compound

Abstract

The present invention relates to compounds of formula (I) that have the ability to inhibit CD151. JPEG2023535496000196.jpg53170

Description

[Technical Field]

[0001] The present invention relates to compounds that the applicant has discovered to be inhibitors of CD151. As a result of this activity, these compounds can be used to treat medical indications related to this transmembrane domain cell surface protein. Thus, the compounds can be applied to the treatment of cancer, as well as, for example, asthma, multiple sclerosis, and inflammatory bowel disease. The compounds can also be applied to the treatment of certain animal diseases related to CD151. [Background technology]

[0002] The past 200 years have seen significant advances in medical research, resulting in a dramatic increase in life expectancy due to the development of effective medical treatments for a significant number of diseases / conditions.

[0003] Nevertheless, there remains a continuing drive to provide treatments for diseases and conditions for which effective treatments are not available. Accordingly, there is significant research being conducted into biological targets that may be involved in many medical conditions of interest.

[0004] One area of ​​interest is the tetraspanins, a superfamily of four-transmembrane domain cell surface proteins that includes the tumor suppressor KAI1 / CD82 and tumor promoter CD151. Tetraspanins are expressed in a wide variety of cell types and have been implicated in cancer progression. In particular, tetraspanins may be involved in cell adhesion, cell motility, and tumor suppression or activation. Tetraspanins are thought to regulate their activity through the organization of cell surface membrane microdomains that facilitate interactions with a range of other proteins, such as integrins, immune receptors, and signaling molecules.

[0005] CD151 is a member of the tetraspanin superfamily that associates with integrins, membrane receptors, intracellular signaling molecules (such as PI4K and PKC), immunoglobulins, and other tetraspanins, and these tetraspanin-enriched microdomains (TEMs) act as molecular facilitators (Kumari S et al, Biomarkers in Cancer 2015;7:7-11).

[0006] CD151 is involved in wound healing, platelet aggregation, epithelial cell integrity, cell migration, angiogenesis, and tumor metastasis. Its expression is ubiquitous, but it is often overexpressed in cancer cells and is associated with cancer progression and metastasis.

[0007] Overexpression of CD151 has been associated with a wide range of common human cancers, including prostate cancer (Ang J et al., Cancer Epidemiol Biomarkers Prev 2004;13(11 Pt 1):1717-1721), breast cancer (Yang XH et al., Cancer Res 2008;68:3204-3213), pancreatic cancer (Zhu GH et al., Dig Dis Sci 2011;56:1090-1098), colon cancer (Hashida H et al., Br J Cancer 2003;89:158-167), and non-small cell lung cancer (Tokuhara T et al., Clin Cancer Res 2001;7:4109-4114). Other cancers in which CD151 is overexpressed include hepatocellular carcinoma (Ke AW et al, Hepatology 2009;49:491-503), intrahepatic cholangiocarcinoma (Huang XY et al, Cancer 2010;116:5440-5451), renal cell carcinoma (Yoo SH et al, Histopathology 2011;58:191-197), endometrial carcinoma (Voss MA et al, Br J Cancer 2011;104:1611-1618), esophageal carcinoma (Suzuki S et al, Ann Surg Oncol 2011;18:888-893), squamous cell carcinoma (Li Q et al, Oncogene 2013;32:1772-1783), and glioblastoma multiforme (Lee D et al, J Surg Oncol 2013;107:646-652), melanoma (Saito N et al, Pigment Cell Melanoma Res 2009;22:601-610), and ovarian cancer (Medrano M et al, Cell Rep 2017;18:2343-2358).

[0008] Several non-cancerous medical conditions are also associated with CD151 overexpression, such as asthma (Qiao Y et al, J Allergy Clin Immunol 2017;139:82-92), inflammatory bowel disease (Zelman-Toister E et al, Inflamm Bowel Dis 2016;22:257-267), and multiple sclerosis (Lombardo, SD; Mazzon, E.; Basile, MS; Campo, G.; Corsico, F.; Presti, M.; Bramanti, P.; Mangano, K.; Petralia, MC; Nicoletti, F.; Fagone, P. Modulation of Tetraspanin 32 (TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis. Int. J. Mol. Sci. 2019, 20, 4323. and cytomegalovirus infection (Hochdorfer D et al, Journal of Virology 2016;90:6430-6442), and human papillomavirus type 16 infection (associated with cancer of the female genital tract) (Spoden G et al, PLoS One 2008;3:1-15). Other infectious agents associated with CD151 include Neisseria meningitidis, the etiologic agent of meningococcal meningitis (Hauck CR et al, Curr Opin Microbiol 2003;6:43-49 and Green LR et al, Infect Immun 2001;79:2241-2249), and influenza virus (Qiao Y et al, Allergy Clin Immunol 2018;141:1799-1817).

[0009] There is therefore great interest in developing inhibitors of CD151, as compounds with this ability would be expected to be useful in the treatment of these disorders. Summary of the Invention

[0010] Therefore, the applicant has studied the expression of CD151 with the aim of identifying inhibitors of its function that may be applied in the treatment of conditions involving its overexpression.

[0011] As a result of these studies, applicants have identified compounds that inhibit CD151.

[0012] Thus, in one embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 , R 2 , and R 3 are each independently H and C1 to C 12 is selected from the group consisting of alkyl, R 4 is H and C1 to C 12 is selected from the group consisting of alkyl, R 5 is H, optionally substituted C6-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C-C 18 Aryl C1-C 12 Alkyl- and optionally substituted C1-C 18 Heteroaryl C1-C 12 alkyl-, R 6 H, C1~C 12 is selected from the group consisting of alkyl, C3-C6 cycloalkyl, and C1-C5 heterocycloalkyl; R 7 is H and C1 to C 12 is selected from the group consisting of alkyl, R 8 H, C1~C 12 Alkyl, optionally substituted C-C 18 Aryl optionally substituted C1-C 18 Heteroaryl, optionally substituted C-C 18 Aryl C1-C 12Alkyl- and optionally substituted C1-C 18 Heteroaryl C1-C 12 alkyl-, Or R 7 and R 8 When combined with the nitrogen atom to which they are attached, C2 to C 12 forming a heterocyclic group), or a pharmaceutically acceptable salt thereof.

[0013] It has been found that compounds of the present invention have the ability to inhibit CD151 in humans and therefore can be used in the treatment of conditions associated with expression of this gene.

[0014] Additionally, in a still further aspect, the present invention provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable diluent, excipient, or carrier. [Brief explanation of the drawings]

[0015] [Figure 1] To measure cell invasion under compound treatment, the upper chamber of the CIM plate was coated with 5% Matrigel diluted in SF RPMI (20 μl) and incubated for 4 hours in a tissue culture incubator at 37°C. An assembly tool was used to support the chamber, and the lower chamber was filled with medium (160 μl) containing specific concentrations of compounds ranging from 25 μM to 1 μM and two controls (DMSO 0.1% and ESFAM 4C 10 μM). DETAILED DESCRIPTION OF THE INVENTION

[0016] In this specification, several terms are used that are well known to those skilled in the art. However, for the sake of clarity, several terms are defined. Throughout the description and claims of this specification, the term "comprise" and variations of terms such as "comprising" and "comprises" are not intended to exclude other additives, components, integers or steps.

[0017] The term "inhibit" and variations thereof, such as "inhibiting," mean to prevent, block, or reduce the function of the entity being inhibited. The term does not require complete inhibition; at least a 50% reduction in activity is considered inhibition.

[0018] In the definitions of some substituents below, it is stated that "the group may be a terminal group or a bridging group." This means that the use of this term is intended to encompass situations where the group is a linker between two other parts of a molecule, as well as situations where the group is a terminal moiety. As an example, using the term alkyl, some publications use the term "alkylene" for a bridging group, and therefore these other publications distinguish between the term "alkyl" (terminal group) and the term "alkylene" (bridging group). In the present application, no such distinction is made, and most groups can be either a bridging group or a terminal group.

[0019] Terms used herein are well known to those skilled in the art, however, for clarity, some of these terms are defined.

[0020] As used herein, the term "unsubstituted" means that there are no substituents or that the substituents are only hydrogen.

[0021] The term "optionally substituted" as used throughout this specification means that a group may or may not be further substituted or fused with one or more non-hydrogen substituents (so as to form a fused polycyclic ring system). When optional substituents are present, the substituents are independently selected from halogen, ═O, ═S, —CN, —NO, —CF, —OCF, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl. , alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)R e , -C(=O)OR e , C(=O)NR e R f , C(=NOH)R e , C(=NR e )NR f R g , N.R. e R f , N.R. e C(=O)Rf , N.R. e C(=O)OR f , N.R. e C(=O)NR f R g , N.R. e C(=NR f )NR g R h , N.R. e SO2R f , -SR e , SO2NR e R f , -OR e , OC(=O)NR e R f , OC(=O)R e and acyl.

[0022] In the formula, R e , R f , R g , and R h are each independently H, C1 to C 12 Alkyl, C1-C 12 Haloalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 10 Heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C1-C 12 Heterocycloalkyl, C1-C 12 Heterocycloalkenyl, C6-C 18 Aryl, C1-C 18 or R is selected from the group consisting of heteroaryl, and acyl a , R b , R c , and R d When taken together with the atoms to which they are attached, any two or more of the following may form a heterocyclic ring system having from 3 to 12 ring atoms:

[0023] In some embodiments, each optional substituent is independently selected from the group consisting of halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminoalkyl, -COOH, -SH, and acyl.

[0024] Examples of particularly suitable optional substituents include F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, and CN.

[0025] "Acyl" refers to the group RC(=O)-, where R can be an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, as defined herein. Examples of acyl include acetyl and benzoyl. The group can be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through the carbonyl carbon.

[0026] "Acylamino" refers to the group RC(=O)-NH-, where R can be an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group as defined herein. The group can be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through the nitrogen atom.

[0027] "Alkenyl," as a group or part of a group, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched, preferably having 2 to 12 carbon atoms, more preferably 2 to 10 carbon atoms, and most preferably 2 to 6 carbon atoms in the linear chain. The group may contain multiple double bonds in the linear chain, and the orientation for each is independently E or Z. The alkenyl group is preferably a 1-alkenyl group. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, and nonenyl. The group may be a terminal group or a bridging group.

[0028] "Alkenyloxy" refers to an alkenyl-O- group, where alkenyl is as defined herein. Preferred alkenyloxy groups are C1-C6 alkenyloxy groups. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through an oxygen atom.

[0029] "Alkyl", as a group or part of a group, unless otherwise specified, refers to a straight or branched chain aliphatic hydrocarbon group, preferably C1 to C 12 Alkyl, more preferably C1-C 10 It refers to alkyl, most preferably C1-C6. Examples of suitable straight and branched C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, etc. The group may be a terminal group or a bridging group.

[0030] "Alkylamino" includes both monoalkylamino and dialkylamino unless otherwise specified. "Monoalkylamino" refers to an alkyl-NH- group, where alkyl is as defined herein. "Dialkylamino" refers to an (alkyl)2N- group, where each alkyl may be the same or different and is as defined herein for alkyl. The alkyl group is preferably a C1-C6 alkyl group. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the nitrogen atom.

[0031] "Alkylaminocarbonyl" refers to a group of the formula (alkyl) x (H) y " refers to the group NC(=O)-, where alkyl is as defined herein, x is 1 or 2, and the sum of X+Y=2. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the rest of the molecule through the carbonyl carbon.

[0032] "Alkyloxy" refers to an alkyl-O- group, where alkyl is as defined herein. Preferably, the alkyloxy is a C1-C6 alkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal or bridging group.

[0033] "Alkyloxyalkyl" refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl portions are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkyl group.

[0034] "Alkyloxyaryl" refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the aryl group.

[0035] "Alkyloxycarbonyl" refers to an alkyl-OC(=O)- group, where alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through the carbonyl carbon.

[0036] "Alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl portions are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the cycloalkyl group.

[0037] "Alkyloxyheteroaryl" refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the heteroaryl group.

[0038] "Alkyloxyheterocycloalkyl" refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl portions are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the heterocycloalkyl group.

[0039] "Alkylsulfinyl" refers to an alkyl-S-(=O)- group, where alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkylsulfinyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through a sulfur atom.

[0040] "Alkylsulfonyl" refers to an alkyl-S(=O)2- group, where alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through a sulfur atom.

[0041] "Alkynyl," as a group or part of a group, means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched, preferably having 2 to 12 carbon atoms, more preferably 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms in the linear chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.

[0042] "Alkynyloxy" refers to an alkynyl-O- group, where alkynyl is as defined herein. Preferred alkynyloxy groups are C1-C6 alkynyloxy groups. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through an oxygen atom.

[0043] "Aminoalkyl" means an NH-alkyl group, where alkyl is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is attached to the remainder of the molecule via the alkyl group.

[0044] "Aminosulfonyl" refers to the group NH2-S(=O)2-. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the rest of the molecule through the sulfur atom.

[0045] "Aryl," as a group or part of a group, refers to (i) an optionally substituted monocyclic or fused polycyclic aromatic carbocyclic ring (a ring structure having all carbon ring atoms), preferably having 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, etc.; (ii) phenyl and C 5~7 Cycloalkyl or C 5~7 Cycloalkenyl groups include optionally substituted partially saturated bicyclic aromatic carbocyclic moieties fused together to form a ring structure such as tetrahydronaphthyl, indenyl, or indanyl. The groups may be terminal or bridging groups. Typically, aryl groups are C6-C 18 It is an aryl group.

[0046] "Arylalkenyl" refers to an aryl-alkenyl-group, where aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkenyl group.

[0047] "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl portions are as defined herein. Preferred arylalkyl groups are 1~5 It contains an alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl, and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the rest of the molecule via the alkyl group.

[0048] "Arylalkyloxy" refers to the group aryl-alkyl-O-, where alkyl and aryl are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through an oxygen atom.

[0049] "Arylamino" includes both monoarylamino and diarylamino unless otherwise specified. Monoarylamino refers to a group of the formula arylNH-, where aryl is as defined herein. Diarylamino refers to a group of the formula (aryl)N-, where each aryl may be the same or different and is as defined herein for aryl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the nitrogen atom.

[0050] "Arylheteroalkyl" means an arylheteroalkyl group in which the aryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the heteroalkyl group.

[0051] "Aryloxy" refers to an aryl-O- group, where aryl is as defined herein. Preferably, aryloxy is a C-C 18 Aryloxy, more preferably C6-C 10 The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the rest of the molecule through an oxygen atom.

[0052] "Arylsulfonyl" means an aryl-S(=O)2- group, where the aryl group is as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through the sulfur atom.

[0053] A "bond" is a connection between atoms in a compound or molecule. A bond may be a single bond, double bond, or triple bond.

[0054] "Cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. A cycloalkenyl group may be substituted with one or more substituents. Cycloalkenyl groups typically have a C3 to C6 carbon atom. 12 It is an alkenyl group. The group may be a terminal group or a bridging group.

[0055] "Cycloalkyl," unless otherwise specified, refers to a saturated monocyclic or fused or spiropolycyclic carbocyclic ring, preferably containing 3 to 9 carbons per ring, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. Cycloalkyl groups are typically C3 to C6 12 It is an alkyl group. The group may be a terminal group or a bridging group.

[0056] "Cycloalkylalkyl" refers to a cycloalkylalkyl group in which the cycloalkyl and alkyl portions are as defined herein. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cycloheptylmethyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkyl group.

[0057] "Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkenyl group.

[0058] "Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl portions are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the heteroalkyl group.

[0059] "Cycloalkyloxy" refers to a cycloalkyl-O- group, where cycloalkyl is as defined herein. Preferably, the cycloalkyloxy is a C1-C6 cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via an oxygen atom.

[0060] "Cycloalkenyloxy" refers to a cycloalkenyl-O- group, where cycloalkenyl is as defined herein. Preferably, the cycloalkenyloxy is a C1-C6 cycloalkenyloxy. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through an oxygen atom.

[0061] "Haloalkyl" refers to an alkyl group, as defined herein, in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine. Haloalkyl groups are typically of the formula C n H (2n+1-m) X m where each X is independently selected from the group consisting of F, Cl, Br, and I. In this type of group, n is typically 1 to 10, more preferably 1 to 6, and most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyl include fluoromethyl, difluoromethyl, and trifluoromethyl.

[0062] "Haloalkenyl" refers to an alkenyl group, as defined herein, in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br, and I.

[0063] "Haloalkynyl" refers to an alkynyl group, as defined herein, in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br, and I.

[0064] "Halogen" refers to chlorine, fluorine, bromine or iodine.

[0065] "Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having 2 to 12 carbons, more preferably 2 to 6 carbons, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with a heteroatom group selected from S, O, P, and NR', where R' is H, optionally substituted C1-C 12 Alkyl, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C-C 18 Aryl and optionally substituted C1-C 18 Heteroaryl is selected from the group consisting of: alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl also include hydroxyC1-C6 alkyl, C1-C6 alkyloxyC1-C6 alkyl, aminoC1-C6 alkyl, C1-C6 alkylaminoC1-C6 alkyl, and di(C1-C6 alkyl)aminoC1-C6 alkyl. The group may be a terminal group or a bridging group.

[0066] "Heteroalkyloxy" refers to a heteroalkyl-O- group, where heteroalkyl is as defined herein. Preferably, the heteroalkyloxy is a C2-C6 heteroalkyloxy. The group may be a terminal or bridging group.

[0067] "Heteroaryl," either alone or as part of a group, refers to a group containing an aromatic ring (preferably a 5- or 6-membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring, with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen, and sulfur. The group may be a monocyclic or bicyclic heteroaryl group. Examples of heteroaryls include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xanthrene, phenoxathine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isopropyl alcohol, methyl ... methyl alcohol, methyl methyl methyl alcohol, methyl methyl methyl alcohol, methyl methyl methyl alcohol, methyl methyl methyl alcohol, methyl methyl methyl alcohol, methyl methyl methyl alcohol, methyl methyl methyl methyl alcohol, methyl methyl methyl methyl alcohol, methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl Heteroaryl groups typically include C1-C4 isoquinolinone, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl, 1-, 2-, or 3-indolyl, and 2- or 3-thienyl. 18 It is a heteroaryl group. The group may be a terminal group or a bridging group.

[0068] "Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl portions are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl portion. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkyl group.

[0069] "Heteroarylalkenyl" means a heteroaryl-alkenyl-group in which the heteroaryl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkenyl group.

[0070] "Heteroarylheteroalkyl" means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the heteroalkyl group.

[0071] "Heteroaryloxy" refers to a heteroaryl-O- group, where heteroaryl is as defined herein. Preferably, heteroaryloxy is a C1-C 18 Heteroaryloxy. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the rest of the molecule through an oxygen atom.

[0072] "Heterocyclic" refers to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur, and oxygen as a ring atom. Examples of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl, and heteroaryl.

[0073] "Heterocycloalkenyl" refers to a heterocycloalkyl group, as defined herein, but containing at least one double bond. Heterocycloalkenyl groups are typically C2-C6 12 It is a heterocycloalkenyl group. The group may be a terminal group or a bridging group.

[0074] "Heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom, preferably 1 to 3 heteroatoms, selected from nitrogen, sulfur, and oxygen in at least one ring. Each ring preferably has 3 to 10 members, more preferably 4 to 7 members. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. Heterocycloalkyl groups are typically C2 to C6. 12 It is a heterocycloalkyl group. The group may be a terminal group or a bridging group.

[0075] "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl portions are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkyl group.

[0076] "Heterocycloalkylalkenyl" refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl portions are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the alkenyl group.

[0077] "Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via the heteroalkyl group.

[0078] "Heterocycloalkyloxy" refers to a heterocycloalkyl-O- group, where heterocycloalkyl is as defined herein. Preferably, the heterocycloalkyloxy is a C1-C6 heterocycloalkyloxy. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via an oxygen atom.

[0079] "Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O- group, where heterocycloalkenyl is as defined herein. Preferably, the heterocycloalkenyloxy is a C1-C6 heterocycloalkenyloxy. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule via an oxygen atom.

[0080] "Hydroxyalkyl" refers to an alkyl group, as defined herein, in which one or more of the hydrogen atoms has been replaced with an OH group. Hydroxyalkyl groups are typically of the formula C n H (2n+1-x) (OH) x In groups of this type, n is typically 1 to 10, more preferably 1 to 6, and most preferably 1 to 3. x is typically 1 to 6, more preferably 1 to 3.

[0081] "Sulfinyl" refers to the RS(=O)- group, where R can be OH, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, as defined herein. The group can be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through a sulfur atom.

[0082] "Sulfinylamino" refers to the group RS(=O)-NH-, where R can be OH, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, as defined herein. The group can be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through the nitrogen atom.

[0083] "Sulfonyl" refers to the R-S(=O)- group, where R can be OH, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, as defined herein. The group can be a terminal group or a bridging group. When the group is a terminal group, it is attached to the remainder of the molecule through the sulfur atom.

[0084] "Sulfonylamino" refers to the group RS(=O)2-NH-. The group may be a terminal group or a bridging group. When the group is a terminal group, it is attached to the rest of the molecule through the nitrogen atom.

[0085] It is understood that included in the family of compounds of formula (I) are isomeric forms, including diastereomers, enantiomers, tautomers, and geometric isomers in "E" or "Z" configuration isomers or mixtures of E and Z isomers. It is also understood that some isomeric forms, such as diastereomers, enantiomers, and geometric isomers, can be separated by physical and / or chemical methods and by one skilled in the art. For compounds that may be geometric isomers, applicant has depicted the isomer that the compound is believed to be, but it is understood that other isomers may be the correct structural assignment.

[0086] Some of the compounds of the presently disclosed embodiments may exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers, and all such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the described and claimed subject matter.

[0087] Additionally, Formula (I) is intended to encompass, where applicable, solvated and unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including hydrated as well as unhydrated forms.

[0088] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, and heterocyclic carboxylic and sulfonic acid classes, including formic acid, acetic acid, propanoic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Similarly, base addition salts can be prepared using organic or inorganic bases by techniques well known in the art. Examples of suitable organic bases include simple amines such as methylamine, ethylamine, and triethylamine. Examples of suitable inorganic bases include NaOH, KOH, and the like. Additional information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. For drugs that are solid, the compounds, drugs and salts of the invention may exist in different crystalline or polymorphic forms, and it will be understood by those skilled in the art that all of these forms are intended to be within the scope of the invention and particular formula.

[0089] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect a beneficial or desired clinical result. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, inhibit, or slow the progression of a disease state.

[0090] As noted above, the compounds of the present invention have the formula (I): [ka] or a pharmaceutically acceptable salt thereof.

[0091] As with any group of structurally related compounds that have particular utility, certain embodiments of the variables of the compounds of formula (I) are particularly useful in their end use applications.

[0092] In the compounds of the present invention, R 1 , R 2 , and R 3 are each independently H and C1 to C 12 alkyl.

[0093] In some embodiments, R 1 is H. In some embodiments, R 1 is C1~C 12 In some embodiments, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.

[0094] In some embodiments, R 2 is H. In some embodiments, R 2 is C1~C 12 In some embodiments, R 2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.

[0095] In some embodiments, R 3 is H. In some embodiments, R 3 is C1~C 12 In some embodiments, R 3is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.

[0096] In some embodiments of the compounds of the present invention, R 1 is H, which is represented by the formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as described above.

[0097] In some embodiments of the compounds of the present invention, R 2 is H, which is represented by the formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as described above.

[0098] In some embodiments of the compounds of the present invention, R 3 is H, which has the formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 2 , R 4 , R 5 , R6 , R 7 and R 8 is as described above.

[0099] In some embodiments of the compounds of the present invention, R 1 is H and R 2 is H and R 3 is H, which is represented by the formula (II): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 4 , R 5 , R 6 , R 7 and R 8 is as described above.

[0100] R 4 is H and C1 to C 12 In some embodiments, R 4 is H. In some embodiments, R 4 is C1~C 12 In some embodiments, R 4 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.

[0101] In some embodiments of the compounds of the present invention, R 1 is H and R 2 is H and R 3 is H and R 4 is H, which is represented by formula (III): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 5 , R 6 , R 7 and R8 is as described above.

[0102] In the compounds of the present invention, R 5 is H, optionally substituted C6-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C-C 18 Aryl C1-C 12 Alkyl- and optionally substituted C1-C 18 Heteroaryl C1-C 12 alkyl- is selected from the group consisting of

[0103] In some embodiments, R 5 is H. In some embodiments, R 5 is an optionally substituted C6-C 18 In some embodiments, R 5 is an optionally substituted C1 to C 18 In some embodiments, R is heteroaryl. 5 is an optionally substituted C6-C 18 Aryl C1-C 12 In some embodiments, R 5 is an optionally substituted C1 to C 18 Heteroaryl C1-C 12 It is alkyl-.

[0104] In some embodiments, R 5 is an optionally substituted C6-C 18 aryl. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl. In some embodiments, R 5 is an optionally substituted phenyl.

[0105] In some embodiments, R 5 is the formula A: [ka] (In the formula, each Ra are independently H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 Haloalkyl Optionally substituted C2-C 12 Alkenyl, optionally substituted C-C 12 Alkynyl, optionally substituted C-C 12 Heteroalkyl, optionally substituted C-C 12 Cycloalkyl, optionally substituted C-C 12 Cycloalkenyl, optionally substituted C-C 12 Heterocycloalkyl, optionally substituted C-C 12 Heterocycloalkenyl, optionally substituted C-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy, optionally substituted C-C 12 Alkenyloxy, optionally substituted C-C 12 Alkynyloxy, optionally substituted C-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy, optionally substituted C-C 12 Heterocycloalkyloxy, optionally substituted C-C 12 Heterocycloalkenyloxy, optionally substituted C-C 18 Aryloxy, optionally substituted C1-C 18 Heteroaryloxy, optionally substituted C1-C 12 Alkylamino, SR 9 , SO3H, SO2NR 9 R 10 , SO2R 9 ,SONR 9 R 10 , SOR 9 , C.O.R. 9 , COOH, COOR9 ,CONR 9 R 10 , N.R. 9 COR 10 , N.R. 9 COOR 10 , N.R. 9 SO2R 10 , N.R. 9 CONR 9 R 10 , N.R. 9 R 10 and acyl; R 9 and R 10 are each independently H and C1 to C 12 alkyl).

[0106] In some embodiments, R 5 teeth, [ka] (In the formula, each R a is an optionally substituted phenyl moiety selected from the group consisting of:

[0107] In some embodiments of the present invention, each R a are independently H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 alkyloxy.

[0108] In some embodiments, each R a are independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH 3、 Cl, Br, F, I, OH, NO2, NH2, N(CH3)2, NHCOCH3, NHSO2CH 3、 NHSO2CH2CH2CH 3、 CN, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2OCH3、 OC6H5, OCH2C(CH3)3, OCH2 cyclopropyl, O-tetrahydropyran, piperazine, 4-methylpiperazine, 4-acyl-piperazine, morpholine, CF3, OCHF 2、 and OCF3.

[0109] In some embodiments of the compounds of the present invention, R 1 is H and R 2 is H and R 3 is H and R 4 is H and R 5 is a moiety of formula A, which is represented by formula (IV): [ka] or a pharmaceutically acceptable salt thereof. In the formula, R a , R 6 , R 7 and R 8 is as described above.

[0110] In some embodiments, the group R 5 is an optionally substituted C1 to C 18Heteroaryl group.Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xanthrene, phenoxathine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine, pyridyl, quinolyl, isoquinolinyl, indolyl, and thienyl.In each case where multiple substitution sites are possible on the heteroaryl ring, all possible attachment points are contemplated. By way of example only, when heteroaryl is a pyridyl moiety, it can be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

[0111] In some embodiments, R 5 teeth, [ka] (In the formula, each V 1 , V 2 , V 3 and V 4 are, independently, N and CR B is selected from the group consisting of Each R B are independently H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 Haloalkyl Optionally substituted C2-C 12 Alkenyl, optionally substituted C-C 12 Alkynyl, optionally substituted C-C 12 Heteroalkyl, optionally substituted C-C 12 Cycloalkyl, optionally substituted C-C 12Cycloalkenyl, optionally substituted C-C 12 Heterocycloalkyl, optionally substituted C-C 12 Heterocycloalkenyl, optionally substituted C-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy, optionally substituted C-C 12 Alkenyloxy, optionally substituted C-C 12 Alkynyloxy, optionally substituted C-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy, optionally substituted C-C 12 Heterocycloalkyloxy, optionally substituted C-C 12 Heterocycloalkenyloxy, optionally substituted C-C 18 Aryloxy, optionally substituted C1-C 18 Heteroaryloxy, optionally substituted C1-C 12 Alkylamino, SR 9 , SO3H, SO2NR 9 R 10 , SO2R 9 ,SONR 9 R 10 , SOR 9 , C.O.R. 9 , COOH, COOR 9 ,CONR 9 R 10 , N.R. 9 COR 10 , N.R. 9 COOR 10 , N.R. 9 SO2R 10 , N.R. 9 CONR 9 R 10 , N.R. 9 R 10 and acyl; R 9 and R 10are each independently H and C1 to C 12 alkyl).

[0112] Y is selected from the group consisting of S, O, and NH.

[0113] In one embodiment, R 5 teeth, [ka] (In the formula, R B is as defined above).

[0114] In one embodiment, R 5 teeth, [ka] (In the formula, each R B is as defined above).

[0115] In some embodiments of the present invention, each R B are independently H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 alkyloxy.

[0116] In some embodiments, each R B are independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH 3、 Cl, Br, F, I, OH, NO2, NH2, NHSO2CH2CH2CH 3、 CN, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3) 2、 OC6H5, OCH2CCH, OCH2cyclopropyl, CF3, OCHF 2、 and OCF3.

[0117] In some embodiments of the present invention, R 5 is an optionally substituted C6-C 18 Aryl C1-C 12 In these embodiments, optionally substituted C-C alkyl- 18 Aryl is R 5 Alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.

[0118] In some embodiments of the present invention, R 5 is the substitution C1~C 18 Heteroaryl C1-C 12 In these embodiments, optionally substituted C1-C alkyl- 18 Heteroaryl is R 5 Alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.

[0119] In the compounds of the present invention, R 6 H, C1~C 12 In one embodiment, R 6 is H. In one embodiment, R 6 is C1~C 12 In one embodiment, R 6 is C-C cycloalkyl. In one embodiment, R 6 is a C1-C5 heterocycloalkyl.

[0120] In one particular embodiment, R 6 is C1~C 12 R is alkyl.6 Examples of suitable values ​​of R include methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. 6 A particularly preferred value for is isopropyl.

[0121] In one particular embodiment, R 6 is C3-C6 cycloalkyl. 6 Examples of suitable values ​​include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0122] In one particular embodiment, R 6 is a C1-C5 heterocycloalkyl. 6 Examples of suitable values ​​of include azetidine, oxetane, thietane, pyrrolidine, oxolane, thiolane, piperidine, oxane, and thiane.

[0123] In the compounds of the present invention, R 7 is H and C1 to C 12 alkyl, or R 7 and R 8 when taken together with the nitrogen atom to which they are attached, form a monocyclic or bicyclic C2-C 12 It forms a heterocycloalkyl group.

[0124] In one embodiment, R 7 is H.

[0125] In one embodiment, R 7 is C1~C 12 R is alkyl. 7 Examples of suitable values ​​of R include methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. 7is methyl.

[0126] In the compounds of the present invention, R 8 H, C1~C 12 Alkyl, optionally substituted C-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C-C 18 Aryl C1-C 12 Alkyl- and optionally substituted C1-C 18 Heteroaryl C1-C 12 alkyl- is selected from the group consisting of

[0127] In one embodiment, R 8 is H.

[0128] In one embodiment, R 8 is C1~C 12 R is alkyl. 8 Examples of suitable values ​​of R include methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. 8 is methyl.

[0129] In one embodiment, R 8 is an optionally substituted C6-C 18 aryl. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl. In some embodiments, R 8 is an optionally substituted phenyl.

[0130] In some embodiments, R 8 is the formula B: [ka] (In the formula, each R care independently H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 Haloalkyl Optionally substituted C2-C 12 Alkenyl, optionally substituted C-C 12 Alkynyl, optionally substituted C-C 12 Heteroalkyl, optionally substituted C-C 12 Cycloalkyl, optionally substituted C-C 12 Cycloalkenyl, optionally substituted C-C 12 Heterocycloalkyl, optionally substituted C-C 12 Heterocycloalkenyl, optionally substituted C-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy, optionally substituted C-C 12 Alkenyloxy, optionally substituted C-C 12 Alkynyloxy, optionally substituted C-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy, optionally substituted C-C 12 Heterocycloalkyloxy, optionally substituted C-C 12 Heterocycloalkenyloxy, optionally substituted C-C 18 Aryloxy, optionally substituted C1-C 18 Heteroaryloxy, optionally substituted C1-C 12 Alkylamino, SR 9 , SO3H, SO2NR 9 R 10 , SO2R 9 ,SONR 9 R 10 , SOR 9 , C.O.R. 9 , COOH, COOR 9 ,CONR9 R 10 , N.R. 9 COR 10 , N.R. 9 COOR 10 , N.R. 9 SO2R 10 , N.R. 9 CONR 9 R 10 , N.R. 9 R 10 and acyl; R 9 and R 10 are each independently H and C1 to C 12 alkyl).

[0131] In some embodiments, R 8 teeth, [ka] (In the formula, each R c is an optionally substituted phenyl moiety selected from the group consisting of:

[0132] In some embodiments of the present invention, each R c are independently H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 alkyloxy.

[0133] In some embodiments, each R c are independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH 3、 Cl, Br, F, I, OH, NO2, NH2, NHSO2CH2CH2CH 3、 CN, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3) 2、 OC6H5, OCH2CCH, OCH2cyclopropyl, CF3, OCHF 2、and OCF3.

[0134] In one embodiment, R 8 is an optionally substituted C1 to C 18 Heteroaryl. Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xanthrene, phenoxathine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine, pyridyl, quinolyl, isoquinolinyl, indolyl, and thienyl. In each case where multiple substitution sites are possible on the heteroaryl ring, all possible attachment points are contemplated. By way of example only, when heteroaryl is a pyridyl moiety, it can be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

[0135] In some embodiments, R 8 teeth, [ka] (In the formula, each V 1 , V 2 , V 3 and V 4 are, independently, N and CR D is selected from the group consisting of Each R D are independently H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 Haloalkyl Optionally substituted C2-C 12 Alkenyl, optionally substituted C-C12 Alkynyl, optionally substituted C-C 12 Heteroalkyl, optionally substituted C-C 12 Cycloalkyl, optionally substituted C-C 12 Cycloalkenyl, optionally substituted C-C 12 Heterocycloalkyl, optionally substituted C-C 12 Heterocycloalkenyl, optionally substituted C-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy, optionally substituted C-C 12 Alkenyloxy, optionally substituted C-C 12 Alkynyloxy, optionally substituted C-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy, optionally substituted C-C 12 Heterocycloalkyloxy, optionally substituted C-C 12 Heterocycloalkenyloxy, optionally substituted C-C 18 Aryloxy, optionally substituted C1-C 18 Heteroaryloxy, optionally substituted C1-C 12 Alkylamino, SR 9 , SO3H, SO2NR 9 R 10 , SO2R 9 ,SONR 9 R 10 , SOR 9 , C.O.R. 9 , COOH, COOR 9 ,CONR 9 R 10 , N.R. 9 COR 10 , N.R. 9 COOR 10 , N.R. 9 SO2R 10 , N.R. 9 CONR 9R 10 , N.R. 9 R 10 and acyl; R 9 and R 10 are each independently H and C1 to C 12 alkyl).

[0136] Y is selected from the group consisting of S, O, and NH.

[0137] In one embodiment, R 8 teeth, [ka] (In the formula, R D is as defined above).

[0138] In one embodiment, R 8 teeth, [ka] (In the formula, each R D is as defined above).

[0139] In some embodiments of the present invention, each R D are independently H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 alkyloxy.

[0140] In some embodiments, each R D are independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH 3、 Cl, Br, F, I, OH, NO2, NH2, NHSO2CH2CH2CH 3、 CN, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3) 2、OC6H5, OCH2CCH, OCH2cyclopropyl, CF3, OCHF 2、 and OCF3.

[0141] In some embodiments of the present invention, R 8 is an optionally substituted C6-C 18 Aryl C1-C 12 In these embodiments, optionally substituted C-C alkyl- 18 Aryl is R 8 As described above for (I). The alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. In one particular embodiment, the alkyl is methyl, and thus the alkyl is a methylene group linking the aryl group to the nitrogen.

[0142] In some embodiments of the present invention, R 8 is an optionally substituted C1 to C 18 Heteroaryl C1-C 12 In these embodiments, optionally substituted C1-C alkyl- 18 Heteroaryl is R 8 Alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.

[0143] In some embodiments, R 7 and R 8 When combined with the nitrogen atom to which they are attached, C2 to C 12 Forms a heterocyclic group. C2-C 12 The heterocyclic group may be any suitable C-C 12It may be a heterocyclic group, and may be a monocyclic or bicyclic heterocyclic group. In one embodiment, 12 The heterocyclic group is monocyclic. In one embodiment, 12 The heterocyclic group is bicyclic.

[0144] C2~C 12 A heterocyclic group may consist of fully saturated rings, fully unsaturated rings, or a combination thereof, for example, it may contain one saturated ring and one unsaturated ring.

[0145] In one embodiment, C2 to C 12 The heterocyclic group has the formula C: [ka] (In the formula, each R D are independently H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 Haloalkyl Optionally substituted C2-C 12 Alkenyl, optionally substituted C-C 12 Alkynyl, optionally substituted C-C 12 Heteroalkyl, optionally substituted C-C 12 Cycloalkyl, optionally substituted C-C 12 Cycloalkenyl, optionally substituted C-C 12 Heterocycloalkyl, optionally substituted C-C 12 Heterocycloalkenyl, optionally substituted C-C 18 Aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy, optionally substituted C-C 12 Alkenyloxy, optionally substituted C-C 12 Alkynyloxy, optionally substituted C-C 10 Heteroalkyloxy, optionally substituted C3-C 12Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy, optionally substituted C-C 12 Heterocycloalkyloxy, optionally substituted C-C 12 Heterocycloalkenyloxy, optionally substituted C-C 18 Aryloxy, optionally substituted C1-C 18 Heteroaryloxy, optionally substituted C1-C 12 Alkylamino, SR 9 , SO3H, SO2NR 9 R 10 , SO2R 9 ,SONR 9 R 10 , SOR 9 , C.O.R. 9 , COOH, COOR 9 ,CONR 9 R 10 , N.R. 9 COR 10 , N.R. 9 COOR 10 , N.R. 9 SO2R 10 , N.R. 9 CONR 9 R 10 , N.R. 9 R 10 and acyl; Each R 9 and R 10 are independently H and C1 to C 12 is selected from the group consisting of alkyl, and n is an integer selected from 1 and 2.

[0146] In one embodiment, C2 to C 12 The heterocyclic group is a group of formula D: [ka]

[0147] In one embodiment, C2 to C 12 The heterocyclic group is a group of formula E: [ka]

[0148] In some embodiments of compounds of Formulas D and E, each R D are independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH 3、 Cl, Br, F, I, OH, NO2, NH2, NHSO2CH2CH2CH 3、 CN, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3) 2、 OC6H5, OCH2C(CH3)3, OCH2cyclopropyl, CF3, OCHF 2、 and OCF3.

[0149] R 9 In some embodiments of compounds of the invention containing a group, R 9 The group is selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, and hexyl. 9 is selected from the group consisting of H, methyl, and ethyl. In some embodiments, R 9 is H. In some embodiments, R 9 is methyl. In some embodiments, R 9 is ethyl.

[0150] R 10 In some embodiments of compounds of the invention containing a group, R 10 The group is selected from the group consisting of H, methyl, cyclopropylmethyl, ethyl, isopropyl, propyl, cyclopropyl, 3,3-dimethyl-propyl, butyl, isobutyl, cyclobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, hexyl, phenyl, and pyridin-2-yl. 10 is selected from the group consisting of H, methyl, and ethyl. In some embodiments, R 10is H. In some embodiments, R 10 is methyl. In some embodiments, R 10 is ethyl.

[0151] Many, if not all, of the variables discussed above may be optionally substituted. When a variable is optionally substituted, each optional substituent may independently be selected from the group consisting of halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxya. Alkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)R e , -C(=O)OR e , C(=O)NR e R f , C(=NOH)R e , C(=NR e )NR f Rg , N.R. e R f , N.R. e C(=O)R f , N.R. e C(=O)OR f , N.R. e C(=O)NR f R g , N.R. e C(=NR f )NR g R h , N.R. e SO2R f , -SR e , SO2NR e R f , -OR e , OC(=O)NR e R f , OC(=O)R e and acyl; In the formula, R e , R f , R g , and R h are each independently H, C1 to C 12 Alkyl, C1-C 12 Haloalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 10 Heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C1-C 12 Heterocycloalkyl, C1-C 12 Heterocycloalkenyl, C6-C 18 Aryl, C1-C 18 or R is selected from the group consisting of heteroaryl, and acyl a , R b , R c , and R d When taken together with the atoms to which they are attached, any two or more of the following may form a heterocyclic ring system having from 3 to 12 ring atoms:

[0152] In some embodiments, each optional substituent is independently selected from the group consisting of F, Cl, Br, ═O, ═S, —CN, —NO, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, —C(O)OR a , COOH, SH and acyl.

[0153] In some embodiments, each optional substituent is independently selected from the group consisting of F, Br, Cl, ═O, ═S, —CNmethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethylpropyl, 3,3-dimethylpropyl, butyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, pentyl, 2-methylpentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH, —NO, phenoxy, hydroxy, methoxy, trifluoromethoxy, ethoxy, and methylenedioxy.

[0154] In some embodiments, each optional substituent is independently H, CH, CHCH, CHCH, CH(CH), (CH)CH 3、 Selected from the group consisting of Cl, Br, F, I, OH, NO2, NH2, CN, OCH3, OCH2CH2CH3, CF3 and OCF3.

[0155] Alternatively, two optional substituents on the same moiety, when taken together, may be linked to form a fused ring substituent attached to the optionally substituted moiety. Thus, the term optionally substituted includes fused rings such as cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings.

[0156] Specific examples of the compounds of formula (I) of the present invention include: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] or a pharmaceutically acceptable salt thereof.

[0157] The compound has the ability to inhibit CD151. The ability to inhibit CD151 may be the result of the compound acting directly and independently on CD151 to regulate / enhance biological activity. However, it is understood that the compound may also at least partially act on other factors related to CD151 activity.

[0158] The inhibition of CD151 can be carried out by any of several methods known in the art.For example, when it is desired to inhibit CD151 in vitro, an appropriate amount of compound can be added to the solution containing CD151.In the situation when it is desired to inhibit CD151 in humans, the inhibition of CD151 typically involves administering a compound to humans containing CD151.

[0159] Thus, the present compounds may find multiple uses that can take advantage of their ability to inhibit CD151 as described above.

[0160] The compounds of the invention are therefore expected to have useful therapeutic properties, particularly with respect to conditions such as cancer. Examples of cancers associated with CD151 activity include prostate cancer, breast cancer, pancreatic cancer, colon cancer, non-small cell lung cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, renal cell carcinoma, endometrial cancer, esophageal cancer, esophageal / gastroesophageal junction cancer, osteosarcoma, Wilms' tumor, mesothelial tumor, squamous cell carcinoma, glioblastoma multiforme, melanoma, and ovarian cancer.

[0161] CD151 activity has also been implicated in diseases such as asthma, multiple sclerosis and inflammatory bowel disease.

[0162] Expression of CD151 is also associated with infection by infectious agents. Inhibition of such CD151 can aid in the treatment of conditions mediated by infectious agents. Examples of this type of infectious agent include human papillomavirus, influenza virus, and meningococcus.

[0163] Administration of compounds within Formula (I) to humans can be via any of the accepted modes of enteral administration, such as oral or rectal, or parenteral administration, such as subcutaneous, intramuscular, intravenous, and intradermal routes. Injection can be via bolus or constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent, and is included in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the activator compound can be selectively toxic to, or more toxic to, rapidly proliferating cells, such as cancerous tumors, than normal cells.

[0164] The compounds of the present invention can be administered in any form or manner that makes the compound bioavailable. Those skilled in the art of preparing formulations can easily select an appropriate form and mode of administration depending on the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated, and other relevant circumstances. For further information, see Remington's Pharmaceutical Sciences, 1999. th See the 1995 edition, Mack Publishing Co.

[0165] The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. Although the compounds of the present invention are effective in themselves, they are typically formulated and administered in the form of their pharmaceutically acceptable salts, as these forms are typically more stable, more easily crystallized and have increased solubility.

[0166] However, compounds are typically used in the form of pharmaceutical compositions formulated according to the desired mode of administration. Thus, in some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. The compositions are prepared by methods well known to those skilled in the art.

[0167] In other embodiments, the present invention provides pharmaceutical packs or kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the present invention. In such packs or kits, containers containing unit dosage amounts of the drug may be found. The kits may contain compositions containing the active agent, which may be provided as a concentrate (including lyophilized compositions) or at a working concentration that can be further diluted before use, and the vials may contain one or more dosage amounts. Conveniently, the kits may provide single dosage amounts in sterile vials, with the vials containing the desired amount and concentration of drug, so that the physician can use the vials directly. Such containers may be associated with various written materials, such as instructions for use or notices in the form prescribed by government agencies regulating the manufacture, use, or sale of pharmaceutical or biological products, which notice reflects the agency's approval of the manufacture, use, or sale for human administration.

[0168] The compounds of the present invention may be used or administered in combination with one or more additional drugs for the treatment of the disorders / diseases mentioned. The components may be administered in the same formulation or in separate formulations. When administered in separate formulations, the compounds of the present invention may be administered sequentially or simultaneously with the other drugs.

[0169] In addition to being able to be administered in combination with one or more additional drugs, the compound of the present invention can be used in combination therapy.When this is done, the compound is typically administered in combination with each other.Therefore, one or more of the compounds of the present invention can be administered simultaneously (as a combined preparation) or sequentially to achieve desired effects.This is particularly desirable when the therapeutic profile of each compound is different, and therefore the combined effect of the two drugs provides improved therapeutic results.

[0170] The pharmaceutical compositions of the present invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders, which are to be reconstituted immediately before use into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (olive oil, etc.), and injectable organic esters such as ethyl oleate. The appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0171] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0172] If desired, and for more effective distribution, the compounds can be incorporated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres.

[0173] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0174] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or enhancers such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0175] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0176] Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0177] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0178] The liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.In addition to active compound, liquid dosage form can contain the inert diluent commonly used in the art, such as water or other solvent, solubilizer and emulsifier, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed, peanut, corn, germ, olive, castor and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan and their mixtures.

[0179] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0180] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0181] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0182] Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments, and inhalants. The active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and any needed preservatives, buffers, or propellants which may be required.

[0183] The amount of compound administered preferably treats, reduces or alleviates the condition. The therapeutically effective amount can be easily determined by a diagnostician using conventional techniques and by observing the results obtained under similar circumstances. When determining the therapeutically effective amount, several factors should be taken into consideration, including but not limited to the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the patient's response to treatment, the specific compound administered, the mode of administration, the bioavailability of the administered preparation, the selected dosage regime, the use of other medications, and other relevant circumstances.

[0184] A preferred dosage ranges from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage ranges from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, and even more preferably from 0.2 to 50 mg per kilogram of body weight per day. A suitable dose may be administered in multiple subdoses per day.

[0185] Synthesis of Compounds of the Invention The compounds for use in the methods of the present invention can be prepared using known organic synthesis techniques and can be synthesized using readily available starting materials and techniques available in the art according to any of a number of possible synthetic routes, including the reaction routes and synthetic schemes described below. The preparation of the compounds of the embodiments is described in detail in the examples below, but one of ordinary skill in the art will recognize that the chemical reactions described can be readily adapted to prepare other agents of various embodiments.

[0186] The reaction for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of two or more solvents. Depending on the reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0187] The preparation of compounds of the present invention 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. Buts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0188] 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., H or C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0189] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are understood in the art and generally refer to a temperature, such as a reaction temperature, which is about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20° C. to about 30° C.

[0190] The present invention will now be described by way of example, which should not be construed as a limitation on the invention. Additional compounds, other than those described below, can be prepared using the methods and synthetic protocols described herein, or suitable variations or modifications thereof. [Example]

[0191] Definition: AcOH (acetic acid), atm (atmosphere), BocO (di-tert-butyl dicarbonate), c-Hex (cyclohexane), CDCl3 (deuterated chloroform), CD3OD (deuterated methanol), CHCl3 (chloroform), conc. (concentration), DCM (dichloromethane), DIPEA (N,N-diisopropylethylamine), DMAP (4-dimethylaminopyridine), DMSO (dimethyl sulfoxide), DMSO-d6 (deuterated dimethyl sulfoxide), eq (equivalent), ES-API (electrospray atmospheric pressure ionization), Et3N (triethylamine), Et2O (diethyl ether), EtOAc (ethyl acetate), EtOH (ethanol), g (grams), h (hour), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HCl (hydrochloric acid / hydrogen chloride), 1 H NMR (proton nuclear magnetic resonance), Hz (Hertz), L (liters), LCMS (liquid chromatography-mass spectrometry), LiHMDS (lithium bis(trimethylsilyl)amide), M (mol), MeOH (methanol), mg (milligrams), MHz (megahertz), min (minutes), mL (milliliter), mmol (millimol), MsCl (methanesulfonyl chloride), n-BuLi (n-butyllithium), NaH (sodium hydride), NaHCO3 (sodium bicarbonate), NaOH (sodium hydroxide), Na2SO4 (sodium sulfate), Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with DCM), PE (petroleum ether), ppm (parts per million), RT (room temperature), TFA (trifluoroacetic acid), THF (tetrahydrofuran).

[0192] Most of the materials were purchased commercially as reagent grade.

[0193] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance-400 spectrometer (at 400.13 MHz). 1 H, 100.62MHz 13Spectroscopic data were obtained using a NMR spectrometer (NMR spectroscopy, NMR spectroscopy, NMR spectra). Proton chemical shifts are reported in ppm from an internal standard of residual chloroform (7.26 ppm), dimethyl sulfoxide (2.50 ppm), or methanol (3.31 ppm). Each resonance was assigned according to the following convention: chemical shift (δ) (multiplicity, coupling constant in Hz, integration). Carbon chemical shifts are reported in parts per million (ppm) using an internal standard of residual chloroform (77.16 ppm), dimethyl sulfoxide (39.52 ppm), or methanol (49.00 ppm). Chemical shifts were reported as δ values ​​in parts per million (ppm). The following abbreviations have been used in reporting spectral data: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sext, sextet; m, multiplet; app, apparent; and br, broad.

[0194] Electrospray mass spectrometry (MS) was performed using the following method.

[0195] Method A: 1. Instrument information, LC model: Agilent 1200 (pump type: binary pump, detector type: DAD) MS model: Agilent G6110A quadrupole.

[0196] LCMS-LC parameters: Column: Xbridge-C18, 3.5 μm, 2.1 × 50 mm, Column temperature: 30 °C, Acquisition wavelength: 214 nm, 254 nm, Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN, Run time: 5 min, MS: Ion source: ES+ (or ES-) MS range: 70-900 m / z, Fragmenter: 60, Drying gas flow rate: 12-13 L / min, Sprayer pressure: 35 psi, Drying gas temperature: 350 °C, Vcap: 3.5 kV. [Table 2]

[0197] Method B: 1) LC: Agilent Technologies 1290 Series, binary pump, diode array detector. Column: Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 × 50 mm. Mobile phase: A: 0.05% formate (v / v) in water, B: 0.05% formate (v / v) in MeCN. Flow rate: 1.0 mL / min at 40 °C. Detectors: 214 nm, 254 nm. [Table 3]

[0198] MS: G6120A, quadrupole LC / MS; ion source: ESI, signal: positive, TIC: 70-1000 m / z, fragmentor: 60, threshold: 5, gain: 1, drying gas flow rate: 10 L / min, sprayer pressure: 35 psi,

[0199] LCMS-P2~3 min-1)LC: Agilent Technologies 1290 Series, binary pump, diode array detector. Column: Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 × 50 mm. Mobile phase: A: 0.05% formate in water (v / v), B: 0.05% formate in MeCN (v / v). Flow rate: 1.0 mL / min at 40 °C. Detectors: 214 nm, 254 nm. [Table 4]

[0200] MS: G6120A, quadrupole LC / MS, ion source: ESI, signal: positive, TIC: 70-1000 m / z, fragmentor: 60, threshold: 5, gain: 1, drying gas flow rate: 10 L / min, sprayer pressure: 35 psi

[0201] Method C-LC model: Waters 2695 Alliance (Pump: Quaternary Pump, Detector: 2996 Photodiode Array Detector), MS model: Micromass ZQ. LCMS-LC parameters: Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm, Column temperature: 30 °C. Acquisition wavelengths: 214 nm, 254 nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 5 min. MS: Ion source: ES+ (or ES-) MS range: 50-900 m / z. Capillary: 3.5 kV, Cone: 35 V, Extractor: 3 V. Drying gas flow rate: 350 L / hr, Cone: 50 L / hr. Desolvation temperature: 300 °C. Source temperature: 120 °C. Run time: 5 min. [Table 5]

[0202] Sample preparation—Samples were dissolved in methanol to a concentration of approximately 1–10 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1–10 μL).

[0203] Method D LC model: Waters 2695 Alliance (Pump: Quaternary Pump, Detector: 2996 Photodiode Array Detector), MS model: Micromass ZQ, LCMS-LC parameters: Column: Xbridge-C18, 3.5 μm, 2.1 × 50 mm. Column temperature: 20 °C. Acquisition wavelengths: 214 nm, 254 nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 8 min. MS: Ion source: ES+ (or ES-) MS range: 100-1000 m / z. Capillary: 3 kV, Cone: 40 V, Extractor: 3 V. Drying gas flow rate: 800 L / hr, Cone: 50 L / hr. Desolvation temperature: 500 °C. Source temperature: 120 °C. Run time: 8 min. [Table 6]

[0204] Sample preparation—Samples were dissolved in methanol to a concentration of approximately 1–10 mg / mL and then filtered through a 0.22 μm syringe filter (injection volume: 1–10 μL).

[0205] Thin layer chromatography (TLC) was used to monitor reactions and chromatographic fractions on Merck Kieselgel 60 F254 aluminum-backed plates. Silica gel 60 F254 was used as the stationary phase for flash chromatography. Unless otherwise stated, gradient elution with ethyl acetate (EtOAc) and hexane was used for analytical grade.

[0206] All glassware used in reactions requiring anhydrous conditions was oven dried (120°C) and then cooled under nitrogen before use.

[0207] General schemes for the formation of some compounds of the invention are shown below in Schemes 1 and 2, which can be modified as necessary to make some compounds of the invention. As shown in Scheme 1, the typical first step is to synthesize the heteroaromatic core molecule (in situations where this is not readily available).

[0208] In general, a suitably protected diacid moiety (I) is reacted with a suitably functionalized acetylene in the presence of a strong base to form II. Compound II is then reacted with hydrazine to form a five-membered heterocyclic compound (III). Compound III is then reacted with a suitably substituted diacid to form amide IV, which is then cyclized to form bicyclic heteroaromatic compound V. Finally, to further elaborate the ring substituents, compound V is reacted with POCl to insert a chloro group (compound VI). This scheme illustrates one form of formation of an advanced intermediate for the synthesis of compounds of the present invention, as will be understood by those skilled in the art. Variation of the R group on the acetylene and the ester group on the starting diacid allows for the creation of a large number of different advanced intermediates using this technique. [ka]

[0209] Once advanced intermediate VI has been prepared using the procedures shown in Scheme 1, it can be elaborated into compounds of the invention using the procedures of Scheme 2, as shown below. Typically, a compound of formula VI is subjected to Suzuki coupling with a suitable heteroaromatic boronic acid to introduce the heteroaromatic group and form a compound of formula VII. Reaction of compound VII with a suitably substituted diamine provides a compound of formula VIII, which is then saponified to remove the acid protecting group and generate the free acid IX. This is then subjected to amide coupling with a suitable aromatic amine to form a compound of formula X. [ka]

[0210] As will be appreciated by those skilled in the art, the procedures outlined in Schemes 1 and 2 can be modified using methods well known in the art to arrive at any number of compounds of the present invention. Additionally, in the Examples below, modifications of the reactions shown in these Schemes are provided as examples of how this can be done.

[0211] Compound synthesis Example 1 - 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (1) [ka] Compound 1 was synthesized using the procedure shown in Scheme 3. [ka]

[0212] Step 1: Ethyl 5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (XII). A solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (10 g, 64.40 mmol), 3-ethoxy-3-oxopropanoic acid (8.9 g, 67.74 mmol), DCC (17.3 g, 83.85 mmol), pyridine (15.3 g, 0.02 mmol), and DMAP (800 mg, 6.42 mmol) in DCM (100 mL) was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 20 / 1) to give the title product (10.5 g, 60.7%) as a pale yellow solid. LCMS (Method A): R t =0.51 min; [M+H] + =270.1

[0213] Step 2: Ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (XIII) A mixture of ethyl 5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (10.5 g, 39.02 mmol) and DMAP (14.3 g, 117.2 mmol) in ethanol (110 mL) and HO (110 mL) was stirred at 80° C. overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and HO (200 mL, 1 / 1). The organics were dried over NaSO and concentrated under reduced pressure to give the title product (11.3 g, 70%) as a white solid. LCMS (Method A): R t =0.69 min; [M+H] + =224.2

[0214] Step 3: Ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (XIV) A solution of ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (11.3 g, 50.72 mmol) in phosphorus oxychloride (113 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure to give a residue that was poured into ice water and extracted with EtO (3×300 mL). The combined organics were washed with brine (100 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EtOAc, 5:1) to give the title product (4.6 g, 35%) as a white solid. LCMS (Method A): R t = 1.41 min; [M+H] + =261.0.

[0215] Step 4: Ethyl 5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XV) A mixture of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (500 mg, 1.92 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (408 mg, 1.92 mmol), NaCO (0.384 g, 3.85 mmol), and Pd(dppf)Cl (140.6 mg, 3.85 mmol) in degassed 1,4-dioxane (35 mL) and HO (7 mL) was stirred at 80 °C overnight under N. The mixture was poured into water and extracted with EtOAc (100 mL × 3). The combined organics were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 80:1) to give the title product (137 mg, 25%) as a yellow solid. LCMS (Method A):R t = 2.34 min; [M+H] + =292.0

[0216] Step 5: Ethyl 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XVI) A mixture of ethyl 5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (380 mg, 1.31 mmol), N-methyl-1-phenylmethanamine (316 mg, 2.61 mmol), and TEA (264 mg, 2.61 mmol) in DMF (15 mL) was stirred at 80° C. overnight. The mixture was diluted with water, and the precipitate was filtered under reduced pressure and purified by silica gel column chromatography (DCM:MeOH, 80:1) to give the desired product (400 mg, 81%) as a yellow solid. LCMS: (Method A), R t =2.45 min, [M+H] + =377.1.

[0217] Step 6: 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XVII) To a solution of ethyl 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (400 mg, 1.06 mmol) in THF (8 mL) and MeOH (8 mL) at 0 °C was added aqueous KOH (1 M, 4 mL) slowly. The reaction mixture was stirred at 90 °C overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between water (10 mL) and EtO (10 mL). The organics were discarded, and the aqueous solution was acidified to pH 2 with aqueous HCl (1 M). The aqueous phase was extracted with CHCl (100 mL × 3), and the combined organic extracts were dried over NaSO and concentrated under reduced pressure to give the desired product (340 mg, 89%) as a yellow solid. LCMS: (Method A), R t =2.22 min, [M+H] + =349.1.

[0218] Step 7: 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XVIII) A mixture of 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (100 mg, 0.29 mmol), 3-aminophenol (34.5 mg, 0.32 mmol), HATU (142 mg, 0.37 mmol), and DIEA (931 mg, 9.20 mmol) in DMF (4 mL) was stirred at room temperature overnight. The mixture was diluted with water, and the solid was filtered under reduced pressure and purified by silica gel column chromatography (DCM:MeOH / , 30:1) to give the desired product (8 mg, 6.3%) as a yellow solid. LCMS: (Method A), R t =2.28 min, [M+H] + =440.2. 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.02(s, 1H), 9.45(s, 1H), 9.34(s, 1H), 8.70(d, J=2.8Hz, 1 H), 7.37-7.14(m, 8H), 6.53(s, 2H), 4.95(s, 2H), 3.60(s, 1H), 3.19(s, 3H).

[0219] Following the method described for the synthesis of compound 1, the following compounds were similarly prepared from the appropriate starting material 1 (SM1) in step 7.

[0220] Example 2 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (2) [ka] Starting material 1-ammonia, used in step 7 of the synthesis 1 HNMR (400MHz, DMSO-d6)δ 13.47(s, 1H), 9.36-9.22(m, 1H), 8.81-8.58(m, 1H), 8.05(s, 1H), 7.45(s, 1 H), 7.36-7.24(m, 5H), 7.14(s, 1H), 6.38(s, 1H), 4.94(s, 2H), 3.17(s, 3H). LCMS (Method A):R t = 1.91 min; [M+H] + =348.0.

[0221] Example 3 - N-benzyl-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (3) [ka] Starting material 1-benzylamine, used in step 7 of the synthesis 1 HNMR (400MHz, DMSO-d6)δ 13.47(s, 1H), 9.27(s, 1H), 9.12(s, 1H), 8.72(s, 1H), 7.37-7.25(m, 10H), 7.15(s, 1H), 6.42(s, 1H), 4.93(s, 2H), 4.53(d, J=6.4Hz, 2H), 3.17(s, 3H). LCMS (Method A):R t = 2.34 min; [M+H] + =438.2;

[0222] Example 4 - 5-(benzyl(methyl)amino)-N-(4-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (4) [ka] Starting material 1-4-aminophenol, used in step 7 of the synthesis 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 9.97(s, 1H), 9.34(s, 1H), 9.30(s, 1H), 8.71(s, 1H), 7.56(d, J=8.9Hz, 2H), 7. 37-7.24(m, 5H), 7.16(s, 1H), 6.77(d, J=8.8Hz, 2H), 6.50(s, 1H), 4.94(s, 2H), 3.19(s, 3H). LCMS (Method A):R t = 2.54 min; [M+H] + =440.0.

[0223] Example 5 - 5-(benzyl(methyl)amino)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (5) [ka] Starting material used in step 7 of the synthesis: 1-3-methoxyaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.15(s, 1H), 9.35(s, 1H), 8.72(s, 1H), 7.54(t, J=2.4Hz, 1H), 7.43(s, 1H), 7.3 8-7.26(m, 6H), 7.19(s, 1H), 6.74(s, 1H), 6.55(s, 1H), 4.95(s, 2H), 3.78(s, 3H), 3.19(s, 3H). LCMS (Method A):R t = 2.45 min; [M+H] + =454.1.

[0224] Example 6 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (6) [ka] Starting material 1 - pyridin-3-amine used in step 7 of the synthesis; 1 HNMR (400MHz, DMSO-d6)δ 13.53(d, J=8.0Hz, 1H), 10.40(s, 1H), 9.28(d, J=3.6Hz, 1H), 9.02(d, J=2.4Hz, 1H), 8.79(d, J=1.6Hz, 1H), 8.37(dd, J=3.6, 1.1 Hz, 1H), 8.29-8.24(m, 1H), 7.47(dd, J=8.4, 4.8Hz, 1H), 7.38-7.24(m, 5H), 7.20(s, 1H), 6.57(s, 1H), 4.95(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 2.41 min; [M+H] + =425.0.

[0225] Example 7 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (7) [ka] Starting material 1 - pyridin-4-amine used in step 7 of the synthesis; 1 HNMR(400MHz,DMSO-d6)δ 13.62-13.44(m, 1H), 10.57(s, 1H), 9.31(s, 1H), 8.73(s, 1H), 8.54(d, J=6.4Hz, 2H), 7.93 (d, J=6.4Hz, 2H), 7.38-7.25(m, 5H), 7.21(s, 1H), 6.60(s, 1H), 4.95(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 2.31 min; [M+H] + =425.2;

[0226] Example 8 - 5-(benzyl(methyl)amino)-N-(2-methoxypyridin-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (8) [ka] Starting material 1-2-methoxypyridin-4-amine used in step 7 of the synthesis; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.44(s, 1H), 9.30(s, 1H), 8.73(s, 1H), 8.11(d, J=6.0Hz, 1 H), 7.51-7.16(m, 8H), 6.58(s, 1H), 4.95(s, 2H), 3.86(s, 3H), 3.20(s, 3H). LCMS (Method A):R t = 2.90 min; [M+H] + =455.1.

[0227] Example 9 - 5-(benzyl(methyl)amino)-N-(3,5-dimethoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (9) [ka] Starting material used in step 7 of the synthesis: 1 - 3,5-dimethoxyaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.07(s, 1H), 9.33(s, 1H), 8.70(s, 1H), 7.37-7.25(m, 5H), 7.17(d , J=3.6Hz, 3H), 6.55(s, 1H), 6.30(s, 1H), 4.95(s, 2H), 3.77(s, 6H), 3.20(s, 3H). LCMS (Method C):R t = 3.09 min; [M+H] + =484.2.

[0228] Example 10 - 5-(benzyl(methyl)amino)-N-(3,5-dimethylisoxazol-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (10) [ka] Starting material used in step 7 of the synthesis: 1 - 3,5-dimethylisoxazol-4-amine; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 9.81(s, 1H), 9.33(s, 1H), 8.70(s, 1H), 7.37-7.25(m, 5H), 7. 20(s, 1H), 6.51(s, 1H), 4.95(s, 2H), 3.19(s, 3H), 2.34(s, 3H), 2.17(s, 3H). LCMS (Method C):R t =3.68 min; [M+H] + =442.9.

[0229] Example 11 - 5-(benzyl(methyl)amino)-N,7-di(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (11) [ka] Starting material 1 - 1H-pyrazol-4-amine used in step 7 of the synthesis; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 12.64(s, 1H), 10.38(s, 1H), 9.34(s, 1H), 8.74(s, 1H), 7.92(s , 2H), 7.37-7.25(m, 5H), 7.17(s, 1H), 6.50(s, 1H), 4.95(s, 2H), 3.19(s, 3H). LCMS (Method C):R t = 1.35 min; [M+H] + =414.2

[0230] Example 12 - 5-(benzyl(methyl)amino)-N-(4-cyanophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (12) [ka] Starting material used in step 7 of the synthesis: 1-4-aminobenzonitrile; 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.55(s, 1H), 9.31(s, 1H), 8.72(s, 1H), 8.08(d, J=8.8Hz, 2H), 7.86(d, J=8.8Hz, 2H), 7.40-7.24(m, 5H), 7.20(s, 1H), 6.59(s, 1H), 4.95(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 2.46 min; [M+H] + =449.0.

[0231] Example 13 - 5-(benzyl(methyl)amino)-N-(3-cyanophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (13) [ka] Starting material used in step 7 of the synthesis: 1-3-aminobenzonitrile; 1 HNMR (400MHz, DMSO-d6)δ 13.59(s, 1H), 10.52(s, 1H), 9.39(s, 1H), 8.80(s, 1H), 8.37(s, 1H), 8.26-8.23(m, 1H), 7.6 9(t, J=6.4Hz, 2H), 7.43-7.31(m, 5H), 7.26(s, 1H), 6.64(s, 1H), 5.02(s, 2H), 3.26(s, 3H). LCMS (Method C):R t =3.01 min; [M+H] + =449.1

[0232] Example 14 - 5-(benzyl(methyl)amino)-N-(3-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (18) [ka] Starting material used in synthesis step 7: 1-3-isopropoxyaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.09(s, 1H), 9.31(s, 1H), 8.70(s, 1H), 7.49(t, J=2.4Hz, 1H), 7.40-7.33(m, 3H), 7.32-7.24(m, 4H) ), 7.16(s, 1H), 6.70(d, J=8.0Hz, 1H), 6.55(s, 1H), 4.94(s, 2H), 4.60(s, 1H), 3.19(s, 3H), 1.30(d, J=6.0Hz, 6H). LCMS (Method A):R t = 3.25 min; [M+H] + =482.2

[0233] Example 15 - 5-(benzyl(methyl)amino)-N-(3-(difluoromethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (19) [ka] Starting material used in synthesis step 7: 1 - 3-(difluoromethoxy)aniline; A 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.32(s, 1H), 9.32(s, 1H), 8.71(s, 1H), 7.79(t, J=2.4Hz, 1H), 7.75-7.70(m, 1H), 7.46-7.41(m, 1H), 7. 38-7.33(m, 2H), 7.32-7.26(m, 3H), 7.24-7.04(m, 2H), 6.96(dd, J=8.0Hz, 1H), 6.56(s, 1H), 4.95(s, 2h), 3.19(s, 3H). LCMS (Method A):R t = 3.15 min; [M+H] + =489.9

[0234] Example 16 - 5-(benzyl(methyl)amino)-N-(3-(dimethylamino)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (20) [ka] Starting material 1 -N1,N1-dimethylbenzene-1,3-diamine used in step 7 of the synthesis; 1 HNMR (400MHz, DMSO-d6)δ 9.97(s, 1H), 9.03(s, 1H), 8.42(s, 1H), 7.38-7.25(m, 6H), 7.19-7.16(m, 3H), 6.54(s, 1H), 4.95(s, 2H), 3.19(s, 3H), 2.94(s, 6H). LCMS (Method A):R t =3.84 min; [M+H] + =467.2

[0235] Example 17 - 5-(benzyl(methyl)amino)-N-(methylsulfonyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (21) [ka]

[0236] Starting material 1 - methanesulfonamide used in step 7 of the synthesis; 1 HNMR (400MHz, DMSO-d6)δ 9.97(s, 1H), 9.59(s, 1H), 8.51(s, 1H), 7.37-7.26(m, 5H), 6.79(s, 1H), 6.66(s, 1H), 4.89(s, 2H), 3.47(s, 3H), 3.24(s, 4H). LCMS (Method A):R t = 3.58 min; [M+H] + =425.1.

[0237] Example 18 - 5-(benzyl(methyl)amino)-N-(3-(4-methylpiperazin-1-yl)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (22) [ka] Starting material used in step 7 of the synthesis: 1 - 3-(4-methylpiperazin-1-yl)aniline; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 9.99(s, 1H), 9.33(s, 1H), 8.70(s, 1H), 7.48(s, 1H), 7.39-7.14(m, 8H), 6 .73(d, J=8.2Hz, 1H), 6.53(s, 1H), 4.95(s, 2H), 3.33(s, 4H), 3.19(s, 7H), 2.26(s, 3H). LCMS (Method A):R t = 2.97 min; [M+H] + =522.0.

[0238] Example 19 - 5-(benzyl(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (29) [ka] Starting material used in step 7 of the synthesis: 1-4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.29(s, 1H), 9.33(s, 1H), 8.72(s, 1H), 7.88(d, J=8.8Hz, 2H), 7.45(d, J=8.8Hz, 2H), 7.37-7.25(m, 5H), 7.19(s, 1H), 6.55(s, 1H), 4.96(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 3.27 min; [M+H] + =458.0.

[0239] Example 20 - 5-(benzyl(methyl)amino)-N-(3-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (30) [ka] Starting material used in step 7 of the synthesis: 1-3-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 10.32(s, 1H), 9.05(s, 1H), 8.01(s, 1H), 7.84(d, J=8.0Hz, 1H), 7.45-7.20(m, 8H), 6.56(s, 1H), 4.96(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 4.29 min; [M+H] + =458.1.

[0240] Example 21 - 5-(benzyl(methyl)amino)-N-(2-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (31) [ka] Starting material used in step 7 of the synthesis: 1-2-chloroaniline; 1HNMR (400MHz, DMSO-d6)δ 13.56(s, 1H), 9.98(s, 1H), 9.18(s, 1H), 8.70(s, 1H), 8.10(d, J=8.0Hz, 1H), 7.62( dd, J=6.8Hz, 1.2Hz, 1H), 7.44-7.22(m, 8H), 6.56(s, 1H), 4.96(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 4.39 min; [M+H] + =458.1

[0241] Example 22 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (32) [ka] Starting material used in step 7 of the synthesis: 1 - 4-(trifluoromethyl)aniline; 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.49(s, 1H), 9.34(s, 1H), 8.73(s, 1H), 8.10(d, J=8.4Hz, 2H), 7.77(d, J=8.8Hz, 2H), 7.40-7.24(m, 5H), 7.20(s, 1H), 6.59(s, 1H), 4.96(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 3.35 min; [M+H] + =492.1

[0242] Example 23 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (33) [ka] Starting material used in step 7 of the synthesis: 1 - 3-(trifluoromethyl)aniline; 1HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.47(s, 1H), 9.35(s, 1H), 8.73(s, 1H), 8.30(s, 1H), 8.18(d, J=8.4Hz, 1H), 7.64(t, J=8. 0Hz, 1H), 7.49(d, J=7.8Hz, 1H), 7.39-7.23(m, 5H), 7.20(s, 1H), 6.58(s, 1H), 4.95(s, 2H), 3.20(s, 3H). LCMS (Method A):R t = 3.34 min; [M+H] + =492.13.

[0243] Example 24 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (34) [ka] Starting material used in step 7 of the synthesis: 1 - 2-(trifluoromethyl)aniline; 1 HNMR (400MHz, DMSO-d6)δ 13.57(s, 1H), 9.91(s, 1H), 9.15(s, 1H), 8.68(s, 1H), 8.02(d, J=8.0Hz, 1H), 7.85-7.74(m, 2H) , 7.49(t, J=7.6Hz, 1H), 7.38-7.24(m, 5H), 7.22(s, 1H), 6.55(s, 1H), 4.96(s, 2H), 3.19(s, 3H). LCMS (Method A):R t = 4.44 min; [M+H] + =492.2;

[0244] Example 25 - 5-(benzyl(methyl)amino)-N-(4-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (35) [ka] Starting material used in step 7 of the synthesis: 1 - 4-fluoroaniline; 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.28(s, 1H), 9.33(s, 1H), 8.72(s, 1H), 7.84(dd, J=5.2H z, 2.0Hz, 2H), 7.37~7.18(m, 8H), 6.57(s, 1H), 4.95(s, 2H), 3.19(s, 3H). LCMS (Method C):R t = 3.05 min; [M+H] + =488.1

[0245] Example 26 - 5-(benzyl(methyl)amino)-N-(3-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (36) [ka] Starting material used in step 7 of the synthesis: 1 - 3-fluoroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.33(s, 1H), 9.32(s, 1H), 8.72(s, 1H), 7.81(d, J=11.6Hz, 1H), 7.67(d, J=8.4Hz, 1H), 7.47-7.24(m, 6H), 7.19(s, 1H), 6.97(td, J=8.6Hz, 2.4Hz, 1H), 6.56(s, 1H), 4.95(s, 2H), 3.19(s, 3H). LCMS (Method A):R t = 3.12 min; [M+H] + =442.03.

[0246] Example 27 - 5-(benzyl(methyl)amino)-N-(2-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (37) [ka] Starting material used in step 7 of the synthesis: 1 - 2-fluoroaniline; 1HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.00(s, 1H), 9.28(s, 1H), 8.72(s, 1H), 7.78(td, J=7.8, 2.1Hz , 1H), 7.39-7.22(m, 8H), 7.19(s, 1H), 6.53(s, 1H), 4.95(s, 2H), 3.19(s, 3H). LCMS (Method A):R t =3.10 min; [M+H] + =442.09.

[0247] Following the methods described for the synthesis of compound 1 in Scheme 3 above, the following compounds were similarly prepared from the appropriate starting material in Step 5 and the appropriate starting material 2 in Step 7.

[0248] Example 28 - (S)-N-(3-methoxyphenyl)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (14) [ka] Starting material (S)-N-methyl-1-phenylethan-1-amine used in Step 5; Starting material 3-methoxyaniline used in Step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.14(s, 1H), 9.35(s, 1H), 8.75(s, 1H), 7.54(d, J=2.4Hz, 1H), 7.45-7.27(m, 7H), 7.19(s, 1H), 6 .73(dd, J=8.2Hz, 2.0Hz, 1H), 6.56(s, 1H), 6.27-6.11(m, 1H), 3.79(s, 3H), 2.90(s, 3H), 1.60(d, J=6.8Hz, 3H). LCMS (Method A):R t = 2.53 min; [M+H] + =468.0

[0249] Example 29 (S)—N-(3-hydroxyphenyl)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (15) [ka] Starting material S)-N-methyl-1-phenylethan-1-amine used in Step 5; Starting material 3-aminophenol used in Step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.04(s, 1H), 9.40(d, J=16Hz, 2H), 8.74(s, 1H), 7.40-7.14(m, 9H) , 6.54(s, 2H), 6.18(dd, J=2.8Hz, 1.2Hz, 1H), 2.89(s, 3H), 1.60(d, J=6.8Hz, 3H). LCMS (Method A):R t = 2.34 min; [M+H] + =454.0.

[0250] Example 30 - (S)-5-(methyl(1-phenylethyl)amino)-N-phenyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (16) [ka] Starting material S)-N-methyl-1-phenylethan-1-amine used in step 5; starting material aniline used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.17(s, 1H), 9.35(s, 1H), 8.75(s, 1H), 7.84(d, J=7.8Hz, 2H), 7 .52-7.07(m, 9H), 6.55(s, 1H), 6.19(s, 1H), 2.89(s, 3H), 1.60(d, J=6.4Hz, 3H). LCMS (Method A):R t = 3.15 min; [M+H] + =438.0.

[0251] Example 31 - (S)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (17) [ka] Starting material (S)-N-methyl-1-phenylethan-1-amine used in step 5; starting material ammonia used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.46(s, 1H), 9.30(d, J=1.6Hz, 1H), 8.70(d, J=2.8Hz, 1H), 8.04(s, 1H), 7.51-7 .14(m, 7H), 6.39(s, 1H), 6.30-6.06(m, 1H), 2.87(s, 3H), 1.58(d, J=6.8Hz, 3H). LCMS (Method A):R t = 2.09 min; [M+H] + =362.0.

[0252] Example 32 - 5-(isoindolin-2-yl)-N-phenyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (23) [ka] Starting material isoindoline used in step 5; starting material aniline used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.19(s, 1H), 9.38(s, 1H), 8.78(s, 1H), 7.48(d, J=7.6Hz, 2H), 7 .45-7.35(m, 6H), 7.15(d, J=7.2Hz, 1H), 7.09(s, 1H), 6.60(s, 1H), 4.97(s, 4H). LCMS (Method C):R t =3.01 min; [M+H] + =422.1.

[0253] Example 33 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (24) [ka] Starting material isoindoline used in step 5, starting material 3-aminophenol used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.19(s, 1H), 9.45(s, 1H), 9.08(s, 2H), 7.45(s, 2H), 7.38(t, J=2.8 Hz, 3H), 7.23(s, 1H), 7.15(d, J=7.2Hz, 1H), 7.09(s, 1H), 6.57(s, 2H), 4.97(s, 4H). LCMS (Method A):R t = 3.66 min; [M+H] + =438.1.

[0254] Example 34 - 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (25) [ka] Starting material isoindoline used in step 5, starting material 3-methoxyaniline used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.15(s, 1H), 9.38(s, 1H), 8.77(s, 1H), 7.54-7.36(m, 6H), 7.30(t, J=7 .2Hz, 1H), 7.09(s, 1H), 6.73(d, J=7.6Hz, 1H), 6.60(s, 1H), 4.97(s, 4H), 3.97(s, 3H). LCMS (Method C):R t =3.01 min; [M+H] + =452.1

[0255] Example 35 - 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (26) [ka] Starting material isoindoline used in step 5; Starting material 3-trifluoromethoxyaniline used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.55(s, 1H), 10.45(s, 1H), 9.37(s, 1H), 8.79(d, J=7.8Hz, 1H), 8.01(s, 1H), 7. 93-7.86(m, 1H), 7.56-7.33(m, 5H), 7.17-7.08(m, 2H), 6.63(s, 1H), 4.97(s, 4H). LCMS (Method A):R t = 3.37 min; [M+H] + =506.0.

[0256] Example 36 - N-(3-ethoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (27) [ka] Starting material isoindoline used in step 5; Starting material 3-ethoxyaniline used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.14(s, 1H), 9.38(s, 1H), 8.77(s, 1H), 7.56-7.23(m, 7H), 7.10(s, 1H), 6.7 1(d, J=8.4Hz, 1H), 6.61(s, 1H), 4.98(d, J=1.6Hz, 4H), 4.05(d, J=6.8Hz, 2H), 1.37(s, 3H). LCMS (Method A):R t = 3.17 min; [M+H] + =466.11.

[0257] Example 37 - 5-(isoindolin-2-yl)-N-(3-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (28) [ka] Starting material isoindoline used in step 5; Starting material 3-isopropoxyaniline used in step 7; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.12(s, 1H), 9.37(s, 1H), 8.77(s, 1H), 7.53-7.35(m, 6H), 7.27(t, J=8.2Hz, 1H), 7.10( s, 1H), 6.70(dd, J=8.2, 1.9Hz, 1H), 6.61(s, 1H), 4.98(s, 4H), 4.66-4.56(m, 1H), 1.31(d, J=6.0Hz, 6H). LCMS (Method A):R t = 3.25 min; [M+H] + =480.11.

[0258] Example 38 - N-(4-chlorophenyl)-5-((4-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (38) [ka] Starting material used in step 5 - 1-(4-methoxyphenyl)-N-methylmethanamine; Starting material used in step 7 - 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.28(s, 1H), 9.32(s, 1H), 8.71(s, 1H), 7.88(d, J=8.8Hz, 2H), 7.45(d, J=8.8Hz, 2H), 7.26(s, 1H), 7.24(s, 1H), 7.17(s, 1H), 6.91(s, 1H), 6.89(s, 1H), 6.54(s, 1H), 4.86(s, 2H), 3.72(s, 3H), 3.16(s, 3H). LCMS (Method A):R t= 4.22 min; [M+H] + =488.1.

[0259] Example 39 - N-(4-chlorophenyl)-5-((3-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (39) [ka] Starting material 1-(3-methoxyphenyl)-N-methylmethanamine used in Step 5; Starting material 4-chloroaniline used in Step 7; 1 HNMR (400MHz, DMSO-d6)δ 10.29(s, 1H), 9.02(s, 1H), 8.71(s, 1H), 7.88(d, J=7.2Hz, 2H), 7.45(d, J=8.8Hz, 2H), 7.26(t, J=7.6Hz, 1 H), 7.17(s, 1H), 6.91(t, J=7.2Hz, 3H), 6.55(s, 1H), 5.77(s, 1H), 4.91(s, 2H), 3.72(s, 3H), 3.16(s, 3H). LCMS (Method A):R t = 3.47 min; [M+H] + =488.2.

[0260] Example 40 N-(4-chlorophenyl)-5-((2-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (40) [ka] Starting material 1-(2-methoxyphenyl)-N-methylmethanamine used in Step 5; Starting material 4-chloroaniline used in Step 7; 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.28(s, 1H), 9.32(s, 1H), 8.71(s, 1H), 7.88(d, J=7.2Hz, 2H), 7.44(d, J=8.8Hz, 2H), 7.25(t, J=6.4Hz , 1H), 7.17(s, 1H), 7.05(d, J=8.0Hz, 2H), 6.89(t, J=6.8Hz, 1H), 6.52(s, 1H), 4.86(s, 2H), 3.72(s, 3H), 3.16(s, 3H). LCMS (Method A):R t = 4.26 min; [M+H] + =488.2.

[0261] Example 41 - N-(4-chlorophenyl)-5-(methyl(4-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (41) [ka] Starting material used in step 5 - 1-(4-trifluoromethoxyphenyl)-N-methylmethanamine; Starting material used in step 7 - 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.30(s, 1H), 9.34(s, 1H), 8.73(s, 1H), 7.88(d, J=8.8Hz, 2H), 7.71(d, J=8.0 Hz, 2H), 7.48(dd, J=16.0Hz, 8.0Hz, 4H), 7.19(s, 1H), 6.55(s, 1H), 5.04(s, 2H), 3.23(s, 3H). LCMS (Method C):R t = 3.46 min; [M+H] + =525.9.

[0262] Example 42 - N-(4-chlorophenyl)-5-(methyl(3-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (42) [ka] Starting material used in Step 5: 1-(3-trifluoromethoxyphenyl)-N-methylmethanamine; Starting material used in Step 7: 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.30(s, 1H), 9.33(s, 1H), 8.73(s, 1H), 7.88(d, J=8.8Hz, 2H), 7.69(s, 1H), 7.71-7.63(m, 1H) , 7.59(d, J=5.2Hz, 2H), 7.45(dd, J=8.80Hz, 2.8Hz, 2H), 7.19(s, 1H), 6.55(s, 1H), 5.04(s, 2H), 3.23(s, 3H). LCMS (Method A):R t = 4.45 min; [M+H] + =526.1.

[0263] Example 43 N-(4-chlorophenyl)-5-(methyl(2-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (43) [ka] Starting material used in step 5 - 1-(2-trifluoromethoxyphenyl)-N-methylmethanamine; Starting material used in step 7 - 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.29(s, 1H), 9.34(s, 1H), 8.73(s, 1H), 7.91-7.77(m, 3H), 7.62(t, J=7. 6Hz, 1H), 7.53-7.41(m, 3H), 7.33-7.17(m, 2H), 6.53(s, 1H), 5.11(s, 2H), 3.24(s, 3H). LCMS (Method A):R t = 4.62 min; [M+H] + =526.1.

[0264] Example 44 - 5-((4-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (44) [ka] Starting material used in step 5 - 1-(4-chlorophenyl)-N-methylmethanamine; Starting material used in step 7 - 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.30(s, 1H), 9.33(s, 1H), 8.72(s, 1H), 7.88(d, J=8.9Hz, 2H), 7.47-7. 38(m, 4H), 7.33(d, J=8.5Hz, 2H), 7.17(s, 1H), 6.55(s, 1H), 4.93(s, 2H), 3.19(s, 3H). LCMS (Method A):R t = 4.39 min; [M+H] + =492.1.

[0265] Example 45 - 5-((3-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (45) [ka] Starting material used in step 5 - 1-(3-chlorophenyl)-N-methylmethanamine; Starting material used in step 7 - 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.30(s, 1H), 9.33(s, 1H), 8.73(s, 1H), 7.88(d, J=8.9Hz, 2H), 7.45(d, J=8.8Hz, 2 H), 7.41-7.31(m, 3H), 7.26(d, J=7.4Hz, 1H), 7.17(s, 1H), 6.56(s, 1H), 4.95(s, 2H), 3.21(s, 3H). LCMS (Method A):R t = 3.36 min; [M+H] +=492.02.

[0266] Example 46 - 5-((2-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (46) [ka] Starting material used in step 5 - 1-(2-chlorophenyl)-N-methylmethanamine; Starting material used in step 7 - 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.30(s, 1H), 9.33(s, 1H), 8.74(s, 1H), 7.88(d, J=4.4Hz, 2H), 7.51(d, J=6.0Hz, 1H), 7 .44(d, J=8.8Hz, 2H), 7.31(t, J=2.8Hz, 2H), 7.19-7.16(m, 2H), 6.54(s, 1H), 5.00(s, 2H), 3.24(s, 3H). LCMS (Method A):R t = 4.54 min; [M+H] + =429.1.

[0267] Example 47 - 5-(isoindolin-2-yl)-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (47) [ka] Starting material used in step 5 - isoindoline; Starting material used in step 7 - 3-morpholinoaniline; 1HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.05(s, 1H), 9.37(s, 1H), 8.74(s, 1H), 7.48(d, J=2.0Hz, 1H), 7.39-7.34(m, 3H), 7.23(t, J=8.0Hz, 1H ), 7.09(s, 1H), 6.75(dd, J=6.0Hz, 2.0Hz, 1H), 6.60(s, 1H), 4.97(s, 4H), 3.77(t, J=5.2Hz, 4H), 3.13(t, J=4.8Hz, 4H). LCMS (Method A):R t =3.91 min; [M+H] + =507.2.

[0268] Example 48 - 5-(isoindolin-2-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (48) [ka] Starting material used in step 5 - isoindoline; Starting material used in step 7 - 3-(4-methylpiperazin-1-yl)aniline; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.05(s, 1H), 9.36(d, J=1.6Hz, 1H), 8.78(d, J=1.6Hz, 1H), 7.54-7.20(m, 7H), 7.09(s, 1H), 6.83-6.72(m, 1H), 6.60(s, 1H), 4.97(s, 4H), 3.26(s, 8H), 2.82(s, 3H). LCMS (Method A):R t = 3.09 min; [M+H] + =520.16

[0269] Example 49 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (49) [ka] Starting material used in step 5 - isoindoline, starting material used in step 7 - 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.05(s, 1H), 9.36(s, 1H), 8.78(s, 1H), 7.51(s, 1H), 7.45(s, 2H), 7.37-7.33(m, 3H), 7.09(s , 1H), 6.76(d, J=8.0Hz, 1H), 6.60(s, 1H), 4.97(s, 4H), 3.61(s, 4H), 3.19(s, 2H), 3.12(s, 2H), 2.06(s, 3H). LCMS (Method A):R t =3.69 min; [M+H] + =548.2;

[0270] Example 50 - N-(3-cyclobutoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (50) [ka] Starting material used in step 5 - isoindoline, starting material used in step 7 - 3-cyclobutoxyaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.14(s, 1H), 9.37(d, J=2.8Hz, 1H), 8.77(s, 1H), 7.57-7.21(m, 8H), 7.09(s, 1H), 6.62(d, J =11.2Hz, 2H), 4.98(d, J=2.8Hz, 4H), 4.80-4.56(m, 1H), 2.51(s, 1H), 2.15-2.01(m, 2H), 1.86-1.61(m, 2H). LCMS (Method A):R t = 4.47 min; [M+H] + =492.2;

[0271] Example 51 - N-(3,5-dimethoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (51) [ka] Starting material used in step 5 - isoindoline, starting material used in step 7 - 3,5-dimethoxyaniline; 1 HNMR(400MHz, DMSO-d6)δ 13.53(s, 1H), 10.05(s, 1H), 9.35(s, 1H), 8.80(s, 1H), 7.44(d, J=2.8Hz, 2H), 7.37-7.35(m, 2H), 7.16(d, J=2.0Hz, 2H), 7.09(s, 1H), 6.60(s, 1H), 6.31(s, 1H), 4.97(s, 4H), 3.77(s, 6H). LCMS (Method A):R t = 4.10 min; [M+H] + =482.2.

[0272] Example 52 - N-(3-chloro-5-methoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (52) [ka] Starting material used in step 5 - isoindoline, starting material used in step 7 - 3-chloro-5-methoxyaniline; 1 HNMR(400MHz, DMSO-d6)δ 13.53(s, 1H), 10.29(s, 1H), 9.35(s, 1H), 8.80(s, 1H), 7.61(s, 1H), 7.55(s, 1H), 7.45(s, 2 H), 7.37(d, J=2.8Hz, 2H), 7.11(s, 1H), 6.82(s, 1H), 6.62(s, 1H), 4.97(s, 4H), 3.81(s, 3H). LCMS (Method A):R t = 4.49 min; [M+H] + =486.1.

[0273] Example 53 - N-(4-chloro-3-methoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (53) [ka] Starting material used in step 5 - isoindoline; Starting material used in step 7 - 4-chloro-3-methoxyaniline; 1 HNMR(400MHz, DMSO-d6)δ 13.56(s, 1H), 10.30(s, 1H), 9.37(s, 1H), 9.00-8.59(m, 1H), 7.79(d, J=2.0Hz, 1H) , 7.57-7.32(m, 6H), 7.10(s, 1H), 6.62(s, 1H), 4.97(d, J=1.6Hz, 4H), 3.89(s, 3H). LCMS (Method A):R t = 4.27 min; [M+H] + =486.1

[0274] Example 54 - 5-(isoindolin-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (54) [ka] Starting material used in step 5 - isoindoline; Starting material used in step 7 - 4-methoxyaniline; 1 HNMR(400MHz, DMSO-d6)δ 13.53(s, 1H), 10.09(s, 1H), 9.37(s, 1H), 8.77(s, 1H), 7.71(s, 2H), 7.41(d, J =8.0Hz, 4H), 7.08(s, 1H), 6.97(s, 2H), 6.58(s, 1H), 4.97(s, 4H), 3.71(s, 3H). LCMS (Method A):R t = 3.93 min; [M+H] + =452.2.

[0275] Example 55 - N-(4-ethoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (55) [ka] Starting material used in step 5 - isoindoline, starting material used in step 7 - 4-ethoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 10.09(s, 1H), 9.38(s, 1H), 8.77(s, 1H), 7.70(d, J=8.8Hz, 2H), 7.53-7.32(m, 4H), 7.08 (s, 1H), 6.95(d, J=8.8Hz, 2H), 6.57(s, 1H), 4.97(s, 4H), 4.03(q, J=6.4Hz, 2H), 1.34(t, J=6.0Hz, 3H). LCMS (Method A):R t = 3.18 min; [M+H] + =466.04.

[0276] Example 56 - 5-(isoindolin-2-yl)-N-(4-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (56) [ka] Starting material used in step 5 - isoindoline, starting material used in step 7 - 4-isopropoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.55(s, 1H), 10.09(s, 1H), 9.35(s, 1H), 8.77(s, 1H), 7.66(d, J=8.8Hz, 2H), 7.44(d, J=3.2Hz, 2H), 7.37-7.35 (m, 2H), 7.07(s, 1H), 6.95(d, J=8.8Hz, 2H), 6.57(s, 1H), 4.97(s, 4H), 4.62-4.55(m, 1H), 1.27(t, J=6.0Hz, 3H). LCMS (Method A):R t = 42.2 min; [M+H] +=480.2.

[0277] Example 57 - 5-(5-chloroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (61) [ka] Starting material used in step 5 - 5-chloroisoindoline, starting material used in step 7 - 4-methoxyaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.55(s, 1H), 10.16(s, 1H), 9.37(s, 1H), 8.75(s, 1H), 7.50(d, J=3.2Hz, 5H), 7.30(s, 1H), 7.07(s, 1H), 6.75(s, 1H), 6.60(s, 1H), 4.97(s, 4H), 3.79(s, 3H). LCMS (Method A):R t = 4.37 min; [M+H] + =466.1;

[0278] Example 58 - 5-(5-chloroisoindolin-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (62) [ka] Starting material used in step 5 - 5-chloroisoindoline, starting material used in step 7 - 4-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.04(s, 1H), 9.43(s, 1H), 8.74(s, 1H), 7.53(s, 1H), 7.47(d, J=8.0Hz, 1H), 7.42-7.38(m, 3H) , 7.22(d, J=7.6Hz, 1H), 7.15(t, J=8.0Hz, 1H), 7.06(s, 1H), 6.59(s, 1H), 4.55(d, J=8.0Hz, 1H), 4.95(s, 4H). LCMS (Method A):R t=3.90 min; [M+H] + =472.1.

[0279] Example 59 - 5-(5-Fluoroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (63) [ka] Starting material used in step 5 - 5-fluoroisoindoline, starting material used in step 7 - 4-methoxyaniline; 1 HNMR (400MHz, DMSO-d6)δ 13.54(s, 1H), 10.16(s, 1H), 9.37(s, 1H), 8.76(s, 1H), 7.65-7.00(m, 7H), 6.83-6.47(m, 2H), 5.20-4.73(m, 4H), 3.79(s, 3H). LCMS (Method A):R t = 4.10 min; [M+H] + =470.1.

[0280] Example 60 - 5-(5-Fluoroisoindolin-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (64) [ka] Starting material used in step 5 - 5-fluoroisoindoline, starting material used in step 7 - 4-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.53(s, 1H), 10.06(s, 1H), 9.53-9.29(m, 2H), 8.75(s, 1H), 7.49-7.43(m, 1H), 7.38(s , 1H), 7.32-7.12(m, 4H), 7.06(s, 1H), 6.65-6.50(m, 2H), 4.94(dd, J=2.0Hz, 1.2Hz, 4H). LCMS (Method A):R t = 3.93 min; [M+H] + =456.1.

[0281] Following the methods described for the synthesis of Compound 1, the following compounds were similarly prepared from the appropriate starting material in Step 4, the appropriate starting material in Step 5, and the appropriate starting material in Step 7.

[0282] Example 61 - 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (57) [ka] Starting material used in step 4 - 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; Starting material used in step 5 - isoindoline; Starting material used in step 7 - 4-methoxyaniline; 1 HNMR(400MHz, DMSO-d6)δ 10.05(s, 1H), 9.31(s, 1H), 8.77(s, 1H), 7.57(t, J=2.0Hz, 1H), 7.34(t, J=8.8Hz, 2H), 7.37-7.35(m, 2H), 7.30(t , J=8.4Hz, 1H), 7.07(s, 1H), 6.73(dd, J=6.0Hz, 2.0Hz, 1H), 6.60(s, 1H), 4.97(s, 4H), 4.00(s, 3H), 3.79(s, 3H). LCMS (Method A):R t = 4.23 min; [M+H] + =466.2.

[0283] Example 62 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (58) [ka] Starting material used in step 4 - 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, starting material used in step 5 - isoindoline, starting material used in step 7 - 4-aminophenol; 1 HNMR (400MHz, DMSO-d6)δ 9.95(s, 1H), 9.46(s, 1H), 9.31(s, 1H), 8.70(s, 1H), 7.44-7.36(m, 5H), 7.24(t, J=7.6Hz, 1H), 7.16(t, J=8.0Hz, 1H), 7.07(s, 1H), 6.75(t, J=8.0Hz, 2H), 4.97(s, 4H), 4.03(s, 3H). LCMS (Method A):R t =3.81 min; [M+H] + =452.1.

[0284] Example 63 - 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (59) [ka] Starting material used in step 4 - 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, starting material used in step 5 - isoindoline, starting material used in step 7 - 4-methoxyaniline; 1 HNMR (400MHz, DMSO-d6) δ 9.85(s, 1H), 7.62-7.18(m, 7H), 6.78-6.46(m, 3H), 4.94(s, 4H), 3.78(d, J=8.8Hz, 6H), 2.25(d, J=6.4Hz, 6H). LCMS (Method A):R t = 4.20 min; [M+H] + =494.2.

[0285] Example 64 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (60) [ka] Starting material used in step 4 - 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, starting material used in step 5 - isoindoline, starting material used in step 7 - 4-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 9.68(s, 1H), 9.41(s, 1H), 7.49-7.31(m, 5H), 7.18-7.07(m, 2H), 6.61(s, 1 H), 6.55-6.48(m, 2H), 4.93(s, 4H), 3.80(s, 3H), 2.29(s, 3H), 2.20(s, 3H). LCMS (Method A):R t =3.81 min; [M+H] + =480.2.

[0286] Example 65 - 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide [ka] Compound 65 was made using the procedure outlined in Scheme 4. [ka]

[0287] Step 1: Ethyl 3-cyano-2-oxobutanoate (IXX) To a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 13.7 mL, 13.71 mmol) in THF (15 mL) under N cooled to −78°C was added dropwise over 5 min, and the mixture was stirred at −78°C for 1 h. Diethyl oxalate (2.01 g, 13.72 mmol) was added dropwise over 5 min, and the reaction mixture was stirred at −78°C for 45 min and then at 0°C for 1 h. HO (100 mL) was added, and the organic phase was stripped with EtO (100 mL). The aqueous phase was adjusted to pH 5 with aqueous HCl (6 M) and extracted with EtO (3 × 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (7.5 g, 89%) as a yellow oil. LCMS (Method A): R t = 2.36 min; [M+H] + =157.1

[0288] Step 2: Ethyl 5-amino-4-methyl-1H-pyrazole-3-carboxylate (XX) A mixture of ethyl 3-cyano-2-oxobutanoate (8.8 g, 44.00 mmol) and hydrazine hydrate (4.47 g, 89.20 mmol) in AcOH (10 mL) and toluene (100 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (DCM:MeOH, 100 / 1) to give the title product (3.6 g, 38%) as a yellow oil. LCMS (Method A): R t = 2.54 min; [M+H] + =170.2

[0289] Step 3: Ethyl 5-(3-ethoxy-3-oxopropanamido)-4-methyl-1H-pyrazole-3-carboxylate (XXI) A mixture of ethyl 5-amino-4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 5.92 mmol), 3-ethoxy-3-oxopropanoic acid (0.82 g, 6.22 mmol), DCC (1.59 g, 7.71 mmol), pyridine (1.40 g, 17.76 mmol), and DMAP (72 mg, 0.59 mmol) in DCM (15 mL) was stirred at room temperature overnight. The mixture was filtered, rinsed with DCM (2 × 10 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the title product (1.46 g, 87%) as a yellow oil. LCMS (Method A): R t = 2.91 min; [M+H] + =284.1

[0290] Step 4: Ethyl 5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXII) A mixture of ethyl 5-(3-ethoxy-3-oxopropanamido)-4-methyl-1H-pyrazole-3-carboxylate (1.46 g, 5.16 mmol) and DMAP (1.89 g, 15.48 mmol) in ethanol (15 mL) and HO (15 mL) was stirred at 80° C. overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (50 mL) and HO (50 mL). The organics were dried over NaSO and concentrated under reduced pressure to give the title product (1.6 g, 100%) as a white solid. LCMS (Method A): R t = 4.00 min; [M+H] + =238.1

[0291] Step 5: Ethyl 5,7-dichloro-3-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXIII) A mixture of ethyl 5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (2.3 g, 9.71 mmol) in phosphorus oxychloride (25 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure, and the residue was poured into ice water and extracted with EtO (3×300 mL). The combined organics were washed with brine (100 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EtOAc, 10:1) to give the title product (1.6 g, 60.4%) as a yellow oil. LCMS (Method A): R t = 2.93 min; [M+H] + =274.0.

[0292] Step 6: Ethyl 5-chloro-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XXIV) A mixture of ethyl 5,7-dichloro-3-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (3 g, 11.15 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (2.3 g, 11.15 mmol), NaCO (2.3 g, 22.30 mmol), and Pd(dppf)Cl (0.80 g, 1.11 mmol) in degassed 1,4-dioxane (50 mL) and HO (10 mL) was stirred at 80 °C overnight under N. The mixture was poured into water and extracted with EtOAc (100 mL × 3). The combined organics were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the title product (1.5 g, 45%) as a yellow solid. LCMS (Method A):R t = 3.75 min; [M+H] + =306.1

[0293] Step 7: Ethyl 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XXV) A mixture of ethyl 5-chloro-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1.5 g, 4.91 mmol), isoindoline (1.5 g, 9.86 mmol), and triethylamine (2.0 g, 19.61 mmol) in DMF (20 mL) was stirred at 80° C. overnight. The mixture was diluted with water, and the solid was filtered under reduced pressure. The solid was purified by silica gel column chromatography (DCM:MeOH, 90:10) to give the desired product (1 g, 53%) as a yellow solid. LCMS: (Method A), R t =4.97min, [M+H] + =389.2

[0294] Step 8: 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XXVI) To a solution of ethyl 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1 g, 2.62 mmol) in THF (12 mL) and MeOH (12 mL) at 0 °C was slowly added an aqueous solution of KOH (1 M, 6 mL). The reaction mixture was stirred at 90 °C overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between HO and EtO (50 mL, 1 / 1). The organics were discarded, and the aqueous solution was acidified to pH 2 with aqueous HCl (2 M). The aqueous phase was extracted with CHCl (100 mL × 3), and the combined organics were dried over NaSO and concentrated under reduced pressure to give the desired product (860 mg, 93%) as a yellow solid. LCMS: (Method A), R t =4.22 min, [M+H] + =361.1

[0295] Step 9: 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XXVII) (Compound 65 A mixture of 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (200 mg, 0.56 mmol), 3-aminophenol (68 mg, 0.62 mmol), HATU (319 mg, 0.84 mmol), and DIEA (142 mg, 1.12 mmol) in DMF (2 mL) was stirred at room temperature overnight. The mixture was diluted with water, and the solid was filtered under reduced pressure. The filtered cake was dried and purified by silica gel column chromatography (DCM:MeOH 90:10) to give the title product (58 mg, 23%) as a yellow solid. LCMS: (Method A), R t =4.10 min, [M+H] + =452.1. 1 HNMR(400MHz, DMSO-d6)δ 13.47(s, 1H), 9.99(s, 1H), 9.41(s, 1H), 8.97(s, 1H), 7.46-7.35(m, 6H), 7.22(t, J=8.0Hz , 1H), 7.14(t, J=8.0Hz, 1H), 7.06(s, 1H), 6.53(d, J=6.0Hz, 1H), 4.96(s, 4H), 2.42(s, 3H).

[0296] Example 66 - 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (66) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 3-methoxyaniline, 1 HNMR(400MHz, DMSO-d6)δ 13.51(s, 1H), 10.0(s, 1H), 9.36(s, 1H), 8.74(s, 1H), 7.55(s, 1H), 7.45-7.35(m, 5H), 7.28( t, J=8.0Hz, 1H), 7.06(s, 1H), 6.72(d, J=6.0Hz, 1H), 4.96(s, 4H), 3.79(s, 3H), 2.42(s, 3H). LCMS: (Method A), R t=4.61min, [M+H] + =465.2.

[0297] Example 67 - 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (67) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 3-(trifluoromethoxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.40(s, 1H), 9.36(s, 1H), 8.74(s, 1H), 8.01(s, 1H), 7.88(t, J=7.6Hz, 1H ), 7.53-7.46(m, 3H), 7.37-7.35(m, 2H), 7.11(t, J=7.6Hz, 2H), 4.78(s, 4H), 2.42(s, 3H). LCMS: (Method A), R t =3.54 min, [M+H] + =520.1.

[0298] Example 68 - 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (68) [ka] Starting material used in step 7 - N-methyl-1-phenylmethanamine, starting material used in step 9 - 3-aminophenol, 1HNMR (400MHz, DMSO-d6)δ 13.46(s, 1H), 9.97(s, 1H), 9.40(s, 1H), 9.30(s, 1H), 8.68(s, 1H), 7.41(s, 1H), 7.34(s, 4H), 7.27(s, 1H), 7.21(d, J=8.0Hz, 1H), 7.13(t, J=7.6Hz, 2H), 6.52(d, J=7.6Hz, 1H), 4.96(s, 2H), 3.21(s, 3H), 2.37(s, 3H). LCMS: (Method A), R t =4.13 min, [M+H] + =454.2.

[0299] Example 69 - 5-(benzyl(methyl)amino)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (69) [ka] Starting material used in step 7 - N-methyl-1-phenylmethanamine, Starting material used in step 9 - 3-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.46(s, 1H), 10.06(s, 1H), 9.32(s, 1H), 8.69(s, 1H), 7.54(t, J=2.4Hz, 1H), 7.43(d, J=8.0Hz, 1H), 7.35(t, J=3.2Hz , 4H), 7.28(t, J=8.0Hz, 2H), 7.15(s, 1H), 6.71(d, J=6.0Hz, 1H), 4.96(s, 2H), 3.78(s, 3H), 3.21(s, 3H), 2.37(s, 3H). LCMS: (Method A), R t =4.62 min, [M+H] + =468.2.

[0300] Example 70 - 5-(benzyl(methyl)amino)-3-methyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (70) [ka] Starting material used in step 7 - N-methyl-1-phenylmethanamine, Starting material used in step 9 - 3-(trifluoromethoxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.46(s, 1H), 10.36(s, 1H), 9.32(s, 1H), 8.70(s, 1H), 8.01(s, 1H), 7.88(d, J=8.0Hz, 1H), 7.51(t, J=7.6Hz, 1H) , 7.43(s, 4H), 7.27(d, J=3.2Hz, 1H), 7.16(s, 1H), 7.11(d, J=8.0Hz, 1H), 4.96(s, 2H), 3.21(s, 3H), 2.37(s, 3H). LCMS: (Method A), R t =3.2 min, [M+H] + =521.2.

[0301] Example 71 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (71) [ka] Compound 71 was made using the procedure outlined in Scheme 5. [ka]

[0302] Step 1: Ethyl 3-cyano-4-methyl-2-oxopentanoate (XXVIII) To a solution of LiHMDS (1.0 M in THF, 342 mL, 0.34 mol) in dry THF (450 mL) at −78 °C under N 2 , 3-methylbutanenitrile (43 mL, 0.41 mol) was added dropwise over 10 min, and the mixture was stirred at −78 °C for 1 h. Diethyl oxalate (46 mL, 0.34 mol) was added dropwise over 5 min and stirred at −78 °C for 1 h, then at 0 °C for 1 h. The mixture was diluted with HO, and the organics were extracted with Et 2 O (200 mL). The aqueous phase was adjusted to pH 5 with aqueous HCl (1 M), and the organics were then extracted with Et 2 O (2 × 200 mL). The organics were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (44.2 g, 71%) as a yellow oil.

[0303] Step 2: Ethyl 5-amino-4-isopropyl-1H-pyrazole-3-carboxylate (IXXX) A mixture of ethyl 5-amino-4-isopropyl-1H-pyrazole-3-carboxylate (44.2 g, 0.24 mol) and N2H4H2O (23 mL, 0.31 mol) in AcOH (40 mL) and toluene (400 mL) was refluxed overnight using a Dean Stark trap. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO3 (100 mL, 1 / 1). The organics were washed with Na2SO4 4, After drying over 100° C., filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (23 g, 51%) as a yellow solid.

[0304] Step 3: Ethyl 5-(3-ethoxy-3-oxopropanamido)-4-isopropyl-1H-pyrazole-3-carboxylate (XXX) To a mixture of ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (20 g, 0.16 mol), DCC (30.7 g, 0.15 mol), pyridine (27.2 g, 0.34 mol), and DMAP (1.4 g, 0.01 mol) in anhydrous DCM (220 mL) was added 3-ethoxy-3-oxopropanoic acid (15.8 g, 0.12 mol) dropwise over 10 min at 0 °C. The reaction mixture was stirred at RT overnight. The solids were removed by filtration and washed with DCM. The combined organics were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (35.6 g, 99.7%) as a yellow oil. LCMS: (Agilent 5 min), R t =1.83 min, [M+H] + =311.8.

[0305] Step 4: Ethyl 5,7-dihydroxy-3-isopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXXI) A mixture of ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (1.5 g, 4.79 mmol) and DMAP (1.8 g, 14.4 mmol) in ethanol (15 mL) and HO (15 mL) was stirred at 80° C. overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (200 mL) and water (50 mL). The organics were washed with brine, dried, and concentrated under reduced pressure to give the title product (1.0 g, 78%) as a white solid. LCMS: (Agilent 5 min), R t =0.91min, [M+H] + =266.0

[0306] Step 5: Ethyl 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXXII) A solution of ethyl 5,7-dihydroxy-3-isopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1.0 g, 3.76 mol) in phosphorus oxychloride (15 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure, the residue poured into ice water, extracted with DCM (3×20 mL), and the combined organics washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the desired product (700 mg, 62%) as a white solid. LCMS: (Agilent 5 min), R t =4.54 min, [M+H] + =302.0

[0307] Step 6: Ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XXXIII) A mixture of ethyl 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1.0 g, 3.32 mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (704 mg, 3.32 mmol), NaCO (704 mg, 6.64 mmol), and Pd(dppf)Cl (243 mg, 0.39 mmol) in degassed 1,4-dioxane (40 mL) and HO (8 mL) was stirred at 80 °C overnight under a N atmosphere. The mixture was poured into water and extracted with DCM (20 mL × 3). The organics were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (525 mg, 61%) as a yellow solid. LCMS (Method A), R t = 4.20 min; [M+H] + =334.1.

[0308] Step 7: Ethyl 5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XXXIV) A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (800 mg, 2.40 mmol), isoindoline hydrochloride (747 mg, 4.80 mmol), and triethylamine (968 mg, 9.58 mmol) in DMF (10 mL) was stirred at 80° C. overnight. The mixture was diluted with HO and filtered to give the crude product. The crude product was purified by silica gel column (DCM / MeOH=75 / 1) to give the desired product (862 mg, 86%) as a yellow solid. LCMS: (Method A), R t =3.70 min, [M+H] + =417.1.

[0309] Step 8: 5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XXXV) A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (862 mg, 2.1 mmol) and KOH (2N, 10 mL, 20.0 mmol) in THF (20 mL) and MeOH (20 mL) was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo and then poured into HO. The aqueous phase was adjusted to pH 3-4 with HCl, filtered, and dried to give the desired product (750 mg, 93%) as a yellow solid. LCMS: (Method A), R t =3.20 min, [M+H] + =389.1

[0310] Step 9: N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XXXVI) A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (200 mg, 0.52 mmol), 3-aminophenol (62 mg, 0.57 mmol), HATU (294 mg, 0.77 mmol), and DIEA (134 mg, 1.04 mmol) in DMF (5 mL) was stirred overnight at RT. The mixture was diluted with HO, and the residue was filtered and then purified by silica gel column chromatography (DCM:MeOH, 100:0 to 98:2) to give the title product (142 mg, 58%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 10.05(s, 1H), 9.40(s, 1H), 9.27(s, 1H), 8.71(s, 1H), 7.47-7.35(m, 5H), 7.22(d, J=8.4Hz, 1H), 7.14(t, J=8Hz, 1H), 7.04(s, 1H), 6.53(d, J=1.6Hz, 1H), 4.97(s, 4H), 3.83-3.76(m, 1H), 1.46(d, J=7.2Hz, 6H). LCMS: (Method A), R t =4.61min, [M+H] + =480.2.

[0311] Following the method described for the synthesis of compound 71, the following compounds were similarly prepared using the appropriate starting materials in steps 7 and 9 of scheme 5.

[0312] Example 72 - 5-(isoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (72) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 3-methoxyaniline, 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.45(s, 1H), 9.48-9.11(m, 1H), 8.94-8.53(m, 1H), 8.02(s, 1H), 7.87(d, J=8.0Hz, 1H), 7.56-7.42 (m, 3H), 7.36(dd, J=5.6Hz, 3.2Hz, 2H), 7.16-7.04(m, 2H), 4.98(s, 4H), 3.88-3.74(m, 1H), 1.47(d, J=7.2Hz, 6H). LCMS: (Method A), R t =4.16 min, [M+H] + =548.1

[0313] Example 73 - 5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (73) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 3-(trifluoromethoxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.45(s, 1H), 9.48-9.11(m, 1H), 8.94-8.53(m, 1H), 8.02(s, 1H), 7.87(d, J=8.0Hz, 1H), 7.56-7.42 (m, 3H), 7.36(dd, J=5.6Hz, 3.2Hz, 2H), 7.16-7.04(m, 2H), 4.98(s, 4H), 3.88-3.74(m, 1H), 1.47(d, J=7.2Hz, 6H). LCMS: (Method A), R t =4.16 min, [M+H] + =548.1

[0314] Example 74 - 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (74) [ka] Starting material used in step 7 - N-methyl-1-phenylmethanamine, Starting material used in step 9 - 3-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.45(s, 1H), 10.0(s, 1H), 9.40(s, 1H), 9.22(s, 1H), 8.65(s, 1H), 7.42-7.10(m, 9H), 6.53( dd, J=8.0Hz, 1.3Hz, 1H), 4.93(s, 2H), 3.81-3.65(m, 1H), 3.20(s, 3H), 1.37(d, J=7.2Hz, 6H). LCMS (Method A):R t =4.45min, [M+H] + =482.2.

[0315] Example 75 - 5-(benzyl(methyl)amino)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (75) [ka] Starting material used in step 7 - N-methyl-1-phenylmethanamine, starting material used in step 9 - 3-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.45(s, 1H), 10.10(s, 1H), 9.23(s, 1H), 8.66(s, 1H), 7.54(s, 1H), 7.43-7.39(m, 1H), 7.34(d, J=4.4Hz, 4H), 7.27(t, J =8.0Hz, 2H), 7.13(s, 1H), 6.70(dd, J=8.0Hz, 2.0Hz, 1H), 4.93(s, 2H), 3.78(s, 4H), 3.21(s, 3H), 1.37(d, J=7.2Hz, 6H). LCMS (Method A):R t =3.26 min, [M+H] + =496.2

[0316] Example 76 - 5-(benzyl(methyl)amino)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (76) [ka] Starting material used in step 7 - N-methyl-1-phenylmethanamine, Starting material used in step 9 - 3-(trifluoromethoxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 10.36(s, 1H), 9.24(s, 1H), 8.68(s, 1H), 8.0(s, 1H), 7.85(d, J=8.0Hz, 1H), 7.50(t, J=7.6Hz, 1H), 7.3 4(s, 4H), 7.27(d, J=4.0Hz, 1H), 7.12(t, J=8.0Hz, 2H), 4.93(s, 2H), 3.78(s, 1H), 3.21(s, 3H), 1.37(d, J=6.4Hz, 6H). LCMS (Method A):R t =3.96 min, [M+H] + =550.1

[0317] Example 77 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (77) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 3-methoxyaniline, 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.15(s, 1H), 9.28(s, 1H), 8.71(s, 1H), 7.58-7.48(m, 2H), 7.44-7.31(m, 2H), 7.28(t, J=8.8Hz, 1H), 7 .19(t, J=8.0Hz, 1H), 7.04(s, 1H), 6.71(d, J=6.4Hz, 1H), 4.95(d, J=12.0Hz, 4H), 3.79(s, 4H), 1.46(d, J=7.2Hz, 6H). LCMS (Method A):R t =3.53 min, [M+H] + =512.2.

[0318] Example 78 - N-(3-acetamidophenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (78) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - N-(3-aminophenyl)acetamide, 1 HNMR (400MHz, DMSO-d6)δ 10.17(s, 1H), 9.99(s, 1H), 9.02(s, 2H), 8.13(s, 1H), 7.67-6.98(m, 7H), 4.93(s, 4H), 3.80(s, 1H), 3.21(s, 3H), 1.46(s, 6H). LCMS (Method A):R t =4.42 min, [M+H] + =539.2.

[0319] Example 79 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (79) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one; 1 HNMR(400MHz, DMSO-d6)δ 13.50(s, 1H), 10.03(s, 1H), 9.28(s, 1H), 8.71(s, 1H), 7.58-7.16(m, 6H), 7.02(s, 1H), 6.75(d, J=1.6Hz, 1H), 4.93(s, 4H), 3.85-3.78(m, 1H), 3.61(s, 4H), 3.18-3.11(m, 4H), 2.06(s, 3H), 1.46(d, J=7.2Hz, 6H). LCMS (Method A):R t =4.54 min, [M+H] + =608.3

[0320] Example 80 - N-(4-(4-acetylpiperazin-1-yl)phenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (80) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one, 1 HNMR(400MHz, DMSO-d6)δ 13.49(s, 1H), 10.0(s, 1H), 9.28(s, 1H), 8.70(s, 1H), 7.68(d, J=6.8Hz, 1H), 7.49(s, 1H), 7.35(s, 1H), 7.19(t, J=6.8Hz, 1H), 6.99(t , J=6.4Hz, 3H), 4.94(t, J=11.2Hz, 4H), 3.83-3.79(m, 1H), 3.61(s, 4H), 3.14(s, 2H), 3.08(s, 2H), 2.05(s, 3H), 1.46(d, J=7.2Hz, 6H). LCMS (Method A):R t =4.44min, [M+H] + =608.3

[0321] Example 81 - 5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (81) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 3-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.0(s, 1H), 9.28(s, 1H), 8.70(s, 1H), 7.54(s, 3H), 7.42(s, 2H), 7.27(t, J=8.0Hz, 1H ), 7.03(s, 1H), 6.71(d, J=6.4Hz, 1H), 4.94(s, 4H), 3.78(s, 4H), 1.46(d, J=7.2Hz, 6H), LCMS (Method A):R t =3.86min, [M+H] + =528.2.

[0322] Example 82 - N-(3-acetamidophenyl)-5-(5-chloroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (82) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - N-(3-aminophenyl)acetamide, 1 HNMR (400MHz, DMSO-d6)δ 13.47(s, 1H), 10.17(s, 1H), 9.99(s, 1H), 8.73(s, 1H), 8.13(s, 1H), 7.66-7.36(m, 5H), 7.27(t, J =4.8Hz, 1H), 7.03(s, 1H), 4.94(s, 4H), 3.80(t, J=7.2Hz, 1H), 2.06(s, 3H), 1.46(d, J=7.2Hz, 6H). LCMS (Method A):Rt =4.72 min, [M+H] + =555.2

[0323] Example 83 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-5-(5-chloroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (83) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one, 1 HNMR (400MHz, DMSO-d6)δ 13.47(s, 1H), 10.03(s, 1H), 9.27(s, 1H), 8.70(s, 1H), 7.55-7.16(m, 6H), 7.02(s, 1H), 6.75(d, J=6.4Hz, 1H), 4 .95(s, 4H), 3.83-3.78(m, 1H), 3.61(s, 4H), 3.18(d, J=2.4Hz, 4H), 2.06(d, J=7.6Hz, 3H), 1.46(d, J=6.8Hz, 6H). LCMS (Method A):R t =4.81min, [M+H] + =623.2.

[0324] Example 84 - N-(4-(4-acetylpiperazin-1-yl)phenyl)-5-(5-chloroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (84) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one, 1HNMR (400MHz, DMSO-d6)δ 13.47(s, 1H), 10.03(s, 1H), 9.27(s, 1H), 8.70(s, 1H), 7.70-7.40(m, 5H), 7.0(t, J=7.2Hz, 3H), 4.95(s, 4H), 3.8 2(t, J=6.8Hz, 1H), 3.59(d, J=4.0Hz, 4H), 3.14(s, 2H), 3.07(s, 2H), 2.06(d, J=7.6Hz, 3H), 1.46(d, J=6.8Hz, 6H). LCMS (Method A):R t =4.62 min, [M+H] + =624.2.

[0325] Example 85 - 5-(5-Fluoroisoindolin-2-yl)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (99) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 3-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.05(s, 1H), 9.41(s, 1H), 9.27(s, 1H), 8.70(s, 1H), 7.42(s, 1H), 7.23-7.12(m, 4H), 7.03(s, 1) H), 6.54(d, J=9.2Hz, 1H), 4.95(d, J=11.6Hz, 4H), 3.83-3.76(m, 1H), 3.21-3.17(m, 1H), 1.46(d, J=7.0Hz, 6H). LCMS: (Method A), R t =4.66min, [M+H] + =498.2

[0326] Example 86 - 5-(5-chloroisoindolin-2-yl)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (100) [ka] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 3-aminophenol. 1 HNMR(400MHz, DMSO-d6)δ 13.48(s, 1H), 10.04(s, 1H), 9.39(s, 1H), 9.26(s, 1H), 8.70(s, 1H), 7.57-7.40(m, 4H), 7.22(d, J=8.4Hz, 1H), 7 .14(t, J=8.0Hz, 1H), 7.02(s, 1H), 6.54(d, J=6.5Hz, 1H), 4.96(s, 4H), 3.83-3.76(m, 1H), 1.46(d, J=6.8Hz, 6H). LCMS (Method A):R t =4.69min;[MH] += 514.2.

[0327] Example 87 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (101) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 3-morpholinoaniline, 1 HNMR(400MHz, DMSO-d6)δ 13.49(s, 1H), 10.01(s, 1H), 9.27(s, 1H), 8.69(s, 1H), 7.55-7.29(m, 4H), 7.23-7.16(m, 2H), 7.02(s, 1H), 6.73(d, J=1.6Hz, 1H), 4.94(d, J=11.6Hz, 4H), 3.85-3.76(m, 5H), 3.1-3.11(m, 4H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =3.42 min, [M+H] + =567.2.

[0328] Example 88 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-N-(4-(2-methoxyethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (102) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 4-(2-methoxyethoxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 10.06(s, 1H), 9.29(s, 1H), 8.70(s, 1H), 7.71(d, J=8.8Hz, 2H), 7.49-7.16(m, 3H), 7.02(s, 1H), 6.96(d, J=9.2Hz, 2H), 4.94(d, J=12.0Hz, 4H), 4.10(t, J=4.8Hz, 2H), 3.85-3.78(m, 1H), 3.67(t, J=4.4Hz, 2H), 3.33(s, 3H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =4.81min, [M+H] + =556.2.

[0329] Example 89 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-N-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (103) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 7-amino-3,4-dihydroquinolin-2(1H)-one, 1HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.14(d, J=14.8Hz, 2H), 9.27(s, 1H), 8.71(s, 1H), 7.57-7.35(m, 3H), 7.25-7.14(m, 3H), 7.02(s, 1H), 4.95(d, J=11.6Hz, 4H), 3.84-3.77(m, 1H), 2.85(t, J=7.2Hz, 2H), 2.47-2.44(m, 2H), 1.45(d, J=6.8Hz, 6H). LCMS: (Method A), R t =4.71 min, [M+H] + =551.2

[0330] Example 90 - 5-(5-Fluoroisoindolin-2-yl)-N-(1H-indazol-6-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (104) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 1H-indazol-6-amine, 1 HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 12.98(s, 1H), 10.30(s, 1H), 9.31(s, 1H), 8.72(s, 1H), 8.30(s, 1H), 8.02(s, 1H), 7.73(d, J=8.8Hz, 1H), 7 .54-7.32(m, 3H), 7.20(t, J=8.8Hz, 1H), 7.04(s, 1H), 4.96(d, J=11.6Hz, 4H), 3.86-3.79(s, 1H), 1.48(d, J=7.0Hz, 6H). LCMS: (Method A), R t =4.66min, [M+H] + =522.2

[0331] Example 91 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-N-(3(methylsulfonamido)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (105) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - N-(3-aminophenyl)methanesulfonamide, 1 HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.25(s, 1H), 9.76(s, 1H), 9.27(s, 1H), 8.71(s, 1H), 7.84(s, 1H), 7.52(d, J=8.4Hz, 2H), 7.32(t, J=8.0Hz, 2H ), 7.19(t, J=10.8Hz, 1H), 7.04-6.96(m, 2H), 4.95(d, J=11.6Hz, 4H), 3.83-3.75(m, 1H), 3.03(s, 3H), 1.46(d, J=7.2Hz, 6H). LCMS: (Method A), R t =4.64min, [M+H] + =575.2

[0332] Example 92 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-N-(4-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (106) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 4-morpholinoaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 9.99(s, 1H), 9.28(s, 1H), 8.70(s, 1H), 7.69-7.40(m, 5H), 7.01(s, 1H), 6.96(d, J=8.4Hz, 2H), 4. 94(s, 4H), 4.10(q, J=5.2Hz, 1H), 3.84-3.76(m, 5H), 3.17(d, J=5.6Hz, 2H), 3.09(s, 4H), 1.45(d, J=7.2Hz, 6H). LCMS: (Method A), R t =3.11 min, [M+H + =567.2.

[0333] Example 93 - 5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(4-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (107) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 4-morpholinoaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 9.99(s, 1H), 9.28(s, 1H), 8.70(s, 1H), 7.69-7.40(m, 5H), 7.01(s, 1H), 6.96(d, J=8.4Hz, 2H), 4. 94(s, 4H), 4.10(q, J=5.2Hz, 1H), 3.84-3.76(m, 5H), 3.17(d, J=5.6Hz, 2H), 3.09(s, 4H), 1.45(d, J=7.2Hz, 6H). LCMS: (Method A), R t =2.67min, [M+H] + =583.1

[0334] Example 94 - 5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (108) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 3-morpholinoaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.02(s, 1H), 9.27(s, 1H), 8.70(s, 1H), 7.53-7.03(m, 8H), 6.74(s, 1H), 4.95(s, 4H), 3.77(s, 4H), 3.12(m, 4H), 1.45(d, J=6.0Hz, 6H). LCMS: (Method A), R t=2.96 min, [M+H] + =583.2.

[0335] Example 95 - 5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(4-(2-methoxyethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (109) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 4-(2-methoxyethoxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 10.06(s, 1H), 9.29(s, 1H), 8.70(s, 1H), 7.71(d, J=8.8Hz, 2H), 7.59-7.40(m, 3H), 7.02-6. 95(m, 3H), 4.95(s, 4H), 4.10(s, 2H), 3.84-3.78(m, 1H), 3.67(s, 2H), 3.33(s, 3H), 1.45(d, J=6.8Hz, 6H). LCMS: (Method A), R t =3.59 min, [M+H] + =572.2.

[0336] Example 96 - 5-(5-chloroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (117) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 3-((tetrahydro-2H-pyran-4-yl)oxy)aniline, 1HNMR(400MHz, DMSO-d6)δ 13.49(s, 1H), 10.12(s, 1H), 9.26(s, 1H), 8.70(s, 1H), 7.53-7.40(m, 5H), 7.26(t, J=8.0Hz, 1H), 7.03(s, 1H), 6.76(d, J=8.2Hz, 1H) , 4.95(s, 4H), 4.59-4.53(m, 1H), 3.90-3.76(m, 3H), 3.54-3.48(m, 2H), 2.02-1.98(m, 2H), 1.66-1.57(m, 2H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =2.70 min, [M+H] + =598.4

[0337] Example 97 - 5-(5-chloroisoindolin-2-yl)-N-(2-fluoro-3-methoxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (118) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 2-fluoro-3-methoxyaniline, 1 HNMR(400MHz, DMSO-d6)δ 13.53(s, 1H), 9.87(s, 1H), 9.21(s, 1H), 8.70(s, 1H), 7.57-7.39(m, 4H), 7.19-7.1 4(m, 1H), 7.06-7.02(m, 2H), 4.94(s, 4H), 3.92-3.85(m, 4H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =2.94 min, [M+H] + =546.4

[0338] Example 98 - 5-(5-chloroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (119) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 4-((tetrahydro-2H-pyran-4-yl)oxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 10.06(s, 1H), 9.28(s, 1H), 8.70(s, 1H), 7.73-7.40(m, 5H), 7.02-6.98(m, 3H), 4.95(s, 4H), 4. 55-4.58(m, 1H), 3.89-3.78(m, 3H), 3.52-3.46(m, 2H), 1.97(s, 2H), 1.63-1.55(m, 2H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =2.74 min, [M+H] + =598.2

[0339] Example 99 - 5-(5-chloroisoindolin-2-yl)-N-(2-fluoro-5-methoxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (120) [ka] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 2-fluoro-5-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 9.83(s, 1H), 9.18(s, 1H), 8.69(s, 1H), 7.59-7.39(m, 4H), 7.28-7.23(m, 1H), 7.0 5(s, 1H), 6.81-6.77(m, 1H), 4.95(s, 4H), 3.94-3.87(m, 1H), 3.78(s, 3H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =4.14 min, [M+H] + =545.2

[0340] Example 100 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (121) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 3-((tetrahydro-2H-pyran-4-yl)oxy)aniline, 1 HNMR(400MHz, DMSO-d6)δ 10.12(s, 1H), 9.00(s, 2H), 7.53-7.16(m, 6H), 7.03(s, 1H), 6.76(dd, J=8.2Hz, 2.0Hz, 1H), 4.95(d, J=11.6Hz, 4H), 4 .59-4.52(m, 1H), 3.90-3.76(m, 3H), 3.54-3.48(m, 2H), 2.06-1.93(m, 2H), 1.68-1.55(m, 2H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =2.43 min, [M+H] + =582.2.

[0341] Example 101 - N-(2-fluoro-3-methoxyphenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (122) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 2-fluoro-3-methoxyaniline, 1HNMR (400MHz, DMSO-d6)δ 13.52(s, 1H), 9.88(s, 1H), 9.23(s, 1H), 8.71(s, 1H), 7.12-7.05(m, 7H), 4.95(s, 3H), 3.89(s, 4H), 2.69(s, 1H), 1.45(d, J=7.0Hz, 6H). LCMS: (Method A), R t =2.88min, [M+H] + =530.1

[0342] Example 102 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (123) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 4-((tetrahydro-2H-pyran-4-yl)oxy)aniline, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.06(s, 1H), 9.28(s, 1H), 8.71(s, 1H), 7.71(d, J=8.2Hz, 2H), 7.43(m, 3H), 7.01(t, J=13.2Hz, 3H), 4.95(d, J =10.8Hz, 4H), 4.55(s, 1H), 3.94-3.76(m, 3H), 3.53-3.46(m, 2H), 1.98(d, J=8.8Hz, 2H), 1.58(s, 2H), 1.45(d, J=6.6Hz, 6H). LCMS: (Method A), R t =2.23 min, [M+H] + =582.2

[0343] Example 103 - N-(2-fluoro-5-methoxyphenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (124) [ka] Starting material used in step 7 - 5-fluoroisoindoline, starting material used in step 9 - 2-fluoro-5-methoxyaniline, 1 HNMR (400MHz, DMSO-d6) δ 13.56(s, 1H), 9.84(s, 1H), 7.68-6.98(m, 7H), 6.78(s, 1H), 4.95(s, 4H), 3.78(s, 5H), 1.46(s, 6H). LCMS: (Method A), R t =2.83 min, [M+H] + =530.2

[0344] Example 104 - 5-(4-Fluoroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (125) [ka] Starting material used in step 7 - 4-fluoroisoindoline, starting material used in step 9 - 3-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.15(s, 1H), 9.28(s, 1H), 8.74(s, 1H), 7.55(s, 1H), 7.44-7.26(m, 4H), 7.19(t, J=9.2Hz, 1H), 7 .09(s, 1H), 6.71(dd, J=6.4Hz, 2.0Hz, 1H), 5.01(s, 4H), 3.86-3.79(m, 1H), 3.78(s, 3H), 1.46(d, J=7.2Hz, 6H). LCMS: (Method A), R t =2.46 min, [M+H] + =512.2.

[0345] Example 105 - 5-(4-chloroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (126) [ka] Starting material used in step 7 - 4-chloroisoindoline, starting material used in step 9 - 3-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.15(s, 1H), 9.28(s, 1H), 8.74(s, 1H), 7.55-7.38(m, 5H), 7.27(s, 1H), 7.09(s , 1H), 6.71(dd, J=8.2Hz, 2.0Hz, 1H), 5.04(d, J=0.8Hz, 4H), 3.78(s, 4H), 1.46(d, J=7.0Hz, 6H). LCMS: (Method A), R t =2.94 min, [M+H] + =528.0.

[0346] Example 106 - 5-(5-Fluoroisoindolin-2-yl)-3-isopropyl-N-(2-methoxypyridin-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (127) [ka] Starting material used in step 7 - 4-fluoroisoindoline, Starting material used in step 9 - 2-methoxypyridin-4-amine, 1 HNMR (400MHz, DMSO-d6)δ 13.51(s, 1H), 10.46(s, 1H), 9.26(s, 1H), 8.69(s, 1H), 8.10(d, J=6.0Hz, 1H), 7.52-7.36(m, 4H), 7.19(d, J=7.6Hz, 1H), 7.05(s, 1H), 4.95(d, J=11.6Hz, 4H), 3.86(s, 3H), 3.82-3.74(m, 1H), 1.46(d, J=7.0Hz, 6H). LCMS: (Method A), R t =3.28 min, [M+H] + =513.2.

[0347] Example 107 - 3-Cyclopropyl-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (93) [ka] Compound 93 was made using the procedure outlined in Scheme 6. [ka]

[0348] Step 1: Ethyl 3-cyano-3-cyclopropyl-2-oxopropanoate (XXXVII) To a solution of LiHMDS (1.0 M in THF, 240 mL, 0.24 mol) in dry THF (450 mL) at −78 °C under N was added 2-cyclopropylacetonitrile (29 mL, 0.28 mol) dropwise over 10 min, and the mixture was stirred at −78 °C for 1 h. Diethyl oxalate (33 mL, 0.24 mol) was added dropwise over 5 min and stirred at −78 °C for 1 h, then at 0 °C for 1 h. The mixture was diluted with HO, and the organics were extracted with EtO (200 mL). The aqueous phase was adjusted to pH 5 with aqueous HCl (1 M), and the organics were then extracted with EtO (2 × 200 mL). The organics were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (28 g, 65%) as a yellow oil. LCMS: (Method A), R t =3.02min, [M+H] + =182.1.

[0349] Step 2: Ethyl 5-amino-4-cyclopropyl-1H-pyrazole-3-carboxylate (XXXVIII) A mixture of ethyl 3-cyano-3-cyclopropyl-2-oxopropanoate (28.0 g, 0.15 mol) and N2H4H2O (15.5 g, 0.31 mol) in AcOH (40 mL) and toluene (400 mL) was refluxed overnight using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (18 g, 60%) as a yellow solid. LCMS: (Method A), R t =3.80min, [M+H] + =196.1

[0350] Step 3: Ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (XXXIX) To a mixture of ethyl 5-amino-4-cyclopropyl-1H-pyrazole-3-carboxylate (18 g, 0.09 mol), DCC (24.6 g, 0.11 mol), pyridine (21.8 g, 0.28 mol), and DMAP (1.1 g, 0.01 mol) in anhydrous DCM (300 mL) was added 3-ethoxy-3-oxopropanoic acid (12.8 g, 0.10 mol) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The solid was removed by filtration and washed with DCM. The combined organics were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 70:1) to give the desired product (20 g, 71%) as a yellow solid. LCMS: (Agilent 5 min), R t =4.17min, [M+H] + =543.2.

[0351] Step 4: Ethyl 3-cyclopropyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (XL) A mixture of ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (20 g, 64.70 mmol) and DMAP (23.7 g, 0.194 mmol) in ethanol (200 mL) and HO (200 mL) was stirred at 80° C. overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (200 mL) and water (200 mL). The organics were washed with brine, dried, and concentrated under reduced pressure to give the title product (17 g, 100%) as a yellow solid. LCMS: (Agilent 5 min), R t =2.60 min, [M+H] + =264.1.

[0352] Step 5: Ethyl 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XLI) A solution of ethyl 3-cyclopropyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (17.0 g, 0.06 mol) in phosphorus oxychloride (400 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure, the residue poured into ice water, extracted with DCM (3×300 mL), and the combined organics washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the desired product (11 g, 57%) as a yellow solid. LCMS: (Agilent 5 min), R t =4.27min, [M+H] + =300.0.

[0353] Step 6: Ethyl 5-chloro-3-cyclopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XLII) A mixture of ethyl 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (2 g, 6.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2 g, 6.7 mmol), NaCO (1.4 g, 13.4 mmol), and Pd(dppf)Cl (490 mg, 0.67 mmol) in degassed 1,4-dioxane (100 mL) and HO (20 mL) was stirred overnight at 80 °C under a N atmosphere. The mixture was poured into water and extracted with DCM (100 mL × 3). The organics were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (1.4 g, 61%) as a yellow solid. LCMS (Method A): t = 4.05 min; [M+H] + =332.2.

[0354] Step 7: Ethyl-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XLIII) A mixture of ethyl 5-chloro-3-cyclopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (2 g, 6.04 mmol), isoindoline hydrochloride (1.9 g, 12.08 mmol), and triethylamine (2.4 g, 24.16 mmol) in DMF (30 mL) was stirred at 80 °C overnight. The mixture was diluted with HO and filtered to give the crude product. The crude product was purified by silica gel column (DCM / MeOH = 50 / 1) to give the desired product (2.4 g, 96%) as a yellow solid. LCMS: (Method A), R t =4.66min, [M+H] + =465.2.

[0355] Step 8: 3-Cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XLIV) A mixture of ethyl 3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (2.4 g, 5.8 mmol) and aqueous KOH (2 M, 29 mL, 58.0 mmol) in THF (30 mL) and MeOH (30 mL) was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo and then poured into H2O. The aqueous phase was adjusted to pH 3-4 with 2 M HCl, and the formed precipitate was filtered and dried under reduced pressure to give the desired product (750 mg, 93%) as a yellow solid. LCMS: (Method A), R t =3.39 min, [M+H] + =387.1.

[0356] Step 9: 3-Cyclopropyl-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XLV) A mixture of 3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (200 mg, 0.52 mmol), 3-methoxyaniline (70 mg, 0.57 mmol), HATU (296 mg, 0.78 mmol), and DIEA (134 mg, 1.04 mmol) in DMF (8 mL) was stirred overnight at RT. The mixture was diluted with HO, and the residue was filtered and then purified by silica gel column chromatography (DCM:MeOH, 100:0 to 98:2) to give the title product (85 mg, 33%) as a yellow solid. 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.12(s, 1H), 9.29(s, 1H), 8.70(s, 1H), 7.56-7.42(m, 4H), 7.38-7.34(m, 2H), 7.28(t, J=16Hz, 1H), 7.02 (s, 1H), 6.72(d, J=6Hz,1.6Hz, 1H), 4.93(s, 4H), 3.78(s, 3H), 2.61-2.55(m, 1H), 1.49-1.45(m, 2H), 0.85-0.81(m, 2H). LCMS: (Method A), R t =3.19 min, [M+H] + =492.2.

[0357] Following the method described for the synthesis of Compound 93, and using the appropriate starting materials in Steps 7 and 9 of Scheme 6, the following compounds were similarly prepared.

[0358] Example 108 - 3-Cyclopropyl-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (94) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 3-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.02(s, 1H), 9.41(s, 1H), 9.28(s, 1H), 8.70(s, 1H), 7.46-7.35(m, 5H), 7.23-7.12(m, 2H), 7.0 2(s, 1H), 6.53(d, J=6.4Hz, 1.6Hz, 1H), 4.93(s, 4H), 2.60-2.50(m, 1H), 1.47-1.45(m, 2H), 0.84-0.82(m, 2H). LCMS: (Method A), R t =4.29 min, [M+H] + =478.2

[0359] Example 109 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (95) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one; 1 HNMR(400MHz, DMSO-d6)δ 13.50(s, 1H), 10.01(s, 1H), 9.28(s, 1H), 8.70(s, 1H), 7.55-7.31(m, 6H), 7.23(t, J=8Hz, 1H), 7.03(s, 1H), 6.75(d, J=8Hz) , 1H), 4.94(s, 4H), 3.61(s, 4H), 3.20-3.11(m, 4H), 2.63-2.56(m, 1H), 2.06(s, 3H), 1.49-1.46(m, 2H), 0.85-0.81(m, 2H). LCMS: (Method A), R t =4.42 min, [M+H] + =588.3.

[0360] Example 110 - 3-Cyclopropyl-5-(isoindolin-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (96) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 4-methoxyaniline, 1HNMR (400MHz, DMSO-d6)δ 13.48(s, 1H), 10.04(s, 1H), 9.30(s, 1H), 8.71(s, 1H), 7.73(d, J=8Hz, 2H), 7.47(s, 2H), 7.37-7.34(m, 4H), 7.01(s , 1H), 6.96(d, J=8.8Hz, 2H), 4.93(s, 4H), 3.77(s, 3H), 2.69-2.58(m, 1H), 1.47(d, J=3.2Hz, 2H), 0.87-0.77(m, 2H). LCMS: (Method A), R t =4.56 min, [M+H] + =492.2.

[0361] Example 111 - N-(3-acetamidophenyl)-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (97) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - N-(3-aminophenyl)acetamide, 1 HNMR (400MHz, DMSO-d6)δ 13.49(s, 1H), 10.15(s, 1H), 9.99(s, 1H), 9.30(s, 1H), 8.71(s, 1H), 8.13(s, 1H), 7.47-7.35(m, 6H), 7.27(t, J= 8.0Hz, 1H), 7.02(s, 1H), 4.94(s, 4H), 2.61-2.54(m, 1H), 2.06(s, 3H), 1.46(d, J=3.2Hz, 2H), 0.84-0.81(m, 2H). LCMS: (Method A), R t =4.25 min, [M+H] + =519.2.

[0362] Example 112 - N-(3-chlorophenyl)-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (98) [ka] Starting material used in step 7 - isoindoline, starting material used in step 9 - 3-chloroaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.30(s, 1H), 9.30(s, 1H), 8.71(s, 1H), 8.03(s, 1H), 7.83(d, J=9.2Hz, 1H), 7.47-7.33(m, 5H ), 7.19(d, J=8.0Hz, 1H), 7.03(s, 1H), 4.93(s, 4H), 2.61-2.54(m, 1H), 1.49-1.45(s, 2H), 0.86-0.81(m, 2H). LCMS: (Method A), R t =3.71 min, [M+H] + =496.1

[0363] Example 113 - 3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (85) [ka] Compound 85 was made using the procedure outlined in Scheme 7. [ka]

[0364] Step 1: 3,3-Dimethylbutanenitrile (XLVI) To a stirred solution of 1-bromo-2,2-dimethylpropane (25.0 g, 0.165 mol) in DMSO (250 mL) was added sodium cyanide (19.4 g, 0.297 mol). The resulting mixture was heated at 90 °C overnight. The reaction mixture was filtered through a plug of Celite, and the solid was rinsed with DCM (2 × 20 mL). The combined filtrate was concentrated under reduced pressure to give 3,3-dimethylbutanenitrile (12.48 g, 77%) as a yellow oil. 1HNMR (400MHz, CDCl3) δ 3.66-3.63 (m, 4H), 2.14 (s, 2H), 1.76 (s, 3H).

[0365] Step 2: Ethyl 3-cyano-4,4-dimethyl-2-oxopentanoate (XLVII) To a mixture of lithium bis(trimethylsilyl)amide (1.0 M in THF, 40 mL, 40.00 mmol) in THF (50 mL) under N at −78 °C, 3,3-dimethylbutanenitrile (5.0 g, 51.00 mmol) was added dropwise over 5 min, and the mixture was stirred at −78 °C for 1 h. Diethyl oxalate (6.25 g, 40.00 mmol) was added dropwise over 5 min, and the solution was stirred at −78 °C for 45 min and then at 0 °C for 1 h. The mixture was diluted with HO (100 mL), and the organics were removed with EtO (2 × 100 mL). The aqueous phase was adjusted to pH 5 with an aqueous solution of HCl (6 M), and the aqueous phase was extracted with EtO (3 × 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (7.5 g, 89%) as a yellow oil. LCMS (Method A): R t = 2.44 min; [M+H] + =198.1, 1 HNMR (400MHz, CDCl3) δ 4.37 (d, J=7.2Hz, 2H), 1.34-1.32 (m, 3H), 1.15 (s, 9H).

[0366] Step 3: Ethyl 5-amino-4-(tert-butyl)-1H-pyrazole-3-carboxylate (XLVIII) A mixture of ethyl 3-cyano-4,4-dimethyl-2-oxopentanoate (8.8 g, 44.00 mmol) and hydrazine hydrate (4.47 g, 89.20 mmol) in AcOH (10 mL) and toluene (100 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (DCM:MeOH, 100:1) to give the title product (3.6 g, 38%) as a yellow oil. LCMS (Method A): R t = 2.60 min; [M+H]+ =212.1, 1 HNMR (400MHz, CDCl3) δ 4.30 (d, J=7.2Hz, 2H), 1.40-1.29 (m, 12H).

[0367] Step 4: Ethyl 4-(tert-butyl)-5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (XLIX) A mixture of ethyl 5-amino-4-(tert-butyl)-1H-pyrazole-3-carboxylate (3.6 g, 17.00 mmol), 3-ethoxy-3-oxopropanoic acid (2.36 g, 17.00 mmol), DCC (4.57 g, 22.00 mmol), pyridine (4.04 g, 51.00 mmol), and DMAP (208 mg, 1.70 mmol) in DCM (36 mL) was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the title product (5.5 g, 95%) as a yellow oil. LCMS (Method A): R t = 3.28 min; [M+H] + =326.1, 1 HNMR (400MHz, DMSO-d6) δ 13.52(s, 1H), 9.67(s, 1H), 4.33-4.22(m, 2H), 4.13-4.07(m, 2H), 3.39(d, J=12.0Hz, 2H), 1.35-1.21(m, 15H).

[0368] Step 5: Ethyl 3-(tert-butyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (L) A mixture of ethyl 4-(tert-butyl)-5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (5.5 g, 17.00 mmol) and DMAP (6.2 g, 51.00 mmol) in ethanol (112 mL) and HO (112 mL) was stirred at 80° C. overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (100 mL) and HO (100 mL). The organics were dried over NaSO and concentrated under reduced pressure to give the title product (3.0 g, 64%) as a white solid. LCMS (Method A): R t = 2.83 min; [M+H] + =280.1

[0369] Step 6: Ethyl 3-(tert-butyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (LI) A mixture of ethyl 3-(tert-butyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (4.0 g, 14.00 mmol) in phosphorus oxychloride (200 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure, and the residue was poured into ice water and extracted with EtO (3×300 mL). The combined organics were washed with brine (100 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EtOAc, 10 / 1) to give the title product (1.0 g, 22%) as a yellow oil. LCMS (Method A): R t = 3.49 min; [M+H] + =316.9. 1 HNMR (400MHz, DMSO-d6) δ 6.92 (s, 1H), 4.41 (q, J=6.8Hz, 2H), 1.51 (s, 3H), 1.47 (s, 9H).

[0370] Step 7: Ethyl 3-(tert-butyl)-5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LII) A mixture of ethyl 3-(tert-butyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (1.15 g, 3.60 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (1.07 g, 3.60 mmol), NaCO (0.774 g, 7.20 mmol), and Pd(dppf)Cl (534 mg, 0.73 mmol) in degassed 1,4-dioxane (35 mL) and HO (7 mL) was stirred at 80 °C overnight under N. The mixture was poured into water and extracted with EtOAc (100 mL × 3). The combined organics were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the title product (600 mg, 61%) as a yellow solid. LCMS (Method A): t = 4.36 min; [M+H] + =348.1. 1 HNMR (400MHz, DMSO-d6) δ 8.69(s, 1H), 7.19(s, 1H), 7.03(s, 1H), 4.41(q, J=7.2Hz, 2H), 1.49(s, 9H), 1.36(t, J=7.2Hz, 3H).

[0371] Step 8: Ethyl 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LIII) A mixture of 3-(tert-butyl)-5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (800 mg, 2.30 mmol), isoindoline (714 mg, 4.36 mmol), and triethylamine (931 mg, 9.20 mmol) in DMF (20 mL) was stirred at 80° C. overnight. The mixture was diluted with water, and the solid was filtered. The filter cake was dried and purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (230 mg, 49%) as a yellow solid. LCMS: (Method A), R t =4.97min, [M+H] + =431.2.1 HNMR (400MHz, DMSO-d6) δ 8.67(s, 2H), 7.39-7.31(m, 4H), 6.53(s, 1H), 4.94(s, 4H), 4.45(q, J=7.8Hz, 2H), 1.56(s, 9H), 1.44(t, J=7.6Hz, 3H).

[0372] Step 9: 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (LIV) To a solution of 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (600 mg, 1.39 mmol) in THF (24 mL) and HO (24 mL) at 0 °C, aqueous KOH (1 M, 12 mL) was added slowly over 15 min. The reaction mixture was stirred at 90 °C overnight. The solution was concentrated under reduced pressure, and the residue was partitioned between HO (20 mL) and EtO (20 mL). The organics were discarded, and the aqueous layer was acidified to pH 2 with aqueous HCl (2 M). The aqueous phase was extracted with CHCl (100 mL × 3), and the combined organics were dried over NaSO and concentrated under reduced pressure to give the title product (560 mg, 100%) as a yellow solid. LCMS: (Method A), R t =4.22 min, [M+H] + =403.1. 1 HNMR (400MHz, DMSO-d6) δ 8.77(s, 2H), 7.55-7.38(m, 4H), 6.99(s, 1H), 4.99(s, 4H), 1.54(s, 9H).

[0373] Step 10: 3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (LV) A mixture of 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (100 mg, 0.25 mmol), 3-aminophenol (34 mg, 0.28 mmol), HATU (142 mg, 0.37 mmol), and DIEA (931 mg, 9.20 mmol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was diluted with water, and the solid was removed by filtration. The combined solid was purified by silica gel column chromatography (DCM:MeOH, 99:1) to give the title product (50 mg, 39%) as a yellow solid. LCMS: (Method A), R t =2.26 min, [M+H] + =508.2. 1 HNMR (400MHz, DMSO-d6)δ 13.47(s, 1H), 10.55(s, 1H), 9.01(s, 1H), 8.63(s, 1H), 7.50-7.47(m, 3H), 7.37-7.35(m, 3H), 7 .26(t, J=8.0Hz, 1H), 7.0(s, 1H), 6.70(d, J=6.0Hz, 1H), 4.96(s, 4H), 3.76(s, 3H), 1.55(s, 9H).

[0374] Following the method described for the synthesis of compound 85 and using the appropriate starting materials in steps 8 and 10 of scheme 7, the following compounds were similarly prepared.

[0375] Example 114 - N-(3-acetamidophenyl)-3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (86) [ka] Starting material used in step 8 - isoindoline, starting material used in step 10 - N-(3-aminophenyl)acetamide, 1HNMR (400MHz, DMSO-d6)δ 13.44(s, 1H), 10.57(s, 1H), 9.98(s, 1H), 9.01(s, 1H), 8.64(s, 1H), 8.08(s, 1H), 7.46(d, J=7.6Hz , 3H), 7.37-7.35(m, 3H), 7.26(t, J=8.0Hz, 1H), 7.0(s, 1H), 4.96(s, 4H), 2.05(s, 3H), 1.55(s, 9H). LCMS: (Method A), R t =3.610min, [M+H] + =535.2.

[0376] Example 115 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (87) [ka] Starting material used in step 8 - isoindoline, starting material used in step 10 - 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one, 1 HNMR (400MHz, DMSO-d6)δ 13.44(s, 1H), 10.43(s, 1H), 9.00(s, 1H), 8.66(s, 1H), 7.51-7.47(m, 3H), 7.37-7.35(m, 3H), 7.27-7.18(m, 2H), 7 .0(s, 1H), 6.74(d, J=7.2Hz, 1H), 4.96(s, 4H), 3.60(t, J=4.8Hz, 4H), 3.17-3.08(m, 4H), 2.05(s, 3H), 1.55(s, 9H). LCMS: (Method D), R t =5.53 min, [M+H] + =604.3.

[0377] Example 116 - 3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (88) [ka] Starting material used in step 8 - isoindoline. Starting material used in step 10 - 3-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.41(s, 1H), 10.44(s, 1H), 9.40(s, 1H), 8.66(s, 1H), 7.50-7.34(m, 6H), 7. 16-7.09(m, 2H), 7.0(s, 1H), 6.51(d, J=7.2Hz, 1H), 4.96(s, 4H), 1.55(s, 9H). LCMS: (Method A), R t =3.67min, [M+H] + =494.2.

[0378] Example 117 - 3-(tert-butyl)-5-(5-chloroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (89) [ka] Starting material used in step 8 - 5-chloroisoindoline, starting material used in step 10 - 3-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.44(s, 1H), 10.55(s, 1H), 8.94(s, 1H), 8.63(s, 1H), 7.50-7.23(m, 6H), 6.98(s, 1H), 6.70(d, J=7.0Hz, 1H), 4.96(s, 4H), 3.76(s, 3H), 1.55(s, 9H). LCMS: (Method A), R t= 3.88min, [M+H] + =542.2.

[0379] Example 118 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(tert-butyl)-5-(5-chloroisoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (90) [ka] Starting material used in step 8 - 5-chloroisoindoline, Starting material used in step 10 - Starting material: 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one. 1 HNMR (400MHz, DMSO-d6)δ 13.42(s, 1H), 10.43(s, 1H), 8.81(s, 2H), 7.51-7.18(m, 6H), 6.98(s, 1H), 6.74(d, J=8Hz, 1 H), 4.95(d, J=4.8Hz, 4H), 3.59(s, 4H), 3.16(s, 2H), 3.10(s, 2H), 2.05(s, 3H), 1.55(s, 9H). LCMS (Method D):R t =5.86min;[MH] += 638.3.

[0380] Example 119 - 3-(tert-butyl)-5-(5-fluoroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (91) [ka] Starting material used in step 8 - 5-fluoroisoindoline, starting material used in step 10 - 3-methoxyaniline, 1 HNMR (400MHz, DMSO-d6)δ 13.44(s, 1H), 10.55(s, 1H), 9.0(s, 1H), 8.63(s, 1H), 7.50(s, 2H), 7.36(d, J=8.0Hz, 2H), 7.26(t, J=8.0Hz, 1H ), 7.19(t, J=9.2Hz, 1H), 6.98(s, 1H), 6.70(d, J=6.4Hz, 1H), 4.96(d, J=12.4Hz, 4H), 3.76(s, 3H), 1.55(s, 9H). LCMS: (Method A), R t =2.11 min, [M+H] + =526.2.

[0381] Example 120 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(tert-butyl)-5-(5-fluoroisoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (92) [ka] Starting material used in step 8 - 5-fluoroisoindoline, starting material used in step 10 - 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one, 1 HNMR(400MHz, DMSO-d6)δ 13.45(s, 1H), 10.42(s, 1H), 8.99(s, 1H), 8.62(s, 1H), 7.5(s, 2H), 7.39-7.18(m, 4H), 6.98(s, 1H), 6 .74(s, 1H), 4.93(d, J=13.2Hz, 4H), 3.59(s, 4H), 3.16(s, 2H), 3.10(s, 2H), 2.05(s, 3H), 1.55(s, 9H). 1 HNMR(400MHz, DMSO-d6)δ 13.45(s, 1H), 10.42(s, 1H), 8.99(s, 1H), 8.62(s, 1H), 7.5(s, 2H), 7.39-7.18(m, 4H), 6.98(s, 1H), 6 .74(s, 1H), 4.93(d, J=13.2Hz, 4H), 3.59(s, 4H), 3.16(s, 2H), 3.10(s, 2H), 2.05(s, 3H), 1.55(s, 9H).

[0382] Example 121 - N-(3-chlorophenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (110) [ka] Compound 110 was made using the procedure outlined in Scheme 8. [ka]

[0383] Step 1: 2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (LVI) To a suspension of NaH (60% in oil, 4.4 g, 0.11 mol) in diethyl ether (300 mL) cooled to 0 °C, diethyl(cyanomethyl)phosphonate (19.5 g, 0.11 mol) was added dropwise, followed by the dropwise addition of a solution of tetrahydro-4H-pyran-4-one (10 g, 0.10 mol) in diethyl ether (300 mL). The reaction mixture was stirred at RT overnight. The mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title product (7.0 g, 57%) as a yellow oil. LCMS (Method A): R t =0.34 min; [M+H] + =124.1, 1 HNMR (400MHz, CDCl3) δ 5.10 (s, 1H), 3.72-3.66 (m, 4H), 2.63-2.50 (m, 2H), 2.36-2.27 (m, 2H).

[0384] Step 2: 2-(tetrahydro-2H-pyran-4-yl)acetonitrile (LVII) To a solution of 2-(tetrahydro-4H-pyran-4-ylidene)acetonitrile (2.6 g, 21.14 mmol) in PE (25 mL) and acetic acid (1 mL) was added Pd / C (10%, 100 mg). The reaction mixture was purged with H and stirred under 1 atm of hydrogen overnight. The reaction was filtered through Celite, and the filtrate was concentrated in vacuo to give the title product as a yellow oil. LCMS (Method A): R t =0.71 min; [M+H] + =126.1. 1 HNMR (400MHz, CDCl3) δ 4.02-3.98(m, 2H), 3.43-3.37(m, 2H), 2.32(d, J=8.4Hz, 2H), 2.08(s, 1H), 1.99-1.86(m, 1H), 1.77-1.72(m, 2H).

[0385] Step 3: Ethyl 3-cyano-2-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (LVIII) To a mixture of lithium bis(trimethylsilyl)amide (1.0 M in THF, 13.3 mL, 13.30 mmol) in dry THF (50 mL) under N cooled to −78°C, 2-(tetrahydro-2H-pyran-4-yl)acetonitrile (2.0 g, 15.90 mmol) was added dropwise over 5 min, and the mixture was stirred at −78°C for 1 h. Diethyl oxalate (1.95 g, 13.30 mmol) was added dropwise over 5 min at −78°C, and the solution was stirred at 0°C for 45 min. The mixture was diluted with HO (100 mL), and the organics were extracted with EtO (2 × 100 mL). The aqueous layer was adjusted to pH 5 with 6 M HCl, and then the organics were extracted with EtO (3 × 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title product (7.5 g, 89%) as a yellow oil. LCMS (Method A): R t =0.868min;[M+H] + =226.1.

[0386] Step 4: Ethyl 5-amino-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (LIX) A mixture of ethyl 3-cyano-2-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (24.22 g, 0.11 mol) and hydrazine hydrate (10.7 g, 0.21 mol) in AcOH (50 mL) and toluene (500 mL) was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the product (8 g, 31%) as a yellow oil. LCMS (Method A): R t = 2.34 min; [M+H] + =240.1

[0387] Step 5: Ethyl 5-(3-ethoxy-3-oxopropanamido)-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (LX) A mixture of ethyl 5-amino-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (7.0 g, 29.29 mmol), 3-ethoxy-3-oxopropanoic acid (4.05 g, 30.70 mmol), DCC (7.84 g, 38 mmol), pyridine (6.91 g, 87.80 mmol), and DMAP (357 mg, 2.92 mmol) in DCM (70 mL) was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the title product (6.6 g, 56%) as a yellow oil. LCMS (Method A): R t = 2.76 min; [M+H] + =354.1

[0388] Step 6: Ethyl 5,7-dihydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LXI) A mixture of 5-(3-ethoxy-3-oxopropanamido)-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (5.6 g, 15.86 mmol) and DMAP (5.8 g, 47.58 mmol) in ethanol (112 mL) and HO (112 mL) was stirred at 80° C. overnight. The mixture was concentrated, and the residue was dissolved in EtOAc (200 mL) and washed with water (100 mL). The organics were dried over NaSO and concentrated under reduced pressure to give the title product (3.5 g, 72%) as a white solid. LCMS (Method A): R t = 2.23 min; [M+H] + =308.1

[0389] Step 7: Ethyl 5,7-dichloro-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LXII) A mixture of 5,7-dihydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (2.0 g, 5.83 mmol) in phosphorus oxychloride (50 mL) was stirred at 110 °C overnight. The mixture was concentrated under reduced pressure. The residue was poured into ice water and extracted with EtO (3 × 300 mL), and the combined organics were washed with brine (100 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE:EtOAc, 20:1) to give the title product (1.0 g, 45%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6)δ 7.05(s, 1H), 4.51(d, J=7.1Hz, 2H), 4.13-4.06(m, 2H), 3.75(tt, J=12.8Hz, 3.6Hz, 1H), 3.56(d, J= 1.2Hz, 2H), 2.47(dd, J=13.1Hz, 4.4Hz, 2H), 1.69(dd, J=12.8Hz, 2.0Hz, 2H), 1.47(t, J=7.2Hz, 3H).

[0390] Step 8: Ethyl 5-chloro-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LXIII) A mixture of ethyl 5,7-dichloro-3(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1.2 g, 3.49 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (1.02 g, 3.49 mmol), NaCO (741 mg, 6.99 mmol), and Pd(dppf)Cl (511 mg, 0.70 mmol) in 1,4-dioxane (35 mL) and HO (7 mL) was stirred at 80 °C overnight under N. The mixture was poured into water and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (MeOH:DCM, 1:100) to give the title product (600 mg, 61%) as a yellow solid. LCMS (Method A): t=3.71 min; [M+H] + =376.1

[0391] Step 9: Ethyl 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LXIV) A mixture of ethyl 5-chloro-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (800 mg, 2.13 mmol), isoindoline (661 mg, 4.26 mmol), and triethylamine (861 mg, 8.53 mmol) in DMF (20 mL) was stirred at 80 °C overnight. The mixture was poured into water (20 mL), and the precipitate formed was collected by filtration. The residue was further purified by silica gel column chromatography (MeOH / DCM = 1 / 100, v / v) to give the desired product (870 mg, 89%) as a yellow solid. LCMS: (Method A), R t =4.25 min, [M+H] + =459.2

[0392] Step 10: 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (LXV) To a solution of ethyl 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (870 mg, 1.89 mmol) in THF (24 mL) and HO (24 mL) at 0° C., aqueous KOH (1 M, 12 mL, 48 mmol) was added slowly over 15 min. The reaction mixture was stirred at 70° C. overnight. The solvent was removed under reduced pressure, and the remaining aqueous solution was washed with EtO (2×30 mL) and then acidified to pH 2 with 1 M aqueous HCl. The aqueous phase was extracted with CHCl (3×100 mL), and the combined organics were dried over NaSO and concentrated under reduced pressure to give the title product (800 mg, 99%) as a solid. LCMS: (Method A), R t =3.60min, [M+H] + =431.1

[0393] Step 11: N-(3-chlorophenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (LXVI) A mixture of 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (100 mg, 0.25 mmol), 3-chloroaniline (36 mg, 0.28 mmol), HATU (142 mg, 0.37 mmol), and DIEA (120 mg, 0.93 mmol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was diluted with water to form a suspension, which was filtered. The filtered cake was dried and purified by silica gel column (MeOH / DCM = 1 / 100, v / v) to give the desired product (60 mg, 48%) as a yellow solid. LCMS: (Method D), R t =6.16min, [M+H] + =540.2. 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.37(s, 1H), 9.30(s, 1H), 8.72(s, 1H), 8.03(s, 1H), 7.82(d, J=7.6Hz, 1H) 7.51-7.35(m, 5H), 7.19(d, J=7.6Hz, 1H), 7.07(s, 1H), 4.98(s, 4H), 3.99(d, J=8.4Hz, 2H), 3.68(t, J=10.0Hz, 1H), 3.44(d, J=7.2Hz, 2H), 2.54(s, 2H), 1.59(d, J=12.0Hz, 2H)

[0394] Following the methods described for the synthesis of compound 110, and using the appropriate starting materials from steps 9 and 11 of scheme 8, the following compounds were similarly prepared.

[0395] Example 122 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (111) [ka] Starting material used in step 9 - isoindoline, starting material used in step 11 - 3-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.09(s, 1H), 9.42(s, 1H), 9.27(s, 1H), 8.71(s, 1H), 7.45-7.13(m, 7H), 7.05(s, 1H), 6.53(d, J=8.8H) z, 1H), 4.98(s, 4H), 4.0(d, J=10.4Hz, 2H), 3.66(s, 1H), 3.44(d, J=11.6Hz, 2H), 3.33(s, 2H), 1.60(d, J=12.0Hz, 2H). LCMS: (Method B), R t =2.27 min, [M+H] + =522.2.

[0396] Example 123 - 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (112) [ka] Starting material used in step 9 - isoindoline, starting material used in step 11 - 3-methoxyaniline. 1 HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.17(s, 1H), 9.28(s, 1H), 8.72(s, 1H), 7.45-7.42(m, 4H), 7.38 -7.35(m, 2H), 7.28(t, J=12.0Hz, 1H), 7.06(s, 1H), 6.72(dd, J=5.6Hz, 1.6Hz, 1H ), 4.98(s, 4H), 3.98(dd, J=7.2Hz, 3.2Hz, 2H), 3.78(s, 3H), 3.72-3.64(m, 1H), 3.44(d, J=11.2Hz, 2H), 3.33(s, 2H), 2.57-2.53(m, 1H), 1.60(d, J=12.0Hz, 2H). LCMS: (Method D), R t =5.51min, [M+H] + =536.2.

[0397] Example 124 - 5-(isoindolin-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (113) [ka] Starting material used in step 9 - isoindoline, starting material used in step 11 - 4-methoxyaniline, 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.09(s, 1H), 9.29(s, 1H), 8.72(s, 1H), 7.73(d, J=9.2Hz, 2H), 7.49-7.35(m, 4H), 7.05(s, 1H), 6.95(d, J=6.8Hz, 2H) ), 4.97(s, 4H), 3.99(d, J=7.2Hz, 2H), 3.77(s, 3H), 3.70(s, 1H), 3.34(t, J=11.2Hz, 2H), 2.57-2.53(m, 2H), 1.60(d, J=12.0Hz, 2H). LCMS: (Method A), R t =2.45 min, [M+H] + =536.2.

[0398] Example 125 - 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (114) [ka] Starting material used in step 9 - N-methyl-1-phenylmethanamine, Starting material used in step 11 - 3-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.45(s, 1H), 10.03(s, 1H), 9.40(s, 1H), 9.22(s, 1H), 8.65(s, 1H), 7.43(t, J=3.2Hz, 1 H), 7.37-7.34(m, 4H), 7.28-7.24(m, 1H), 7.19(d, J=8.4Hz, 1H), 7.15-7.11(m, 2H), 6.5 2(d, J=6.4Hz, 1H), 4.93(s, 2H), 3.92(dd, J=7.6Hz, 4.4Hz, 2H), 3.67-3.57(m, 1H), 3.38 (t, J=11.2Hz, 2H), 3.23(s, 3H), 2.39(dd, J=8.4Hz, 4.0Hz, 2H), 1.60(d, J=12.0Hz, 2H). LCMS: (Method A), R t =1.91min, [M+H] + =523.2.

[0399] Example 126 - 5-(5-Fluoroisoindolin-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (115) [ka] Starting material used in step 9 - 5-fluoroisoindoline, starting material used in step 11 - 3-aminophenol, 1 HNMR (400MHz, DMSO-d6)δ 13.45(s, 1H), 10.05(s, 1H), 8.94(s, 2H), 7.41-7.12(m, 7H), 6.99(s, 1H), 6.53(d, J=6.8Hz, 1H), 4.95(d, J=13.2Hz, 4H), 3.98(d, J=7.6Hz, 2H), 3.69-3.63(m, 2H), 3.43(t, J=11.6Hz, 3H), 1.60(d, J=12.0Hz, 2H). LCMS: (Method A), R t =2.08min, [M+H] + =540.1.

[0400] Example 127 - 5-(5-chloroisoindolin-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (116) [ka] Starting material used in step 9 - 5-chloroisoindoline, starting material used in step 11 - 3-aminophenol, 1HNMR (400MHz, DMSO-d6)δ 13.50(s, 1H), 10.09(s, 1H), 9.40(s, 1H), 9.26(s, 1H), 8.70(s, 1H), 7.44-7.40(m, 4H), 7.21-7.11(m, 2H), 7.03(s, 1H), 6.53(d, J=7.2Hz) , 1H), 4.96(s, 4H), 4.09(q, J=2.8Hz, 1.6Hz, 2H), 4.0(d, J=4.4Hz, 2H), 3.70-3.61(m, 1H), 3.43(t, J=11.2Hz, 2H), 1.60(d, J=12.0Hz, 2H). LCMS: (Method A), R t =2.37min, [M+H] + =556.2.

[0401] Example 128 Biological Activity. 1.1 Cell culture Culture medium, antibiotics, and serum were purchased from Invitrogen (Life Technologies). PC3 cells were purchased from ATCC (Granville, NSW, Australia). PC3 cells were grown in cell culture T75 flasks with vented caps and then stored at low passage numbers. The medium used for PC3 cells was RPMI (GlutaMAX) supplemented with 10% FCS and 1% penicillin / streptomycin (culture medium). Cells were maintained at 37°C in a humidified 95% (v / v) air / 5% (v / v) CO2 atmosphere and grown to 80% confluence.

[0402] 1.2 x CELLigence Plates XCELLigence® Real-Time Cell Analysis (RTCA) instrument (ACEA Biosciences), 16-well ACEA CIM-plates, 16-well ACEA E-plates, and assembly tools were purchased from ELITech Group empowering IVD (Braeside, Australia). Matrigel was purchased from Corning (Australia).

[0403] 1.2.1 Cell seeding on CIM plates and cell invasion and proliferation on xCELLigence RTCA DP To measure cell invasion under compound treatment, the upper chamber of the CIM plate was coated with 5% Matrigel diluted in SF RPMI (20 μl) and incubated for 4 hours in a tissue culture incubator at 37 °C. Using an assembly tool to support the chamber, the lower chamber was filled with medium (160 μl) containing specific concentrations of compound (25 μM–1 μM) and two controls (DMSO 0.1% and ESFAM 4C 10 μM) (see schematic diagram in Figure 1). Once the upper chamber was placed on top of the lower chamber, compound-containing serum-free (SF) RPMI (40 μl) was added, as described above. After 1 hour of calibration at 37 °C, the plate was placed in the xCELLigence station, and baseline electrical impedance was measured to confirm that all wells and connections were functioning properly. If a connection problem occurred, the software automatically notified the researcher of the nature of the problem in the message section. The cells were then trypsinized, harvested, and counted, followed by dilution in SF RPMI to the desired density (3 × 10). 4 ) and seeded into the wells (100 μl). After a 30-minute incubation at room temperature to allow cell attachment, the plate was placed in the xCELLigence RTCA DP instrument. Cell invasion was monitored in real time for 72 hours.

[0404] It is important to note that the same procedure was followed with minor modifications to measure cell proliferation under compound treatment, but cell proliferation was monitored in real time using the E-Plate and xCELLigence station (see Figure 1).

[0405] 1.3 Software and Data Analysis The xCELLigence system automatically monitored the electrical impedance values ​​of each well and expressed them as Cell Index (CI) values ​​at 72 hours. Data for treatments were automatically grouped as mean ± standard deviation. The software version used in these experiments was 1.2.1. Electronic records of experimental data were automatically saved in files that researchers could not alter or modify.

[0406] Statistical analysis was performed using Microsoft® Office EXCEL and GraphPad Prism 7. IC50s were calculated from four-parameter dose-response curves (log(inhibitor) vs. response-variable slope). Raw data were inserted into GraphPad Prism 7 (dose-response x-log(dose)) and analyzed for XY nonlinear regression (curve fitting), dose-response-inhibition, log(inhibitor) vs. response-variable slope (four parameters). For IC90 calculations, the formula log(IC50) = log(IC90) - (1 / HillSlope) * log(9) was used in EXCEL based on the raw data and dose-response curves extracted from the xCELLigence system.

[0407] Representative inhibition data is shown in the table below. [Table 7]

[0408] Finally, it will be understood that various modifications and variations of the methods and compositions of the present invention described herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are apparent to those skilled in the art are intended to be within the scope of the present invention.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ , R ２ , and R ３ are each independently H and C １ ~C １２ is selected from the group consisting of alkyl, R ４ is H and C １ ~C １２ is selected from the group consisting of alkyl, R ５ is H, optionally substituted C ６ ~C １８ Aryl, optionally substituted C １ ~C １８ Heteroaryl, optionally substituted C ６ ~C １８ Aryl C １ ~C １２ Alkyl- and optionally substituted C １ ~C １８ Heteroaryl C １ ~C １２ alkyl-, R ６ is H, C １ ~C １２ Alkyl, C ３ ~C ６ Cycloalkyl and C １ ~C ５ heterocycloalkyl; R ７ and R ８ when taken together with the nitrogen atom to which they are attached, form a heterocyclic group of the formula formula: 【Chemistry 2】 wherein each R D is independently H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 haloalkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 Heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 2 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 2 -C 12 heterocycloalkyloxy, optionally substituted C 2 -C 12 heterocycloalkenyloxy, optionally substituted C 6 -C 18 aryloxy, optionally substituted C 1 -C 18 heteroaryloxy, optionally substituted C 1 -C 12 alkylamino, SR 9 , SO 3 H, SO 2 NR 9 R 10 , SO 2 R 9 , SONR 9 R 10 , SOR 9 , COR 9 , COOH, COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 COOR 10 , NR 9 SO 2 R 10 , NR 9 CONR 9 R 10 , NR 9 R 10 , and acyl; each R 9 and R 10 is independently selected from the group consisting of H and C 1 -C 12 alkyl; or a pharmaceutically acceptable salt thereof.

2. R １ and R ３ The compound of claim 1 , wherein is H.

3. R ２ The compound of claim 1 , wherein is H.

4. R ４ The compound of claim 1 , wherein is H.

5. R ５ is optionally substituted C ６ ~C １８ The compound of claim 1 which is aryl.

6. R ５ 6. The compound of claim 5, wherein is optionally substituted phenyl.

7. R ６ is C １ ~C １２ The compound of claim 1 , wherein the aryl group is alkyl.

8. R ６ The compound of claim 7, wherein is isopropyl or tert-butyl. 【Request Item 9】 【Table 1-1】 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 10. The compound of claim 1, selected from the group consisting of: 【Request Item 10】 【Chemistry 3】 10. The compound of claim 1, selected from the group consisting of: 【Request Item 11】 【Chemistry 4】 2. The compound of claim 1, wherein: 【Request Item 12】 【Chemistry 5】 2. The compound of claim 1, wherein: 【Request Item 13】 【Chemistry 6】 2. The compound of claim 1, wherein: 【Request Item 14】 【Chemistry 7】 2. The compound of claim 1, wherein: 【Request Item 15】 【Chemistry 8】 2. The compound of claim 1, wherein: 【Request Item 16】 【Chemistry 9】 2. The compound of claim 1, wherein:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable diluent, excipient, or carrier.

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