step 7.2-amino-N-[1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetateThe tert-butyl 3-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6- yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate (54 mg, 0.107 mmol, from Example 1, Step 6) was taken up in CH2Cl2 (2 mL), and trifluoroacetic acid (0.6 mL, 7 mmol) was added at room temperature. After 1 h, the volatiles were evaporated. The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient buffered at pH 2 with 0.1% trifluoroacetic acid) to give the title compound as a white solid.1H NMR (600 MHz, DMSO-d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5, 1.7 Hz, 1H), 8.44 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz, 1H), 5.51 (p, J = 7.0 Hz, 1H), 4.70– 4.59 (m, 2H), 4.19 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H); LCMS calculated forC19H20ClN7O2Na (M+Na)+: m / z = 436.1; found: 436.1. Example 2.2-amino-N-[1-(4-chloro-7-ethoxy-2-ethyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroaThis compound was synthesized according to the procedure described for Example 1, substituting triethyloxonium tetrafluoroborate instead of trimethyloxonium tetrafluoroborate in Step 4.1H NMR (600 MHz, DMSO-d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5, 1.7 Hz, 1H), 8.48 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz, 1H), 5.50 (p, J = 7.0 Hz, 1H), 4.69 (dq, J = 9.6, 7.0 Hz, 1H), 4.63 (dq, J = 9.6, 7.2 Hz, 1H), 4.47 (q, J = 7.3 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H); LCMS calculated for C20H22ClN7O2 (M+Na)+: m / z = 450.1; found: 450.1. Examples 3a & 3b. 2-amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoro omers isolated)Step 1.1-(4-chloro-7-ethoxy-1H-indazol-This compound was synthesized according to the procedure described in Example 1, Step 5, starting from 1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethanone (450 mg, 1.9 mmol, from Example 1, Step 3). LCMS calculated for C11H10ClN1O (M-NH2)+: m / z = 223.1; found: 223.1. Step 2. tert-butyl 3-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin- 2-ylcarbamateThis compound was synthesized according to the procedure described in Example 1, Step 6, starting with 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine (prepared in the previous step). The product was purified by flash chromatography (0-100% EtOAc / hexanes) to afford the racemic title compound as an off white solid (560 mg, 59%). LCMS calculated for C23H27ClN7O4 (M+H)+: m / z = 500.2; found: 500.2. A fraction of this material (120 mg) was separated by chiral HPLC (Chiral Technologies Chiralcel AD-H, 5µm, 20 x 250 mm, eluting with 20% EtOH / hexanes, 18 mL / min) to afford enantiomer 1 (first to elute, retention time 8.4 min; 30 mg) and enantiomer 2 (second to elute, retention time 11.2 min; 30 mg). Step 3.2-amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetate (single enantiomers isolated)After removal of solvent in vacuo, each enantiomer from Example 3, Step 2 was deprotected separately by stirring with TFA (0.5 mL) in CH2Cl2 (2 mL) for 0.5 h. The volatiles were removed in vacuo to afford the title compound as single enantiomers, which did not require purification.Enantiomer 1 (Example 3a): 1H NMR (600 MHz, DMSO-d6) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.13 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 5.55 (p, J = 7.0 Hz, 1H), 4.29 (d, J = 6.7 Hz, 2H), 1.52 (d, J = 7.0 Hz, 3H), 1.46 (t, J = 7.0 Hz, 3H). LCMS calculated for (M+H)+: m / z = 400.1; found: 400.2. Enantiomer 2 (Example 3b): LCMS calculated for C18H18ClN7O2 (M+H)+: m / z = 400.1; found: 400.2. Example 4.2-amino-N-[1-(4-chloro-7-ethoxy-1-methyl-1H-indazol-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroaStep 1. tert-butyl 3-(1-(4-chloro-7-ethoxy-1-methyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5- a]pyrimidin-2-ylcarbamate & tert-butyl 3-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6- yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamateTo a solution of tert-butyl [3-({[1-(4-chloro-7-ethoxy-1H-indazol-6- yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate (30 mg, 0.06 mmol, fromExample 3, Step 2) in DMF (0.5 mL) was added potassium carbonate (16 mg, 0.12 mmol), followed by methyl iodide (6 µL, 0.09 mmol) and the reaction mixture was heated to 60 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL). The organic layer was dried over MgSO4, filtered and concentrated, and the product was used without purification. The title compounds were obtained in approximately a 1:1 ratio. LCMS calculated for C24H29ClN7O4 (M+H)+: m / z = 514.2; found: 514.1. Step 2.2-amino-N-[1-(4-chloro-7-ethoxy-1-methyl-1H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetate & 2-amino-N-(1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateThe deprotection was performed as described in Example 1, Step 7. Along with the desired indazole N1 regioisomer, the N2 regioisomer was also obtained in a ~1:1 ratio. The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient [37.4-57.4% acetonitrile] buffered at pH 2 with 0.1% trifluoroacetic acid). The title compounds were separable and each was obtained as a white solid. N1 isomer (Example 4): Retention time = 5.9 min. LCMS calculated for C19H21ClN7O2 (M+H)+: m / z = 414.1; found: 414.1. N2 isomer (Example 1): Retention time = 4.9 min.Examples 5-13 were synthesized via an alkylation with the appropriate alkyl halide and subsequent deprotection as described for Example 4. In each case, the alkylation step afforded a varying mixture of N1 and N2 indazole regioisomers. These isomers were separable by preparative HPLC after deprotection, unless otherwise noted. The N1 regioisomers prepared and thecorresponding data are listed in Table 1. The N2 regioisomers prepared and the corresponding data are listed in Table 2.Table 1.Example 14.2-amino-N-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetateStep 1.6-acetyl-4-chloro-3-methyl-2-nitrophenyl trifluoromethanesulfonateTrifluoromethanesulfonic anhydride (1M / CH2Cl2, 13 mL, 13 mmol) was added to a solution of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone (2.0 g, 8.7 mmol, from Oakwood) and triethylamine (2.4 mL, 17 mmol) in THF (20 mL) at -78 °C. The solution was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was diluted with EtOAc (30 mL) and quenched with sat. NaHCO3 (20 mL). The layers were separated and the organic layer was washed with sat. NaCl (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-15% EtOAc / hexanes) to afford the product as an orange oil (3.2 g, 100%). LCMS calculated for C10H8ClF3NO6S (M+H)+: m / z = 362.0; found: 361.8. Step 2.1-(4-chloro-5-methyl-6-nitrobiphenyl-2-yl)ethanoneTo a solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyl trifluoromethanesulfonate (3.2 g, 8.8 mmol) in toluene (20 mL) was added a solution of sodium bicarbonate (1.4 g, 17 mmol) in water (20 mL), followed by phenylboronic acid (1.2 g, 10.0 mmol)and tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.41 mmol). Nitrogen was bubbled through the solution for 5 min, and the reaction mixture was heated at 80 °C (bath temp) for 2 h. The reaction mixture was diluted with EtOAc (30 mL), the layers were separated and the organic layer was washed with saturated NaCl (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-10% EtOAc / hexanes) to afford the title compound as a white solid (2.3 g, 88%). LCMS calculated for C15H13ClNO3 (M+H)+: m / z = 290.1; found: 290.0. Step 3.1-(6-amino-4-chloro-5-methylbiphe eThis compound was synthesized according to the procedure described in Example 1, Step 2, starting from 1-(4-chloro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (2.25 g, 7.77 mmol). The crude product was purified by flash chromatography on silica gel (0-20% EtOAc / hexanes) to afford the title compound as a white solid (1.57 g, 78%). LCMS calculated for C15H15ClNO (M+H)+: m / z = 260.1; found: 260.0. Step 4.1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanoneThis compound was synthesized according to the procedure described in Example 1, Step 3, starting from 1-(6-amino-4-chloro-5-methylbiphenyl-2-yl)ethanone (1.57 g, 6.04 mmol). The product was obtained as an orange solid (1.64 g, 100%). LCMS calculated for C15H12ClN2O (M+H)+: m / z = 271.1; found: 271.0. Step 5.1-(4-chloro-7-phenyl-1H-indazol-This compound was synthesized according to the procedure described in Example 1, Step 5, starting from 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (591 mg, 2.18 mmol). The product was used without purification (theoretical yield assumed). LCMS calculated for C15H12ClN2 (M-NH2)+: m / z = 255.1; found: 255.1. Step 6. tert-butyl 3-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin- 2-ylcarbamateThis compound was synthesized according to the general procedure described in Example 1, Step 6, starting from 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanamine (593 mg, 2.18 mmol). The product was purified by flash chromatography on silica gel (0-60% EtOAc / hexanes) to afford the title compound as an off white solid (562 mg, 48%). LCMS calculated for C27H26ClN7O3 (M+H)+: m / z = 532.2; found: 532.2. Step 7. 2-amino-N-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetateThe deprotection was performed as described in Example 1, Step 7, starting from tert-butyl 3- (1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate (10 mg, 0.020 mmol). The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient buffered at pH 2 with 0.1% trifluoroacetic acid) to give the title compound as a white solid. LCMS calculated for C22H19ClN7O (M+H)+: m / z = 432.1; found: 432.1. Examples 15 & 16.2-amino-N-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate & 2-amino-N-(1-(4-chloro-2- methyl-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetateStep 1. tert-butyl 3-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5- a]pyrimidin-2-ylcarbamate & tert-butyl 3-(1-(4-chloro-2-methyl-7-phenyl-2H-indazol-6- yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamateThis compound was synthesized according the procedure described in Example 4, Step 1, starting with tert-butyl 3-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5- a]pyrimidin-2-ylcarbamate (30 mg, 0.060 mmol, from Example 14, Step 6). The title compounds were obtained in ~1:1.5 of N2:N1 regioisomers. The products were used without purification (theoretical yield assumed). Peak 1: LCMS calculated for C28H29ClN7O3 (M+H)+: m / z = 546.2; found 546.2. Peak 2: LCMS calculated for C28H29ClN7O3 (M+H)+: m / z = 546.2; found 546.3. Step 2.2-amino-N-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetate & 2-amino-N-(1-(4-chloro-2-methyl-7-phenyl-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateThe deprotection was performed as described in Example 1, Step 7, starting from a 1:1.5 mixture of tert-butyl 3-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6- yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate and tert-butyl 3-(1-(4-chloro-2-methyl-7- phenyl-2H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate (32.7 mg, 0.060 mmol). The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient [38.5-58.5% acetonitrile] buffered at pH 2 with 0.1% trifluoroacetic acid). The title compounds were separable and each was obtained as a white solid. Peak 1 (Example 16): Retention time = 5.6 min. LCMS calculated for C23H21ClN7O (M+H)+: m / z = 446.1; found: 446.2. Peak 2 (Example 15): Retention time = 7.0 min.1H NMR (600 MHz, DMSO-d6) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.47 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.56– 7.45 (m, 4H), 7.45– 7.40 (m, 1H), 7.24 (s, 1H), 7.00 (dd, J = 6.7, 4.5 Hz, 1H), 5.16 (p, J = 6.9 Hz, 1H), 4.11 (s, 3H), 1.38 (d, J = 6.9 Hz, 3H); LCMS calculated for C23H21ClN7O (M+H)+: m / z = 446.1; found: 446.2. LCMS calculated for C23H21ClN7O (M+H)+: m / z = 446.1; found: 446.2. Examples 17 & 18.2-amino-N-(1-(4-chloro-1-((1-methyl-1H-pyrazol-3-yl)methyl)-7-phenyl-1H- indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate & 2-amino-N-(1- (4-chloro-2-((1-methyl-1H-pyrazol-3-yl)methyl)-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateThese compounds were synthesized according to the procedure described for Example 15, utilizing 3-(chloromethyl)-1-methyl-1H-pyrazole (from Maybridge) instead of methyl iodide. The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient [36.4-56.4% acetonitrile] buffered at pH 2 with 0.1% trifluoroacetic acid). The title compounds were separable and each was obtained as a white solid. Peak 1 (Example 18): Retention time = 5.4 min.1H NMR (500 MHz, DMSO-d6) δ 8.89 (dd, J = 6.7, 1.6 Hz, 1H), 8.53 (dd, J = 4.5, 1.6 Hz, 1H), 8.42 (s, 1H), 8.07 (d, J = 6.7 Hz, 1H), 7.69 (s, 1H), 7.54– 7.45 (m, 4H), 7.45– 7.40 (m, 2H), 7.22 (s, 1H), 6.98 (dd, J = 6.7, 4.5 Hz, 1H), 5.42 (s, 2H), 5.13 (p, J = 6.9 Hz, 1H), 3.76 (s, 3H), 1.36 (d, J = 6.9 Hz, 3H). LCMS calculated for C27H25ClN9O (M+H)+: m / z = 526.2; found: 526.2. LCMS calculated for C27H25ClN9O (M+H)+: m / z = 526.2; found: 526.2. Peak 2 (Example 17): Retention time = 6.2 min. LCMS calculated for C27H25ClN9O (M+H)+: m / z = 526.2; found: 526.2. Example 19.2-amino-N-(1-(4-chloro-1-(2-morpholinoethyl)-7-phenyl-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamideThis compound was synthesized according to the procedure described for Example 15, utilizing 4-(2-bromoethyl)morpholine instead of methyl iodide. The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient buffered at pH 10 with 0.1% ammonium hydroxide) to give the title compound as a white solid.1H NMR (600 MHz, DMSO-d6) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.57 (dd, J = 4.5, 1.6 Hz, 1H), 8.17 (s, 1H), 8.12 (d, J = 6.6 Hz, 1H), 7.67– 7.63 (m, 1H), 7.63– 7.59 (m, 1H), 7.59– 7.53 (m, 2H), 7.49– 7.46 (m, 1H), 7.32 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 6.41 (s, 2H), 4.85 (p, J = 6.8 Hz, 1H), 3.81– 3.64 (m, 2H), 3.47– 3.39 (m, 4H), 2.41– 2.32 (m, 2H), 2.13– 2.04 (m, 4H), 1.35 (d, J = 7.0 Hz, 3H); LCMS calculated for C28H30ClN8O2 (M+H)+: m / z = 545.2; found: 545.2. Example 20.2-amino-N-(1-(4-chloro-2-(2-morpholino-2-oxoethyl)-7-phenyl-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamideThis compound was synthesized according to the procedure described for Example 15, utilizing 2-chloro-1-morpholinoethanone instead of methyl iodide. The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient buffered at pH 10 with 0.1% ammonium hydroxide) to give the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.89 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5, 1.6 Hz, 1H), 8.39 (s, 1H), 8.09 (d, J = 6.7 Hz, 1H), 7.55– 7.43 (m, 4H), 7.43– 7.36 (m, 1H), 7.24 (s, 1H), 6.98 (dd, J = 6.7, 4.5 Hz, 1H), 6.39 (s, 2H), 5.45 (s, 2H), 5.12 (p, J = 6.9 Hz, 1H), 3.61– 3.57 (m, 2H), 3.57– 3.53 (m, 2H), 3.50– 3.46 (m, 2H), 3.43– 3.39 (m, 2H), 1.38 (d, J = 6.9 Hz, 3H); LCMS calculated for C28H28ClN8O3 (M+H)+: m / z = 559.2; found: 559.2. Example 21 & 22.2-amino-N-(1-(2-(2-aminoethyl)-4-chloro-7-phenyl-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate & 2-amino-N-(1-(1-(2- aminoethyl)-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateStep 1. tert-butyl 3-(1-(4-chloro-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-7-phenyl-2H-indazol-6- yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate & tert-butyl 3-(1-(4-chloro-1-(2-(1,3- dioxoisoindolin-2-yl)ethyl)-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2- ylcarbamateTo a solution of tert-butyl 3-(1-(4-chloro-7-phenyl-1H-indazol-6- yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate (30 mg, 0.06 mmol, from Example 14, Step 6) in DMF (0.5 mL) was added potassium carbonate (23 mg, 0.17 mmol), followed by N-(2- bromoethyl)phthalimide (43 mg, 0.17 mmol) and the reaction mixture was heated to 80 °C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The title compounds, which were obtained in ~1:1 ratio, were used without purification (theoretical yield assumed). Peak 1: LCMS calculated for C37H33ClN8O5 (M+H)+: m / z = 705.2; found: 705.2. Peak 2: LCMS calculated for C37H33ClN8O5 (M+H)+: m / z = 705.2; found: 705.2. Step 2.2-amino-N-(1-(4-chloro-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-7-phenyl-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide & 2-amino-N-(1-(4-chloro-1-(2-(1,3- dioxoisoindolin-2-yl)ethyl)-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamideThe mixture of products from the previous step (42 mg, 0.060 mmol, ~1.5:1 mixture with the N1 substituted isomer) was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid (0.5 mL, 6 mmol) was added at room temperature. After 0.5 h, the volatiles were removed in vacuo and the residue was used without purification (theoretical yield assumed). Peak 1: LCMS calculated for C32H26ClN8O3 (M+H)+: m / z = 605.2; found: 605.2. Peak 2: LCMS calculated for C32H26ClN8O3 (M+H)+: m / z = 605.2; found: 605.2. Step 3.2-amino-N-(1-(2-(2-aminoethyl)-4-chloro-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetate & 2-amino-N-(1-(1-(2-aminoethyl)-4-chloro-7-phenyl- 1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateThe mixture of products from the previous step (36 mg, 0.06 mmol) was taken up in MeOH (2 mL) and treated with hydrazine (90 3 mmol) at room temperature. After 2 h, the volatiles were evaporated and the residue was partitioned between water (10 mL) and EtOAc (10 mL). The layers were separated, and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with awater:acetonitrile gradient [23-43% acetonitrile] buffered at pH 2 with 0.1% trifluoroacetic acid). The title compounds were separable, and each was obtained as a white solid. Peak 1 (Example 21): Retention time = 4.43. LCMS calculated for C24H24ClN8O (M+H)+: m / z = 475.2; found: 475.2. Peak 2 (Example 22): Retention time = 4.67. LCMS calculated for C24H24ClN8O (M+H)+: m / z = 475.2; found: 475.2. Example 23.2-amino-N-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanoneTo a solution of 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (39 mg, 0.14 mmol, from Example 14, Step 4) in DMF (2 mL) was added N-bromosuccinimide (31 mg, 0.17 mmol) at room temperature. After stirring for 2 h, the reaction mixture was quenched with saturated NaHCO3 (5 mL) and extracted with EtOAc (10 mL). The layers were separated, and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0- 35% EtOAc / hexanes) to afford the title compound as an orange solid (47 mg, 93%). LCMS calculated for C15H11BrClN2O (M+H)+: m / z = 349.0; found: 348.9. Step 2.1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanamineTo a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (30.0 mg, 0.0858 mmol) in ammonia (2M / EtOH, 2 mL) was added titanium tetraisopropoxide (51 μL, 0.17 mmol) and the reaction mixture was heated at 60 °C overnight. The resulting solution was cooled to room temperature, then 0 °C, and sodium borohydride (9.7 mg, 0.26 mmol) was added. After stirring for 0.5 h, the reaction mixture was quenched with 1M NH4OH, filtered, and the filtrate was washed with EtOAc (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated. The product was used without purification (theoretical yield assumed). LCMS calculated for C15H11BrClN2 (M-NH2)+: m / z = 333.0; found: 333.0. Step 3. tert-butyl 3-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5- a]pyrimidin-2-ylcarbamateThis compound was synthesized according to the procedure described in Example 1, Step 6, starting from 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanamine (30 mg, 0.086 mmol). The product was used without purification (theoretical yield assumed). LCMS calculated forC27H25BrClN7O3 (M+H)+: m / z = 610.1; found: 610.1. Step 4.2-amino-N-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetateThe deprotection was performed as described in Example 1, Step 7, starting from tert-butyl 3- (1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2- ylcarbamate (52 mg, 0.086 mmol). The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient buffered at pH 2 with 0.1%trifluoroacetic acid) to give the title compound as a white solid. LCMS calculated forC22H18BrClN7O (M+H)+: m / z = 510.0; found: 510.0. Example 24.2-amino-N-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanoneTo a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (30.0 mg, 0.0858 mmol, from Example 23, Step 1) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (6.3 mg, 0.0086 mmol) in dioxane (1 mL) was added 1.0 M dimethylzinc in heptane (90.1 μL, 0.0901 mmol) dropwise at room temperature, and the reaction mixture was heated to reflux for 2 h. LCMS indicated 50% conversion so an additional 05 equiv dimethylzinc was added and heating was continued for an additional 1 h. The reaction mixture was filtered and the volatiles were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (0-35% EtOAc / hexanes) to afford the title compound as a colorless oil (7 mg, 29%). LCMS calculated for C16H14ClN2O (M+H)+: m / z = 285.1; found: 285.1. Step 2.1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanamineThis compound was synthesized according to the procedure described in Example 23, Step 2, starting from 1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanone (7 mg, 0.024 mmol). The product was used without purification (theoretical yield assumed). LCMS calculated for C16H14ClN2 (M-NH2)+: m / z = 269.1; found: 269.0. Step 3. tert-butyl 3-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5- a]pyrimidin-2-ylcarbamateThis compound was synthesized according to the procedure described in Example 1, Step 6, starting from 1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethanamine (7 mg, 0.024 mmol). The product was used without purification (theoretical yield assumed). LCMS calculated forC28H29ClN7O3 (M+H)+: m / z = 546.2; found: 546.2. Step 4.2-amino-N-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetateThe deprotection was performed as described in Example 1, Step 7, starting from tert-butyl 3- (1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2- ylcarbamate (13 mg, 0.024 mmol). The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient buffered at pH 2 with 0.1%trifluoroacetic acid) to give the title compound as a white solid. LCMS calculated for C23H21ClN7O (M+H)+: m / z = 446.1; found: 446.1. Example 25.2-amino-N-(1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethanoneTo a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (20.0 mg, 0.0857 mmol, from Example 23, Step 1) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (4.2 mg, 0.0057 mmol) in dioxane (1 mL) was added 1.0 M dimethylzinc in heptane (110 μL, 0.11 mmol) dropwise at room temperature, and the reaction mixture was heated to reflux for 4 h. The reaction mixture was filtered and the volatiles were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (0-35% EtOAc / hexanes) to afford the title compound as a colorless oil (10 mg, 67%). LCMS calculated for C17H17N2O (M+H)+: m / z = 265.1; found: 265.1. Steps 2-4.2-amino-N-(1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetateThis compound was synthesized starting from 1-(3,4-dimethyl-7-phenyl-1H-indazol-6- yl)ethanone (10 mg, 0.038 mmol) following the procedure described for Example 24, steps 2-4. The residue was dissolved in MeOH and purified by preparative HPLC (C-18 column eluting with a water:acetonitrile gradient buffered at pH 2 with 0.1% trifluoroacetic acid) to give the title compound as a white solid. LCMS calculated for C24H24N7O (M+H)+: m / z = 426.2; found: 426.3. Example 26.2-Amino-N-{1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (mixture of diastereomers prepared) ^Step 1. Methyl 2,5-dichloronicotinateA solution of 2,5-dichloronicotinic acid (20.0 g, 104 mmol, OChem) in DCM (520 mL) was treated with oxalyl chloride (26. mL, 310 mmol) followed by DMF (0.015 mL, 0.19 mmol). The reaction was stirred overnight. The reaction mixture was then concentrated in vacuo. The acid chloride was diluted with DCM (200 mL), cooled to 0 °C and treated with MeOH (110 mL). After stirring for 30 minutes, solvents were removed in vacuo. The crude residue was dissolved in DCM and washed sequentially with saturated NaHCO3 solution, water, and saturated NaCl solution. The organic layer was dried over Na2SO4, filtered, and concentrated to afford a white crystalline solid that was used without further purification. Yield: 18.8 g, 90%. LCMS calculated for C7H6Cl2NO2 (M+H)+: m / z = 206.0; found: 206.0. Step 2. Methyl 2,5-dichloronicotinate 1-oxide^H2O2 (30% in water, 19.6 mL, 640 mmol) was added to methyl 2,5-dichloronicotinate (19.4 g, 94.2 mmol, prepared as in Step 1) in TFA (118 mL). The reaction mixture was heated to 70 ^C for 1 hour. Solvent was removed in vacuo and the product was purified by flash chromatography, eluting with a gradient from 0-100% ethyl acetate in hexanes to afford a white solid. Yield: 17.4 g, 83%. LCMS calculated for C7H6Cl2NO3 (M+H)+: m / z = 222.0; found: 222.0. Step 3. Methyl 2,5-dichloro-6-cyanonicotinate ^ Triethylamine (16.6 mL, 119 mmol) and trimethylsilyl cyanide (25.9 mL, 194 mmol) were added to a solution of methyl 2,5-dichloronicotinate 1-oxide (17.4 g, 78.4 mmol, from Step 2) in acetonitrile (150 mL). The reaction mixture was heated to 70 ^C for 20 minutes. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, and the solution was quenched by slow addition to a cold solution of aqueous K2CO3 (500 mL). The resulting aqueous mixture was extracted with DCM. The combined organic extracts were washed with water, followed by brine, dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-50% EtOAc / hexanes. Yield: 16.3 g, 90%. LCMS calculated for C8H4Cl2N2O2 (M+H)+: m / z = 231.0; found: 231.0. Step 4. Methyl 5-chloro-6-cyano-2-(3-fluorophenyl)nicotinate^A degassed mixture of methyl 2,5-dichloro-6-cyanonicotinate (5.0 g, 22 mmol, from Step 3), (3-fluorophenyl)boronic acid (3.33 g, 23.8 mmol, Aldrich), bis(triphenylphosphine)palladium(II) chloride (1.05 g, 1.50 mmol), K2CO3 (6.52 g, 47.2 mmol) in water (39.0 mL), and 1,4-dioxane (101 mL) was heated at 80 °C for 1 hour. The reaction mixture was diluted with EtOAc and water. The aqueous layer was separated and extracted with additional EtOAc. The combined organic extracts were washed with water, followed by brine, dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes to afford the product as a light yellow solid. Yield: 5.5 g, 87%. LCMS calculated for C14H9ClFN2O2 (M+H)+: m / z = 291.0; found: 291.0. Step 5. Methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinate acetate salt^A solution of methyl 5-chloro-6-cyano-2-(3-fluorophenyl)nicotinate (5.5 g, 19 mmol, from Step 4) in acetic acid (55 mL) was degassed and then stirred under 1 atm of H2 over Pd on C (5%, 2.4 g, 1.1 mmol) for 3 hours. The mixture was filtered through Celite® and solvent was removed in vacuo to afford a crystalline solid. The solid was slurried in water and filtered, and the solids were washed with water to give the desired compound as the acetate salt, contaminated with a small amount of the des-chloro byproduct, the bulk of which remained in the filtrate. Yield: 1.9 g, 26%. LCMS calculated for C14H13ClFN2O2 (M+H)+: m / z = 295.1; found: 295.0. Step 6. Methyl 6-[(acetylamino)methyl]-5-chloro-2-(3-fluorophenyl)nicotinate^To methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinate acetate (0.90 g, 2.5 mmol, from Step 5) and N,N-diisopropylethylamine (0.88 mL, 5.1 mmol) in N,N-dimethylformamide (7.4 mL) was added acetic anhydride (0.26 mL, 2.8 mmol). After 30 minutes, the mixture was quenched with saturated NaHCO3 solution and diluted with water. The aqueous mixture was extracted with EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over Na2SO4, and concentrated to give product that was used without further purification. Yield: 0.85 g, 100%. LCMS calculated for C16H15ClFN2O3 (M+H)+: m / z = 337.1; found: 337.1. Step 7. Methyl 8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylate^Methyl 6-[(acetylamino)methyl]-5-chloro-2-(3-fluorophenyl)nicotinate (0.85 g, 2.5 mmol, from Step 6) in POCl3 (10 mL, 110 mmol) was heated to 90 ^C for 35 minutes. The mixture was then evaporated to remove POCl3. The product was purified by flash chromatography, eluting with a gradient from 0-100% EtOAc (containing 1%MeOH and 1%NH4OH) in hexanes. Yield: 0.70 g, 78%. LCMS calculated for C16H13ClFN2O2 (M+H)+: m / z = 319.1; found: 319.1. Step 8.8-Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylic acid^Methyl 8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylate (230 mg, 0.72 mmol, from Step 7) in MeOH (5 mL) was treated with 3.0 M NaOH in water (0.96 mL, 2.9 mmol) and stirred for 5 hours. The mixture was acidified with acetic acid and the solvents were removed in vacuo. Trituration with water gave the desired compound as a light yellow solid, which was isolated by filtration and air dried. Yield: 0.20 g, 91%. LCMS calculated for C15H11ClFN2O2 (M+H)+: m / z = 305.0; found: 305.0. Step 9.8-Chloro-5-(3-fluorophenyl)-N-methoxy-N,3-dimethylimidazo[1,5-a]pyridine-6-carboxamide^To a suspension of 8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridine-6-carboxylic acid (0.20 g, 0.66 mmol, from Step 8) in DMF (1.8 mL) was added N,N-diisopropylethylamine (0.572 mL, 3.28 mmol), N,O-dimethylhydroxylamine hydrochloride (0.192 g, 1.97 mmol), 0.6 M 1-hydroxy- 7-azabenzotriazole in DMF (0.219 mL, 0.131 mmol), and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (0.189 g, 0.984 mmol). The precipitate slowly dissolved, and the resulting solution was stirred overnight. Saturated NaHCO3 was added, and the mixture was extracted with three portions of EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over Na2SO4, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient of 0-80% EtOAc in hexanes to afford product as a yellow solid. Yield: 0.18 g, 79%. LCMS calculated for C17H16ClFN3O2 (M+H)+: m / z = 348.1; found: 348.0. Step 10.1-[8-Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanone^3.0 M Methylmagnesium bromide in THF (0.78 mL, 2.3 mmol) was added dropwise to a 0 ^C solution of 8-chloro-5-(3-fluorophenyl)-N-methoxy-N,3-dimethylimidazo[1,5-a]pyridine-6- carboxamide (0.18 g, 0.52 mmol, from Step 9) in anhydrous THF (5.0 mL, 62 mmol) under N2. The solution was stirred at 0 ^C for 1.5 hours. The reaction was quenched at 0 ^C by the addition of 1.0 M HCl in water (2.6 mL, 2.6 mmol). The mixture was then made basic by the addition of saturated NaHCO3 solution. The mixture was extracted with EtOAc (75 mL). The organic extract was washed with water, followed by brine, dried over Na2SO4, filtered, and concentrated to afford the product as a yellow solid, which was used without further purification. Yield: 0.14 g, 89%. LCMS calculated for C16H13ClFN2O (M+H)+: m / z = 303.1; found: 303.0. Step 11.1-[8-Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanamine (mixture of diastereomers prepared)A mixture of 1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanone (0.14 g, 0.46 mmol, from Step 10) and ammonium acetate (0.356 g, 4.62 mmol) in methanol (5.2 mL) was heated at 65 ^C for 1 hour. Sodium cyanoborohydride (87 mg, 1.4 mmol) was then added and heating was continued for 1 hour. Additional ammonium acetate (0.356 g, 4.62 mmol) and sodium cyanoborohydride (0.087 g, 1.4 mmol) were added and heating was continued for a total of 22 hours. Upon cooling to room temperature, saturated NaHCO3 solution was added and the mixture was extracted with two portions of EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. To remove further impurities, the residue was dissolved in 1N HCl and washed with EtOAc. The aqueous layer was made basic again by the addition of NaHCO3 solution, and was extracted with EtOAc. The extract was again dried over Na2SO4, filtered, and concentrated. The product was purified by preparative HPLC-MS (pH 10). Yield: 61 mg, 43%. LCMS calculated for C16H16ClFN3 (M+H)+: m / z = 304.1; found: 304.1. Step 12.2-Amino-N-{1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (mixture of diastereomers prepared)1-[8-Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanamine (20. mg, 0.066 mmol, from Step 11) in DMF (0.45 mL) was added to a mixture of 2-[(tert- butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (18 mg, 0.066 mmol, J&W Pharmlab), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (30. mg, 0.079 mmol) and N,N-diisopropylethylamine (23 μL, 0.13 mmol) in DMF (0.4 mL). After stirring for 40 minutes, water was added and the precipitated product was isolated by filtration and air dried. The white solid so obtained was stirred with TFA (0.2 mL) in DCM (0.5 mL) for 30 minutes. Solvent was removed in vacuo and the residue was reconstituted in acetonitrile and purified by preparative HPLC- MS (pH 2). Yield: 20 mg.1H NMR (400 MHz, DMSO-d6, mixture of diastereomers) δ 8.95– 8.88 (m, 2H), 8.60– 8.50 (m, 2H), 8.09– 7.95 (m, 2H), 7.87 (s, 2H), 7.76– 7.59 (m, 4H), 7.59– 7.42 (m, 4H), 7.35 (s, 1H), 7.34 (s, 1H), 7.05– 6.99 (m, 2H), 6.43 (br s, 4H), 4.68– 4.38 (m, 2H), 1.88 (s, 3H), 1.88 (s, 3H), 1.41 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 6.9 Hz, 3H); LCMS calculated for C23H20ClFN7O (M+H)+: m / z = 464.1; found: 464.1. Example 27.2-Amino-N-(1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetate salt (single enantiomer prepared)Step 1. Methyl 5-chloro-6-cyano-2-phenylnicotinateThe title compound was prepared as in Example 26, Step 4, using 2,5-dichloro-6- cyanonicotinate (5.80 g, 25.1 mmol, prepared as in Example 26, Step 3) and phenylboronic acid (3.67 g, 30.1 mmol, Aldrich). Yield: 6.33 g, 93%.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.57– 7.48 (m, 5H), 3.74 (s, 3H); LCMS calculated for C14H20ClN2O2 (M+H)+: m / z = 273.0; found: 273.0. Step 2. Methyl 6-(aminomethyl)-5-chloro-2-phenylnicotinateTo methyl 5-chloro-6-cyano-2-phenylnicotinate (1.01 g, 3.70 mmol, from Step 1) in methanol (50. mL) was added Raney Ni (1.0 mL of Raney® Nickel suspension in water). The mixture was degassed and stirred under H2 (1 atm) for 2 hours. The mixture was filtered through Celite®, and the Celite® was washed with methanol. Solvent was removed from the filtrate to afford product, which was used without further purification in Step 3. Yield: 1.0 g, 97%. LCMS calculated forC14H14ClN2O2 (M+H)+: m / z = 277.1; found: 277.1. Step 3. Methyl 5-chloro-6-[(formylamino)methyl]-2-phenylnicotinateFormic acid (6.7 mL, 180 mmol) and acetic anhydride (1.7 mL, 18 mmol) were combined and stirred for 40 minutes, then the mixture was added dropwise into a 0 ^C solution of methyl 6- (aminomethyl)-5-chloro-2-phenylnicotinate (1.0 g, 3.6 mmol, from Step 2) in DCM (20 mL). After stirring for 50 minutes at 0 ^C, the solution was warmed to room temperature and stirred overnight. Solvent was removed in vacuo to afford 1.34 g of crude product which was used without further purification in Step 4. LCMS calculated for C15H14ClN2O3 (M+H)+: m / z = 305.1; found: 305.0. Step 4. Methyl 8-chloro-5-phenylimidazo[1,5-a]pyridine-6-carboxylateMethyl 5-chloro-6-[(formylamino)methyl]-2-phenylnicotinate (1.13 g, 3.71 mmol, from Step 3) in POCl3 (5.5 mL, 59 mmol) was heated to 75 ^C for 35 minutes. Upon cooling to room temperature, the mixture was poured slowly onto crushed ice, and the ice-cold mixture was neutralized by the addition of solid Na2CO3. The aqueous mixture was extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes. Yield: 0.76 g, 71%.1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.65 (s, 1H), 7.63– 7.57 (m, 3H), 7.56– 7.49 (m, 2H), 7.41 (s, 1H), 3.57 (s, 3H); LCMS calculated for C15H12ClN2O2 (M+H)+: m / z = 287.1; found: 287.1. Step 5.8-Chloro-5-phenylimidazo[1,5-a]pyridine-6-carboxylic acidThe title compounds was prepared as in Example 26, Step 8, using methyl 8-chloro-5- phenylimidazo[1,5-a]pyridine-6-carboxylate (0.75 g, 2.6 mmol, from Step 4). Yield: 0.70 g, 98%. LCMS calculated for C14H10ClN2O2 (M+H)+: m / z = 273.0; found: 273.0. Step 6.8-Chloro-N-methoxy-N-methyl-5-phenylimidazo[1,5-a]pyridine-6-carboxamideThe title compound was prepared as in Example 26, Step 9, using 8-chloro-5- phenylimidazo[1,5-a]pyridine-6-carboxylic acid (0.70 g, 2.6 mmol, from Step 5). Yield: 0.62 g, 76%. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.64 (s, 1H), 7.60 (s, 5H), 7.22 (s, 1H), 3.49 (br s, 3H), 3.00 (br s, 3H); LCMS calculated for C16H15ClN3O2 (M+H)+: m / z = 316.1; found: 316.0. Step 7.1-(8-Chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanoneThe title compound was prepared from 8-chloro-N-methoxy-N-methyl-5-phenylimidazo[1,5- a]pyridine-6-carboxamide (0.62 g, 2.0 mmol, from Step 6) by the procedure of Example 26, Step 10. The product was used without further purification in Step 8.1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.75 (s, 1H), 7.71– 7.61 (m, 3H), 7.53– 7.42 (m, 2H), 7.37 (s, 1H), 1.96 (s, 3H); LCMS calculated for C15H12ClN2O (M+H)+: m / z = 271.1; found: 271.1. Step 8.1-(8-Chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanamine (scalemic mixture prepared)A solution of 1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanone (0.28 g, 0.83 mmol, from Step 7) and (R)-2-methylpropane-2-sulfinamide (0.22 g, 1.8 mmol, CombiBlocks) in THF (3.0 mL) was treated with titanium(IV) ethoxide (380 μL, 1.8 mmol, Strem), and was heated to 70 °C in a sealed reaction vessel overnight. The reaction mixture was cooled to -44 °C and 1.0 M L-Selectride® in THF (2.9 mL, 2.9 mmol) was added dropwise. The reaction mixture was warmed to room temperature over 1 hour. The reaction mixture was then cooled to 0 °C and was quenched by the addition of MeOH (0.50 mL). Upon warming to room temperature, the mixture was diluted with EtOAc (25 mL) and brine (0.20 mL) and was stirred for 5 minutes. The slurry was filtered through Celite®, and the filter cake was washed with EtOAc. The filtrate was concentrated to give a residue. LCMS indicated a mixture of diastereomers, a major and a minor isomer, which were not separated. The residue was dissolved in methanol (7.5 mL) and treated with 4.0 N HCl in dioxane (6.2 mL, 25 mmol) for 1 hour. Solvent was removed in vacuo and the residue was reconstituted in MeOH and purified via preparative HPLC-MS (pH = 2). The fractions containing product were evaporated to remove most of the acetonitrile. The aqueous mixture was made basic (pH 10) by the addition of sodium carbonate. The basic aqueous mixture was saturated with NaCl and extracted twice with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford product as a white solid. Yield: 91 mg, 40%.1H NMR (400 MHz, DMSO-d6) δ 7.69– 7.56 (m, 4H), 7.54 (s, 1H), 7.52– 7.47 (m, 2H), 7.38 (s, 1H), 3.65 (q, J = 6.5 Hz, 1H), 1.90 (br s, 2H), 1.16 (d, J = 6.6 Hz, 3H); LCMS calculated for C15H15ClN3 (M+H)+: m / z = 272.1; found: 272.1. Step 9. tert-Butyl [3-({[-1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6- yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate (single enantiomer isolated)A solution of 1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethanamine (84 mg, 0.31 mmol, from Step 8) in DMF (2.1 mL) was added to a mixture of 2-[(tert- butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.34 mmol, J&W Pharmlab), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (130 mg, 0.34 mmol) and N,N-diisopropylethylamine (110 μL, 0.62 mmol) in DMF (2 mL). After 30 minutes, saturated NaHCO3 was added. Dilution with water resulted in a precipitate, which was isolated by filtration. The solid product was washed with water, and was air dried. The solid was then dissolved in DCM, and the solution was filtered to remove insoluble impurities. The filtrate was concentrated to afford the product as a light yellow solid. Yield: 0.15 g, 91%. LCMS calculated for C27H27ClN7O3 (M+H)+: m / z = 532.2; found: 532.2. The scalemic mixture was separated by HPLC (Phenomenex Lux Cellulose C-1, 5 µm, 21.2 x 250 mm, 9 mg / 900µL loading, eluting with 20% EtOH in hexanes at 18 mL / min over 13 min). This provided Enantiomer 1 (first to elute, major component, retention time 8.3 min, Yield: 76 mg), and Enantiomer 2 (second to elute, minor component, retention time 10.9 min, Yield: 10 mg). Step 10.2-Amino-N-[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetate salt (single enantiomer)tert-Butyl [3-({[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6- yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate (76 mg, 0.14 mmol, Enantiomer 1 from Step 9) was stirred with TFA (0.5 mL) in DCM (2.0 mL) for 30 minutes. The solvents were removed in vacuo, and the product was reconstituted in acetonitrile and purified by preparative HPLC-MS (pH 2). Yield: 69 mg, 83%, (1.4 x TFA salt).1H NMR (500 MHz, DMSO-d6) δ 8.90 (dd, J = 6.7, 1.6 Hz, 1H), 8.54 (dd, J = 4.5, 1.6 Hz, 1H), 8.02 (d, J = 6.4 Hz, 1H), 7.96 (s, 1H), 7.84– 7.78 (m, 1H), 7.76 (s, 1H), 7.72– 7.66 (m, 1H), 7.66– 7.60 (m, 2H), 7.60– 7.54 (m, 1H), 7.35 (s, 1H), 6.99 (dd, J = 6.7, 4.5 Hz, 1H), 4.75 (p, J = 7.0 Hz, 1H), 1.41 (d, J = 7.0 Hz, 3H); LCMS calculated for C22H19ClN7O (M+H)+: m / z = 432.1; found: 432.1. Example 28.2-Amino-N-[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetate salt (single enantiomer)tert-Butyl [3-({[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6- yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate (10 mg, 0.019 mmol, Enantiomer 2 from Example 27, Step 9) was stirred with TFA (0.2 mL) in DCM (1.0 mL) for 30 minutes. The solvents were removed in vacuo, and the product was reconstituted in acetonitrile and purified by preparative HPLC-MS (pH = 2). Yield: 4.9 mg, 45%.1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 6.7, 1.5 Hz, 1H), 8.56 (dd, J = 4.5, 1.5 Hz, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.87– 7.77 (m, 2H), 7.77– 7.52 (m, 5H), 7.32 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 4.76 (p, J = 6.8 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H); LCMS calculated for C22H19ClN7O (M+H)+: m / z = 432.1; found: 432.1. Example 29.2-Amino-N-{1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (mixture ofdiastereomers prepared)Step 1.1-[5-(3-Fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanone ^A solution of 1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethanone (0.046 g, 0.15 mmol, from Example 26, Step 10) and 1.0 M dimethylzinc in heptane (0.30 mL, 0.30 mmol) in 1,4-dioxane (2 mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.011 g, 0.015 mmol) was added. The reaction mixture was heated to 100 °C for 2 hours in a sealed reaction vial. The reaction mixture was then poured into saturated NaHCO3 and the aqueous mixture was extracted with three portions of EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-100% EtOAc / hexanes. LCMS calculated for C17H16FNO2 (M+H)+: m / z = 283.1; found: 283.1. Step 2.1-[5-(3-Fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanamine (mixture of diastereomers prepared)^Titanium tetraisopropoxide (0.052 mL, 0.18 mmol) was added to a mixture of 1-[5-(3- fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanone (0.025 g, 0.088 mmol, prepared as in Step 1) in 2.0 M ammonia in ethanol (0.22 mL, 0.44 mmol). The reaction was heated to 60 °C for 2 hours. The reaction mixture was then cooled to 0 °C, and NaBH4 (0.0050 g, 0.13 mmol) was added. After 30 minutes, the reaction mixture was quenched with water and insoluble material was removed by filtration. The solids were washed with acetonitrile. The filtrate was concentrated and the product was used without further purification in Step 3. LCMS calculated for C17H19FN3 (M+H)+: m / z = 284.1; found: 284.1. Step 3.2-Amino-N-{1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (mixture of diastereomers prepared)A solution of 1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6-yl]ethanamine (0.025 g, 0.088 mmol, as a mixture of diastereomers from Step 2) in DMF (2 mL) was treated with 2- [(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.039 g, 0.14 mmol, J&W Pharmlab), N,N-diisopropylethylamine (0.046 mL, 0.26 mmol) and N,N,N',N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate (0.074 g, 0.19 mmol). After stirring for 2 hours, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was deprotected by stirring with TFA (1 mL) in DCM (1 mL) for 1 hour. The solvents were removed in vacuo and the residue was reconstituted in MeCN and purified via preparative HPLC-MS (pH 2). Yield: 8 mg.1H NMR (400 MHz, CD3OD, mixture of diastereomers) δ 8.74– 8.68 (m, 2H), 8.58– 8.53 (m, 2H), 8.00 (s, 2H), 7.77– 7.58 (m, 4H), 7.50– 7.35 (m, 4H), 7.17 (s, 2H), 7.04– 6.95 (m, 2H), 4.82– 4.69 (m, 2H), 2.53 (s, 6H), 2.09 (s, 6H), 1.51 (d, J = 6.9 Hz, 3H), 1.50 (d, J = 6.9 Hz, 3H); LCMS calculated for C24H23FN7O (M+H)+: m / z = 444.1; found: 444.1. Example 30.2-Amino-N-[1-(8-cyano-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetate saltStep 1.6-Acetyl-5-phenylimidazo[1,5-a]pyridine-8-carbonitrileA microwavable vial was charged with 1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6- yl)ethanone (50. mg, 0.18 mmol, from Example 27, Step 7), Zn(CN)2 (24 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (11 mg, 0.011 mmol), and 2- (dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (7.6 mg, 0.018 mmol). DMF (3.35 mL) and water (17 μL, 0.92 mmol) were added. The mixture was degassed and the reaction was heated in the microwave to 150 °C for 30 minutes. The reaction mixture was poured into saturated NaHCO3 and extracted with three portions of EtOAc. The combined organic extracts were washed with water, then brine, dried over Na2SO4, filtered and concentrated. The product was purified by flashchromatography, eluting with a gradient from 0-40% EtOAc / hexanes, to afford a yellow solid. Yield: 37 mg, 77%. LCMS calculated for C16H11N3O (M+H)+: m / z = 262.1; found: 262.2. Step 2.6-(1-Aminoethyl)-5-phenylimidazo[1,5-a]pyridine-8-carbonitrile (racemic mixture prepared) ^6-Acetyl-5-phenylimidazo[1,5-a]pyridine-8-carbonitrile (36 mg, 0.14 mmol, from Step 1) was dissolved in MeOH (1.5 mL) and ammonium acetate (106 mg, 1.38 mmol) was added. The resulting mixture was heated at 65 ^C for 1 hour. Sodium cyanoborohydride (26 mg, 0.41 mmol) was added and the solution was heated at 65 ^C ovrnight. Upon cooling to room temperature, the reaction was quenched by the addition of water was added. The mixture was diluted with acetonitrile and the product was purified by preparative HPLC-MS (pH 10; eluting with a gradient from 19.4 - 37.4% MeCN in water in 12 minutes), which afforded two peaks with the desired mass. The desired product was Peak 1, the minor isomer (eluting at a retention time of 7.0 min), which on evaporation, afforded a yellow solid that was used in Step 3. Yield: 2.8 mg, 8%. LCMS calculated for C16H15N4 (M+H)+: m / z = 263.1; found: 263.1. Step 3.2-Amino-N-[1-(8-cyano-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetate salt (racemic mixture prepared)A mixture of 2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3.3 mg, 0.012 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (4.5 mg, 0.012 mmol) and N,N-diisopropylethylamine (3.7 0.021 mmol) in DMF (0.20 mL) was stirred for 5 minutes, and 6-(1-aminoethyl)-5-phenylimidazo[1,5-a]pyridine-8- carbonitrile (2.8 mg, 0.011 mmol, Peak 1 from Step 2) in DMF (0.22 mL) was then added. After 30 minutes, the reaction was diluted with saturated NaHCO3, followed by water. The aqueous mixture was extracted with EtOAc and the solvent was removed in vacuo. The crude product was stirred with TFA (0.10 mL) in DCM (0.50 mL) for 1 hour and the solvents were evaporated. The residue was dissolved in acetonitrile and purified by preparative HPLC-MS (pH = 2). Yield: 2.5 mg.1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 6.7, 1.5 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.05 (d, J = 6.2 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.78– 7.57 (m, 6H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 6.44 (br s, 2H), 4.74 (p, J = 6.7 Hz, 1H), 1.44 (d, J = 7.0 Hz, 3H); LCMS calculated for C23H19N8O (M+H)+: m / z = 423.1; found: 423.1. Examples 31A-31B.2-Amino-N-((1S)-1-(8-chloro-5-(2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetate salt (Isomers 1-2, scalemic mixture prepared)Step 1. Benzyl 2-methylthiomorpholine-4-carboxylate 1,1-dioxide (single isomers)^To the suspension of 2-methylthiomorpholine 1,1-dioxide hydrochloride (0.25 g, 1.4 mmol) (racemic mixture, Enamine Building Blocks, EN300-137734) in dichloromethane (4.5 mL) was added triethylamine (0.75 mL, 3.5 mmol). The mixture was cooled to 0 °C. Benzyl chloroformate (0.29 mL, 2.0 mmol) was added dropwise. White suspension was observed. The reaction mixture was warmed to room temperature and stirred for 2 h before the solvent was removed under vacuum. The crude product was purified by flash column chromatography (0.35 g, 93% yield). The purified product was submitted for chiral HPLC purification (Phenomenex Lux Amylose 1 column) to afford the two enantio-pure isomers. Step 2.2-Methylthiomorpholine 1,1-dioxide rs) ^A solution of benzyl 2-methylthiomorpholine-4-carboxylate 1,1-dioxide (0.12 g, 0.42 mmol, peak 2, step 1) in ethyl acetate (2 ml) was degassed with nitrogen gas for 3 minutes before palladium (10% on carbon, 0.045 g, 0.04 mmol) was added. After degassing for another 3 min, the mixture was put under vacuum and hydrogen (1 atm) was then charged into the reaction vessel. The mixture was stirred at room temperature for 12 h. After filtration through Celite, the resulting solution was concentrated under vacuum to afford 2-methylthiomorpholine 1,1-dioxide (single isomer 1, 0.06 g, 0.402 mmol, 95 % yield). Single isomer 2 was synthesized according to the above procedure, using peak 1 from step 1 as the starting material. Step 3.1-(8-Chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethan-1-one (single isomer)A solution of 1-(5,8-dichloroimidazo[1,5-a]pyridin-6-yl)ethan-1-one (0.64 g, 2.8 mmol) (Example 130, Step 7), 2-methylthiomorpholine 1,1-dioxide (single isomer 1, step 2, 0.54 g, 3.6 mmol) and N,N-diethylpropan-2-amine (1.3 mL, 8.4 mmol) in acetonitrile (9 mL) was heated at 140 °C in a microwave reactor and stirred for 5 h. After cooling to room temperature, the solvents were removed under vacuum and the resulting residue was purified by flash column chromatography (0- 100% ethyl acetate in hexane to 0-35% methanol in ethyl acetate) to afford 1-(8-chloro-5-(2-methyl- 1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethan-1-one (0.9 g, 94 % yield) LCMS calculated for C14H17O3N3SCl (M+H)+: m / z = 342.1; found 342.0. Step 4. (S)-N-((1S)-1-(8-Chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6- yl)ethyl)-2-methylpropane-2-sulfinamide (single isomer, scalemic mixture)To a suspension of 1-(8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5- a]pyridin-6-yl)ethan-1-one (1.9 g, 5.6 mmol) and (S)-2-methylpropane-2-sulfinamide (6.7 g, 55.6 mmol) in cyclopentyl methyl ether (4 mL) was added titanium tetraisopropoxide (4.9 mL, 16.6 mmol). The reaction mixture was heated to 100 °C and stirred for 36 h. The reaction mixture was cooled to 0 oC and sodium tetrahydroborate (1.05 g, 27.8 mmol) was added in one portion. The mixture was warmed to room temperature and stirred for 8 h. The reaction mixture was cooled to 0 °C and was quenched by the dropwise addition of methanol (1 mL). The resulting solution was poured into brine. The suspension was filtered through celite. The filtrate was diluted with ethyl acetate and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated, and the residue was purified by flash column chromatography to afford the desired product (1.9 g, 77% yield). LCMS calculated for (M+H)+: m / z = 447.1; found 447.2. Step 5. (1S)-1-[1,8-Dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6- yl]ethanamine hydrogen chloride salt (single diasteromer, scalemic mixture)To the solution of (S)-N-(1-(8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5- a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamide (1.9 g, 4.2 mmol) in methanol (10 mL) was added hydrogen chloride (4M in dioxane, 10 mL) at 0 oC. The mixture was warmed to room temperature and stirred for 1 h. Volatiles were removed under vacuum to afford the crude product as a HCl salt, which was used without further purification. LCMS calculated for C14H20ClN4O2S (M+H)+: m / z = 343.1; found 343.1. Step 6.2-Amino-N-(1-[8-chloro-5-(2-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (single diasteromer, scalemic mixture)N,N-Diethylpropan-2-amine (2.45 ml, 15.8 mmol) was added to 2-((tert- butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.32 g, 4.7 mmol) and N,N,N', N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.65 g, 4.3 mmol) in N,N- dimethylformamide (8 mL). After stirring for 10 minutes a suspension of (1S)-1-[1,8-dichloro-5-(1,1- dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethanamine hydrogen chloride salt (step 5, 1.5 g, 3.9 mmol) in N,N-dimethylformamide (3 mL) was added dropwise. The reaction was stirred for 1 h at room temperature. The reaction was diluted with water (100 mL) and filtered. The cake was washed with water (10 mL) and air-dried for 2 h. Trifluoroacetic acid (10 mL) was added to a solution of the crude product in dichoromethane (10 mL). After stirring for 1 h at room temperature, volatiles were removed in vacuo and the product was purified by preparative LCMS (pH 2) to afford 2-amino-N-(1-[8-chloro-5-(2-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (Isomer 1, 0.2 g, 8.2% yield). LCMS calculated for Isomer 1: C21H24O3N8SCl (M+H)+: m / z = 503.1; found 503.1.1H NMR (600 MHz, DMSO, mixture of scalemic isomers): δ 9.31 (s, 0.6H), 8.94– 8.86 (m, 1H), 8.82 (s, 0.4H), 8.62– 8.48 (m, 1H), 8.16– 8.01 (m, 1H), 7.88 (s, 0.6 H), 7.73 (s, 0.4 H), 7.26 (m, 1H), 7.06– 6.91 (m, 1H), 5.54 (p, J = 7.0 Hz, 0.4 H), 5.20 (p, J = 6.9 Hz, 0.6 H), 3.89– 3.77 (m, 0.6 H), 3.77– 3.51 (m, 4H), 3.50– 3.36 (m, 0.4 H), 3.34– 3.17 (m, 2H), 1.56 (m, 3H), 1.27 (d, J = 6.9 Hz, 1H), 1.17 (d, J = 6.8 Hz, 2H).Isomer 2 was synthesized according to steps 3-6, using single isomer 2 from step 2 as starting material for step 3. LCMS calculated for Isomer 2: C21H24O3N8SCl (M+H)+: m / z = 503.1; found 503.1. Examples 32-40.The following Examples 32-40 in Table 3 were prepared by the method of Example 149. NMR data for representative compounds of Table 3 are provided in Table 3a.Example 41.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1. Ethyl 2-amino-5-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyrimidine-3-carboxylateTrifluoromethanesulfonic anhydride (2 mL, 9 mmol) was added dropwise to ethyl 2-amino-5- oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (0.7 g, 3 mmol) in dichloromethane (20 mL) and triethylamine (3 mL, 20 mmol) at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched by adding sodium bicarbonate (sat.) at -78°C. The mixture was futher diluted with dichloromethane (10 mL) and stirred from -78°C to room temperature. After aqueous workup, the combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography (0-20% methanol in dichloromethane) afforded the desired product (0.09 g, 8%). LCMS calculated for C10H10F3N4O5S (M+H)+: m / z = 355.0; found: 355.0. Step 2. Ethyl 2-amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylateA suspension of ethyl 2-amino-5-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyrimidine-3- carboxylate (0.02 g, 0.06 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.017 g, 0.073 mmol) (676624, Aldrich), dichloro(bis{di-tert-butyl[4- (dimethylamino)phenyl]phosphoranyl})palladium (0.004 g, 0.006 mmol), sodium carbonate (0.01 g, 0.1 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was degassed with nitrogen gas and then heated at 80 °C for 1 h. The mixture was cooled to room temperature, diluted with methanol, filtered through Celite, and concentrated under vacuum. The residue was purified by flash column chromatography to afford the desired product (0.020 g, 100%). LCMS calculated for C15H16N5O3 (M+H)+: m / z = 314.1; found: 314.0. Step 3.2-Amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidLithium hydroxide (14 mg, 0.42 mmol) was added to a solution of ethyl 2-amino-5-(5- methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.014 g, 0.042 mmol) in methanol (1 mL). The mixture was heated to 80°C for 2 h. The solvent was evaporated under vacuum. The residue was used in the next step without purification. LCMS calculated for C13H12N5O3 (M+H)+: m / z = 286.1; found: 286.1. Step 4.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideTo the mixture of crude 2-amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (from step 3), 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine (Examples 3a-3b, Step 1, 0.010 g, 0.042 mmol) and N,N-diisopropylethylamine (20 0.1 mmol) in anhydrous N,N- dimethylformamide (1 mL) was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.016 g, 0.042 mmol) and the resultant mixture was stirred at room temperature for 1 h. Ice-water (0.2 mL) was added to the reaction mixture and then stirred for 10 min. The mixture was diluted with methanol (4 mL). Purification by preparative LCMS (pH 10) afforded the desired product (9 mg, 20% over two steps). LCMS calculated for C24H24ClN8O3 (M+H)+: m / z = 507.2; found: 507.1. Example 42.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5- (hydroxymethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideThis compound was synthesized according to the procedure of Example 41, using [5- (hydroxymethyl)pyridin-3-yl]boronic acid (BB-3541, Combi-Blocks) to replace 3-methoxy-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as one of the starting materials in step 2. LCMS calculated for (M+H)+: m / z = 507.2; found: 507.2. Example 43.2-Amino-N-(1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin- 3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate saltStep 1.1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethanone^To a solution of 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (90 mg, 0.4 mmol) in N,N- dimethylformamide (2 mL) was added N-chlorosuccinimide (76 mg, 0.56 mmol) at roomtemperature. After stirring for 4 h, the reaction mixture was diluted with EtOAc, washed with sodium carbonate (sat.), dried over sodium sulfate and concentrated under vacuum. Purification by flash column chromatography afforded the desired product. LCMS calculated for C11H11Cl2N2O2 (M+H)+: m / z = 273.0; found: 273.0. Step 2.1-(3,4-Dichloro-7-ethoxy-1H-indazol-6-yl)ethanamine To a solution of 1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethanone (0.10 g, 0.37 mmol) in 2.0 M ammonia in ethanol (4 mL, 8 mmol) was added titanium tetraisopropoxide (300 μL, 1 mmol). The reaction mixture was heated at 80 °C for 3 h and then cooled to 0 °C. Sodium tetrahydroborate (40 mg, 1 mmol) was added to the mixture. After stirring for 0.5 h, the reaction was quenched with ammonium hydroxide (1 M), filtered, and the solid was washed with acetonitrile. The volatiles were removed in vacuo, and the residue dissolved in EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was used directly in the next step without purification. LCMS calculated for C11H14Cl2N3O (M+H)+: m / z = 274.1; found: 274.0. Step 3.2-Amino-5-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidThis compound was synthesized according to the procedure of Example 41, using 1-(3,4- dichloro-7-ethoxy-1H-indazol-6-yl)ethanamine to replace 1-(4-chloro-7-ethoxy-1H-indazol-6- yl)ethanamine as the starting material in step 4. LCMS calculated for C24H23Cl2N8O3 (M+H)+: m / z = 541.1; found: 541.11H NMR (400 MHz, DMSO) δ 13.76 (s, 1H), 9.12– 8.98 (m, 2H), 8.49 (d, J = 2.7 Hz, 1H), 8.25 (d, J = 6.9 Hz, 1H), 8.15 (s, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.29 (s, 1H), 5.68– 5.23 (m, 1H), 4.45– 4.02 (m, 2H), 3.95 (s, 3H), 1.59 (d, J = 6.9 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). Example 44.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(piperidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate saltTo a solution of ethyl 2-amino-5-{[(trifluoromethyl)sulfonyl]oxy}pyrazolo[1,5-a]pyrimidine- 3-carboxylate (Example 43, Step 1, 20 mg, 0.056 mmol) in acetonitrile (0.6 mL) was added piperidine (0.017 mL, 0.17 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol). The resultant mixture was stirred at 80 oC for 1 h. To the mixture was added lithium hydroxide in water (4.0 M, 0.1 mL, 0.6 mmol). The resultant mixture was heated at 80 oC for 1 h. The solvent was removed and the residue was purified by preparative LCMS (pH 10) to afford the desired product (14 mg, 95% yield). LCMS calculated for C12H16N5O2 (M+H)+: m / z = 262.1; found: 262.0. Step 2.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(piperidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetate saltTo a vial containing 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine trifluoroacetic acid (5.4 mg, 0.015 mmol), 2-amino-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4.0 mg, 0.015 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.8 mg, 0.015 mmol) was added N,N-dimethylformamide (0.7 mL), followed by dropwise addition of N,N-diisopropylethylamine (10 μL, 0.08 mmol) at room temperature. After stirring for 1 h, ice- water (0.2 mL) was added to the reaction mixture and stirred for 10 min. The mixture was diluted with methanol (4 mL). Purification by preparative LCMS (pH 2) afforded the desired product. LCMS calculated for C23H28ClN8O2 (M+H)+: m / z = 483.2; found: 483.2. Example 45.2-Amino-6-chloro-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)imidazo[1,2- b]pyridazine-3-carboxamideStep 1.6-chloro-3-iodoimidazo[1,2-b]p ridazin-2-amine ^To a solution of 6-chloroimidazo[1,2-b]pyridazin-2-amine (0.50 g, 2.96 mmol) (32325, Affinity Research Chemicals) in N,N-Dimethylformamide (20 mL) at 0 oC was added N- iodosuccinimide (0.80 g, 3.6 mmol). The resulting solution was stirred at room temperature for 1 h. Water (20 mL) was added to quench the reaction. After aqueous work up, the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vaccum. Purification with flash column chromatography afforded the desired product (0.87 g, 62% yield). LCMS calculated for C6H5ClIN4 (M+H)+: m / z = 294.9; found: 294.8. Step 2. Methyl 2-amino-6-chloroimidazo[12-b ridazine-3-carboxylate ^In a 40 mL vial, 6-chloro-3-iodoimidazo[1,2-b]pyridazin-2-amine (300 mg, 1.0 mmol) in methanol (20 mL) and triethylamine (0.52 mL, 3.8 mmol) was degassed with a stream of nitrogen for 5 min. To the solution was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (40 mg, 0.05 mmol). The solution was saturated with carbon monoxide by bubbling the carbon monoxide gas through the reaction subsurface for 3 min. The vessel was sealed and heated to 55°C for 12 h. The reaction was cooled to room temperature and the solvents were removed under vacuum. Purification by flash column chromatography afforded the desired product (0.12 g, 52% yield). LCMS calculated for (M+H)+: m / z = 227.0; found: 227.0. Step 3.2-Amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid ^A mxiture of methyl 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (15 mg, 0.066 mmol) and lithium hydroxide (8 mg, 0.3 mmol) in tetrahydrofuran (1 mL) and water (0.050 mL) was heated at 80 oC for 3 h. The reaction mixture was cooled to room temperature and diluted with methanol (4 mL). Purification by preparative LCMS (pH 10) afforded the desired product (14 mg, 60% yield). LCMS calculated for C7H6ClN4O2 (M+H)+: m / z = 213.0; found: 213.0. Step 4.2-Amino-6-chloro-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)imidazo[1,2-b]pyridazine- 3-carboxamideTo a mixture of 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (20 mg, 0.09 mmol), 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine (Examples 3a-3b, Step 1, 32 mg, 0.13 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43 mg, 0.11 mmol) in N,N-dimethylformamide (2.4 mL) was added N,N-diisopropylethylamine (50 0.3 mmol) and the resultant mixture was stirred at room temperature for 1 h. Ice-water was added to the reaction mixture and then stirred for 10 min. The mixture was further diluted with methanol (4 mL). Purification by preparative LCMS (pH10) afforded the desired product. (14 mg, 60% yield). LCMS calculated for C18H18Cl2N7O2 (M+H)+: m / z = 434.1; found: 434.2. Example 46.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-methylimidazo[1,2- b]pyridazine-3-carboxamideStep 1. Methyl 2-amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylateTo a vial containing the mixture of trimethylboroxine (25 0.18 mmol), dicyclohexyl(2',4', 6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (6 mg, 0.008 mmol), and potassium phosphate (56 mg, 0.26 mmol) was added a solution of methyl 2-amino-6- chloroimidazo[1,2-b]pyridazine-3-carboxylate (Example 45, Step 2, 0.020 g, 0.088 mmol) in 1,4- dioxane (1 mL) and water (100 μL). The reaction was degassed with nitrogen and stirred at 50 oC for 5 h. After cooling to room temperature, the mixture was diluted with methanol (4 mL) and purified by preparative LCMS (pH 10) to afford the desired product (12.0 mg, 67% yield). LCMS calculated for C9H11N4O2 (M+H)+: m / z = 207.1; found: 207.1 Step 2.2-Amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acidThis compound was synthesized according to the procedure of Example 45, step 3, using methyl 2-amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylate to replace methyl 2-amino-6- chloroimidazo[1,2-b]pyridazine-3-carboxylate as the starting material. LCMS calculated for C8H9N4O2 (M+H)+: m / z = 193.1; found: 193.1. Step 3.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-methylimidazo[1,2-b]pyridazine- 3-carboxamideThis compound was synthesized according to the procedure of Example 45, step 4, using 2- amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid to replace 2-amino-6-chloroimidazo[1,2- b]pyridazine-3-carboxylic acid as the starting material. LCMS calculated for C19H21ClN7O2 (M+H)+: m / z = 414.1; found: 414.1. Example 47.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(piperidin-1- yl)imidazo[1,2-b]pyridazine-3-carboxamideThis compound was synthesized according to the procedure of Example 44, using methyl 2- amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (Example 45, Step 2) to replace ethyl 2- amino-5-{[(trifluoromethyl)sulfonyl]oxy}pyrazolo[1,5-a]pyrimidine-3-carboxylate as one of the starting materials in step 1. LCMS calculated for C23H28ClN8O2 (M+H)+: m / z = 483.2; found: 483.2. Example 48.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(5- (hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamideStep 1. Methyl 2-amino-6-(5-(hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylateA suspension of methyl 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (Example 45, Step 2, 0.02 g, 0.09 mmol), [5-(hydroxymethyl)pyridin-3-yl]boronic acid (0.018 g, 0.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.003 g, 0.004 mmol), sodium carbonate (0.028 g, 0.26 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was degassed by bubbling nitrogen. The mixture was heated to 80 oC and stirred for 1 h. After cooling to room temperature, the mixture was diluted with methanol (8 mL), filtered through Celite, and concentrated under vacuum. Purification by flash column chromatography afforded the desired product. (20.0 mg, 80% yield). LCMS calculated for C14H14N5O3 (M+H)+: m / z = 300.1; found: 300.1. Step 2.2-Amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acidThis compound was synthesized according to the procedure of Example 45, step 3, using methyl 2-amino-6-(5-(hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylate to replace methyl 2-amino-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate as the starting material. LCMS calculated for C13H12N5O3 (M+H)+: m / z = 286.1; found: 286.1. Step 3.2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-methylimidazo[1,2-b]pyridazine- 3-carboxamideThis compound was synthesized according to the procedure of Example 45, step 4, using 2- amino-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid to replace 2-amino-6-chloroimidazo[1,2- b]pyridazine-3-carboxylic acid as the starting material. LCMS calculated for C24H24ClN8O3 (M+H)+: m / z = 507.2; found: 507.1. Example 49.2-Amino-N-(1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(5- (hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamideThis compound was synthesized according to the procedure of Example 48, using 1-(3,4- dichloro-7-ethoxy-1H-indazol-6-yl)ethanamine (Example 43, Step 2) to replace 1-(4-chloro-7-ethoxy- 1H-indazol-6-yl)ethanamine as the starting material in step 3. LCMS calculated for C24H23Cl2N8O3 (M+H)+: m / z = 541.1; found: 541.1. Example 50.2-Amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]-5-pyridin-3- ylpyrazolo[1,5-a]pyrimidine-3-carboxamide bis(trifluoroacetate)This compound was synthesized according to the procedure of Example 41, using 3- pyridylboronic acid to replace 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as one of the starting materials in step 2. LCMS calculated for C23H22ClN8O2 (M+H)+: m / z = 477.2; found: 477.2. Example 51.2-Amino-N-(1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethanoneTo a solution of 1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (60.0 mg, 0.172 mmol, from Example 23, Step 1) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (6 mg, 0.008 mmol) in dioxane (1 mL) was added 1.0 M diethyl zinc in hexanes (0.26 mL, 0.26 mmol) at room temperature and the reaction mixture was heated to 80 °C for 2 h. After cooling to room temperature, the volatiles were evaporated in vacuo and the residue was purified by flash chromatography (0-30% EtOAc / hexanes) to afford the title compound as a white solid (27 mg, 53%), contaminated with a minor amount of the bis-ethylated product (from Cl coupling). LCMS calculated for C17H16ClN2O (M+H)+: m / z = 299.1; found: 299.1. Step 2.1-(4-chloro-3-ethyl-7-phenyl- ineThis compound was synthesized according to the procedure described in Example 23, Step 2, starting from 1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethanone (27 mg, 0.090 mmol). The product was used without purification (theoretical yield assumed). LCMS calculated for C17H16ClN2 (M-NH2)+: m / z = 283.1; found: 283.1. Step 3.2-amino-N-(1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetateTo a vial containing 1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethanamine (27 mg, 0.090 mmol), 2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (28 mg, 0.099 mmol, from J&W Pharmlab), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (38 mg, 0.099 mmol) was added DMF (2 mL), followed by dropwise addition of N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) at room temperature. After stirring for 1 h, the reaction mixture was diluted with EtOAc (10 mL) and quenched with water (5 mL). The layers were separated, and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was stirred with TFA (1 mL) in CH2Cl2 (2 mL) for 0.5 h. The volatiles were removed in vacuo and the residue was dissolved in MeOH and purified by preparative HPLC (pH 2).1H NMR (600 MHz, DMSO) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.62 (br s, 1H), 7.57 (br s, 2H), 7.53– 7.47 (m, 1H), 7.39 (br s, 1H), 7.21 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 5.07 (p, J = 6.9 Hz, 1H), 3.08 (q, J = 7.5 Hz, 2H), 1.36 (d, J = 6.9 Hz, 3H), 1.30 (t, J = 7.5 Hz, 3H). LCMS calculated for C24H23ClN7O (M+H)+: m / z = 460.2; found: 460.1. Example 52.2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanoneTo a solution of 1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (100 mg, 0.419 mmol, from Example 1, Step 3) in DMF (2 mL) was added N-bromosuccinimide (89 mg, 0.50 mmol) at room temperature. After stirring for 2 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to afford an orange solid that was used without purification. LCMS calculated for C11H11BrClN2O2 (M+H)+: m / z = 317.0; found: 316.9. Step 2.1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamineThis compound was synthesized according to the procedure described in Example 23, Step 2, starting from 1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanone (120 mg, 0.380 mmol). The product was used without purification (theoretical yield assumed). LCMS calculated forC11H11BrClN2O (M-NH2)+: m / z = 301.0; found: 300.9. Step 3. tert-butyl 3-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5- a]pyrimidin-2-ylcarbamateThis compound was synthesized according to the procedure described in Example 1, Step 6, starting from 1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethanamine (120 mg, 0.380 mmol). The residue was purified by flash chromatography (0-100% EtOAc / hexanes) to afford the product as an off white solid. LCMS calculated for C23H26BrClN7O4 (M+H)+: m / z = 578.1; found: 578.0. Step 4.2-amino-N-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateThis compound was synthesized according to the procedure described in Example 1, Step 7, starting from tert-butyl 3-(1-(3-bromo-4-chloro-7-ethoxy- 1H-indazol-6-yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate (10 mg, 0.02 mmol). The residue was purified by preparative HPLC (pH 2) to afford the product as a white solid.1H NMR (600 MHz, DMSO) δ 13.92 (s, 1H), 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.18 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 6.45 (br s, 2H), 5.51 (p, J = 7.0 Hz, 1H), 4.28– 4.19 (m, 2H), 1.52 (d, J = 7.0 Hz, 3H), 1.45 (t, J = 7.0 Hz, 3H). LCMS calculated forC18H18BrClN7O2 (M+H)+: m / z = 478.1; found: 478.0. Examples 53-54.2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-2-(2-hydroxyethyl)-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 53) & 2-Amino-N-(1-(3-bromo-4- chloro-7-ethoxy-1-(2-hydroxyethyl)-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetate (Example 54)To a solution of tert-butyl 3-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6- yl)ethylcarbamoyl)pyrazolo[1,5-a]pyrimidin-2-ylcarbamate (35 mg, 0.060 mmol, from Example 52, Step 3) in DMF (1 mL) was added potassium carbonate (40 mg, 0.3 mmol), followed by 2- iodoethanol (50 µL, 0.60 mmol) and the reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in DCM (2 mL), and TFA (1 mL) was added. After stirring for 0.5 h, the volatiles were removed in vacuo and the residue was purified by preparative HPLC (pH 2) to afford the title compounds, which were readily separable (36.1-56.1% MeCN / water gradient). Peak 1 (Example 53): Retention time = 5.05. LCMS calculated for C20H22BrClN7O3 (M+H)+: m / z = 522.1; found: 522.1. Peak 2 (Example 54): Retention time = 5.68. LCMS calculated for C20H22BrClN7O3 (M+H)+: m / z = 522.1; found: 522.1. Example 55.2-Amino-N-(1-(4-chloro-3-cyano-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(4-chloro-3-iodo-7-phenyl-1H-indazol-6-yl)ethanoneTo a solution of 1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethanone (Example 14, Step 4, 500 mg, 1.85 mmol) in DMF (9 mL) was added N-iodosuccinimide (540 mg, 2.4 mmol) and the reaction mixture was stirred overnight. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-35% EtOAc / hexanes) to afford the title compound (640 mg, 87%) as an off white solid. LCMS calculated for C15H11ClIN2O (M+H)+: m / z = 397.0; found: 396.9. Step 2. methyl 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylateA solution of 1-(4-chloro-3-iodo-7-phenyl-1H-indazol-6-yl)ethanone (40 mg, 0.101 mmol), Pd(dppf)Cl2 (4 mg, .005 mmol), and triethylamine (42 μL, 0.30 mmol) in DMF (1.6 mL) and MeOH (0.4 mL) was saturated with CO for 10 min. The reaction mixture was then heated at 90 oC under balloon pressure of CO overnight. The volatiles were evaporated and the residue was purified by flash chromatography (0-40% EtOAc / hexanes) to afford the title compound (33 mg, quant.) as a yellow oil. LCMS calculated for C17H14ClN2O3 (M+H)+: m / z = 329.1; found: 329.0. Step 3.6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylic acidTo a solution of methyl 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylate (33.0 mg, 0.100 mmol) in THF / methanol / water (1:1:1) was added sodium hydroxide (40 mg, 1 mmol) and the reaction mixture was heated at 65 °C for 4 h. After cooling to room temperature, the volatiles were evaporated in vacuo and the residue was treated with 1M HCl, forming a precipitate, which was solubilized by addition of EtOAc. The solution was diluted with additional EtOAc and 1M HCl, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound (31 mg, 98%) that was used without purification. LCMS calculated for C16H12ClN2O3 (M+H)+: m / z = 315.1; found: 315.0. Step 4.6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxamideTo a mixture of 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxylic acid (31.0 mg, 0.0985 mmol), ammonium chloride (10 mg, 0.20 mmol), and HATU (75 mg, 0.20 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (86 µL, 0.49 mmol) at room temperature. After stirring overnight, the reaction mixture was diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (0-100% EtOAc / hexanes) to afford the product as a white solid, still containing residual DMF. Quantitative yield was assumed. LCMS calculated for C16H13ClN3O2 (M+H)+: m / z = 314.1; found: 314.0. Step 5.6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carbonitrile To a suspension of 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carboxamide (30.0 mg, 0.0956 mmol) in CH2Cl2 (39 mmol) at 0 °C was added Et3N (40 µL, 0.29 mmol), followed by dropwise addition of 1.0 M trifluoromethanesulfonic anhydride (1M / CH2Cl2, 0.29 mL, 0.29 mmol). During the addition, the white suspension gradually became a yellow, then deep red solution. After the addition was complete, the ice bath was removed and the solution was stirred at room temperature for 1 h. The reaction was quenched with saturated NaHCO3 and the resulting mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-45% EtOAc / hexanes) to afford the title compound (8.2 mg, 29%) as a reddish solid. LCMS calculated for C16H11ClN3O (M+H)+: m / z = 296.0; found: 296.0. Step 6.6-(1-aminoethyl)-4-chloro-7-phenyl-1H-indazole-3-carbonitrileThis compound was synthesized according to the procedure described in Example 23, Step 2, starting from 6-acetyl-4-chloro-7-phenyl-1H-indazole-3-carbonitrile (8.0 mg, 0.027 mmol). The product was used without purification (theoretical yield assumed). LCMS calculated for C16H11ClN3 (M-NH2)+: m / z = 280.0; found: 280.0. Step 7.2-amino-N-(1-(4-chloro-3-cyano-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide trifluoroacetateThis compound was synthesized according to the procedure described in Example 26, Step 3, starting from 6-(1-aminoethyl)-4-chloro-7-phenyl-1H-indazole-3-carbonitrile (8.0 mg, 0.027 mmol). The residue was purified by preparative HPLC (pH 2) to afford the title compound as a white solid (2.5 mg, 20%). LCMS calculated for C23H18ClN8O (M+H)+: m / z = 457.1; found: 457.1. Example 56.2-Amino-N-(1-(4-chloro-7-(4-cyanopiperidin-1-yl)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-amino-2-methoxypyridinium 2,4-dinitrobenzenolateTo a solution of O-(2,4-dinitrophenyl)hydroxylamine (9.1 g, 46 mmol) in acetonitrile (30 mL, 600 mmol) was added 2-methoxypyridine (4.8 mL, 46 mmol) and the reaction mixture was heated to 40 °C over the weekend. The solvent was removed in vacuo and the solid was filtered, washed with diethyl ether (20 mL), and dried to yield the title compound (9.17 g, 65%) as a light orange solid.1H NMR (400 MHz, DMSO) δ 8.61 (d, J = 3.1 Hz, 1H), 8.56 (dd, J = 6.5, 1.4 Hz, 1H), 8.32– 8.22 (m, 1H), 7.85 (dd, J = 9.7, 3.1 Hz, 1H), 7.74– 7.71 (m, 3H), 7.55– 7.44 (m, 1H), 6.43 (d, J = 9.7 Hz, 1H), 4.27 (s, 3H). LCMS calculated for C6H9N2O (M)+: m / z = 125.1; found 125.1. Step 2. ethyl 7-methoxypyrazolo[1,5-a]pyridine-3-carboxylateTo a suspension of 1-amino-2-methoxypyridinium 2,4-dinitrobenzenolate (9.17 g, 29.7 mmol) in DMF (79 mL) was added potassium carbonate (6.2 g, 45 mmol), followed by dropwise addition of ethyl propiolate (4.5 mL, 45 mmol) at room temperature. After stirring for 2 hthe reaction mixture was poured into water and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-60% EtOAc / hexanes) to afford the title compound (3.1 g, 47%) as a beige solid.1H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 7.69 (dd, J = 8.7, 1.0 Hz, 1H), 7.65– 7.57 (m, 1H), 6.70– 6.63 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.15 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). LCMS calculated for C11H13N2O3 (M+H)+: m / z = 221.1; found 221.1. Step 3. ethyl 6-chloro-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylateTo a solution of ethyl 7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (294 mg, 1.34 mmol) in DMF (6.0 mL) was added N-chlorosuccinimide (187 mg, 1.40 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4 and concentrated, and the residue was purified by flash chromatography (0-15% EtOAc / hexanes) to afford the title compound (237 mg, 70%) as an off white solid.1H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 7.83 (d, J = 9.4 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.22 (s, 3H), 1.34 (t, J = 7.1 Hz, 4H). LCMS calculated for C11H12ClN2O3 (M+H)+: m / z = 255.1; found 255.1. Step 4. ethyl 6-acetyl-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylateTo a mixture of ethyl 6-chloro-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (237.0 mg, 0.93 mmol), cesium fluoride (280 mg, 1.9 mmol), and XPhos Pd G2 (70 mg, 0.09 mmol) in 1,4- dioxane (5.0 mL) was added tributyl(1-ethoxyvinyl)tin (0.38 mL, 1.1 mmol) and the reaction mixture was heated to reflux for 4 h. After cooling to room temp, 1M HCl was added and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-30% EtOAc / hexanes) to afford the title compound (621 mg, 91%) as a white solid. LCMS calculated for C13H15N2O4 (M+H)+: m / z = 263.1; found 263.1. Step 5. ethyl 6-acetyl-7-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylateA solution of ethyl 6-acetyl-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (300.0 mg, 1.144 mmol) in 2.0 M ammonia in ethanol (7.0 mL, 14 mmol) was heated to 60 °C for 2 h. The volatiles were removed in vacuo, the resulting solid was suspended in acetic acid (9.0 mL, 160 mmol) and N-chlorosuccinimide (460 mg, 3.4 mmol) was added. The reaction mixture was heated to 45 °C for 3 h. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-25% EtOAc / hexanes) to afford the title compound (208 mg, 65%). LCMS calculated for C12H13ClN3O3 (M+H)+: m / z = 282.1; found 282.1. Step 6. ethyl 6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carboxylate Ethyl 6-acetyl-7-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate (413 mg, 1.47 mmol) was dissolved in conc. HCl (6.0 mL) and acetic acid (6.0 mL) and cooled to 0 °C. A solution of sodium nitrite (300 mg, 4.4 mmol) in water (1.0 mL) was added dropwise, and the solution changed from yellow to dark green. After 0.5 h, the reaction mixture was diluted with water and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, and concentrated. The resulting dark brown solid was washed with hexanes, filtered, and air dried to afford the title compound (410 mg, 93%) as a light brown solid. LCMS calculated for C12H11Cl2N2O3 (M+H)+: m / z = 301.0; found 301.0. Step 7.1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethanoneEthyl 6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carboxylate (410 mg, 1.4 mmol) was taken up in 6M HCl (6.0 mL) and acetic acid (6.0 mL), and heated to 100 °C overnight. After cooling to room temp, the reaction mixture was partitioned between water and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-20% EtOAc / hexanes) to afford the title compound (296 mg, 95%) as a yellow solid. LCMS calculated for C9H7Cl2N2O (M+H)+: m / z = 229.0; found 229.0. Step 8.1-(6-acetyl-4-chloropyrazolo[1,5-a]pyridin-7-yl)piperidine-4-carbonitrileA mixture of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethanone (15.0 mg, 0.065 mmol), piperidine-4-carbonitrile (11 μL, 0.098 mmol), and cesium carbonate (43 mg, 0.13 mmol) was taken up in acetonitrile (2.0 mL, 38 mmol) and heated to 70 °C for 1.5 h. The reaction mixture was partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was used without purification(theoretical yield assumed). LCMS calculated for C15H16ClN4O (M+H)+: m / z = 303.1; found 303.1. Step 9.2-amino-N-(1-(4-chloro-7-(4-cyanopiperidin-1-yl)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate To a solution of 1-(6-acetyl-4-chloropyrazolo[1,5-a]pyridin-7-yl)piperidine-4-carbonitrile (19.0 mg, 0.0628 mmol) in 2.0 M ammonia in ethanol (3.0 mL, 6.0 mmol) was added titanium tetraisopropoxide (56 μL, 0.19 mmol) and the reaction mixture was heated at 60 °C overnight. The resulting solution was cooled to room temperature, then 0 °C, and sodium borohydride (7.1 mg, 0.19 mmol) was added. After stirring for 0.5 h, the reaction was quenched with 1M NH4OH, filtered, and the solid was washed with EtOAc. The filtrate was washed with water, brine, dried over MgSO4, and concentrated. The product was used without purification. To a vial containing the crude amine, 2- [(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (21 mg, 0.075 mmol), and HATU (29 mg, 0.075 mmol) was added DMF (3 mL), followed by dropwise addition of N,N- diisopropylethylamine (33 μL, 0.19 mmol) at room temperature. After stirring for 1 h, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM (2 mL) and TFA (1.0 mL, 13 mmol) was added at room temp. After stirring for 1 h, the volatiles were evaporated in vacuo and the residue was purified by prep HPLC (pH 2) to afford the title compound (11.2 mg, 39%) as a white solid. LCMS calculated for C22H23ClN9O (M+H)+: m / z = 464.2; found 464.2. Example 57-58. (S)-2-Amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate (Example 57) & (S)-2-Amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate (Example 58)Step 1.1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethanone & 1-(4,7-dichloro-3-fluoropyrazolo[1,5- a]pyridin-6-yl)ethanoneTo a solution of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one (820 mg, 3.58 mmol, from Example 56, Step 7) in acetonitrile (7.0 ml) was added Selectfluor (2.54 g, 7.16 mmol) and the reaction mixture was stirred at room temperature for 8.5 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-10% EtOAc / hexanes) to afford a 1:1 mixture of the title compounds (701 mg, 79%). Peak 1: LCMS calculated for C9H7Cl2N2O (M+H)+: m / z = 229.0; found 229.0. Peak 2: LCMS calculated for C9H6Cl2FN2O (M+H)+: m / z = 247.0; found 247.0. Step 2.1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethan-1-one & 1-(4- chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethan-1-oneA 1:1 mixture of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one and 1-(4,7-dichloro- 3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one (701 mg, ~3.06 mmol), thiomorpholine dioxide (827 mg, 6.12 mmol), and DIPEA (1.069 ml, 6.12 mmol) was heated to 140 °C in the microwave for 1 h. LCMS indicated complete conversion to the desired product. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4 and concentrated. The residue was used without purification. Peak 1: LCMS calculated for C13H15ClN3O3S (M+H)+: m / z = 328.0; found 328.0. Peak 2: LCMS calculated for C13H14ClFN3O3S (M+H)+: m / z = 346.0; found 346.0. Step 3. N-((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfinamide & N-((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3- fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamideTo a solution of 1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6- yl)ethan-1-one and 1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6- yl)ethan-1-one (1.03 g, ~3.14 mmol), and (S)-2-methylpropane-2-sulfinamide (3.81 g, 31.4 mmol) in cyclopentyl methyl ether (20 ml) was added titanium(IV) isopropoxide (2.76 ml, 9.43 mmol) and the reaction mixture was heated to 100 °C overnight. The resulting mixture of sulfinimines was cooled to 0 °C and sodium borohydride (1.189 g, 31.4 mmol) was added in several portions. The reaction mixture was allowed to warm to room temperature and a small amount of EtOH (~0.5 mL) was added dropwise. After stirring for 0.5 h, LCMS indicated complete conversion (6:1 d.r. for bothcompounds). The reaction mixture was cooled to 0 °C, quenched by the dropwise addition of MeOH, and vigorously stirred until no more gas evolution was observed. The solution was poured into brine and the resulting suspension was filtered through celite The filtrate was diluted with EtOAc and water, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-70-100% EtOAc / hexanes). Both of the undesired diastereomers were separated, affording an inseparable 1:1 mixture of the title compounds (842 mg, 62%) as single diastereomers. Peak 1: LCMS calculated for C17H26ClN4O3S2 (M+H)+: m / z = 433.1; found 433.1. Peak 2: LCMS calculated for C17H25ClFN4O3S2 (M+H)+: m / z = 451.1; found 451.1. Step 4. (S)-4-(6-(1-aminoethyl)-4-chloropyrazolo[1,5-a]pyridin-7-yl)thiomorpholine 1,1-dioxide hydrochloride & (S)-4-(6-(1-aminoethyl)-4-chloro-3-fluoropyrazolo[1,5-a]pyridin-7- yl)thiomorpholine 1,1-dioxide hydrochlorideTo a solution of N-((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6- yl)ethyl)-2-methylpropane-2-sulfinamide and N-((S)-1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3- fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)-2-methylpropane-2-sulfinamide (1:1 mixture, 842 mg, ~1.945 mmol) in MeOH (10 ml) was added HCl (4.0M in dioxane) (10 mL, 40 mmol) and the reaction mixture was stirred at room temperature for 0.5 h. LCMS indicated the reaction was complete, and the volatiles were removed in vacuo. The residue was used without purification. Peak 1: LCMS calculated for C13H15ClN3O2S (M-NH2)+: m / z = 312.1; found 312.0. Peak 2: LCMS calculated for C13H14ClFN3O2S (M-NH2)+: m / z = 330.1; found 330.0. Step 5. (S)-2-amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate & (S)-2-amino-N-(1-(4-chloro-7- (1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide trifluoroacetateTo a vial containing (S)-4-(6-(1-aminoethyl)-4-chloropyrazolo[1,5-a]pyridin-7- yl)thiomorpholine 1,1-dioxide hydrochloride and (S)-4-(6-(1-aminoethyl)-4-chloro-3- fluoropyrazolo[1,5-a]pyridin-7-yl)thiomorpholine 1,1-dioxide hydrochloride (1:1 mixture, 710 mg, ~1.944 mmol), 2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (649 mg, 2.333 mmol), and HATU (887 mg, 2.333 mmol) was added DMF (12 ml), followed by dropwise addition of DIPEA (1.018 ml, 5.83 mmol) at room temp. After stirring for 0.5 h, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was dissolved in DCM (6.0 ml) and TFA (6 ml, 78 mmol) was added at room temp. After stirring for 0.5 h, the volatiles were evaporated in vacuo and the products were purified by prep HPLC (pH 2). Peak 1 (Example 57): 1H NMR (600 MHz, DMSO) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.57 (dd, J = 4.5, 1.6 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 7.50 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 5.73 (p, J = 7.0 Hz, 1H), 4.28– 4.24 (m, 1H), 4.17– 4.12 (m, 1H), 3.59– 3.46 (m, 3H), 3.37– 3.21 (m, 3H), 1.56 (d, J = 7.0 Hz, 3H). LCMS calculated for C20H22ClN8O3S (M+H)+: m / z = 489.1; found 489.0. Peak 2 (Example 58): 1H NMR (600 MHz, DMSO) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.57 (dd, J = 4.5, 1.6 Hz, 1H), 8.26 (d, J = 3.7 Hz, 1H), 8.09 (d, J = 6.9 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 6.7, 4.5 Hz, 1H), 5.68 (p, J = 7.0 Hz, 1H), 4.22– 4.15 (m, 1H), 4.13– 4.05 (m, 1H), 3.60– 3.45 (m, 3H), 3.35 (d, J = 13.3 Hz, 1H), 3.26 (m, 2H), 1.55 (d, J = 7.0 Hz, 3H). LCMS calculated for C20H21ClFN8O3S (M+H)+: m / z = 507.1; found 507.1. Example 59.2-Amino-N-(1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)ethanoneA mixture of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethanone (19.0 mg, 0.0829 mmol, from Example 56, Step 7), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (26 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol), and sodium carbonate (18 mg, 0.16 mmol) was taken up in 1,4-dioxane (2.5 mL, 32 mmol) and water (0.5 mL, 30 mmol) and heated to 100 °C for 2 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-100%EtOAc / hexanes) to afford the title compound as a white solid (16.4 mg, 73%). LCMS calculated for C14H11ClN3O (M+H)+: m / z = 272.1; found 272.1. Step 2.2-amino-N-(1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateThis compound was prepared according to the procedure described in Example 56, Step 9, starting from 1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)ethanone instead of 1-(6-acetyl- 4-chloropyrazolo[1,5-a]pyridin-7-yl)piperidine-4-carbonitrile. The residue was purified by preparative HPLC (pH 2) to afford the title compound (4.3 mg, 16%) as a white solid. LCMS calculated for C21H18ClN8O (M+H)+: m / z = 433.1; found 433.0. Example 60.2-Amino-N-(1-(4-chloro-3-cyano-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateStep 1.6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carbonitrileTo a solution of 1-(4,7-dichloropyrazolo[1,5-a]pyridin-6-yl)ethan-1-one (110 mg, 0.480 mmol, from Example 56, Step 7) in acetonitrile (3.0 ml) was added chlorosulfonyl isocyanate (0.13 ml, 1.44 mmol) at room temperature. After stirring for 1 h, the reaction mixture was cooled to 0 °C and DMF (0.11 ml, 1.44 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with EtOAc and quenched with ice chips, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-30% EtOAc / hexanes) to afford the title compound (103 mg, 84%) as a light yellow solid. LCMS calculated for C10H6Cl2N3O (M+H)+: m / z = 254.0; found 253.8. Step 2.6-acetyl-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3-carbonitrileA mixture of 6-acetyl-4,7-dichloropyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.079 mmol), thiomorpholine 1,1-dioxide (21.3 mg, 0.157 mmol), and DIPEA (0.027 ml, 0.157 mmol) was heated to 140 °C in a microwave reactor for 1 h. LCMS indicated complete conversion to the desired product. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated. The product was used without purification. LCMS calculated forC14H14ClN4O3S (M+H)+: m / z = 353.0; found 353.0. Step 3.6-(1-aminoethyl)-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3- carbonitrile hydrochlorideThis compound was prepared according to the procedure described in Examples 57-58, Steps 3-4, starting from 6-acetyl-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3- carbonitrile, with the exception that the diastereomers from the reductive amination step were not separated. The product was used without purification. LCMS calculated for C14H14ClN4O2S (M- NH2)+: m / z = 337.1; found 337.1. Step 4.2-amino-N-(1-(4-chloro-3-cyano-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateThis compound was prepared according to the procedure described in Example 57-58, Step 5, starting from 6-(1-aminoethyl)-4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3- carbonitrile hydrochloride. The product was purified by preparative HPLC (pH 2) to afford the title compound as a white solid. LCMS calculated for C21H21ClN9O3S (M+H)+: m / z = 514.1; found 514.1. Example 61.2-Amino-N-(1-(4-chloro-3-cyano-7-((S)-3-hydroxypiperidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateStep 1. (S)-6-acetyl-4-chloro-7-(3-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile This compound was prepared according to the procedure described in Example 60, Step 2, utilizing (S)-piperidin-3-ol instead of thiomorpholine 1,1-dioxide. LCMS calculated forC15H16ClN4O2 (M+H)+: m / z = 319.1; found 319.0. Step 2.2-amino-N-(1-(4-chloro-3-cyano-7-((S)-3-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate (mixture of diastereomers prepared)This compound was prepared according to the procedure described in Example 56, Step 9, starting from (S)-6-acetyl-4-chloro-7-(3-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile. The product was purified by preparative HPLC (pH 2). LCMS calculated forC22H23ClN9O2 (M+H)+: m / z = 480.2; found 480.0. Example 62.2-amino-N-(1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateStep 1.1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-yl)ethanone To a suspension of copper cyanide (39 mg, 0.44 mmol) in THF (0.8 mL) and HMPA (0.2 mL) at -78 °C was added cyclopentylmagnesium bromide (2M / Et2O, 0.22 mL, 0.44 mmol) dropwise. After stirring at this temperature for 15 min, a solution of 1-(5,8-dichloroimidazo[1,5-a]pyridin-6- yl)ethanone (20.0 mg, 0.0873 mmol, from Example 130, Step 7) in THF (0.5 mL) was added dropwise, and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with 1M HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-40% EtOAc / hexanes) to afford the title compound (11 mg, 48%). LCMS calculated for C14H16ClN2O (M+H)+: m / z = 263.1; found 263.1. Step 2.2-amino-N-(1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateThis compound was prepared according to the procedure described in Example 56, Step 9, starting from 1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-yl)ethanone. The product was purified by preparative HPLC (pH 2) to afford the title compound as a white solid.1H NMR (600 MHz, DMSO) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.51 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.64 (s, 1H), 7.17 (s, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 5.45 (p, J = 6.9 Hz, 1H), 4.10 (p, J = 6.0 Hz, 1H), 2.16– 1.98 (m, 4H), 1.93– 1.85 (m, 2H), 1.84– 1.79 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H). LCMS calculated for C21H23ClN7O (M+H)+: m / z = 424.2; found 424.2. Example 63.2-Amino-N-(1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetateA solution of methyl 2,5-dichloronicotinate (10.7 g, 51.9 mmol, from WO 2011 / 130342, Example 1, Step A, the disclosure of which is incorporated herein in its entirety), phenylboronic acid (6.65 g, 54.5 mmol), and potassium carbonate (15.6 g, 113 mmol) in water (50 mL) and 1,4-Dioxane (200 mL) was degassed with nitrogen (10 min). The reaction mixture was treated withbis(triphenylphosphine)palladium(II) chloride (2 g, 2 mmol), degassed with nitrogen (10 min), and heated at 80 °C for 3 hours. The reaction mixture was diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (0-40% EtOAc / hexanes) to afford the title compound (11.3 g, 88%) as a yellow oil, which solidified upon standing. LCMS calculated for C13H11ClNO2 (M+H)+: m / z = 248.0; found 248.0. Step 2.5-chloro-3-(methoxycarbonyl)-2-phenylpyridine 1-oxide Methyl 5-chloro-2-phenylnicotinate (400.0 mg, 1.615 mmol) was stirred in ethaneperoxoic acid (14 mmol, 3 mL) at 90 °C for 1.5 h. The volatiles were removed in vacuo and the residue was purified by flash chromatography (0-100% EtOAc / hexanes) to afford the title compound (283 mg, 66%) as a viscous oil. LCMS calculated for C13H11ClNO3 (M+H)+: m / z = 264.0; found 264.0. Step 3. methyl 5,6-dichloro-2-phenylnicotinate Methyl 5-chloro-2-phenylnicotinate 1-oxide (243.0 mg, 0.9216 mmol) was stirred in phosphoryl chloride (32 mmol, 3 mL) at 90 °C for 1 h. The black reaction mixture was cooled to room temperature and the volatiles were evaporated. The residue was purified by flashchromatography (0-20% EtOAc / hexanes) to afford the title compound (193 mg, 74%) as a white powder. LCMS calculated for C13H10Cl2NO2 (M+H)+: m / z = 282.0; found 282.0. Step 4. methyl 5-chloro-2-phenyl-6-vinylnicotinate A mixture of methyl 5,6-dichloro-2-phenylnicotinate (54.0 mg, 0.191 mmol),tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.01 mmol), pyridine - trivinylboroxin (1:1) (55 mg, 0.23 mmol), and potassium carbonate (79 mg, 0.57 mmol) in dioxane (2 mL) and water (0.5 mL) was purged with N2 for 5 minutes and heated to 100 °C for 1 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-20% EtOAc / hexanes) to afford the title compound (37 mg, 71%) as a colorless oil. LCMS calculated for C +15H13ClNO2 (M+H) : m / z = 274.1; found 274.0. Step 5. methyl 5-chloro-6-formyl-2-phenylnicotinate To a solution of methyl 5-chloro-2-phenyl-6-vinylnicotinate (254 mg, 0.928 mmol) in THF (4 mL) was added sodium periodate (0.60 g, 2.8 mmol), followed by osmium tetroxide (4% / H2O, 60 µL, 0.009 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and filtered. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was used without purification. LCMS calculated for C14H11ClNO3 (M+H)+: m / z = 276.0; found 276.0. Step 6. methyl 5-chloro-6-(hydrazonomethyl)-2-phenylnicotinate To a solution of methyl 5-chloro-6-formyl-2-phenylnicotinate (254 mg, 0.921 mmol) in methanol (120 mmol) was added hydrazine (58 µL, 1.8 mmol) and the reaction mixture was heated to 55 °C for 0.5 h. The reaction mixture was filtered and the volatiles were evaporated. The residue was used without purification. LCMS calculated for C14H13ClN3O2 (M+H)+: m / z = 290.1; found 290.0. Step 7.1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethanone To a solution of methyl 5-chloro-6-(hydrazonomethyl)-2-phenylnicotinate (267 mg, 0.922 mmol) in DCM (6 mL) was added iodobenzene diacetate (440 mg, 1.4 mmol) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo and the residue was purified by flash chromatography (0-25% EtOAc / hexanes) to afford the title compound (165 mg, 62% over 3 steps). LCMS calculated for C14H11ClN3O2 (M+H)+: m / z = 288.1; found 288.0. Step 8.4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridine-6-carboxylic acid To a solution of methyl 4-chloro-7-phenyl[1,2,3]triazolo[1,5-a]pyridine-6-carboxylate (165 mg, 0.574 mmol) in methanol (74 mmol) was added 3.0 M sodium hydroxide in water (1.91 mL, 5.74 mmol) and the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated in vacuo and the residue was treated with 1M HCl, forming a precipitate, which was solubilized by addition of EtOAc. The solution was diluted with additional EtOAc and 1M HCl, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated, providing a white solid that was used without purification. LCMS calculated for C13H9ClN3O2 (M+H)+: m / z = 274.0; found 274.0. Step 9.4-chloro-N-methoxy-N-methyl-7-phenyl-[1,2,3]triazolo[1,5-a]pyridine-6-carboxamide To a solution of 4-chloro-7-phenyl[1,2,3]triazolo[1,5-a]pyridine-6-carboxylic acid (157 mg, 0.574 mmol), N,O-dimethylhydroxylamine hydrochloride (110 mg, 1.1 mmol), and HATU (440 mg, 1.1 mmol) in DMF (4 mL) was added N,N-diisopropylamine (0.40 mL, 2.9 mmol) and the reaction mixture was stirred at room temperature overnight. After diluting with EtOAc, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-40%EtOAc / hexanes) to afford the title compound (127 mg, 70%). LCMS calculated for C15H14ClN4O2 (M+H)+: m / z = 317.1; found 317.1. Step 10.1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethanone To a solution of 4-chloro-N-methoxy-N-methyl-7-phenyl[1,2,3]triazolo[1,5-a]pyridine-6- carboxamide (127 mg, 0.401 mmol) in THF (3 mL) at 0 °C was added methylmagnesium bromide (3M / THF, 0.53 mL, 1.6 mmol) dropwise. After stirring for 1 h, the reaction was quenched with 1M HCl and warmed to room temperature. The reaction mixture was diluted with EtOAc and poured into saturated aqueous NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-25%EtOAc / hexanes) to afford the title compound (31 mg, 28%) as a white solid. LCMS calculated for C14H11ClN3O (M+H)+: m / z = 272.1; found 271.9. Step 11.2-amino-N-(1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide trifluoroacetateThis compound was prepared according to the procedure described in Example 56, Step 9, starting from 1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6-yl)ethanone. The product was purified by preparative HPLC (pH 2).1H NMR (600 MHz, DMSO) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.57 (dd, J = 4.5, 1.6 Hz, 1H), 8.35 (s, 1H), 8.15– 8.10 (m, 1H), 7.83 (s, 1H), 7.70– 7.57 (m, 4H), 7.56– 7.46 (m, 1H), 7.02 (dd, J = 6.7, 4.5 Hz, 1H), 4.91 (p, J = 6.9 Hz, 1H), 1.48 (d, J = 7.0 Hz, 3H). LCMS calculated for C21H18ClN8O (M+H)+: m / z = 433.1; found 433.1. Example 64.2-Amino-N-{1-[7-(3-aminopropoxy)-4-chloro-1H-indazol-6-yl]ethyl}pyrazolo[1,5- a]pyrimidine-3-carboxamide bis(trifluoroacetate)Step 1. tert-Butyl [3-(6-acetyl-4-chloro-3-methyl-2-nitrophenoxy)propyl]carbamate To a mixture of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone (0.50 g, 2.2 mmol), tert-butyl (3-hydroxypropyl)carbamate (0.74 mL, 4.4 mmol), and triphenylphosphine (1.3 g, 4.9 mmol) in tetrahydrofuran (5.0 mL) at 0 °C was added dropwise diisopropyl azodicarboxylate (0.86 mL, 4.4 mmol). The 0 °C bath was removed, and the reaction mixture was stirred overnight. The reaction mixture was partioned between water and EtOAc. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification via silica gel chromatography (5-40% EtOAc in hexanes) afforded the title compound 0.81 g, 97%) as a white solid. LCMS for C17H23ClN2NaO6 (M+Na)+: calculated m / z = 409.1; found 409.1. Step 2: tert-Butyl [3-(6-acetyl-2-ami -4-chloro-3-methylphenoxy)propyl]carbamateTo a solution of tert-butyl [3-(6-acetyl-4-chloro-3-methyl-2-nitrophenoxy)propyl]carbamate (760 mg, 2.0 mmol) in methanol (10.0 mL) and acetic acid (2.4 mL) was added zinc (604.7 mg, 9.248 mmol). The reaction mixture was stirred rapidly for 1 hour at room temperature. The reaction mixture was filtered through celite, and the filter cake was rinsed with MeOH. The filtrate was concentrated. The resulting residue was dissolved in EtOAc and washed with sat. NaHCO3 and then brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford the title compound (0.75 g, 106%) which was used without further purification. LCMS for C17H25ClN2NaO4 (M+Na)+: calculated m / z = 379.1; found 379.1. Step 3: tert-Butyl {3-[(6-acetyl-4-chloro-1H-indazol-7-yl)oxy]propyl}carbamate To a solution of tert-butyl [3-(6-acetyl-2-amino-4-chloro-3-methylphenoxy)propyl]carbamate (750.0 mg, 2.1 mmol) in acetic acid (10.0 mL) was added dropwise a solution of sodium nitrite (140 mg, 2.1 mmol) in water (11 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the reaction was quenched with sat. NaHCO3 until the aqueous layer reached pH 8. The organic layer was removed, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Mg2SO4, filtered, andconcentrated. Purification on silica gel column using EtOAc / hexane as the eluent gave the title compound (0.60 g, 78%). LCMS for C17H22ClN3NaO4 (M+Na)+: calculated m / z = 390.1; found 390.1 Step 4: tert-Butyl (3-{[6-(1-aminoethyl)-4-chloro-1H-indazol-7-yl]oxy}propyl)carbamate To a solution of tert-butyl {3-[(6-acetyl-4-chloro-1H-indazol-7-yl)oxy]propyl}carbamate (300 mg, 0.82 mmol) in 2.0 M ammonia in ethanol (15 mL, 30. mmol) was added titanium tetraisopropoxide (0.72 mL, 2.4 mmol), and the reaction mixture was heated at 60 °C for 5 hours. The reaction mixture was cooled to room temperature and then 0 °C, and sodium tetrahydroborate (92 mg, 2.4 mmol) was added. The reaction mixture was stirred at 0 °C for 45 min. The mixture was quenched with 1 M NH4OH (5.0 mL), filtered, and the solid was washed with acetonitrile. Volatiles were removed in vacuo. The resulting residue was dissolved in EtOAc and washed with water and brine, sequentially. The organic layer dried over Na2SO4 and concentrated to afford the title compound (0.30 g, 100%), which used in the next step without purification. LCMS forC17H25ClN4NaO3 (M+Na)+: calculated m / z = 391.2; found 391.1 Step 5: tert-Butyl [3-({[1-(7-{3-[(tert-butoxycarbonyl)amino]propoxy}-4-chloro-1H-indazol-6- yl)ethyl]amino}carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamateTo a flask containing 2-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (270 mg, 0.98 mmol), tert-butyl (3-{[6-(1-aminoethyl)-4-chloro-1H-indazol-7- yl]oxy}propyl)carbamat...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:X1 and X2 are each independently C or N, provided X1 and X2 are not simultaneously N;X3 is N, NR3a, or CR3;X4 is N, NR4a, or CR4;X5 is N, NR5a, or CR5;W is CH or N;Y1 is N or CR10;Y2 is N or CR11;one of Z1 and Z2 is N, the other of Z1 and Z2 is C;is a single bond or a double bond to maintain ring A and ring B being aromatic; R1 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or 4-10 membered heterocycloalkyl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently seleted Rj substituents;R2 is OR13, C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein the C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents;R3, R4, R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl- C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3, R4, R5, and R6 are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R3a, R4a, and R5a are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, C(O)Ra, C(O)NRaRa, C(O)ORa, C(=NRa)Ra, C(=NRa)NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a, R4a, and R5a are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R7 is selected from H, halo, CN, -OH, -C(O)O(C1-4 alkyl), -C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, (C1-4 alkyl)SO2NH-, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl, wherein the -C(O)O(C1-4 alkyl), - C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, (C1-4 alkyl)SO2NH-, 4- 10 membered heterocycloalkyl, and 5-10 membered heteroaryl groups of R7 are each optionally substituted with 1 or 2 independently selected Rq substituentsR8, R9, R10 and R11 are each independently H, halo, CN, -OH, -C(O)O(C1-4 alkyl), - C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, and (C1-4 alkyl)SO2NH-, wherein the -C(O)O(C1-4 alkyl), -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2 and (C1-4 alkyl)SO2NH- groups of R8, R9, R10 and R11 are each optionally substituted with 1 or 2 independently selected Rq substituents;each R12 is an independently selected C1-6 alkyl group;R13 is H or C1-6 alkyl optionally substitued with 1, 2 or 3 independently selected Rq substituents;each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents;or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1- 4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1, 2, or 3 independently selected Rd substituents; each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents; or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;each Rd is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re,C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re,NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1, 2, or 3 independently selected Rq substituents;each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg,NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents; each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1, 2, or 3 independently selected Rp substituents;each Rh is selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)- C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl C6 10 aryl 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted with 1, 2, or 3 independently selected Rj substituents;or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they attach form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;each Rj substituent is independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6- membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk;each Rn is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(=NRo)NRoRo, NRoC(=NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo; andeach Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, and 5 or 6-membered heteroaryl; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6- membered heteroaryl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; and each Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, NHR12, NR12R12, and C1-4 haloalkoxy, wherein the C1-4 alkyl, phenyl and 5-6 membered heteroaryl of Rq are each optionally substituted with OH, CN, -COOH, NH2, C1-4 alkoxy, C3-10 cycloalkyl, and 4-6 membered heterocycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:X1 and X2 are each independently C or N, provided X1 and X2 are not simultaneously N;X3 is N, NR3a, or CR3;X4 is N, NR4a, or CR4;X5 is N, NR5a, or CR5;W is CH or N;Y1 is N or CR10;Y2 is N or CR11;one of Z1 and Z2 is N, the other of Z1 and Z2 is C;is a single bond or a double bond to maintain ring A and ring B being aromatic; R1 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or 4-10 membered heterocycloalkyl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently seleted Rj substituents;R2 is OR13, C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein the C3-6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents;R3, R4, R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl- C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3, R4, R5, and R6 are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R3a, R4a, and R5a are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, C(O)Ra, C(O)NRaRa, C(O)ORa, C(=NRa)Ra, C(=NRa)NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a, R4a, and R5a are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;R7, R8, R9, R10 and R11 are each independently H, halo, CN, -OH, -C(O)O(C1-4 alkyl), -C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4 alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, and (C1-4 alkyl)SO2NH-, wherein the -C(O)O(C1-4 alkyl), -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, (C1-4alkyl)C(O)NH-, (C1-4 alkyl)C(O)-, C1-4 alkylthio, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2 and (C1-4 alkyl)SO2NH- groups of R7, R8, R9, R10 and R11 are each optionally substituted with 1 or 2 independently selected Rq substituents;each R12 is an independently selected C1-6 alkyl group;R13 is H or C1-6 alkyl optionally substitued with 1, 2 or 3 independently selected Rq substituents;each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents;or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents; each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1- 4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1, 2, or 3 independently selected Rd substituents; each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;each Rd is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re,C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re,NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1, 2, or 3 independently selected Rq substituents;each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg,NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents; each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1, 2, or 3 independently selected Rp substituents;each Rh is selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)- C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted with 1, 2, or 3 independently selected Rj substituents;or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they attach form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;each Rj substituent is independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6- membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk,NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk;each Rn is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(=NRo)NRoRo, NRoC(=NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo; and each Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, and 5 or 6-membered heteroaryl; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6- membered heteroaryl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; andeach Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, NHR12, NR12R12, and C1-4 haloalkoxy, wherein the C1-4 alkyl, phenyl and 5-6 membered heteroaryl of Rq are each optionally substituted with OH, CN, -COOH, NH2, C1-4 alkoxy, C3-10 cycloalkyl, and 4-6 membered heterocycloalkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is H, C3-6 cycloalkyl, C1-6 haloalkyl or C1-6 alkyl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6 alkoxy, phenyl, or monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl or monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3 independently selected Rj substituents.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2 is 5-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 independently selected Rj substituents.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each Rk is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein each Rc is independently selected from H and C1-6 alkyl.

11. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R3 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-, wherein said C1-6 alkyl, C1-6 alkynyl, C3-10 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein each Rc is independently H or C1-6 alkyl; or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.

15. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R4 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, C1-6 alkyl, or C1-6 haloalkyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R6 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R7 is H, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected Rq substituents.

19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R7, R8, and R9 are each H.

20. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:R1 is H or C1-6 alkyl;R2 is OR13, C6-10 aryl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl; wherein said C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk;R3a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R3a are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents;R4a is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independenly selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5 is H, halo, C1-6 alkyl, or C1-6 haloalkyl;R5a is H or C1-6 alkyl;R6 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; andR7 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl.

21. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:R1 is C1-6 alkyl; R2 is C1-6 alkoxy, phenyl, or monocyclic 5-6 membered heteroaryl; wherein said C6-10 aryl or monocyclic 5-6 membered heteroaryl of R2 are each optionally substituted with 1, 2, or 3 independently selected Rj substituents;each Rj is independently selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, NHORk, ORk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, S(O)2Rk, NRkS(O)2Rk, and S(O)2NRkRk;each Rk is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl;R3a is H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl; wherein said C1-6 alkyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl, and (4-6 membered heterocycloalkyl)-C1-4 alkyl of R3a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, OH, NH2, NHORc, ORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcS(O)Rc, NRcS(O)2Rc, S(O)2Rc and S(O)2NRcRc;R4a is selected from H, C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl-; wherein said C1-6 alkyl, C1-6 alkynyl, C3-7 cycloalkyl, phenyl-C1-4 alkyl-, and (5-6 membered heteroaryl)-C1-4 alkyl- of R4a are each optionally substituted by 1, 2, 3, or 4 independently selected Rb substituents;R3 is H or C1-6 alkyl;R4 is H or C1-6 alkyl;R5a is H or C1-6 alkyl;R5 is H, halo, or C1-6 alkyl;R6 is halo, CN, or C1-6 alkyl; andeach Rc is independently H or C1-6 alkyl;or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents.

22. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:R1 is methyl; R2 is ethoxy, phenyl, or 3-fluorophenyl;R3a is H, methyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2CN, -CH2CH2NH2, -CH2C(O)NH2, benzyl, cyclobutyl, -CH2-(1-methyl-1H-pyrazol-3-yl), or -CH2CH2-(morpholin-4-yl);R4a is H, methyl, ethyl, isopropyl, isobutyl, -CH2C≡CCH3, -CH2CH2OH, - CH2CH2OCH3, -CH2CN, -CH2CH2NH2, cyclobutyl, benzyl, -CH2C(O)NH2, -CH2-(1-methyl- 1H-pyrazol-3-yl), or–CH2C(O)-(morpholin-4-yl);R5 is H, bromo, or methyl; andR6 is chloro, CN, or methyl.

23. The compound of any one of claims 1 to 20, having Formula (II):(II)or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1 to 20, having Formula (X):or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 1 to 20, having Formula (XI):or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1 to 20, having Formula (XII):or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 or 2, selected from:2-amino-N-[1-(4-chloro-7-ethoxy-2-methyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-[1-(4-chloro-7-ethoxy-2-ethyl-2H-indazol-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine- 3-carboxamide;2-amino-N-[1-(4-chloro-7-ethoxy-1-methyl-1H-indazol-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-{1-[4-chloro-7-ethoxy-1-(2-methoxyethyl)-1H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-ethoxy-1-(2-hydroxyethyl)-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-1-(cyanomethyl)-7-ethoxy-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-amino-N-(1-(1-benzyl-4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-ethoxy-1-isobutyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-1-cyclobutyl-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-ethoxy-1-isopropyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-ethoxy-2-(2-methoxyethyl)-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-ethoxy-2-(2-hydroxyethyl)-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-2-(cyanomethyl)-7-ethoxy-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(2-benzyl-4-chloro-7-ethoxy-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-ethoxy-2-isobutyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-2-cyclobutyl-7-ethoxy-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-ethoxy-2-isopropyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(2-(2-amino-2-oxoethyl)-4-chloro-7-ethoxy-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(1-(2-amino-2-oxoethyl)-4-chloro-7-ethoxy-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(2-(but-2-ynyl)-4-chloro-7-ethoxy-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(1-(but-2-yn-1-yl)-4-chloro-7-ethoxy-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide;2-amino-N-(1-(4-chloro-1-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-2-methyl-7-phenyl-2H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide; 2-amino-N-(1-(4-chloro-1-((1-methyl-1H-pyrazol-3-yl)methyl)-7-phenyl-1H- indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-2-((1-methyl-1H-pyrazol-3-yl)methyl)-7-phenyl-2H- indazol-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-1-(2-morpholinoethyl)-7-phenyl-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-2-(2-morpholino-2-oxoethyl)-7-phenyl-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(2-(2-aminoethyl)-4-chloro-7-phenyl-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(1-(2-aminoethyl)-4-chloro-7-phenyl-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(3-bromo-4-chloro-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(4-chloro-3-methyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-amino-N-(1-(3,4-dimethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-{1-[5-(3-fluorophenyl)-3,8-dimethylimidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-cyano-5-phenylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide;or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, selected from:2-Amino-N-(1-[8-chloro-5-(2-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-(3-cyanopyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-amino-N-(1-(8-chloro-5-(3-cyano-3-methylpyrrolidin-1-yl)imidazo[1,5-a]pyridin- 6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)imidazo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-((3S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl)imidazo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-[8-chloro-5-(1-oxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-[8-chloro-5-(3-methyl-1,1-dioxidothiomorpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-[8-chloro-5-(1-imino-1-oxidothiomorpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-[8-chloro-5-(2,2-dimethyl-1,1-dioxidothiomorpholin-4- yl)imidazo[1,5-a]pyridin-6-yl]ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5- (hydroxymethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(5-methoxypyridin- 3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-5-(piperidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-6-chloro-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)imidazo[1,2- b]pyridazine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-methylimidazo[1,2- b]pyridazine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(piperidin-1- yl)imidazo[1,2-b]pyridazine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(5- (hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide;2-Amino-N-(1-(3,4-dichloro-7-ethoxy-1H-indazol-6-yl)ethyl)-6-(5- (hydroxymethyl)pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide;2-Amino-N-[1-(4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl]-5-pyridin-3- ylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-Amino-N-(1-(4-chloro-3-ethyl-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-2-(2-hydroxyethyl)-2H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(3-bromo-4-chloro-7-ethoxy-1-(2-hydroxyethyl)-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-3-cyano-7-phenyl-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-(4-cyanopiperidin-1-yl)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(S)-2-Amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(S)-2-Amino-N-(1-(4-chloro-7-(1,1-dioxidothiomorpholino)-3-fluoropyrazolo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-3-cyano-7-(1,1-dioxidothiomorpholino)pyrazolo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-3-cyano-7-((S)-3-hydroxypiperidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-amino-N-(1-(8-chloro-5-cyclopentylimidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-phenyl-[1,2,3]triazolo[1,5-a]pyridin-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[7-(3-aminopropoxy)-4-chloro-1H-indazol-6-yl]ethyl}pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(4-fluoropiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3,3-difluoropiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3,3-difluoropyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-Amino-N-{1-[8-chloro-5-(4-methylpiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(2,2-dimethylpyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(2R)-2-methylpyrrolidin-1-yl]imidazo[1,5-a]pyridin-6- yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(2S)-2-methylpyrrolidin-1-yl]imidazo[1,5-a]pyridin-6- yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-[(2R)-2-methylpiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-[(2S)-2-methylpiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3-fluoropiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(3R)-3-fluoropyrrolidin-1-yl]imidazo[1,5-a]pyridin-6- yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(3S)-3-fluoropyrrolidin-1-yl]imidazo[1,5-a]pyridin-6- yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3-hydroxy-3-methylpiperidin-1-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3-cyano-3-methylpiperidin-1-yl)imidazo[1,5-a]pyridin- 6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[3-hydroxy-3-(trifluoromethyl)piperidin-1- yl]imidazo[1,5-a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(2-oxo-3-oxa-1,8-diazaspiro[4.5]dec-8-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-(2-methoxyethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-methoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-(difluoromethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide; 2-Amino-N-(1-(4-chloro-7-(2-hydroxyethoxy)-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-7-(2,3-dihydroxypropoxy)-1H-indazol-6- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(4-chloro-3-cyano-7-ethoxy-1H-indazol-6-yl)ethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-(4-hydroxy-4-methylpiperidin-1-yl)imidazo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-(4-cyano-4-methylpiperidin-1-yl)imidazo[1,5-a]pyridin- 6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-(4-hydroxy-4-(trifluoromethyl)piperidin-1- yl)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[4-chloro-7-(3-hydroxypyrrolidin-1-yl)-2H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[4-chloro-7-(3-methoxypyrrolidin-1-yl)-2H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(4-chloro-7-{3-[(methylamino)sulfonyl]pyrrolidin-1-yl}-2H-indazol- 6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(4-chloro-7-{4-[(dimethylamino)sulfonyl]piperidin-1-yl}-2H-indazol- 6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[4-chloro-7-(1,1-dioxidothiomorpholin-4-yl)-2H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;N-(1-{7-[(3S)-3-(Acetylamino)pyrrolidin-1-yl]-4-chloro-2H-indazol-6-yl}ethyl)-2- aminopyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(4-chloro-7-{(3S)-3-[(methylsulfonyl)amino]pyrrolidin-1-yl}-2H- indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(4-chloro-7-{(3R)-3-[(methylsulfonyl)amino]pyrrolidin-1-yl}-2H- indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;Ethyl 4-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4- chloro-2H-indazol-7-yl]cyclohex-3-ene-1-carboxylate;Benzyl 4-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4- chloro-2H-indazol-7-yl]-3,6-dihydropyridine-1(2H)-carboxylate;2-Amino-N-{1-[4-chloro-7-(1,2,3,6-tetrahydropyridin-4-yl)-2H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[4-chloro-7-(4-methoxycyclohex-1-en-1-yl)-2H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-Amino-N-{1-[4-chloro-7-(4-cyanocyclohex-1-en-1-yl)-2H-indazol-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;Methyl 1-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4- chloro-2H-indazol-7-yl]pyrrolidine-3-carboxylate;2-Amino-N-[1-(4-chloro-7-{3-[(methylamino)carbonyl]pyrrolidin-1-yl}-2H-indazol- 6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;N-(1-(7-((S)-3-Acetamidopiperidin-1-yl)-4-chloro-1H-indazol-6-yl)ethyl)-2- aminopyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(4-chloro-7-{(3S)-3-[(methylsulfonyl)amino]piperidin-1-yl}-2H- indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;Ethyl 1-[6-(1-{[(2-aminopyrazolo[1,5-a]pyrimidin-3-yl)carbonyl]amino}ethyl)-4- chloro-2H-indazol-7-yl]piperidine-4-carboxylate;2-Amino-N-[1-(4-chloro-7-{4-[(methylamino)carbonyl]piperidin-1-yl}-2H-indazol- 6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(4-chloro-7-{4-[(dimethylamino)carbonyl]piperidin-1-yl}-2H- indazol-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[4-chloro-7-(1,1-dioxido-1,4-thiazepan-4-yl)pyrazolo[1,5-a]pyridin- 6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[4-chloro-7-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)pyrazolo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[4-chloro-7-(2,2-dimethyl-1,1-dioxidothiomorpholin-4- yl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[3,4-dichloro-7-(2-methyl-1,1-dioxidothiomorpholin-4- yl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[3,4-dichloro-7-(1,1-dioxidothiomorpholin-4-yl)pyrazolo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[3,4-dichloro-7-(1,1-dioxido-1,4-thiazepan-4-yl)pyrazolo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[3,4-dichloro-7-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)pyrazolo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[3,4-dichloro-7-(2,2-dimethyl-1,1-dioxidothiomorpholin-4- yl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-cyclopropyl-5-phenylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-Amino-N-{1-[8-chloro-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-3-methyl-5-pyridin-3-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-3-methyl-5-phenylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[1,8-dichloro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-1-fluoro-3-methyl-5-(1H-pyrazol-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-3-methyl-5-phenyl-1-(trifluoromethyl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-1-cyano-3-methyl-5-phenylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-1-ethynyl-3-methyl-5-phenylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-pyridin-3-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-1-cyano-5-pyridin-3-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-1-methyl-5-pyridin-3-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1H-pyrazol-3-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[5-(methylsulfonyl)pyridin-3-yl]imidazo[1,5-a]pyridin-6- yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-{6-[(methylamino)carbonyl]pyridin-3-yl}imidazo[1,5- a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-pyridin-2-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(5-methoxypyridin-3-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-{4-[(methylamino)sulfonyl]phenyl}imidazo[1,5- a]pyridin-6-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[4-(methylsulfonyl)phenyl]imidazo[1,5-a]pyridin-6- yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-Amino-N-{1-[8-chloro-5-(5-cyanopyridin-3-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-pyrazin-2-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[4-(methylsulfonyl)piperazin-1-yl]imidazo[1,5-a]pyridin- 6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-pyrrolidin-1-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(4-methoxypiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3-methoxypyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-morpholin-4-ylimidazo[1,5-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(4-hydroxypiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[5-(4-bromopiperidin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(3-hydroxypyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(3S,5S)-3,5-dihydroxypiperidin-1-yl]imidazo[1,5- a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(3S)-3-hydroxypiperidin-1-yl]imidazo[1,5-a]pyridin-6- yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(4-cyanopiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(4-methyl-3-oxopiperazin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-Amino-N-(1-{8-chloro-5-[(3R,5R)-3,5-dihydroxypiperidin-1-yl]imidazo[1,5- a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(3R,5S)-3,5-dihydroxypiperidin-1-yl]imidazo[1,5- a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(3R,5R)-3-fluoro-5-hydroxypiperidin-1-yl]imidazo[1,5- a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-{8-chloro-5-[(3S,5R)-3-cyano-5-hydroxypiperidin-1-yl]imidazo[1,5- a]pyridin-6-yl}ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-(1,1-dioxido-1,4-thiazepan-4-yl)-3-methylimidazo[1,5- a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)-1- (trifluoromethyl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{(1S)-1-[1,8-dichloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5- yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{(1S)-1-[1,8-dichloro-5-(5-oxo-1,4-diazepan-1-yl)imidazo[1,5-a]pyridin- 6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[1,8-dichloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[1,8-dichloro-5-(4-cyanopiperidin-1-yl)imidazo[1,5-a]pyridin-6- yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-1-cyano-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5- a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;2-Amino-N-{[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]methyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((8-chloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5- a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((8-chloro-5-(2,2-dimethyl-1,1-dioxidothiomorpholino)imidazo[1,5- a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((1,8-dichloro-5-(2-methyl-1,1-dioxidothiomorpholino)imidazo[1,5- a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((1,8-dichloro-5-(2,2-dimethyl-1,1-dioxidothiomorpholino)imidazo[1,5- a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 2-Amino-N-((8-chloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((1,8-dichloro-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((8-chloro-1-cyano-5-(pyrrolidin-1-yl)imidazo[1,5-a]pyridin-6- yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((8-chloro-1-cyano-5-(2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)propyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;2-Amino-N-((8-chloro-1-cyano-5-(2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)(cyclopropyl)methyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-1-cyano-5-(2-methyl-1,1- dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]propyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]propyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-{1-[8-chloro-5-(1,1-dioxidothiomorpholin-4-yl)imidazo[1,5-a]pyridin-6- yl]-2,2,2-trifluoroethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-(1-(8-chloro-5-(1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6-yl)- 2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-((8-chloro-5-(1,1-dioxidothiomorpholino)imidazo[1,5-a]pyridin-6- yl)(cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-cyclohexylimidazo[1,5-a]pyridin-6-yl)ethyl]pyrazolo[1,5- a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-3-methyl-5-phenyl[1,2,4]triazolo[4,3-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;2-Amino-N-[1-(8-chloro-5-phenyl[1,2,4]triazolo[4,3-a]pyridin-6- yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

30. A method of inhibiting PI3Kγ kinase, comprising contacting the PI3Kγ kinase with a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

31. A method of treating a disease or disorder associated with abnormal expression or activity of PI3Kγ kinase, comprising administering to a patient in need thereof, atherapeutically effective amount of a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease.

33. The method of claim 31, wherein disease or disorder is lung cancer, melanoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, color cancer, endometrial cancer, bladder cancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer, or sarcoma.

34. The method of claim 33, wherein the sarcoma is Askin's tumor, sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma,hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

35. The method of claim 31, wherein the disease or disorder is acute myeloid leukemia, acute monocytic leukemia, small lymphocyctic lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma.

36. The method of claim 35, wherein the mature (peripheral) t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, mycosis fungoides / Sezary syndrome, naplastic large cell lymphoma (T-cell type), enteropathy type T-cell lymphoma, adult T-cell leukemia / lymphoma, or angioimmunoblastic T-cell lymphoma.

37. The method of claim 35, wherein the anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.

38. The method of claim 31, wherein the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma.

39. The method of claim 38, wherein non-Hodgkin’s lymphoma (NHL) is relapsed NHL, refractory NHL, recurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL).

40. The method of claim 38, wherein the diffuse large B cell lymphoma is activated B- cell like (ABC) diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuse large B cell lymphoma.

41. The method of claim 38, wherein the Burkitt’s lymphoma is endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like lymphoma.

42. The method of claim 31, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, asthma, allergy, pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease (e g Crohn’s disease and ulcerative colitis), thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren’s syndrome, osteoarthritis, restenosis, or atherosclerosis.

43. The method of claim 31, wherein the disease or disorder is heart hypertropy, cardiac myocyte dysfunction, chronic obstructive pulmonary disease (COPD), elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft rejection, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, or membranous nephropathy.

44. The method of claim 43, wherein the idiopathic thrombocytopenic purpura (ITP) is relapsed ITP or refractory ITP.

45. The method of claim 43, wherein the vasculitis is Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV).

46. The method of claim 31, wherein the disease or disorder is Alzheimer's disease, central nervous system trauma, or stroke.