RU2846982C1 - Compounds - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which have the ability to inhibit CD151. In formula (I) R¹, R² and R³ each is independently selected from the group consisting of H and C₁-C₁₂ alkyl; R⁴ is H; R⁵ is selected from the group consisting of H and C₆-C₁₈ aryl, optionally substituted with one or more R^a, where each R^a is independently selected from the group consisting of H, halogen, OH, CN, C₁-C₁₂ alkyloxy, halogenC₁-C₁₂ alkyl, C₃-C₆ cycloalkyloxy, diC₁-C₁₂ alkylamino, OCHF₂, OCF₃, NHCOCH₃, NHSO₂CH₃, OCH₂CH₂OCH₃, -O-tetrahydropyran, piperazine, 4-methylpiperazine, 4-acylpiperazine, morpholine, or two R^a, taken together with the atoms to which they are bonded, form a condensed heterocyclic ring system, including 9–10 ring atoms, containing one or two heteroatoms selected from nitrogen, and an optionally substituted group =O; C₃-C₅ heteroaryl containing one or two heteroatoms selected from nitrogen and oxygen, and optionally substituted with one or two groups independently selected from C₁-C₁₂ alkyl and C₁-C₁₂ alkyloxy; and C₆-C₁₈ arylC₁-C₁₂ alkyl-; R⁶ is selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₆ cycloalkyl and C₁-C₅ heterocycloalkyl containing one heteroatom selected from oxygen; R⁷ is C₁-C₁₂ alkyl; R⁸ is selected from C₆-C₁₈ arylC₁-C₁₂ alkyl-, optionally substituted with a group independently selected from halogen, halogenC₁-C₁₂ alkyl and C₁-C₁₂ alkyloxy; or R⁷ and R⁸, taken together with a nitrogen atom to which they are bonded, form a group of formula given below, wherein each R^D is independently selected from the group consisting of H and halogen.

EFFECT: compounds can be used in treating medical indications associated with a transmembrane cell-surface protein domain, for example, in treating cancer, asthma, multiple sclerosis and inflammatory bowel disease.

15 cl, 1 dwg, 1 tbl, 128 ex

Description

Field of technology

The present invention relates to compounds discovered by the applicant to be inhibitors of CD151. Due to this activity, these compounds can be used to treat medical conditions associated with the transmembrane domain of the cell surface protein. Accordingly, the compounds may find application in the treatment of cancer, as well as, for example, asthma, multiple sclerosis, and inflammatory bowel disease. The compounds may also find application in the treatment of certain animal diseases also associated with CD151.

State of the art

Over the past 200 years, significant advances have been made in medical research, such that average life expectancy has increased dramatically as effective treatments have been developed for a significant number of diseases/conditions.

However, there remains a desire to provide treatment for diseases and conditions for which there is no effective treatment. Consequently, significant research is being conducted into biological targets that may be associated with many medical conditions of interest.

One area of interest is tetraspanins. Tetraspanins are a superfamily of four cell surface proteins with a transmembrane domain and include the tumor suppressor KAI1/CD82 and the tumor promoter CD151. Tetraspanins are expressed in a wide variety of cell types and are implicated in cancer progression. Specifically, 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 a microdomain of the cell surface membrane, which facilitates their interactions with a range of other proteins, such as integrins, immunoreceptors, and signaling molecules.

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

CD151 is responsible for maintaining 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, where it is associated with cancer progression and metastasis.

Overexpression of CD151 has been associated with a wide range of common human cancers, including prostate (Ang J et al, Cancer Epidemiol Biomarkers Prev 2004; 13(11 Pt 1): 1717–1721), breast (Yang XH et al, Cancer Res 2008; 68:3204–3213), pancreatic (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 are 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 cancer (Voss MA et al., Br J Cancer 2011; 104: 1611–1618), esophageal cancer (Suzuki S et al., Ann Surg Oncol 2011; 18: 888–893), squamous cell carcinoma (Li Q et al., Oncogene 2013; 32: 1772-1783), 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 carcinoma (Medrano M et al., Cell Rep 2017; 18: 2343-2358).

A number of non-malignant diseases have also been 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, S.D.; Mazzon, E.; Basile, M.S.; Campo, G.; Corsico, F.; Presti, M.; Bramanti, P.; Mangano, K.; Petralia, M.C.; Nicoletti, F.; Fagone, P. Modulation of Tetraspanin 32 (TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis. Int. J. Mol. Sci. 2019f 20, 4323, and cytomegalovirus infection (Hochdorfer D et al., Journal of Virology 2016; 90: 6430-6442), as well as human papillomavirus infection type 16 (associated with female genital tract carcinoma) (Spoden G et al., PLoS One 2008; 3: 1-15). Other infectious agents associated with CD151 include Neisseria meningitidis, the agent responsible for 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, J Allergy Clin Immunol 2018; 141: 1799-1817).

Thus, there is considerable interest in the development of CD151 inhibitors, as compounds with this ability can be expected to be useful in the treatment of these disorders.

The essence of the invention

Thus, the present inventors studied the expression of CD151 in order to identify inhibitors of its function that may find use in the treatment of conditions in which overexpression occurs.

As a result of these studies, the applicants identified compounds that inhibit CD151.

Accordingly, in one embodiment, the present invention provides a compound of formula (I):

Where

R ¹ , R ² and R ³ are each independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl;

R ⁴ is selected from the group consisting of H and C ₁ -C ₁₂ alkyl;

R ⁵ is selected from the group consisting of H, optionally substituted C ₆ -C ₁₈ aryl, optionally substituted C ₁ -C ₁₈ heteroaryl, optionally substituted C ₆ -C ₁₈ arylC ₁ -C ₁₂ alkyl- and optionally substituted C ₁ -C ₁₈ heteroarylC ₁ -C ₁₂ alkyl-;

R ⁶ is selected from the group consisting of H, C ₁ -C ₁₂ alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₅ heterocycloalkyl;

R ⁷ is selected from the group consisting of H and C ₁ -C ₁₂ alkyl;

R ⁸ is selected from the group consisting of H, C ₁ -C ₁₂ alkyl, optionally substituted C ₆ -C ₁₈ aryl, optionally substituted C ₁ -C ₁₈ heteroaryl, optionally substituted C ₆ -C ₁₈ arylC -C ₁₂ alkyl- and optionally substituted C ₁ -C ₁₈ heteroarylC ₁ -C ₁₂ alkyl-;

or R ⁷ and R ⁸ taken together with the nitrogen atom to which they are attached form a C ₂ -C ₁₂ heterocyclic group;

or its pharmaceutically acceptable salt.

The compounds of the present invention have been found to have the ability to inhibit CD151 in humans and thus can be used to treat conditions associated with the expression of this gene.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent, excipient or carrier.

Detailed description

This description uses a number of terms well known to those skilled in the art. However, for clarity, a few terms will be defined.

Throughout the description and claims, the word "comprise" and variations of that word such as "comprising" and "comprises" are not intended to exclude other additives, components, integers, or steps.

The term "inhibit" and its variations, such as "inhibition," refers to the prevention, blocking, or reduction of the function of the substance being inhibited. The term does not require complete inhibition, but a reduction in activity of at least 50% is considered inhibition.

In the definitions of a number of substituents below, it is stated that "the group may be a terminal group or a bridging group." This is intended to indicate that the use of the term is intended to cover the situation where the group is a linker between two other parts of the molecule, as well as when it is a terminal group. Using the term "alkyl" as an example, in some publications the term "alkylene" is used to denote a bridging group, and therefore in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application, no such distinction is made, and most groups can be either an intermediate group or a terminal group.

This description uses terms well known to those skilled in the art. However, for clarity, some of these terms will be defined.

As used herein, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen atoms.

The term "optionally substituted" as used in the description means that the group may or may not be further substituted or fused (to form a fused polycyclic system) with one or more non-hydrogen substituent groups. If an optional substituent is present, the substituent groups are one or more groups independently selected from the group consisting of halogen, =O, =S, -CN, -NO ₂ , -CF ₃ , -OCF ₃ , 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 , NR ^e R ^f , NR ^e C(=O)R ^f , NR ^e C(=O)OR ^f , NR ^e C(=O)NR ^f R ^g , NR ^e C(=NR ^f )NR ^g R ^h , NR ^e SO ₂ R ^f , -SR ^e , SO ₂ NR ^e R ^f , -OR ^e , OC(=O)NR ^e R ^f , OC(=O)R ^e and acyl,

wherein R ^e , R ^f , R ^g and ^Rh are each independently selected from the group consisting of H, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ haloalkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₁ -C ₁₀ heteroalkyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₁ -C ₁₂ heterocycloalkyl, C ₁ -C ₁₂ heterocycloalkenyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ heteroaryl and acyl, or any two or more of R ^a , R ^b , R ^c and R ^d , taken together with the atoms to which they are attached, form a heterocyclic ring system with 3 to 12 ring atoms.

In some embodiments, each optional substituent is independently selected from the group consisting of: halogen, =O, =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, aminosulfonyl, aminoalkyl, -COOH, -SH and acyl.

_Examples of particularly suitable optional substituents include F, Cl, Br, I, _CH3 , _CH2CH3 , OH, _OCH3 , _CF3 , _OCF3 , _NO2 , _NH2, and CN.

"Acyl" means an R-C(=O)- group, in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, as defined herein. Examples of acyl include acetyl and benzoyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through a carbonyl carbon atom.

"Acylamino" means an R-C(=O)-NH- group, in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through a nitrogen atom.

"Alkenyl" as a group or part of a group means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched, preferably with 2-12 carbon atoms, more preferably with 2-10 carbon atoms, most preferably with 2-6 carbon atoms in a straight chain. The group may contain multiple double bonds in a straight chain, and the orientation of each of them is independently E or Z. The alkenyl group is preferably a 1-alkenyl group. Examples of 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.

"Alkenyloxy" refers to an alkenyl-O- group in which alkenyl is defined herein. Preferred alkenyloxy groups are _C1 - _C6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

"Alkyl" as a group or part of a group refers to a straight or branched chain aliphatic hydrocarbon group, preferably _C1 - _C12 alkyl, more preferably _C1 - _C10 alkyl, most preferably _C1 - _C6 , unless otherwise specified. Examples of suitable straight and branched chain _C1 - _C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, hexyl and the like. The group may be a terminal group or a bridging group.

"Alkylamino" includes both monoalkylamino and dialkylamino unless otherwise specified. "Monoalkylamino" means an alkyl-NH- group in which alkyl has the meaning defined herein. "Dialkylamino" means an (alkyl) _2N- group in which each alkyl may be the same or different, and each is 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. If the group is a terminal group, it is bonded to the rest of the molecule through a nitrogen atom.

"Alkylaminocarbonyl" refers to a group of the formula (Alkyl) _x (H) _y NC(=O)-, wherein 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. If the group is a terminal group, it is bonded to the rest of the molecule through the carbonyl carbon.

"Alkyloxy" refers to an alkyl-O- group in which alkyl is as defined herein. Preferably, alkyloxy is _C1 - _C6 alkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.

"Alkyloxyalkyl" refers to an alkyloxy-alkyl group in which the alkyloxy and alkyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through the alkyl group.

"Alkyloxyaryl" refers to an alkyloxy-aryl group in which the alkyloxy and aryl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through the aryl group.

"Alkyloxycarbonyl" refers to an alkyl-OC(=O)- group, wherein alkyl has the meaning 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. If the group is a terminal group, it is bonded to the rest of the molecule through the carbonyl carbon.

"Alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl group in which the alkyloxy and cycloalkyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through the cycloalkyl group.

"Alkyloxyheteroaryl" refers to an alkyloxy-heteroaryl group in which the alkyloxy and heteroaryl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through the heteroaryl group.

"Alkyloxyheterocycloalkyl" refers to an alkyloxy-heterocycloalkyl group in which the alkyloxy and heterocycloalkyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the heterocycloalkyl group.

"Alkylsulfinyl" means an alkyl-S-(=O)- group in which alkyl is as defined herein. The alkyl group is preferably a C ₁ -C ₆ alkyl group. Examples of alkylsulfinyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through a sulfur atom.

"Alkylsulfonyl" refers to an alkyl-S(-O) _2- group in which 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. If the group is a terminal group, it is bonded to the rest of the molecule through a sulfur atom.

"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 containing 2-12 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms in a straight chain. Typical structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.

"Alkynyloxy" refers to an alkynyl-O- group in which alkynyl is defined herein. Preferred alkynyloxy groups are _C1 - _C6 alkynyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

"Aminoalkyl" means an NH2- _alkyl group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the alkyl group.

"Aminosulfonyl" means an NH ₂ -S(=O) ₂ group. The group can be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through a sulfur atom.

"Aryl" as a group or part of a group means (i) an optionally substituted monocyclic or fused polycyclic aromatic carbocycle (a ring structure in which all the atoms in the ring are carbon), preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic group in which phenyl and a C _5-7 cycloalkyl or C _5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl, or indanyl. The group may be a terminal group or a bridging group. Typically, the aryl group is a C ₆ -C ₁₈ aryl group.

"Arylalkenyl" means an aryl-alkenyl group in which the aryl and alkenyl groups are as defined herein. Examples of arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through the alkenyl group.

"Arylalkyl" means an aryl-alkyl group in which the aryl and alkyl groups are as defined herein. Preferred arylalkyl groups contain a C _1-5 alkyl group. Examples of arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl, and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the alkyl group.

"Arylalkyloxy" refers to an aryl-alkyl-O- group in which alkyl and aryl are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through an oxygen atom.

"Arylamino" includes both monoarylamino and diarylamino unless otherwise specified. Monoarylamino means a group of the formula arylN-, in which aryl is defined herein. Diarylamino means a group of the formula (aryl) _2N- , where each aryl may be the same or different, and each is as defined herein for aryl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through a nitrogen atom.

"Arylheteroalkyl" means an aryl-heteroalkyl group in which the aryl and heteroalkyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the heteroalkyl group.

"Aryloxy" refers to an aryl-O- group in which aryl is as defined herein. Preferably, aryloxy is _C6 - _C18 aryloxy, more preferably _C6 - _C10 aryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

"Arylsulfonyl" means an aryl-S(=O) ₂ group in which the aryl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through a sulfur atom.

A "bond" is a connection between atoms in a compound or molecule. A bond can be single, double, or triple.

"Cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having 5-10 carbon atoms per ring. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. The cycloalkenyl group may be substituted with one or more substituent groups. The cycloalkenyl group is typically a C ₃ -C alkenyl group. The group may be a terminal group or a bridging group.

"Cycloalkyl" refers to a saturated monocyclic or fused or spiropolycyclic carbocycle, preferably containing 3-9 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. A cycloalkyl group is typically a C ₃ -C ₁₂ alkyl group. The group may be a terminal group or a bridging group.

"Cycloalkylalkyl" means a cycloalkyl-alkyl group in which the cycloalkyl and alkyl groups are as defined herein. Examples of monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cycloheptylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the alkyl group.

"Cycloalkylalkenyl" means a cycloalkyl-alkenyl group in which the cycloalkyl and alkenyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the alkenyl group.

"Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl group in which the cycloalkyl and heteroalkyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the heteroalkyl group.

"Cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl has the meaning defined herein. Preferably, cycloalkyloxy is _C1 - _C6 cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

"Cycloalkenyloxy" refers to a cycloalkenyl-O- group in which cycloalkenyl is defined herein. Preferably, cycloalkenyloxy is _C1 - _C6 cycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

"Haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine. A haloalkyl group typically has 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 groups of this type, n is typically from 1 to 10, more preferably from 1 to 6, most preferably from 1 to 3. m is typically from 1 to 6, more preferably from 1 to 3. Examples of haloalkyl include fluoromethyl, difluoromethyl, and trifluoromethyl.

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

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

"Halogen" is chlorine, fluorine, bromine, or iodine.

"Heteroalkyl" refers to a straight or branched chain alkyl group, preferably having from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms in the chain, in which one or more carbon atoms (and any associated hydrogen atoms) are each independently substituted with a heteroatomic group selected from S, O, P, and NR', where R' is selected from the group consisting of H, optionally substituted C ₁ -C ₁₂ alkyl, optionally substituted C ₃ -C ₁₂ cycloalkyl, optionally substituted C ₆ -C ₁₈ aryl, and optionally substituted C ₁ -C ₁₈ heteroaryl. Representative heteroalkyls include 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.

"Heteroalkyloxy" refers to a heteroalkyl-O- group in which heteroalkyl is as defined herein. Preferably, heteroalkyloxy is _C2 - _C6 heteroalkyloxy. The group may be a terminal group or a bridging group.

"Heteroaryl," alone or as part of a group, refers to groups containing an aromatic ring (preferably a 5- or 6-membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring, wherein the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include nitrogen, oxygen, and sulfur. The group can be a monocyclic or bicyclic heteroaryl group. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatin, 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, 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. The heteroaryl group is typically a C ₁ -C ₁₈ heteroaryl group. The group may be a terminal group or a bridging group.

"Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl groups are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl group. Examples of heteroarylalkyl groups include pyridylmethyl. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the alkyl group.

"Heteroarylalkenyl" means a heteroaryl-alkenyl group in which the heteroaryl and alkenyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through the alkenyl group.

"Heteroarylheteroalkyl" means a heteroaryl-heteroalkyl group in which the heteroaryl and heteroalkyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the heteroalkyl group.

"Heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined herein. Preferably, heteroaryloxy is _C1 - _C18 heteroaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

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

"Heterocycloalkenyl" refers to a heterocycloalkyl group, as defined herein, but containing at least one double bond. A heterocycloalkenyl group is typically a _C2 - _C12 heterocycloalkenyl group. The group may be a terminal group or a bridging group.

"Heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably 3-10 membered, more preferably 4-7 membered. 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. The heterocycloalkyl group is typically a C ₂ -C ₁₂ heterocycloalkyl group. The group may be a terminal group or a bridging group.

"Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl groups are as defined herein. Examples of heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the alkyl group.

"Heterocycloalkylalkenyl" refers to a heterocycloalkylalkenyl group in which the heterocycloalkyl and alkenyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through the alkenyl group.

"Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl group in which the heterocycloalkyl and heteroalkyl groups are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through the heteroalkyl group.

"Heterocycloalkyloxy" refers to a heterocycloalkyl-O- group in which heterocycloalkyl is defined herein. Preferably, heterocycloalkyloxy is _C1 - _C6 heterocycloalkyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

"Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is defined herein. Preferably, heterocycloalkenyloxy is _C1 - _C6 heterocycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through an oxygen atom.

"Hydroxyalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced by an OH group. A hydroxyalkyl group typically has the formula C _n H _{(2n + 1-x)} (OH) _x . In groups of this type, n is typically from 1 to 10, more preferably from 1 to 6, most preferably from 1 to 3. x is typically from 1 to 6, more preferably from 1 to 3.

"Sulfinyl" means a group RS(=O)-, in which the group R may be OH, alkyl, cycloalkyl, heterocycloalkyl; an aryl or heteroaryl group, as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through a sulfur atom.

"Sulfinylamino" means an R-S(=O)-NH- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl, or an aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through a nitrogen atom.

"Sulfonyl" means an RS(=O) ₂ group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl, or an aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule through a sulfur atom.

"Sulfonylamino" means an RS(=O) ₂ -NH- group. The group can be a terminal group or a bridging group. If the group is a terminal group, it is linked to the rest of the molecule through a nitrogen atom.

It is understood that the family of compounds of formula (I) includes isomeric forms, including diastereoisomers, enantiomers, tautomers, and geometric isomers in the form of the "E" or "Z" configurational isomer or a mixture 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 those skilled in the art. For those compounds where the possibility of geometric isomerism exists, the applicant has drawn the isomer that the compound is believed to be, although it should be understood that another isomer may have the correct structural assignment.

Some of the compounds of the described embodiments may exist as individual stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such individual stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the described and claimed subject matter.

Furthermore, formula (I) is intended to encompass, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the stated structure, including both hydrated and unhydrated forms.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above compounds and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric and phosphoric acids. Suitable organic acids can be selected from the classes of organic aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic acids, examples of which are formic, acetic, propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkylsulfonic, aryl sulfonic. Similarly, base addition salts can be prepared by methods well known in the art using organic or inorganic bases. Examples of suitable organic bases include simple amines such as methylamine, ethylamine, triethylamine, and the like. Examples of suitable inorganic bases include NaOH, KOH, and the like. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. For agents that are solids, those skilled in the art will appreciate that the compounds of the invention, agents, and salts can exist in various crystalline or polymorphic forms, all of which fall within the scope of the present invention and the formulas provided.

The term "therapeutically effective amount" or "effective amount" is an amount sufficient to produce beneficial or desired clinical results. An effective amount may be administered in a single or multiple administrations. An effective amount is typically sufficient to alleviate, reduce, stabilize, reverse, slow, or delay the progression of a disease state.

As indicated above, the compounds of the invention have formula (I):

or its pharmaceutically acceptable salt

As with any group of structurally related compounds having particular utility, certain embodiments of the variable compounds of formula (I) are particularly useful in their end use applications.

In the compounds of the invention, R ¹ , R ² and R ³ are each independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl.

In some embodiments, R ¹ is H. In some embodiments, R ¹ is C ₁ -C ₁₂ alkyl. 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.

In some embodiments, R ² is H. In some embodiments, R ² is C ₁ -C ₁₂ alkyl. 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.

In some embodiments, R ³ is H. In some embodiments, R ³ is C ₁ -C ₁₂ alkyl. In some embodiments, R ³ 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.

In some embodiments of the compounds of the invention, R ¹ is H, and this provides compounds of formula (Ia):

or a pharmaceutically acceptable salt thereof;

where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described above.

In some embodiments of the compounds of the invention, R ² is H, and this provides compounds of formula (Ib):

or a pharmaceutically acceptable salt thereof;

where R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described above.

In some embodiments of the compounds of the invention, R ³ is H, and this provides compounds of formula (Ic):

or a pharmaceutically acceptable salt thereof;

where R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described above.

In some embodiments of the compounds of the invention, R ¹ is H, R ² is H and R ³ is H, resulting in compounds of formula (II):

or a pharmaceutically acceptable salt thereof;

where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described above.

R ⁴ is selected from the group consisting of H and C ₁ -C ₁₂ alkyl. In some embodiments, R ⁴ is H. In some embodiments, R ⁴ is C ₁ -C ₁₂ alkyl. 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.

In some embodiments of the compounds of the invention, R ¹ is H, R ² is H, R ³ is H, and R ⁴ is H, resulting in compounds of formula (III):

or a pharmaceutically acceptable salt thereof;

where R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described above.

In the compounds of the invention, R ⁵ is selected from the group consisting of H, optionally substituted C ₆ -C ₁₈ aryl, optionally substituted C ₁ -C ₁₈ heteroaryl, optionally substituted C ₆ -C ₁₈ arylC ₁ -C ₁₂ alkyl- and optionally substituted C ₁ -C ₁₈ heteroarylC ₁ -C ₁₂ alkyl-.

In some embodiments, R ⁵ is H. In some embodiments, R ⁵ is optionally substituted C ₆ -C ₁₈ aryl. In some embodiments, R ⁵ is an optionally substituted C ₁ -C ₁₈ heteroaryl. In some embodiments, R ⁵ is an optionally substituted C ₆ -C ₁₈ arylC ₁ -C ₁₂ alkyl-. In some embodiments, R ⁵ is an optionally substituted C ₁ -C ₁₈ heteroarylC ₁ -C ₁₂ alkyl-.

In some embodiments, R ⁵ is optionally substituted C ₆ -C ₁₈ aryl. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl. In some embodiments, R ⁵ is optionally substituted phenyl.

In some embodiments, R ⁵ is an optionally substituted phenyl group of formula A:

wherein each R ^a is independently selected from the group consisting of 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 with C ₁ -C ₁₂ alkyloxy, optionally substituted with C ₂ -C ₁₂ alkenyloxy, optionally substituted with C ₂ -C ₁₂ alkynyloxy, optionally substituted with C ₂ -C ₁₀ heteroalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkenyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkenyloxy, optionally substituted with C ₆ -C ₁₈ aryloxy, optionally substituted with C ₁ -C ₁₈ heteroaryloxy, optionally substituted with 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,

where R ⁹ and R ¹⁰ are each independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl.

In some embodiments, R ⁵ is an optionally substituted phenyl group selected from the group consisting of:

where each R ^a is as defined above.

In some embodiments, each R ^a is independently selected from the group consisting of H, halogen, OH, NO ₂ , CN, SH, NH ₂ , NHCOCH ₃ , CF ₃ , OCHF ₂ , OCF ₃ , C ₁ -C ₁₂ alkyl, and C ₁ -C ₁₂ alkyloxy.

In some embodiments, each R ^a is independently selected from the group consisting of H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , (CH ₂ ) ₃ CH ₃ , Cl, Br, F, I, OH, NO ₂ , NH ₂ , N(CH ₃ ) ₂ , NHCOCH ₃ , NHSO ₂ CH ₃ , NHSO ₂ CH ₂ CH ₂ CH ₃ , CN, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH(CH ₃ ) ₂ , OCH ₂ CH ₂ OCH ₃ , OC ₆ H ₅ , OCH ₂ C(CH ₃ )3, OCH ₂ cyclopropyl, O-tetrahydropyran, piperazine, 4-methyl-piperazine, 4-acyl-piperazine, morpholine, CF ₃ , OCHF ₂ and OCF ₃ .

In some embodiments of the compounds of the invention, R ¹ is H, R ² is H, R ³ is H, R ⁴ is H, and R ⁵ is a group of formula A, resulting in compounds of formula (IV):

or a pharmaceutically acceptable salt thereof.

where R ^a , R ⁶ , R ⁷ and R ⁸ are as described above.

In some embodiments, the R ⁵ group is an optionally substituted C ₁ -C ₁₈ heteroaryl group. Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatin, 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 a heteroaryl ring, all possible attachment points are considered. As an example, if a heteroaryl is a pyridyl group, it could be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

In some embodiments, R ⁵ is selected from the group consisting of:

where each V ¹ , V ² , V ³ and V ⁴ is independently selected from the group consisting of N and CR ⁸ ;

wherein each R ⁸ is independently selected from the group consisting of 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 with C ₁ -C ₁₂ alkyloxy, optionally substituted with C ₂ -C ₁₂ alkenyloxy, optionally substituted with C ₂ -C ₁₂ alkynyloxy, optionally substituted with C ₂ -C ₁₀ heteroalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkenyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkenyloxy, optionally substituted with C ₆ -C ₁₈ aryloxy, optionally substituted with C ₁ -C ₁₈ heteroaryloxy, optionally substituted with 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;

where R ⁹ and R ¹⁰ are each independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl.

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

In one embodiment, R ⁵ is selected from the group consisting of:

where R ^B is as described above.

In one embodiment, R ⁵ is selected from the group consisting of:

where each R ^B is as defined above.

In some embodiments, each R ^B is independently selected from the group consisting of H, halogen, OH, NO ₂ , CN, SH, NH ₂ , NHCOCH ₃ , CF ₃ , OCHF ₂ , OCF ₃ , C ₁ -C ₁₂ alkyl, and C ₁ -C ₁₂ alkyloxy.

In some embodiments, each R ^B is independently selected from the group consisting of H _{, CH3} , _CH2CH3 , _CH2CH2CH3 , CH( _CH3 ) ₂ , ( _CH2 ) _3CH3 , Cl _, Br, F, I, OH, NO2, _NH2 , _{NHSO2CH2CH2CH3 , CN, OCH3 , OCH2CH3 , OCH2CH2CH3 , OCH} ( _CH3 ) ₂ , _OC6H5 , _{OCH2CCH , OCH2cyclopropyl , CF3} , _{OCHF2 , and OCF3 .}

In some embodiments, R ⁵ is an optionally substituted C ₆ -C ₁₈ arylC ₁ -C ₁₂ alkyl-. In these embodiments, the optionally substituted C ₆ -C ₁₈ aryl is as described above for 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.

In some embodiments, R ⁵ is a substituted C ₁ -C ₁₈ heteroaryl C ₁ -C ₁₂ alkyl-. In these embodiments, the optionally substituted C ₁ -C ₁₈ heteroaryl is as described above for 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.

In the compounds of the invention, R ⁶ is selected from the group consisting of H, C ₁ -C ₁₂ alkyl, C ₃ -C ₆ cycloalkyl; C ₁ -C ₅ heterocycloalkyl. In one embodiment, R ⁶ is H. In one embodiment, R ⁶ is C ₁ -C ₁₂ alkyl. In one embodiment, R ⁶ is C ₃ -C ₆ cycloalkyl. In one embodiment, R ⁶ is C ₁ -C ₅ heterocycloalkyl.

In one particular embodiment, R ⁶ is C ₁ -C ₁₂ alkyl. Examples of suitable values of R ⁶ 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. A particularly preferred value of R ⁶ is isopropyl.

In one particular embodiment, R ⁶ is C ₃ -C ₆ cycloalkyl. Examples of suitable values for R ⁶ include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In one particular embodiment, R ⁶ is C ₁ -C ₅ heterocycloalkyl. Examples of suitable values for R ⁶ include azetidine, oxetane, thietane, pyrrolidine, oxolane, thiolane, piperidine, oceane, and thiane.

In the compounds of the invention, R ⁷ is selected from the group consisting of H and C ₁ -C ₁₂ alkyl, or R ⁷ and R ⁸ taken together with the nitrogen atom to which they are attached form a monocyclic or bicyclic C ₂ -C ₁₂ heterocycloalkyl group.

In one embodiment, R ⁷ is H.

In one embodiment, R ⁷ is C ₁ -C ₁₂ alkyl. Examples of suitable values for R ⁷ 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. In one preferred embodiment, R ⁷ is methyl.

In the compounds of the invention, R ⁸ is selected from the group consisting of H, C ₁ -C ₁₂ alkyl, optionally substituted C ₆ -C ₁₈ aryl, optionally substituted C ₁ -C ₁₈ heteroaryl, optionally substituted C ₆ -C ₁₈ arylC ₁ -C ₁₂ alkyl- and optionally substituted C ₁ -C ₁₈ heteroarylC ₁ -C ₁₂ alkyl-.

In one embodiment, R ⁸ is H.

In one embodiment, R ⁸ is C ₁ -C ₁₂ alkyl. Examples of suitable values for R ⁸ 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. In one preferred embodiment, R ⁸ is methyl.

In one embodiment, R ⁸ is optionally substituted C ₆ -C ₁₈ aryl. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl. In some embodiments, R ⁸ is optionally substituted phenyl.

In some embodiments, R ⁸ is an optionally substituted phenyl group of formula B:

wherein each R ^c is independently selected from the group consisting of 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 with C ₁ -C ₁₂ alkyloxy, optionally substituted with C ₂ -C ₁₂ alkenyloxy, optionally substituted with C ₂ -C ₁₂ alkynyloxy, optionally substituted with C ₂ -C ₁₀ heteroalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkenyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkenyloxy, optionally substituted with C ₆ -C ₁₈ aryloxy, optionally substituted with C ₁ -C ₁₈ heteroaryloxy, optionally substituted with 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,

where R ⁹ and R ¹⁰ are each independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl.

In some embodiments, R ⁸ is an optionally substituted phenyl group selected from the group consisting of:

where each R ^c is as defined above.

In some embodiments, each R ^c is independently selected from the group consisting of H, halogen, OH, NO ₂ , CN, SH, NH ₂ , NHCOCH ₃ , CF ₃ , OCHF ₂ , OCF ₃ , C ₁ -C ₁₂ alkyl, and C ₁ -C ₁₂ alkyloxy.

In some embodiments, each R ^c is independently selected from the group consisting of H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , (CH ₂ ) ₃ CH ₃ , Cl, Br, F, I, OH, NO ₂ , NH ₂ , NHSO ₂ CH ₂ CH ₂ CH ₃ , CN, OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OCH(CH ₃ ) ₂ , OC ₆ H ₅ , OCH ₂ CCH, OCH ₂ cyclopropyl, CF ₃ , OCHF ₂ and OCF ₃ .

In one embodiment, R ⁸ is optionally substituted C ₁ -C ₁₈ heteroaryl. Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatin, 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 substitutions are possible on a heteroaryl ring, all possible attachment points are considered. As an example, if a heteroaryl is a pyridyl group, it could be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

In some embodiments, R ⁸ is selected from the group consisting of:

where each V ¹ , V ² , V ³ and V ⁴ is independently selected from the group consisting of N and CR ^D ;

wherein each R ^D is independently selected from the group consisting of H, halogen, OH, NO ₂ , CN, SH, NH2, 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 with C ₁ -C ₁₂ alkyloxy, optionally substituted with C ₂ -C ₁₂ alkenyloxy, optionally substituted with C ₂ -C ₁₂ alkynyloxy, optionally substituted with C ₂ -C ₁₀ heteroalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkenyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkenyloxy, optionally substituted with C ₆ -C ₁₈ aryloxy, optionally substituted with C ₁ -C ₁₈ heteroaryloxy, optionally substituted with 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,

where R ⁹ and R ¹⁰ are each independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl.

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

In one embodiment, R ⁸ is selected from the group consisting of:

where RD is as described above.

In one embodiment, R ⁸ is selected from the group consisting of:

where each R ^D is as defined above.

In some embodiments, each R ^D is independently selected from the group consisting of H, halogen, OH, NO ₂ , CN, SH, NH ₂ , NHCOCH ₃ , CF ₃ , OCHF ₂ , OCF ₃ , C ₁ -C ₁₂ alkyl, and C ₁ -C ₁₂ alkyloxy.

In some embodiments, each R ^D is independently selected from the group consisting of H _{, CH3} , _{CH2CH3 , CH2CH2CH3} , CH( _CH3 ) ₂ , ( _CH2 ) _3CH3 , Cl, Br, F, I, OH, NO2, _NH2 , _{NHSO2CH2CH3 , CN} , _{OCH3 , OCH2CH3} , _OCH2CH2CH3 , OCH( _{CH3 ) 2} , _{OC6H5 , OCH2CCH , OCH2cyclopropyl , CF3} , _{OCHF2 , and OCF3} .

In some embodiments, R ⁸ is an optionally substituted C ₆ -C ₁₈ aryl C ₁ -C ₁₂ alkyl-. In these embodiments, the optionally substituted C ₆ -C ₁₈ aryl is as described above for 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. In one particular embodiment, alkyl is methyl, such that the alkyl is a methylene group connecting the aryl group to the nitrogen.

In some embodiments, R ⁸ is an optionally substituted C ₁ -C ₁₈ heteroaryl C ₁ -C ₁₂ alkyl-. In these embodiments, the optionally substituted C ₁ -C ₁₈ heteroaryl is as described above for 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.

In some embodiments, R ⁷ and R ⁸ taken together with the nitrogen atom to which they are attached form a C ₂ -C ₁₂ heterocyclic group. The C ₂ -C ₁₂ heterocyclic group can be any suitable C ₂ -C ₁₂ heterocyclic group, and can be a monocyclic or bicyclic heterocyclic group. In one embodiment, the C ₂ -C ₁₂ heterocyclic group is monocyclic. In one embodiment, the C ₂ -C ₁₂ heterocyclic group is bicyclic.

A _C2 - _C12 heterocyclic group can consist of fully saturated rings, fully unsaturated rings, or combinations of both. For example, it can contain one saturated ring and one unsaturated ring.

In one embodiment, the C ₂ -C ₁₂ heterocyclic group is a group of formula C:

wherein each R ^D is independently selected from the group consisting of 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 with C ₁ -C ₁₂ alkyloxy, optionally substituted with C ₂ -C ₁₂ alkenyloxy, optionally substituted with C ₂ -C ₁₂ alkynyloxy, optionally substituted with C ₂ -C ₁₀ heteroalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkyloxy, optionally substituted with C ₃ -C ₁₂ cycloalkenyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkyloxy, optionally substituted with C ₂ -C ₁₂ heterocycloalkenyloxy, optionally substituted with C ₆ -C ₁₈ aryloxy, optionally substituted with C ₁ -C ₁₈ heteroaryloxy, optionally substituted with 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,

wherein each R ⁹ and R ¹⁰ is independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl;

n is an integer chosen from 1 and 2.

In one embodiment, the C ₂ -C ₁₂ heterocyclic group is a group of formula D:

in one embodiment, the C ₂ -C ₁₂ heterocyclic group is a group of formula E:

In some embodiments of the compounds of formula D and E, each R ^D is independently selected _{from the group consisting of H, CH3, CH2CH3, CH2CH2CH3 , CH ( CH3 ) 2 , ( CH2 ) 3CH3 ,} Cl, Br, F, I _, OH _{, NO2 ,} NH2, _{NHSO2CH2CH2CH3} , CN, _OCH3 , _OCH2CH3 , _OCH2CH2CH3 , _OCH ( _CH3 ) ₂ , _OC6H5 , _OCH2C ( _CH3 ) _{3 , OCH2cyclopropyl} , _{CF3 , OCHF2} , and _OCF3 .

In some embodiments of the compounds of the invention containing an R ⁹ group, the R ⁹ 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. In some embodiments, R 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.

In some embodiments of the compounds of the invention containing an R ¹⁰ group, the R ¹⁰ 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. In some embodiments, R ¹⁰ is selected from the group consisting of H, methyl, and ethyl. In some embodiments, R ¹⁰ is H. In some embodiments, R ¹⁰ is methyl. In some embodiments, R ¹⁰ is ethyl.

Many, if not all, of the variables discussed above can be optionally substituted. If a variable is optionally substituted, then each optional substituent is independently selected from the group consisting of halogen, =O, =S, -CN, -NO ₂ , -CF ₃ , -OCF ₃ , 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 , NR ^e R ^f , NR ^e C(=O)R ^f , NR ^e C(=O)OR ^f , NR ^e C(=O)NR ^f R ^g , NR ^e C(=NR ^f )NR ^g R ^h , NR ^e SO ₂ R ^f , -SR ^e , SO ₂ NR ^e R ^f , -OR ^e , OS(=O)NR ^e R ^f , OC(=O)R ^e and acyl;

wherein R ^e , R ^f , R ^g and ^Rh are each independently selected from the group consisting of H, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ haloalkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₁ -C ₁₀ heteroalkyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₁ -C ₁₂ heterocycloalkyl, C ₁ -C ₁₂ heterocycloalkenyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ heteroaryl and acyl, or any two or more of R ^a , R ^b , R ^c and R ^d , taken together with the atoms to which they are attached, form a heterocyclic ring system with 3 to 12 ring atoms.

In some embodiments, each optional substituent is independently selected from the group consisting of: F, Cl, Br, =O, =S, -CN, -NO ₂ , alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(O)OR ^a , COOH, SH, and acyl.

In some embodiments, each optional substituent is independently selected from the group consisting of: F, Br, Cl, =O, =S, -CN, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH ₂ , -NO ₂ , phenoxy, hydroxy, methoxy, trifluoromethoxy, ethoxy, and methylenedioxy.

_{In some embodiments, each optional substituent is independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH3 , Cl , Br , F , I ,} OH _{, NO2} , _NH2 , CN, _OCH3 , _OCH2CH2CH3 , _{CF3 ,} and _{OCF3 .}

Alternatively, two optional substituents on the same group, taken together, can be joined to form a fused cyclic substituent attached to the group that is optionally substituted. Accordingly, the term "optionally substituted" includes a fused ring, such as a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, or a heteroaryl ring.

Examples of specific compounds of formula (I) according to the present invention include:

or a pharmaceutically acceptable salt thereof.

The compounds exhibit the ability to inhibit CD151. This ability to inhibit CD151 may be due to the compounds acting directly and exclusively on CD151, modulating/potentiating its biological activity. However, it is clear that the compounds may also act, at least in part, on other factors associated with CD151 activity.

Inhibition of CD151 can be accomplished by any of a number of methods known in the art. For example, if inhibition of CD151 in vitro is desired, an appropriate amount of the compound can be added to a solution containing CD151. In circumstances where inhibition of CD151 in humans is desired, inhibition of CD151 typically involves administering a compound containing CD151 to the human.

Accordingly, the compounds may find a variety of applications that utilize their aforementioned ability to inhibit CD151.

Accordingly, the compounds of the invention are expected to have useful therapeutic properties, particularly with respect to conditions such as cancer. Examples of cancers that are 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 carcinoma, esophageal carcinoma, esophageal/gastroesophageal junction carcinoma, osteosarcoma, Wilms' tumor, mesothelioma, squamous cell carcinoma, glioblastoma multiforme, melanoma, and ovarian carcinoma.

CD151 activity is also associated with conditions such as asthma, multiple sclerosis, and inflammatory bowel disease.

CD151 expression has also been linked to infection with an infectious agent. Thus, inhibiting CD151 may aid in the treatment of conditions mediated by an infectious agent. Examples of infectious agents of this type include human papillomavirus, influenza virus, and the bacterium Neisseria meningitidis.

Compounds of formula (I) may be administered to humans by any of the conventional routes of enteral administration, such as oral or rectal, or parenteral administration, such as subcutaneous, intramuscular, intravenous, and intradermal. Injection may be by bolus injection or by continuous or intermittent infusion. The active compound is typically contained in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the activator compound may be selectively toxic or more toxic to rapidly proliferating cells, such as cancer cells, than to normal cells.

The compounds of the invention can be administered in any form or by any route that renders the compound bioavailable. One skilled in the art of formulation can readily select the appropriate form and route of administration depending on the specific characteristics of the selected compound, the condition being treated, the stage of the condition being treated, and other relevant circumstances. The reader is referred to Remingtons Pharmaceutical Sciences, ^19th edition, Mack Publishing Co. (1995) for additional information.

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. The compounds of the invention, although effective on their own, are typically formulated and administered in the form of their pharmaceutically acceptable salts, as these forms are generally more stable, crystallize more readily, and exhibit increased solubility.

However, the compounds are typically used in the form of pharmaceutical compositions, which are formulated depending on the desired route of administration. Thus, in some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. The compositions are prepared by methods well known in the art.

The invention in other embodiments relates to a pharmaceutical package or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical compositions of the invention. Such a package or kit may contain a container with a unit dose of the agent(s). Kits may include a composition containing an effective agent either in the form of concentrates (including lyophilized compositions) that can be further diluted before use, or they may be offered in a concentrate for use, wherein vials may include one or more dosages. For convenience, in kits, single doses can be supplied in sterile vials so that the physician can use the vials directly, wherein the vials will contain the desired amount and concentration of the agent(s). Various written materials may be associated with such container(s), such as instructions for use or a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which reflects the agency's approval of manufacture, use, or sale for human administration.

The compounds of the invention can be used or administered in combination with one or more additional medicinal agents for the treatment of the aforementioned disorder(s). The components can be administered in the same formulation or in separate formulations. When administered in separate formulations, the compounds of the invention can be administered sequentially or simultaneously with the other medicinal agent(s).

In addition to being administered in combination with one or more additional medicinal agents, the compounds of the invention can be used in combination therapy. In this case, the compounds are typically administered in combination with one another. Thus, one or more compounds of the invention can be administered either simultaneously (as a combination drug) or sequentially to achieve the desired effect. This is particularly desirable when the therapeutic profile of each compound is different, so that the combined effect of the two drugs provides an improved therapeutic outcome.

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

These compositions may also contain adjuvants such as a preservative, wetting agents, emulsifiers, and dispersing agents. Prevention of microbial activity can be achieved by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

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

Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

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 bulking agents, 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) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricating agents 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 contain buffering agents.

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

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 formulation art. They may optionally contain opacifying agents and can also be formulated to release the active ingredient(s) only or preferentially in a specific portion of the intestinal tract, optionally in a delayed manner. Examples of coating compositions that can be used include polymeric substances and waxes.

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

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

In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

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

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

Dosage forms for topical administration of the compound of the present invention include powders, patches, sprays, ointments, and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants that may be required.

The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by the treating physician using routine methods and by observing results obtained under similar circumstances. Determining a therapeutically effective amount should take into account a number of factors, including, but not limited to, the animal's species, size, age, and general health, the specific condition, the severity of the condition, the patient's response to treatment, the specific compound administered, the route of administration, the bioavailability of the administered drug, the chosen dosing regimen, the use of other medications, and other relevant circumstances.

The preferred dosage will be in the range of approximately 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range of 0.1 to 100 mg per kilogram of body weight per day, more preferably 0.2 to 80 mg per kilogram of body weight per day, and even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered as multiple subdoses per day.

Synthesis of compounds according to the invention

Compounds for use in the methods of the present invention can be prepared using known methods of organic synthesis and can be synthesized according to any of numerous possible synthetic routes, including reaction methods and synthetic schemes as described below, using methods available in the art, and using readily available starting materials. The preparation of compounds according to embodiments is described in detail in the following examples, but one skilled in the art will appreciate that the described chemical reactions can be readily adapted to produce other agents according to various embodiments.

The reactions to obtain the compounds of the invention can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents need not be substantially reactive with the starting materials (reagents), intermediates, or products at the temperatures at which the reactions are carried out, for example, temperatures that can range from the solvent's freezing point to the solvent's boiling point. A given reaction can be carried out in a single solvent or in a mixture of more than one solvent. Depending on the reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art.

The preparation of compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of suitable protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

Reactions can be monitored by any suitable method known in the art. For example, product formation can be monitored using spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin-layer chromatography.

As used herein, the expressions "ambient temperature," "room temperature," and "rt" are as understood in the art and generally refer to a temperature, such as a reaction temperature, that is approximately equal to the temperature of the room in which the reaction is carried out, such as at a temperature of about 20°C to about 30°C.

The invention will now be illustrated by examples; however, the examples should not be construed as limiting. Additional compounds other than those described below can be prepared using the synthetic methods and protocols, or appropriate variations or modifications thereof, as described herein.

Examples

Definitions:

AcOH (acetic acid);

atm. (atmosphere);

Boc ₂ O (di-tert-butyl dicarbonate);

c-Hex (cyclohexane);

CDCl ₃ (deuterated chloroform);

CD ₃ OD (deuterated methanol);

CHCl ₃ (chloroform);

conc. (concentrated);

DCM (dichloromethane);

DIPEA (N,N-diisopropylethylamine);

DMAP (4-dimethylaminopyridine);

DMSO (dimethyl sulfoxide);

DMSO-d ₆ (deuterated dimethyl sulfoxide);

eq. (equivalent);

EP-IAD (electrospray ionization at atmospheric pressure);

Et ₃ N (triethylamine);

Et ₂ O (diethyl ether);

EtOAc (ethyl acetate);

EtOH (ethanol);

g (gram);

h (hour);

GATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide);

HCl (hydrochloric acid/hydrochloride);

¹ H NMR (proton nuclear magnetic resonance);

Hz (hertz);

l (liter);

LCMS (liquid chromatography - mass spectrometry);

LiHMDS (lithium bis(trimethylsilyl)amide);

M (molar);

MeOH (methanol);

mg (milligrams);

MHz (megahertz);

min (min);

ml (milliliters);

mmol (millimole);

MsCl (methanesulfonyl chloride);

n-BuLi (n-butyllithium);

NaH (sodium hydride);

NaHCO ₃ (sodium bicarbonate);

NaOH (sodium hydroxide);

Na ₂ SO ₄ (sodium sulfate);

Pd(dppf)Cl ₂ ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM);

PE (petroleum ether);

ppm (parts per million);

RT (room temperature);

TFA (trifluoroacetic acid);

THF (tetrahydrofuran).

Most materials are purchased on the market at reagent grade.

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance-400 spectrometer ( ¹ H at 400.13 MHz and ¹³ C at 100.62 MHz). 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 is designated according to the following convention: chemical shift (δ) (multiplicity, coupling constant(s) 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 are reported as 5 values in parts per million (ppm). The following abbreviations are used when reporting spectral data: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sexe, sextet; m, multiplet; app, apparent; and sh, broad.

Electrospray mass spectroscopy (MS) is performed using the following methods;

Method A: 1. Equipment information, LC model: Agilent 1200 (pump type: binary pump, sensor type: DAD) MS model: Agilent G6110A Quadrupole.

LCMS-LC Parameters: Column: Xbridge-C18, 3.5 μm, 2.1×50 mm, Column Temperature: 30°C, Capture Wavelength: 214 nm, 254 nm, Mobile Phase: A: 0.05% HCOOH aqueous solution, B: CAN, Run Time: 5 min, MS: Ion Source: ER+ (or ER-) MS Range: 70~900 m/z, Fragmenter: 60, Drying Gas Flow: 12~13 L/min, Nebulizer Pressure: 35 psi, Drying Gas Temperature: 350°C, Vcap: 3.5 kV.

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 in water (v/v), B: 0.05% formate in MeCN (v/v). Flow rate: 1.0 mL/min at 40°C. Sensor: 214 nm, 254 nm.

Gradient hold time, 3.0 min. Schedule:

MS: G6120A, Quadrupole LC/MS; Ion Source: ESI, Signal: Positive, TIC: 70~1000 m/z, Fragmenter: 60, Threshold: 5, Ion Trap Fill: 1, Drying Gas Flow: 10 L/min, Nebulizer Pressure: 35 psi,

LCMS-R2-3min - 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. Sensor: 214 nm, 254 nm.

Gradient hold time, 3.0 min. Schedule:

MS: G6120A, Quadrupole LC/MS, Ion Source: ESI, Signal: Positive, TIC: 70-1000 m/z, Fragmenter: 60, Threshold: 5, Ion Trap Fill: 1, Drying Gas Flow: 10 L/min, Nebulizer Pressure: 35 psi

Method C - LC model: Waters 2695 alliance, (pump: quaternary pump, sensor: 2996 photodiode array sensor), MS model: Micromass ZO. LCMS-LC parameters: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm, column temperature: 30°C. Wavelength locking: 214 nm, 254 nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 5 min. MS: ion source: ER+ (or ER-) MS range: 50-900 m/z. Capillary: 3.5 kV, in cone: 35 V, extractor: 3 V. Drying gas flow: 350 L/h, in cone: 50 L/h. Desolvation temperature: 300°C. Source temperature: 120°C. Run time: 5 min.

Sample preparation - The sample is dissolved in methanol, the concentration is about 1~10 mg/ml, then filtered through a 0.22 μm syringe filter. (Injection volume: 1~10 μl).

Method D LC model: Waters 2695 alliance, (Pump: Quaternary pump, Sensor: 2996 Photodiode Array Sensor), MS model: Micromass ZO, LCMS -LC Parameters: Column: Xbridge-C18, 3.5 μm, 2.1×50 mm. Column temperature: 20°C. Wavelength locking: 214 nm, 254 nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 8 min. MS: Ion source: ER+ (or ER-) MS range: 100~1000 m/z. Capillary: 3 kV, in cone: 40 V, extractor: 3 V. Drying gas flow: 800 L/h, in cone: 50 L/h. Desolvation temperature: 500°C. Source temperature: 120°C. Run time: 8 min.

Sample preparation - The sample is dissolved in methanol, the concentration is about 1~10 mg/ml, then filtered through a syringe filter with a pore size of 0.22 μm. (Injection volume: 1~10 μl).

Thin-layer chromatography (TLC) is used to monitor reactions and chromatographic fractions on aluminum photographic plates coated with Merck Kieselgel 60 F254 antihalation coating. Silica gel 60 F254 is used as the stationary phase for flash chromatography. Unless otherwise specified, gradient elution is performed using analytical-grade ethyl acetate (EtOAc) and hexane.

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

The general scheme for preparing a number of compounds of the invention is shown in Schemes 1 and 2 below, which can be modified as appropriate to prepare a number of compounds of the invention. As shown in Scheme 1, a typical first step is the synthesis of a heteroaromatic base molecule (in circumstances where this is not always available).

Typically, a suitably protected diacid group (I) is reacted with an appropriately functionalized acetylene in the presence of a strong base to form II. Compound II is then reacted with hydrazine to form a 5-membered heterocyclic ring compound (III). Compound III is then reacted with an appropriately substituted diacid to form amide IV, which is then cyclized to form a bicyclic heteroaromatic compound V. Finally, compound V is then reacted with POCl ₃ to incorporate chlorine groups for further processing of the ring substituents (compound VI). As will be appreciated by one of skill in the art, this scheme depicts one method for forming an improved intermediate for the synthesis of compounds of the invention. Altering the R group in acetylene and the ester group in the starting diacid allows for the preparation of a number of different improved intermediates using this method.

Once the improved intermediate VI is prepared using the procedure shown in Scheme 1, it can be converted to the compounds of the invention using the procedure shown in Scheme 2, as shown below. Typically, the compound of Formula VI is subjected to a Suzuki coupling with a suitable heteroaromatic boronic acid to introduce a heteroaromatic group and form compounds of Formula VII. Reaction of Compound VII with an appropriately substituted diamine yields compounds of Formula VIII, which are then saponified to remove the acid protecting group to yield the free acid IX. This is then subjected to amide coupling with a suitable aromatic amine to form compounds of Formula X.

As will be appreciated by those skilled in the art, the procedure described in Schemes 1 and 2 can be modified using methodologies well known in the art to produce a significant number of compounds of the invention. Furthermore, the following examples provide modifications to the reactions depicted in these schemes as examples of how this can be accomplished.

Synthesis of compounds

Example 1-5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (1)

Compound 1 is synthesized using the procedure shown in Scheme 3.

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 yellow-white solid. LCMS (Method A): R _t = 0.51 min; [M+H] ⁺ =270.1

Step 2: ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrmidine-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 H ₂ O (110 mL) was stirred at 80 °C overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and H ₂ O (200 mL, 1/1). The organic layers were dried over Na ₂ SO ₄ 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

Step 3: Ethyl 5,7-dichloropyrazolo[1,5-a]pyrmidine-2-carboxylate (XIV)

A solution of ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrmidine-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, which was poured into ice-water and extracted with Et ₂ O (3 x 300 mL). The combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ), 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.

Step 4: Ethyl 5-chloro-7-(1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyrmidine-2-carboxylate (XV)

A mixture of ethyl 5,7-dichloropyrazolo[1,5-a]pyrmidine-2-carboxylate (500 mg, 1.92 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (408 mg, 1.92 mmol), _Na2CO3 (0.384 _g , 3.85 mmol), and Pd(dppf) _2Cl2 (140.6 mg, 3.85 mmol) in degassed 1,4-dioxane (35 mL) and _H2O (7 mL) was stirred at 80 °C overnight under _N2 . The mixture was poured _into water and extracted with EtOAc ₍ 100 mL×3). The combined organic layers were washed with water and brine, dried over _Na2SO4 , 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

Step 5: Ethyl 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (XVI)

A mixture of ethyl 5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-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 column chromatography on silica gel (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.

Step 6: 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (XVII)

To a solution of ethyl 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (400 mg, 1.06 mmol) in THF (8 mL) and MeOH (8 mL) at 0°C was slowly added aqueous KOH (1 M, 4 mL). 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 Et ₂ O (10 mL). The organic layers were discarded, and the aqueous layers were acidified to pH 2 with aqueous HCl (1 M). The aqueous phase was extracted with CHCl ₃ (100 mL × 3) and the combined organic extracts were dried over Na ₂ SO ₄ 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.

Step 7: 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (XVIII)

A mixture of 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (100 mg, 0.29 mmol), 3-aminophenol (34.5 mg, 0.32 mmol), GATU (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 solids were filtered under reduced pressure and purified by column chromatography on silica gel (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 H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 10.02 (s, 1H), 9.45 (s, 1H), 9.34 (s, 1H), 8.70 (d, J=2.8 Hz, 1H), 7.37-7.14 (m, 8H), 6.53 (s, 2H), 4.95 (s, 2H), 3.60 (s, 1H), 3.19 (s, 3H).

The following compounds are prepared similarly from the corresponding starting material 1 (SM1) in step 7 according to the method described for the synthesis of compound 1.

Example 2-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (2)

Starting material 1 used in stage 7 of the synthesis - ammonia, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.47 (s, 1H), 9.36-9.22 (m, 1H), 8.81-8.58 (m, 1H), 8.05 (s, 1H), 7.45 (s, 1H), 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+N] ⁺ =348.0.

Example 3 - N-benzyl-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (3)

Starting material 1 used in step 7 of the synthesis benzylamine, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.4 7 (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=6.4 Hz, 2H), 3.17 (s, 3H). LCMS (Method A): R _t = 2.34 min; [M+H] ⁺ = 438.2;

Example 4-5-(benzyl(methyl)amino)-N-(4-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (4)

Starting material 1 used in step 7 of the synthesis is 4-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.9 Hz, 2H), 7.37-7.24 (m, 5H), 7.16 (s, 1H), 6.77 (d, J=8.8 Hz, 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.

Example 5-5-(benzyl(methyl)amino)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (5)

Starting material 1 used in step 7 of the synthesis is 3-methoxyaniline; ¹ P NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.15 (s, 1H), 9.35 (s, 1H), 8.72 (s, 1H), 7.54 (t, J=2.4 Hz, 1H), 7.43 (s, 1H), 7.38-7.26 (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] ⁺ =45 4, 1.

Example 6-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(pyridin-3-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (6)

Starting material 1 used in step 7 of the synthesis of pyridin-3-amine; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (d, J = 8.0 Hz, 1H), 10.40 (s, 1H), 9.28 (d, J = 3.6 Hz, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1H), 8.37 (dd, J = 3.6, 1.1 Hz, 1H), 8.29-8.24 (m, 1H), 7.47 (dd, J = 8.4, 4.8 Hz, 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.

Example 7-5-(benzyl(methyl)amino)-7-{1H-pyrazol-4-yl)-N-(pyridin-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (7)

Starting material 1 used in step 7 of the synthesis is pyridin-4-amine; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.62-13.44 (m, 1H), 10.57 (s, 1H), 9.31 (s, 1H), 8.73 (s, 1H), 8.54 (d, J=6.4 Hz, 2H), 7.93 (d, J=6.4 Hz, 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;

Example 8-5-(benzyl(methyl)amino)-N-(2-methoxypyridin-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (8)

The starting material 1 used in step 7 of the synthesis is 2-methoxypyridin-4-amine; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.54 (s, 1H), 10.44 (s, 1H), 9.30 (s, 1H), 8.73 (s, 1H), 8.11 (d, J=6.0 Hz, 1H), 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.

Example 9-5-(benzyl(methyl)amino)-N-(3,5-dimethoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (9)

The starting material 1 used in step 7 of the synthesis is 3,5-dimethoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=3.6 Hz, 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.

Example 10-5-(benzyl(methyl)amino)-N-(3,5-dimethylisoxazol-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (10)

The starting material 1 used in step 7 of the synthesis is 3,5-dimethylisoxazol-4-amine; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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.

Example 11-5-(benzyl(methyl)amino)-N,7-di(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (11)

Starting material 1 used in step 7 of the synthesis is 1H-pyrazol-4-amine; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

Example 12-5-(benzyl(methyl)amino)-N-(4-cyanophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (12)

The starting material 1 used in step 7 of the synthesis is 4-aminobenzonitrile; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.55 (s, 1H), 9.31 (s, 1H), 8.72 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 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.

Example 13-5-(benzyl(methyl)amino)-N-(3-cyanophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (13)

Starting material 1 used in stage 7 of the synthesis is 3-aminobenzonitrile; ^1H NMR (400 MHz, 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), 7.69 (t, J=6.4 Hz, 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+N] ⁺ =449.1

Example 14-5-(benzyl(methyl)amino)-N-(3-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (18)

The starting material 1 used in stage 7 of the synthesis is 3-isopropoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 10.09 (s, 1H), 9.31 (s, 1H), 8.70 (s, 1H), 7.49 (t, J=2.4 Hz, 1H), 7.40-7.33 (m, 3H), 7.32-7.24 (m, 4H), 7.16 (s, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.55 (s, 1H), 4.94 (s, 2H), 4.60 (s, 1H), 3.19 (s, 3H), 1.30 (d, J=6.0 Hz, 6H). LCMS (Method A): R _t = 3.25 min; [M+H] ⁺ =482.2

Example 15-5-(benzyl(methyl)amino)-N-(3-(difluoromethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (19)

Starting material 1 used in stage 7 of the synthesis is 3-(difluoromethoxy)aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.32 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 7.79 (t, J=2.4 Hz, 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=8.0 Hz, 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

Example 16-5-(benzyl(methyl)amino)-N-(3-(dimethylamino)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (20)

Starting material 1 used in stage 7 of the synthesis is N1,N1-dimethylbenzene-1,3-diamine; ¹ H NMR (4 00 MHz, DMSO-d ₆ ) 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+N] ⁺ =467.2

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

Starting material 1 used in stage 7 of the synthesis is methanesulfonamide; ^1H NMR (400 MHz, 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.

Example 18-5-(benzyl(methyl)amino)-N-(3-(4-methylpiperazin-1-yl)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (22)

Starting material 1 used in step 7 of the synthesis is 3-(4-methylpiperazin-1-yl)aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.2 Hz, 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.

Example 19-5-(benzyl(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (29)

The starting material 1 used in step 7 of the synthesis is 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.54 (s, 1H), 10.29 (s, 1H), 9.33 (s, 1H), 8.72 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 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.

Example 20-5-(benzyl(methyl)amino)-N-(3-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (30)

Starting material 1 used in stage 7 of the synthesis is 3-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 9.05 (s, 1H), 8.01 (s, 1H), 7.84 (d, J=8.0 Hz, 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.

Example 21-5-(benzyl(methyl)amino)-N-(2-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (31)

Starting material 1 used in step 7 of the synthesis is 2-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.56 (s, 1H), 9.98 (s, 1H), 9.18 (s, 1H), 8.70 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.62 (dd, J=6.8 Hz, 1.2 Hz, 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

Example 22-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (32)

Starting material 1 used in step 7 of the synthesis is 4-(trifluoromethyl)aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.49 (s, 1H), 9.34 (s, 1H), 8.73 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.8 Hz, 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

Example 23-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (33)

Starting material 1 used in step 7 of the synthesis is 3-(trifluoromethyl)aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.4 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.49 (d, J=7.8 Hz, 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.

Example 24-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (34)

Starting material 1 used in step 7 of the synthesis is 2-(trifluoromethyl)aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.57 (s, 1H), 9.91 (s, 1H), 9.15 (s, 1H), 8.68 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.85-7.74 (m, 2H), 7.49 (t, J=7.6 Hz, 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;

Example 25-5-(benzyl(methyl)amino)-N-(4-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (35)

Starting material 1 used in stage 7 of the synthesis is 4-fluoroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H), 10.28 (s, 1H), 9.33 (s, 1H), 8.72 (s, 1H), 7.84 (dd, J=5.2 Hz, 2.0 Hz, 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+N] ⁺ =488.1

Example 26-5-(benzyl(methyl)amino)-N-(3-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (36)

Starting material 1 used in step 7 of the synthesis is 3-fluoroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.33 (s, 1H), 9.32 (s, 1H), 8.72 (s, 1H), 7.81 (d, J=11.6 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.47-7.24 (m, 6H), 7.19 (s, 1H), 6.97 (td, J=8.6 Hz, 2.4 Hz, 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.

Example 27-5-(benzyl(methyl)amino)-N-(2-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (37)

The starting material 1 used in step 7 of the synthesis is 2-fluoroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.00 (s, 1H), 9.28 (s, 1H), 8.72 (s, 1H), 7.78 (td, J=7.8, 2.1 Hz, 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.

The following compounds are prepared analogously from the appropriate starting material in Step 5 and the appropriate starting material 2 in Step 7 according to the method described for the synthesis of compound 1 in Scheme 3 above.

Example 28 - (S)-N-(3-methoxyphenyl)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (14)

The starting material used in step 5 is (S)-N-methyl-1-phenylethan-1-amine; The starting material used in step 7 is 3-methoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.14 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.45-7.27 (m, 7H), 7.19 (s, 1H), 6.73 (dd, J=8.2 Hz, 2.0 Hz, 1H), 6.56 (s, 1H), 6.27-6.11 (m, 1H), 3.79 (s, 3H), 2.90 (s, 3H), 1.60 (d, J=6.8 Hz, 3H). LCMS (Method A): R _t = 2.53 min; [M+H] ⁺ =468.0

Example 29 (S)-N-(3-hydroxyphenyl)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (15)

Starting material from step 5, (S)-N-methyl-1-phenylethan-1-amine; starting material from step 7, 3-aminophenol; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 10.04 (s, 1H), 9.40 (d, J=16 Hz, 2H), 8.74 (s, 1H), 7.40-7.14 (m, 9H), 6.54 (s, 2H), 6.18 (dd, J=2.8 Hz, 1.2 Hz, 1H), 2.89 (s, 3H), 1.60 (d, J=6.8 Hz, 3H). LCMS (Method A): R _t = 2.34 min; [M+H] ⁺ =454.0.

Example 30 - (S)-5-(methyl(1-phenylethyl)amino)-N-phenyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (16)

The starting material from step 5 was (S)-N-methyl-1-phenylethan-1-amine; the starting material from step 7 was aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 10.17 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 7.84 (d, J=7.8 Hz, 2H), 7.52-7.07 (m, 9H), 6.55 (s, 1H), 6.19 (s, 1H), 2.89 (s, 3H), 1.60 (d, J=6.4 Hz, 3H). LCMS (Method A): R _t = 3.15 min; [M+H] ⁺ = 438.0.

Example 31 - (S)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (17)

The starting material used in step 5 is (S)-N-methyl-1-phenylethan-1-amine; the starting material used in step 7 is ammonia; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.46 (s, 1H), 9.30 (d, J=1.6 Hz, 1H), 8.70 (d, J=2.8 Hz, 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=6.8 Hz, 3H). LCMS (Method A): R _t =2.09 min; [M+N] ⁺ =362.0.

Example 32-5-(isoindolin-2-yl)-N-phenyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (23)

The starting material from step 5 isoindoline; the starting material from step 7 is aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 10.19 (s, 1H), 9.38 (s, 1H), 8.78 (s, 1H), 7.48 (d, J=7.6 Hz, 2H), 7.45-7.35 (m, 6H), 7.15 (d, J=7.2 Hz, 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.

Example 33 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (24)

The starting material from step 5, isoindoline, the starting material from step 7, 3-aminophenol; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=7.2 Hz, 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.

Example 34-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (25)

The starting material from step 5, isoindoline, the starting material from step 7, 3-methoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=7.2 Hz, 1H), 7.09 (s, 1H), 6.73 (d, J=7.6 Hz, 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

Example 35-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (26)

The starting material used in step 5 is isoindoline; the starting material used in step 7 is 3-trifluoromethoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.55 (s, 1H), 10.45 (s, 1H), 9.37 (s, 1H), 8.79 (d, J=7.8 Hz, 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+N] ⁺ =506.0.

Example 36 - N-(3-ethoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (27)

The starting material in step 5, isoindoline; the starting material in step 7, 3-ethoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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), 6.71 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 4.98 (d, J=1.6 Hz, 4H), 4.05 (d, J=6.8 Hz, 2H), 1.37 (s, 3H). LCMS (Method A): R _t = 3.17 min; [M+H] ⁺ =466.11.

Example 37-5-(isoindolin-2-yl)-N-(3-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (28)

The starting material for step 5 isoindoline; the starting material for step 7 is 3-isopropoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.2 Hz, 1H), 7.10 (s, 1H), 6.70 (dd, J=8.2, 1.9 Hz, 1H), 6.61 (s, 1H), 4.98 (s, 4H), 4.66-4.56 (m, 1H), 1.31 (d, J=6.0 Hz, 6H). LCMS (Method A): R _t = 3.25 min; [M+H] ⁺ = 480.11.

Example 38 - N-(4-chlorophenyl)-5-((4-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (38)

The starting material used in step 5 is 1-(4-methoxyphenyl)-N-methylmethanamine; the starting material used in step 7 is 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.5 0 (s, 1H), 10.28 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 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.

Example 39 - N-(4-chlorophenyl)-5-((3-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (39)

The starting material used in step 5 is 1-(3-methoxyphenyl)-N-methylmethanamine; the starting material used in step 7 is 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 9.02 (s, 1H), 8.71 (s, 1H), 7.88 (d, J=7.2 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.26 (t, J=7.6 Hz, 1H), 7.17 (s, 1H), 6.91 (t, J=7.2 Hz, 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.

Example 40 N-(4-chlorophenyl)-5-((2-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (40)

The starting material used in step 5 is 1-(2-methoxyphenyl)-N-methylmethanamine; the starting material used in step 7 is 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H), 10.28 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 7.88 (d, J=7.2 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.25 (t, J=6.4 Hz, 1H), 7.17 (s, 1H), 7.05 (d, J=8.0 Hz, 2H), 6.89 (t, J=6.8 Hz, 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.

Example 41 - N-(4-chlorophenyl)-5-(methyl(4-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (41)

The starting material for step 5 was 1-(4-trifluoromethoxyphenyl)-N-methylmethanamine; the starting material for step 7 was 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.30 (s, 1H), 9.34 (s, 1H), 8.73 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.48 (dd, J=16.0 Hz, 8.0 Hz, 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.

Example 42 - N-(4-chlorophenyl)-5-(methyl(3-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (42)

The starting material used in step 5 is 1-(3-trifluoromethoxyphenyl)-N-methylmethanamine; the starting material used in step 7 is 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.30 (s, 1H), 9.33 (s, 1H), 8.73 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.69 (s, 1H), 7.71-7.63 (m, 1H), 7.59 (d, J=5.2 Hz, 2H), 7.45 (dd, J=8.80 Hz, 2.8 Hz, 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.

Example 43 - N-(4-chlorophenyl)-5-(methyl(2-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (43)

The starting material for step 5 was 1-(2-trifluoromethoxyphenyl)-N-methylmethanamine; the starting material for step 7 was 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=7.6 Hz, 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.

Example 44-5-((4-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (44)

The starting material for step 5 was 1-(4-chlorophenyl)-N-methylmethanamine; the starting material for step 7 was 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.30 (s, 1H), 9.33 (s, 1H), 8.72 (s, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.47-7.38 (m, 4H), 7.33 (d, J=8.5 Hz, 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.

Example 45-5-((3-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (45)

The starting material for step 5 was 1-(3-chlorophenyl)-N-methylmethanamine; the starting material for step 7 was 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.30 (s, 1H), 9.33 (s, 1H), 8.73 (s, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.41-7.31 (m, 3H), 7.26 (d, J=7.4 Hz, 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.

Example 46-5-((2-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (46)

The starting material used in step 5 is 1-(2-chlorophenyl)-N-methylmethanamine; the starting material used in step 7 is 4-chloroaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.30 (s, 1H), 9.33 (s, 1H), 8.74 (s, 1H), 7.88 (d, J=4.4 Hz, 2H), 7.51 (d, J=6.0 Hz, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.31 (t, J=2.8 Hz, 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.

Example 4 7-5-(isoindolin-2-yl)-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (47)

The starting material used in step 5 is isoindoline; the starting material used in step 7 is 3-morpholinoaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.05 (s, 1H), 9.37 (s, 1H), 8.74 (s, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.39-7.34 (m, 3H), 7.23 (t, J=8.0 Hz, 1H), 7.09 (s, 1H), 6.75 (dd, J=6.0 Hz, 2.0 Hz, 1H), 6.60 (s, 1H), 4.97 (s, 4H), 3.77 (t, J=5.2 Hz, 4H), 3.13 (t, J=4.8 Hz, 4H). LCMS (Method A): R _t = 3.91 min; [M+H] ⁺ = 5 0 7.2.

Example 48-5-(isoindolin-2-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (48)

The starting material in step 5 is isoindoline; the starting material in step 7 is 3-(4-methylpiperazin-1-yl)aniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.54 (s, 1H), 10.05 (s, 1H), 9.36 (d, J=1.6 Hz, 1H), 8.78 (d, J=1.6 Hz, 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

Example 49 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidin-2-carboxamide (49)

The starting material used in step 5 is isoindoline, the starting material used in step 7 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 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;

Example 50 - N-(3-cyclobutoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (50)

The starting material used in step 5 is isoindoline, the starting material used in step 7 is 3-cyclobutoxyaniline; GE NMR (400 MHz, DMSO-d ₆ ) δ 13.54 (s, 1H), 10.14 (s, 1H), 9.37 (d, J=2.8 Hz, 1H), 8.77 (s, 1H), 7.57-7.21 (m, 8H), 7.09 (s, 1H), 6.62 (d, J=11.2 Hz, 2H), 4.98 (d, J=2.8 Hz, 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;

Example 51 - N-(3,5-dimethoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (51)

The starting material in step 5 is isoindoline, the starting material in step 7 is 3,5-dimethoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 10.05 (s, 1H), 9.35 (s, 1H), 8.80 (s, 1H), 7.44 (d, J=2.8 Hz, 2H), 7.37-7.35 (m, 2H), 7.16 (d, J=2.0 Hz, 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.

Example 52 - N-(3-chloro-5-methoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (52)

The starting material for step 5 was isoindoline, the starting material for step 7 was 3-chloro-5-methoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 2H), 7.37 (d, J=2.8 Hz, 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.

Example 53 - N-(4-chloro-3-methoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (53)

The starting material in step 5 is isoindoline; the starting material in step 7 is 4-chloro-3-methoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.56 (s, 1H), 10.30 (s, 1H), 9.37 (s, 1H), 9.00-8.59 (m, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.57-7.32 (m, 6H), 7.10 (s, 1H), 6.62 (s, 1H), 4.97 (d, J=1.6 Hz, 4H), 3.89 (s, 3H). LCMS (Method A): R _t = 4.27 min; [M+H] ⁺ = 486.1

Example 54-5-(isoindolin-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (54)

The starting material in step 5 is isoindoline; the starting material in step 7 is 4-methoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 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.

Example 55 - N-(4-zoxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (55)

The starting material for step 5 is isoindoline, the starting material for step 7 is 4-ethoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (s, 1H), 10.09 (s, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.53-7.32 (m, 4H), 7.08 (s, 1H), 6.95 (d, J=8.8 Hz, 2H), 6.57 (s, 1H), 4.97 (s, 4H), 4.03 (q, J=6.4 Hz, 2H), 1.34 (t, J=6.0 Hz, 3H). LCMS (Method A): R _t = 3.18 min; [M+H] ⁺ = 4 6 6.04.

Example 56-5-(isoindolin-2-yl)-N-(4-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (56)

The starting material for step 5 is isoindoline, the starting material for step 7 is 4-isopropoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.55 (s, 1H), 10.09 (s, 1H), 9.35 (s, 1H), 8.77 (s, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.44 (d, J=3.2 Hz, 2H), 7.37-7.35 (m, 2H), 7.07 (s, 1H), 6.95 (d, J=8.8 Hz, 2H), 6.57 (s, 1H), 4.97 (s, 4H), 4.62-4.55 (m, 1H), 1.27 (t, J=6.0 Hz, 3H). LCMS (Method A): R _t =42.2 min; [M+N] ⁺ =480, 2.

Example 57-5-(5-chloroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (61)

The starting material for step 5 was 5-chloroisoindoline, the starting material for step 7 was 4-methoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.55 (s, 1H), 10.16 (s, 1H), 9.37 (s, 1H), 8.75 (s, 1H), 7.50 (d, J=3.2 Hz, 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;

Example 58-5-(5-chloroisoindolin-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (62)

The starting material used in step 5 is 5-chloroisoindoline, the starting material used in step 7 is 4-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.42-7.38 (m, 3H), 7.22 (d, J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.06 (s, 1H), 6.59 (s, 1H), 4.55 (d, J=8.0 Hz, 1H), 4.95 (s, 4H). LCMS (Method A): R _t = 3.90 min; [M+H] ⁺ = 4 7 2.1.

Example 59-5-(5-fluoroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (63)

The starting material used in the 5-5-fluoroisoindoline stage, the starting material used in the 7-4-methoxyaniline stage; ^1H NMR (400 MHz, 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+N] ⁺ =470.1.

Example 60-5-(5-fluoroisoindolin-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidin-2-carboxamide (64)

Starting material used in step 5-5-fluoroisoindoline, starting material used in step 7-4-aminophenol, ^1H NMR (400 MHz, 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=2.0 Hz, 1.2 Hz, 4H). LCMS (Method A): R _t =3.93 min; [M+H] ⁺ =456.1.

The following compounds are prepared similarly from the appropriate starting material in Step 4, the appropriate starting material in Step 5, and the appropriate starting material in Step 7 according to the method described for the synthesis of compound 1.

Example 61-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (57)

The starting material used in step 4 is 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; the starting material used in step 5 is isoindoline; starting material used in step 7-4-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 7.57 (t, J=2.0 Hz, 1H), 7.34 (t, J=8.8 Hz, 2H), 7.37-7.35 (m, 2H), 7.30 (t, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.73 (dd, J=6.0 Hz, 2.0 Hz, 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.

Example 62 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (58)

The starting material used in step 4 is 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the starting material used in step 5 is isoindoline, the starting material used in step 7 is 4-aminophenol; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=7.6 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.75 (t, J=8.0 Hz, 2H), 4.97 (s, 4H), 4.03 (s, 3H). LCMS (Method A): R _t =3.81 min; [M+N] ⁺ =452, 1.

Example 63-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (59)

The starting material in step 4 is 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the starting material in step 5 is isoindoline, and the starting material in step 7 is 4-methoxyaniline; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.8 Hz, 6H), 2.25 (d, J=6.4 Hz, 6H). LCMS (Method A): R _t = 4.20 min; [M+H] ⁺ = 494.2.

Example 64 - N-{3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (60)

The starting material for step 4 is 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the starting material for step 5 is isoindoline, the starting material for step 7 is 4-aminophenol, πH NMR (400 MHz, DMSO-d ₆ ) δ 9.68 (s, 1H), 9.41 (s, 1H), 7.49-7.31 (m, 5H), 7.18-7.07 (m, 2H), 6.61 (s, 1H), 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+N] ⁺ =480.2.

Example 65-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide

Compound 65 is obtained according to the procedure shown in Scheme 4.

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 ₂ cooled to -78 °C was added propionitrile (0.90 g, 16.42 mmol) 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. H ₂ O (100 mL) was added, and the organic phase was removed with Et ₂ O (100 mL). The aqueous phase was adjusted to pH 5 with aqueous HCl (6 M) and extracted with Et ₂ O (3×100 mL). The combined organic layers 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

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

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, washed with DCM (2×10 mL), and the combined filtrates were 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

Step 4: Ethyl 5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrmidine-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 H ₂ O (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 H ₂ O (50 mL). The organic layers were dried over Na ₂ SO ₄ 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

Step 5: Ethyl 5,7-dichloro-3-methylpyrazolo[1,5-a]pyrmidine-2-carboxylate (XXIII)

A mixture of ethyl 5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrmidine-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 Et ₂ O (3 x 300 mL). The combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ), 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.

Step 6: Ethyl 5-chloro-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (XXIV)

A mixture of ethyl 5,7-dichloro-3-methylpyrazolo[1,5-a]pyrmidine-2-carboxylate (3 g, 11.15 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (2.3 g, 11.15 mmol) _{, Na2CO3} (2.3 g, 22.30 mmol), and Pd(dppf) _2Cl2 (0.80 g, 1.11 mmol) in degassed _1,4 -dioxane (50 mL) and _H2O (10 mL) was stirred at 80°C overnight under _N2 . The mixture was poured into water and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water and brine, dried _{over Na2SO4} , 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

Step 7: Ethyl 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (XXV)

A mixture of ethyl 5-chloro-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-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 solids were filtered under reduced pressure. The solids were purified by column chromatography on silica gel (DCM:MeOH, 90:10) to give the desired product (1 g, 53%) as a yellow solid. LCMS: (Method A), R _t = 4.97 min, [M+H] ⁺ = 389.2

Step 8: 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (XXVI)

To a solution of ethyl 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (1 g, 2.62 mmol) in THF (12 mL) and MeOH (12 mL) at 0 °C was slowly added aqueous 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 H ₂ O and Et ₂ O (50 mL, 1/1). The organic layers were discarded, and the aqueous layers were acidified to pH 2 with aqueous HCl (2 M). The aqueous phase was extracted with CHCl ₃ (100 mL × 3), and the combined organic layers were dried over Na ₂ SO ₄ 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

Step 9: 5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (XXVII) (Compound 65)

A mixture of 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (200 mg, 0.56 mmol), 3-aminophenol (68 mg, 0.62 mmol), GATU (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 solids were filtered under reduced pressure. The filter cake was dried and purified by column chromatography on silica gel (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 H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.06 (s, 1H), 6.53 (d, J=6.0 Hz, 1H), 4.96 (s, 4H), 2.42 (s, 3H).

Example 66-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (66)

The starting material for step 7 is isoindoline, the starting material for step 9 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.06 (s, 1H), 6.72 (d, J=6.0 Hz, 1H), 4.96 (s, 4H), 3.79 (s, 3H), 2.42 (s, 3H). LCMS: (Method A), R _t = 4.61 min, [M+H] ⁺ = 465.2.

Example 67-5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (67)

Starting material used in step 7 - isoindoline, starting material used in step 9-3-(trifluoromethoxy)aniline, ^1H NMR (400 MHz, 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=7.6 Hz, 1H), 7.53-7.46 (m, 3H), 7.37-7.35 (m, 2H), 7.11 (t, J=7.6 Hz, 2H), 4.78 (s, 4H), 2.42 (s, 3H). LCMS: (Method A), R _t = 3.54 min, [M+H] ⁺ = 520.1.

Example 68-5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (68)

The starting material for step 7 was N-methyl-1-phenylmethanamine, the starting material for step 9 was 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.4 6 (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=8.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 2H), 6.52 (d, J=7.6 Hz, 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.

Example 69-5-(benzyl(methyl)amino)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (69)

The starting material for step 7 was N-methyl-1-phenylmethanamine, the starting material for step 9 was 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.46 (s, 1H), 10.06 (s, 1H), 9.32 (s, 1H), 8.69 (s, 1H), 7.54 (t, J=2.4 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.35 (t, J=3.2 Hz, 4H), 7.28 (t, J=8.0 Hz, 2H), 7.15 (s, 1H), 6.71 (d, J=6.0 Hz, 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.

Example 70-5-(benzyl(methyl)amino)-3-methyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (70)

The starting material for step 7 is N-methyl-1-phenylmethanamine, the starting material for step 9 is 3-(trifluoromethoxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.43 (s, 4H), 7.27 (d, J=3.2 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=8.0 Hz, 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.

Example 71 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (71)

Compound 71 is obtained according to the procedure shown in Scheme 5.

Step 1: Ethyl 3-cyano-4-methyl-2-oxopentanoate (XXVIII)

To a solution of LiHMDS (1.0 M in THF, 3 42 mL, 0.3 4 mol) in dry THF (450 mL) under N ₂ at -78 °C was added 3-methylbutanenitrile (43 mL, 0.41 mol) dropwise over 10 min, and the mixture was stirred for 1 h at -78 °C. Diethyl oxalate (46 mL, 0.34 mol) was added dropwise over 5 min and stirred at -78 °C for 1 h and then at 0 °C for 1 h. The mixture was diluted with H ₂ O and the organic phases were extracted with Et ₂ O (200 mL). The aqueous phase was adjusted to pH 5 with aqueous HCl (1 M), and then the organic layers were extracted with Et ₂ O (2 × 200 mL). The organic layers were washed with brine, dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to afford the title product (44.2 g, 71%) as a yellow oil.

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 heated under reflux 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 organic layers were dried over _Na2SO4 , _filtered , concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the desired product (23 g, 51%) as a yellow solid.

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 organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (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.

Step 4: Ethyl 5,7-dihydroxy-3-isopropylpyrazolo[1,5-a]pyrmidine-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 H ₂ O (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 organic layers 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 = 0.91 min, [M+H] ⁺ = 266.0

Step 5: Ethyl 5, 7-dichloro-3-isopropylpyrazolo[1,5-a]pyrmidine-2-carboxylate (XXXII)

A solution of ethyl 5,7-dihydroxy-3-isopropylpyrazolo[1,5-a]pyrmidine-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, and the residue was poured into ice-water, extracted with DCM (3×20 mL), and the combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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

Step 6: Ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (XXXIII)

A mixture of ethyl 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrmidine-2-carboxylate (1.0 g, 3.32 mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (704 mg, 3.32 mmol), _Na2CO3 (704 mg, 6.64 mmol), and Pd(dppf) _{2Cl2 (} 243 mg, 0.39 mmol) in degassed 1,4 _- dioxane (40 mL) and _H2O (8 mL) was stirred under _N2 at 80°C overnight. The mixture was poured into water and extracted with DCM (20 mL × 3). The organic layers were washed with water and brine, dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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.

Step 7: Ethyl 5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (XXXIV)

A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-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 H ₂ O 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.

Step 8: 5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (XXXV)

A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-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 H ₂ O, 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

Step 9: N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (XXXVI)

A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (200 mg, 0.52 mmol), 3-aminophenol (62 mg, 0.57 mmol), GATU (294 mg, 0.77 mmol) and DIEA (134 mg, 1.04 mmol) in DMF (5 mL) was stirred at RT overnight. The mixture was diluted with _H2O and the residue was filtered and then purified by column chromatography on silica gel (DCM:MeOH, 100:0-98:2) to give the title product (142 mg, 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.4 Hz, 1H), 7.14 (t, J=8 Hz, 1H), 7.04 (s, 1H), 6.53 (d, J=1.6 Hz, 1H), 4.97 (s, 4H), 3.83-3.76 (m, 1H), 1.46 (d, J=7.2 Hz, 6H). LCMS: (Method A), R _t = 4.61 min, [M+H] ⁺ = 480.2.

The following compounds are prepared in a similar manner using the appropriate starting materials in step 7 and step 9 of Scheme 5 according to the method described for the synthesis of compound 71.

Example 72-5-(isoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (72)

The starting material in step 7 is isoindoline, the starting material in step 9 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.56-7.42 (m, 3H), 7.36 (dd, J=5.6 Hz, 3.2 Hz, 2H), 7.16-7.04 (m, 2H), 4.98 (s, 4H), 3.88-3.74 (m, 1H), 1.47 (d, J=7.2 Hz, 6H). LCMS: (Method A), R _t =4.16 min, [M+H] ⁺ =548.1

Example 73-5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (73)

The starting material for step 7 is isoindoline, the starting material for step 9 is 3-(trifluoromethoxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.56-7.42 (m, 3H), 7.36 (dd, J=5.6 Hz, 3.2 Hz, 2H), 7.16-7.04 (m, 2H), 4.98 (s, 4H), 3.88-3.74 (m, 1H), 1.47 (d, J=7.2 Hz, 6H). LCMS: (Method A), R _t =4.16 min, [M+H] ⁺ =548.1

Example 74-5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (74)

The starting material for step 7 is N-methyl-1-phenylmethanamine, the starting material for step 9 is 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1.3 Hz, 1H), 4.93 (s, 2H), 3.81-3.65 (m, 1H), 3.20 (s, 3H), 1.37 (d, J=7.2 Hz, 6H). LCMS (Method A): R _t = 4.45 min, [M+H] ⁺ = 482.2.

Example 75-5-(benzyl(methyl)amino)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (75)

The starting material for step 7 is N-methyl-1-phenylmethanamine, the starting material for step 9 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=4.4 Hz, 4H), 7.27 (t, J=8.0 Hz, 2H), 7.13 (s, 1H), 6.70 (dd, J=8.0 Hz, 2.0 Hz, 1H), 4.93 (s, 2H), 3.78 (s, 4H), 3.21 (s, 3H), 1.37 (d, J=7.2 Hz, 6H). LCMS (Method A): R _t =3.26 min, [M+H] ⁺ =496.2

Example 76-5-(benzyl(methyl)amino)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (76)

The starting material for step 7 is N-methyl-1-phenylmethanamine, the starting material for step 9 is 3-(trifluoromethoxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.34 (s, 4H), 7.27 (d, J=4.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 2H), 4.93 (s, 2H), 3.78 (s, 1H), 3.21 (s, 3H), 1.37 (d, J=6.4 Hz, 6H). LCMS (Method A): R _t =3.96 min, [M+H] ⁺ =550.1

Example 77-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (77)

Starting material used in step 7-5-fluoroisoindoline, starting material used in step 9-3-methoxyaniline, ^1H NMR (400 MHz, 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=8.8 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.04 (s, 1H), 6.71 (d, J=6.4 Hz, 1H), 4.95 (d, J=12.0 Hz, 4H), 3.79 (s, 4H), 1.46 (d, J=7.2 Hz, 6H). LCMS (Method A): R _t =3.53 min, [M+H] ⁺ =512.2.

Example 78 - N-(3-acetamidophenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (78)

Starting material used in step 7-5-fluoroisoindoline, starting material used in step 9 - N-(3-aminophenyl)acetamide, ^1H NMR (400 MHz, 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.

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]pyrmidine-2-carboxamide (79)

The starting material used in step 7 is 5-fluoroisoindoline, the starting material used in step 9 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H), 10.03 (s, 1H), 9.28 (s, 1H), 8.71 (s, 1H), 7.58-7.16 (m, bH), 7.02 (s, 1H), 6.75 (d, J=1.6 Hz, 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=7.2 Hz, 6H). LCMS (Method A): R _t =4.54 min, [M+H] ⁺ =608.3

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]pyrmidine-2-carboxamide (80)

The starting material used in step 7 is 5-fluoroisoindoline, the starting material used in step 9 is 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.49 (s, 1H), 10.0 (s, 1H), 9.28 (s, 1H), 8.70 (s, 1H), 7.68 (d, J=6.8 Hz, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 7.19 (t, J=6.8 Hz, 1H), 6.99 (t, J=6.4 Hz, 3H), 4.94 (t, J=11.2 Hz, 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=7.2 Hz, 6H). LCMS (Method A): R _t =4.44 min, [M+H] ⁺ =608.3

Example 81-5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (81)

The starting material used in step 7 is 5-chloroisoindoline, the starting material used in step 9 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.03 (s, 1H), 6.71 (d, J=6.4 Hz, 1H), 4.94 (s, 4H), 3.78 (s, 4H), 1.46 (d, J=7.2 Hz, 6H), LCMS (Method A): R _t = 3.86 min, [M+H] ⁺ =528.2.

Example 82 - N-(3-acetamidophenyl)-5-(5-chloroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (82)

The starting material used in step 7 is 5-chloroisoindoline, the starting material used in step 9 is N-(3-aminophenyl)acetamide, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=4.8 Hz, 1H), 7.03 (s, 1H), 4.94 (s, 4H), 3.80 (t, J=7.2 Hz, 1H), 2.06 (s, 3H), 1.46 (d, J=7.2 Hz, 6H). LCMS (Method A): R _t = 4.72 min, [M+H] ⁺ = 555.2

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]pyrmidine-2-carboxamide (83)

The starting material used in step 7 is 5-chloroisoindoline, the starting material used in step 9 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=6.4 Hz, 1H), 4.95 (s, 4H), 3.83-3.78 (m, 1H), 3.61 (s, 4H), 3.18 (d, J=2.4 Hz, 4H), 2.06 (d, J=7.6 Hz, 3H), 1.46 (d, J=6.8 Hz, 6H). LCMS (Method A): R _t =4.81 min, [M+H] ⁺ =623.2.

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]pyrmidine-2-carboxamide (84)

Starting material used in step 7-5-chloroisoindoline, starting material used in step 9-1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one, ^1H NMR (400 MHz, 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=7.2 Hz, 3H), 4.95 (s, 4H), 3.82 (t, J=6.8 Hz, 1H), 3.59 (d, J=4.0 Hz, 4H) 3.14 (s, 2H), 3.07 (s, 2H), 2.06 (d, J=7.6 Hz, 3H), 1.46 (d, J=6.8 Hz, 6H). LCMS (Method A): R _t =4.62 min, [M+H] ⁺ =624.2.

Example 85-5-(5-fluoroisoindolin-2-yl)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (99)

The starting material used in step 7 is 5-fluoroisoindoline, the starting material used in step 9 is 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 6.54 (d, J=9.2 Hz, 1H), 4.95 (d, J=11.6 Hz, 4H), 3.83-3.76 (m, 1H), 3.21-3.17 (m, 1H), 1.46 (d, J=7.0 Hz, 6H). LCMS: (Method A), R _t =4.66 min, [M+H] ⁺ =498.2

Example 86-5-(5-chloroisoindolin-2-yl)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (100)

The starting material used in step 7 is 5-chloroisoindoline, the starting material used in step 9 is 3-aminophenol. ^1H NMR (400 MHz, 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=8.4 Hz, 1H), 7.14 (t, 17=8.0 Hz, 1H), 7.02 (s, 1H), 6.54 (d, J=6.5 Hz, 1H), 4.96 (s, 4H), 3.83-3.76 (m, 1H), 1.46 (d, J=6.8 Hz, 6H). LCMS (Method A): R _t =4.69 min; [MN] ⁺ =514.2.

Example 87-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (101)

Starting material used in step 7-5-fluoroisoindoline, starting material used in step 9-3-morpholinoaniline, ^1H NMR (400 MHz, 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=1.6 Hz, 1H), 4.94 (d, J=11.6 Hz, 4H), 3.85-3.76 (m, 5H), 3.1-3.11 (m, 4H), 1.45 (d, J=7.0 Hz, 6H). LCMS: (Method A), R _t = 3.42 min, [M+H] ⁺ = 567.2.

Example 88-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-N-(4-(2-methoxyethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (102)

The starting material used in step 7 is 5-fluoroisoindoline, the starting material used in step 9 is 4-(2-methoxyethoxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.48 (s, 1H), 10.06 (s, 1H), 9.29 (s, 1H), 8.70 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.49-7.16 (m, 3H), 7.02 (s, 1H), 6.96 (d, J=9.2 Hz, 2H), 4.94 (d, J=12.0 Hz, 4H), 4.10 (t, J=4.8 Hz, 2H), 3.85-3.78 (m, 1H), 3.67 (t, J=4.4 Hz, 2H), 3.33 (s, 3H), 1.45 (d, J=7.0 Hz, 6H). LCMS: (Method A), R _t =4.81 min, [M+H] ⁺ =556, 2.

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]pyrmidine-2-carboxamide (103)

The starting material used in step 7 is 5-fluoroisoindoline, the starting material used in step 9 is 7-amino-3,4-dihydroquinolin-2(1H)-one, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.49 (s, 1H), 10.14 (d, J=14.8 Hz, 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=11.6 Hz, 4H), 3.84-3.77 (m, 1H), 2.85 (t, J=7.2 Hz, 2H), 2.47-2.44 (m, 2H), 1.45 (d, J=6.8 Hz, 6H). LCMS: (Method A), R _t =4.71 min, [M+H] ⁺ =551.2

Example 90-5-(5-fluoroisoindolin-2-yl)-N-(1H-indazol-6-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (104)

The starting material for step 7 is 5-fluoroisoindoline, the starting material for step 9 is 1H-indazol-6-amine, ^1H NMR (400 MHz, DMSO-d ₆ ) 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=8.8 Hz, 1H), 7.54-7.32 (m, 3H), 7.20 (t, J=8.8 Hz, 1H), 7.04 (s, 1H), 4.96 (d, J=11.6 Hz, 4H), 3.86-3.79 (s, 1H), 1.48 (d, J=7.0 Hz, 6H). LCMS: (Method A), R _t =4.66 min, [M+H] ⁺ =522.2

Example 91-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-N-(3-(methylsulfonamido)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (105)

The starting material used in step 7 is 5-fluoroisoindoline, the starting material used in step 9 is N-(3-aminophenyl)methanesulfonamide, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.4 Hz, 2H), 7.32 (t, J=8.0 Hz, 2H), 7.19 (t, J=10.8 Hz, 1H), 7.04-6.96 (m, 2H), 4.95 (d, J=11.6 Hz, 4H), 3.83-3.75 (m, 1H), 3.03 (s, 3H), 1.46 (d, J=7.2 Hz, 6H). LCMS: (Method A), R _t =4.64 min, [M+H] ⁺ =575.2

Example 92-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-N-(4-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (106)

Starting material used in step 7-5-fluoroisoindoline, starting material used in step 9-4-morpholinoaniline, ^1H NMR (400 MHz, 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=8.4 Hz, 2H), 4.94 (s, 4H), 4.10 (kv, J=5.2 Hz, 1H), 3.84-3.76 (m, 5H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s, 4H), 1.45 (d, J=7.2 Hz, 6H). LCMS: (Method A), R _t =3.11 min, [M+H ⁺ =567.2.

Example 93-5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(4-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (107)

Starting material used in step 7-5-chloroisoindoline, starting material used in step 9-4-morpholinoaniline, ^1H NMR (400 MHz, DMSO- _d6 ) δ 13.4 8 (s, 1H), 9.99 (s, 1H), 9.2 8 (s, 1H), 8.70 (s, 1H), 7.69-7.40 (m, 5H), 7.01 (s, 1H), 6.96 (d, J=8.4 Hz, 2H), 4.94 (s, 4H), 4.10 (kv, J=5.2 Hz, 1H), 3.84-3.76 (m, 5H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s, 4H), 1.45 (d, J=7.2 Hz, 6H). LCMS: (Method A), R _t =2.67 min, [M+H] ⁺ =583.1

Example 94-5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (108)

Starting material used in step 7-5-chloroisoindoline, starting material used in step 9-3-morpholinoaniline, ^1H NMR (400 MHz, 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=6.0 Hz, 6H). LCMS: (Method A), R _t =2.96 min, [M+H] ⁺ =583.2.

Example 95-5-(5-chloroisoindolin-2-yl)-3-isopropyl-N-(4-(2-methoxyethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (109)

The starting material used in step 7 is 5-chloroisoindoline, the starting material used in step 9 is 4-(2-methoxyethoxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.48 (s, 1H), 10.06 (s, 1H), 9.29 (s, 1H), 8.70 (s, 1H), 7.71 (d, J=8.8 Hz, 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=6.8 Hz, 6H). LCMS: (Method A), R _t =3.59 min, [M+H] ⁺ =572.2.

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]pyrmidine-2-carboxamide (117)

The starting material used in step 7 is 5-chloroisoindoline, the starting material used in step 9 is 3-((tetrahydro-2H-pyran-4-yl)oxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.03 (s, 1H), 6.76 (d, J=8.2 Hz, 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=7.0 Hz, 6H). LCMS: (Method A), R _t =2.70 min, [M+H] ⁺ =598.4

Example 97-5-(5-chloroisoindolin-2-yl)-N-(2-fluoro-3-methoxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (118)

Starting material used in step 7-5-chloroisoindoline, starting material used in step 9-2-fluoro-3-methoxyaniline, ^1H NMR (400 MHz, 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), 7.19-7.14 (m, 1H), 7.06-7.02 (m, 2H), 4.94 (s, 4H), 3.92-3.85 (m, 4H), 1.45 (d, J=7.0 Hz, 6H). LCMS: (Method A), R _t = 2.94 min, [M+H] ⁺ = 546.4

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]pyrmidine-2-carboxamide (119)

The starting material used in step 7 is 5-chloroisoindoline, the starting material used in step 9 is 4-((tetrahydro-2H-pyran-4-yl)oxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=7.0 Hz, 6H). LCMS: (Method A), R _t =2.74 min, [M+H] ⁺ =598.2

Example 99-5-(5-chloroisoindolin-2-yl)-N-(2-fluoro-5-methoxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (120)

Starting material used in step 7-5-chloroisoindoline, starting material used in step 9-2-fluoro-5-methoxyaniline, ^1H NMR (400 MHz, 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), 7.05 (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=7.0 Hz, 6H). LCMS: (Method A), R _t = 4.14 min, [M+H] ⁺ = 545.2

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]pyrmidine-2-carboxamide (121)

The starting material used in step 7 is 5-fluoroisoindoline, the starting material used in step 9 is 3-((tetrahydro-2H-pyran-4-yl)oxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 9.00 (s, 2H), 7.53-7.16 (m, 6H), 7.03 (s, 1H), 6.76 (dd, J=8.2 Hz, 2.0 Hz, 1H), 4.95 (d, J=11.6 Hz, 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=7.0 Hz, 6H). LCMS: (Method A), R _t =2.43 min, [M+H] ⁺ =582.2.

Example 101 - N-(2-fluoro-3-methoxyphenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (122)

Starting material used in step 7-5-fluoroisoindoline, starting material used in step 9-2-fluoro-3-methoxyaniline, ^1H NMR (400 MHz, 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=7.0 Hz, 6H). LCMS: (Method A), R _t =2.88 min, [M+H] ⁺ =530.1

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]pyrmidine-2-carboxamide (123)

The starting material for step 7 is 5-fluoroisoindoline, the starting material for step 9 is 4-((tetrahydro-2H-pyran-4-yl)oxy)aniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.49 (s, 1H), 10.06 (s, 1H), 9.28 (s, 1H), 8.71 (s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.43 (m, 3H), 7.01 (t, J=13.2 Hz, 3H), 4.95 (d, J=10.8 Hz, 4H), 4.55 (s, 1H), 3.94-3.76 (m, 3H), 3.53-3.46 (m, 2H), 1.98 (d, J=8.8 Hz, 2H), 1.58 (s, 2H), 1.45 (d, J=6.6 Hz, 6H). LCMS: (Method A), R _t =2.23 min, [M+H] ⁺ =582.2

Example 103 - N-(2-fluoro-5-methoxyphenyl)-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (124)

Starting material used in step 7-5-fluoroisoindoline, starting material used in step 9-2-fluoro-5-methoxyaniline, ^1H NMR (400 MHz, 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

Example 104-5-(4-fluoroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (125)

The starting material used in step 7 is 4-fluoroisoindoline, the starting material used in step 9 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=9.2 Hz, 1H), 7.09 (s, 1H), 6.71 (dd, J=6.4 Hz, 2.0 Hz, 1H), 5.01 (s, 4H), 3.86-3.79 (m, 1H), 3.78 (s, 3H), 1.46 (d, J=7.2 Hz, 6H). LCMS: (Method A), R _t =2.46 min, [M+H] ⁺ =512.2.

Example 105-5-(4-chloroisoindolin-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (126)

The starting material used in step 7 is 4-chloroisoindoline, the starting material used in step 9 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.2 Hz, 2.0 Hz, 1H), 5.04 (d, J=0.8 Hz, 4H), 3.78 (s, 4H), 1.46 (d, J=7.0 Hz, 6H). LCMS: (Method A), R _t = 2.94 min, [M+H] ⁺ = 528.0.

Example 106-5-(5-fluoroisoindolin-2-yl)-3-isopropyl-N-(2-methoxypyridin-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (127)

The starting material used in step 7 is 4-fluoroisoindoline, the starting material used in step 9 is 2-methoxypyridin-4-amine, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 10.46 (s, 1H), 9.26 (s, 1H), 8.69 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.52-7.36 (m, 4H), 7.19 (d, J=7.6 Hz, 1H), 7.05 (s, 1H), 4.95 (d, J=11.6 Hz, 4H), 3.86 (s, 3H), 3.82-3.74 (m, 1H), 1.46 (d, J=7.0 Hz, 6H). LCMS: (Method A), R _t = 3.28 min, [M+H] ⁺ = 513.2.

Example 107-3-cyclopropyl-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (93)

Compound 93 is obtained according to the procedure shown in Scheme 6.

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) under N ₂ at -78 °C was added 2-cyclopropylacetonitrile (29 mL, 0.28 mol) dropwise over 10 min, and the mixture was stirred for 1 h at -78 °C. Diethyl oxalate (33 mL, 0.24 mol) was added dropwise over 5 min, and the mixture was stirred at -78 °C for 1 h and then at 0 °C for 1 h. The mixture was diluted with H ₂ O, and the organic phases were extracted with Et ₂ O (200 mL). The aqueous phase was adjusted to pH 5 with aqueous HCl (1 M), and then the organic layers were extracted with Et ₂ O (2×200 mL). The organic layers were washed with brine, dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to afford the title product (28 g, 65%) as a yellow oil. LCMS: (Method A), R _t = 3.02 min, [M+H] ⁺ = 182.1.

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 a mixture of AcOH (40 mL) and toluene (400 mL) was heated under reflux overnight using a Dean-Stark trap. The reaction mixture _was concentrated under reduced pressure, and the residue was partitioned between EtOAc and aqueous saturated _NaHCO3 solution. The organic layer was dried over _Na2SO4 , filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the desired product (18 g, 60%) as a yellow solid. LCMS: (Method A), R _t = 3.80 min, [M+H] ⁺ = 196.1

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 solids were removed by filtration and washed with DCM. The combined organic layers were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM:MeOH, 70:1) to give the desired product (20 g, 71%) as a yellow solid. LCMS: (Agilent 5 min), R _t =4.17 min, [M+H] ⁺ =543.2.

Step 4: Ethyl 3-cyclopropyl-5,7-dihydroxypyrazolo[1,5-a]pyrmidine-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 H ₂ O (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 organic layers 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.

Step 5: Ethyl 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrmidine-2-carboxylate (XLI)

A solution of ethyl 3-cyclopropyl 5,7-dihydroxypyrazolo[1,5-a]pyrmidine-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, and the residue was poured into ice water, extracted with DCM (3×300 mL), and the combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EtOAc, 10:1) to give the desired product (11 g, 57%) as a yellow solid. LCMS: (Agilent 5 min), R _t =4.27 min, [M+H] ⁺ =300.0.

Step 6: Ethyl 5-chloro-3-cyclopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (XLII)

A mixture of ethyl 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrmidine-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), _Na2CO3 (1.4 g, 13.4 mmol), and Pd _{( dppf)2Cl2 (} 490 mg, 0.67 mmol) in degassed 1,4-dioxane (100 mL) and _H2O (20 mL) was stirred under _N2 at 80°C overnight. The mixture was poured into water and extracted with DCM (100 mL × 3). The organic layers _were washed with water and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the desired product (1.4 g, 61%) as a yellow solid. LCMS (Method A): R _t = 4.05 min; [M+H] ⁺ = 332.2.

Step 7: Ethyl 3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (XLIII)

A mixture of ethyl 5-chloro-3-cyclopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-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 H ₂ O 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 = 4.66 min, [M+H] ⁺ = 465.2.

Step 8: 3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (XLIV)

A mixture of ethyl 3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-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 H ₂ O. The aqueous phase was adjusted to pH 3~4 with 2 M HCl and the resulting 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.

Step 9: 3-cyclopropyl-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (XLV)

A mixture of 3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (200 mg, 0.52 mmol), 3-methoxyaniline (70 mg, 0.57 mmol), GATU (296 mg, 0.78 mmol) and DIEA (134 mg, 1.04 mmol) in DMF (8 mL) was stirred at RT overnight. The mixture was diluted with _H2O and the residue was filtered and then purified by column chromatography on silica gel (DCM:MeOH, 100:0-98:2) to give the title product (85 mg, 33%) as a yellow solid. ^1H NMR (400 MHz, 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=16 Hz, 1H), 7.02 (s, 1H), 6.72 (d, J=6 Hz, 1.6 Hz, 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.

The following compounds are prepared in a similar manner using the appropriate starting materials in step 7 and step 9 of Scheme 6 according to the method described for the synthesis of compound 93.

Example 108-3-cyclopropyl-N-(3-hydroxyphenyl)-5-{isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (94)

The starting material for step 7 is isoindoline, the starting material for step 9 is 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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), 7.02 (s, 1H), 6.53 (d, J=6.4 Hz, 1.6 Hz, 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

Example 109 - N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (95)

The starting material used in step 7 is isoindoline, the starting material used in step 9 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8 Hz, 1H), 7.03 (s, 1H), 6.75 (d, J=8 Hz, 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.

Example 110-3-cyclopropyl-5-(isoindolin-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (96)

The starting material for step 7 is isoindoline, the starting material for step 9 is 4-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.48 (s, 1H), 10.04 (s, 1H), 9.30 (s, 1H), 8.71 (s, 1H), 7.73 (d, J=8 Hz, 2H), 7.47 (s, 2H), 7.37-7.34 (m, 4H), 7.01 (s, 1H), 6.96 (d, J=8.8 Hz, 2H), 4.93 (s, 4H), 3.77 (s, 3H), 2.69-2.58 (m, 1H), 1.47 (d, J=3.2 Hz, 2H), 0.87-0.77 (m, 2H). LCMS: (Method A), R _t = 4.56 min, [M+H] ⁺ = 492.2.

Example 111 - N-(3-acetamidophenyl)-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (97)

The starting material used in step 7 is isoindoline, the starting material used in step 9 is N-(3-aminophenyl)acetamide, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 1H), 7.02 (s, 1H), 4.94 (s, 4H), 2.61-2.54 (m, 1H), 2.06 (s, 3H), 1.46 (d, J=3.2 Hz, 2H), 0.84-0.81 (m, 2H). LCMS: (Method A), R _t = 4.25 min, [M+H] ⁺ = 519.2.

Example 112 - N-(3-chlorophenyl)-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (98)

The starting material for step 7 is isoindoline, the starting material for step 9 is 3-chloroaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=9.2 Hz, 1H), 7.47-7.33 (m, 5H), 7.19 (d, J=8.0 Hz, 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

Example 113-3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (85)

Compound 85 is obtained according to the procedure shown in Scheme 7.

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 pad of Celite, and the solids were washed with DCM (2 x 20 mL). The combined filtrates were concentrated under reduced pressure to give 3,3-dimethylbutanenitrile (12.48 g, 77%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.66–3.63 (m, 4H), 2.14 (s, 2H), 1.76 (s, 3H).

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 ₂ at -78 °C was added 3,3-dimethylbutanenitrile (5.0 g, 51.00 mmol) dropwise over 5 min, and the mixture was stirred for 1 h at -78 °C. 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 H ₂ O (100 mL), and the organic layers were stripped with Et ₂ O (2×100 mL). The aqueous phase was adjusted to pH 5 with aqueous HCl (6 M) and the aqueous layers were extracted with Et ₂ O (3×100 mL). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , 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 H NMR (400 MHz, CDCl ₃ ) δ 4.37 (d, J = 7.2 Hz, 2H), 1.34-1.32 (m, 3H), 1.15 (s, 9H).

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 silica gel chromatography (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, ^1H NMR (400 MHz, CDCl ₃ ) δ 4.30 (d, J=7.2 Hz, 2H), 1.40-1.29 (m, 12H).

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, ^1H NMR (400 MHz, DMSO-d ₆ ) 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=12.0 Hz, 2H), 1.35-1.21 (m, 15H).

Step 5: Ethyl 3-(tert-butyl)-5,7-dihydroxypyrazolo[1,5-a]pyrmidine-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 H ₂ O (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 H ₂ O (100 mL). The organic layers were dried over Na ₂ SO ₄ 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

Step 6: Ethyl 3-(tert-butyl)-5,7-dichloropyrazolo[1,5-a]pyrmidine-2-carboxylate(LI)

A mixture of ethyl 3-(tert-butyl)-5,7-dihydroxypyrazolo[1,5-a]pyrmidine-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 Et ₂ O (3×300 mL). The combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ), 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+N] ⁺ =316.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.92 (s, 1H), 4.41 (sq, J=6.8 Hz, 2H), 1.51 (s, 3H) 1.47 (s, 9H).

Step 7: Ethyl 3-(tert-butyl)-5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (LII)

A mixture of ethyl 3-(tert-butyl)-5,7-dichloropyrazolo[1,5-a]pyrmidine-2-carboxylate (1.15 g, 3.60 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (1.07 g, 3.60 _mmol ), _Na2CO3 (0.774 g, 7.20 mmol), and Pd(dppf) _2Cl2 (534 mg, 0.73 mmol) in degassed 1,4-dioxane (35 mL) and _H2O (7 mL) was stirred at 80 _° C overnight under _N2 . The mixture was poured into water and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water and brine, dried _{over Na2SO4} , 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): R _t = 4.36 min; [M+H] ⁺ = 348.1. ¹ H NMR (400 MHz, EMCO- _d6 ) δ 8.69 (s, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 4.41 (q, J=1.2 Hz, 2H), 1.49 (s, 9H), 1.36 (t, J=7.2 Hz, 3H).

Step 8: Ethyl 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (LIII)

A mixture of ethyl 3-(tert-butyl)-5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-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 solids were filtered. The filter cake was dried and purified by column chromatography on silica gel (DCM:MeOH, 100:1) to give the desired product (230 mg, 49%) as a yellow solid. LCMS: (Method A), R _t = 4.97 min, [M+H] ⁺ = 431.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 2H), 7.39-7.31 (m, 4H), 6.53 (s, 1H), 4.94 (s, 4H), 4.45 (q, J=1.8 Hz, 2H), 1.56 (s, 9H), 1.44 (t, J=7.6 Hz, 3H).

Step 9: 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carbolic acid (LIV)

To a solution of 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (600 mg, 1.39 mmol) in THF (24 mL) and H ₂ O (24 mL) at 0 °C was slowly added aqueous KOH (1 M, 12 mL) 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 H ₂ O (20 mL) and Et ₂ O (20 mL). The organic layers were discarded and the aqueous layer was acidified to pH 2 with aqueous HCl (2 M). The aqueous phase was extracted with CHCl ₃ (100 mL x 3) and the combined organic layers were dried over Na ₂ SO ₄ 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 H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (s, 2H), 7.55-7.38 (m, 4H), 6.99 (s, 1H), 4.99 (s, 4H), 1.54 (s, 9H).

Step 10: 3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (LV)

A mixture of 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylic acid (100 mg, 0.25 mmol), 3-aminophenol (34 mg, 0.28 mmol), GATU (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 solids were removed by filtration. The combined solids were purified by column chromatography on silica gel (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. ^1H NMR (400 MHz, 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=8.0 Hz, 1H), 7.0 (s, 1H), 6.70 (d, J=6.0 Hz, 1H), 4.96 (s, 4H), 3.76 (s, 3H), 1.55 (s, 9H).

The following compounds are prepared in a similar manner using the appropriate starting materials in step 8 and step 10 of Scheme 7 according to the method described for the synthesis of compound 85.

Example 114 - N-(3-acetamidophenyl)-3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (86)

The starting material used in step 8 is isoindoline, the starting material used in step 10 is N-(3-aminophenyl)acetamide, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=1.6 Hz, 3H), 7.37-7.35 (m, 3H), 7.26 (t, J=8.0 Hz, 1H), 7.0 (s, 1H), 4.96 (s, 4H), 2.05 (s, 3H), 1.55 (s, 9H). LCMS: (Method A), R _t = 3.610 min, [M+H] ⁺ = 535.2.

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]pyrmidine-2-carboxamide (87)

Starting material used in step 8 - isoindoline, starting material used in step 10-1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one, ^1H NMR (400 MHz, 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=7.2 Hz, 1H), 4.96 (s, 4H), 3.60 (t, J=4.8 Hz, 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.

Example 116-3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (88)

The starting material used in step 8 is isoindoline. starting material used in step 10-3-aminophenol, ^1H NMR (400 MHz, DMSO- ₆₆ ) 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=7.2 Hz, 1H), 4.96 (s, 4H), 1.55 (s, 9H). LCMS: (Method A), R _t =3.67 min, [M+H] ⁺ =494.2.

Example 117-3-(tert-butyl)-5-(5-chloroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (89)

The starting material used in step 8 is 5-chloroisoindoline, the starting material used in step 10 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=1.0 Hz, 1H), 4.96 (s, 4H), 3.76 (s, 3H), 1.55 (s, 9H). LCMS: (Method A), R _t = 3.88 min, [M+H] ⁺ = 542.2.

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]pyrmidine-2-carboxamide (90)

The starting material used in step 8 is 5-chloroisoindoline, the starting material used in step 10 is the starting material: 1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8 Hz, 1H), 4.95 (d, J=4.8 Hz, 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 =5.86 min; [MN] ⁺ =638.3.

Example 119-3-(tert-butyl)-5-(5-fluoroisoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (91)

The starting material used in step 8 is 5-fluoroisoindoline, the starting material used in step 10 is 3-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.0 Hz, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.19 (t, J=9.2 Hz, 1H), 6.98 (s, 1H), 6.70 (d, J=6.4 Hz, 1H), 4.96 (d, J=12.4 Hz, 4H), 3.76 (s, 3H), 1.55 (s, 9H). LCMS: (Method A), R _t = 2.1 min, [M+H] ⁺ = 526.2.

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]pyrmidine-2-carboxamide (92)

Starting material used in step 8-5-fluoroisoindoline, starting material used in step 10-1-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-one, ^1H NMR (400 MHz, 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=13.2 Hz, 4H), 3.59 (s, 4H), 3.16 (s, 2H), 3.10 (s, 2H), 2.05 (s, 3H), 1.55 (s, 9H). ^1H NMR (400 MHz, 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=13.2 Hz, 4H), 3.59 (s, 4H), 3.16 (s, 2H), 3.10 (s, 2H), 2.05 (s, 3H), 1.55 (s, 9H).

Example 121 - N-(3-chlorophenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (110)

Compound 110 is obtained according to the procedure shown in Scheme 8.

Step 1: 2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (LVI)

To a suspension of NaH (60% oil, 4.4 g, 0.11 mol) in diethyl ether (300 mL) cooled to 0 °C was added diethyl (cyanomethyl)phosphonate (19.5 g, 0.11 mol) dropwise, then a solution of tetrahydro-4H-pyran-4-one (10 g, 0.10 mol) in diethyl ether (300 mL) was added dropwise. 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 Na ₂ SO ₄ , 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, ^1H NMR (400 MHz, CDCl ₃ ) δ 5.10 (s, 1H), 3.72-3.66 (m, 4H), 2.63-2.50 (m, 2H), 2.36-2.27 (m, 2H).

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 flushed with H ₂ and stirred overnight under 1 atm of hydrogen. 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 H NMR (400 MHz, CDCl ₃ ) δ 4.02-3.98 (m, 2H), 3.43-3.37 (m, 2H), 2.32 (d, J=8.4 Hz, 2H), 2.08 (s, 1H), 1.99-1.86 (m, 1H), 1.77-1.72 (m, 2H).

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 ₂ cooled to -78 °C was added 2-(tetrahydro-2H-pyran-4-yl)acetonitrile (2.0 g, 15.90 mmol) 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 for 45 min at 0 °C. The mixture was diluted with H ₂ O (100 mL), and the organic phases were extracted with Et ₂ O (2×100 mL). The aqueous layer was adjusted to pH 5 with 6 M HCl and then the organic layers were extracted with Et ₂ O (3×100 mL). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title product (7.5 g, 8.9%) as a yellow oil. LCMS (Method A): R _t = 0.868 min; [M+H] ⁺ = 226.1.

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 a mixture of 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

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

Step 6: Ethyl 5,7-dihydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (LXI)

A mixture of ethyl 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 H ₂ O (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 organic layers were dried over Na ₂ SO ₄ 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

Step 7: Ethyl 5,7-dichloro-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (LXII)

A mixture of 5,7-dihydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-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, extracted with Et ₂ O (3×300 mL), and the combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc, 20:1) to give the title product (1.0 g, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.05 (s, 1H), 4.51 (d, J=7.1 Hz, 2H), 4.13-4.06 (m, 2H), 3.75 (tt, J=12.8 Hz, 3.6 Hz, 1H), 3.56 (d, J=1.2 Hz, 2H), 2.47 (dd, J=13.1 Hz, 4.4 Hz, 2H), 1.69 (dd, J=12.8 Hz, 2.0 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H).

Step 8: Ethyl 5-chloro-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (LXIII)

A mixture of ethyl 5,7-dichloro-3(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (1.2 g, 3.49 mmol), 1-Boc-pyrazole-4-boronic acid pinacol _{ester (1.02 g, 3.49 mmol), Na2CO3 (} 741 mg, 6.99 mmol), and Pd(dppf _{)2Cl2 (} 511 mg, 0.70 mmol) in 1,4-dioxane (35 mL) and _H2O (7 mL) was stirred at 80°C overnight under N2. The mixture was poured into water and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH:DCM, 1:100) to afford the title product (600 mg, 61%) as a yellow solid. LCMS (Method A): R _t = 3.71 min; [M+H] ⁺ = 376.1

Step 9: Ethyl 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxylate (LXIV)

A mixture of ethyl 5-chloro-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-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 formed precipitate was collected by filtration. This 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

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

Step 11: N-(3-chlorophenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidin-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]pyrmidine-2-carboxylic acid (100 mg, 0.25 mmol), 3-chloroaniline (36 mg, 0.28 mmol), GATU (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 give a suspension, which was filtered. The filter cake was dried and purified on a 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 = 6.16 min, [M+H] ⁺ = 540.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=7.6 Hz, 1H) 7.51-7.35 (m, 5H), 7.19 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 4.98 (s, 4H), 3.99 (d, J=8.4 Hz, 2H), 3.68 (t, J=10.0 Hz, 1H), 3.44 (d, J=7.2 Hz, 2H), 2.54 (s, 2H), 1.59 (d, J=12.0 Hz, 2H)

The following compounds are prepared in a similar manner using the appropriate starting materials in step 9 and step 11 of Scheme 8 according to the method described for the synthesis of compound 110.

Example 122 - N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidin-2-carboxamide (111)

The starting material for step 9 is isoindoline, the starting material for step 11 is 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=8.8 Hz, 1H), 4.98 (s, 4H), 4.0 (d, J=10.4 Hz, 2H), 3.66 (s, 1H), 3.44 (d, J=11.6 Hz, 2H), 3.33 (s, 2H), 1.60 (d, J=12.0 Hz, 2H). LCMS: (Method B), R _t =2.27 min, [M+H] ⁺ =522.2.

Example 123-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (112)

The starting material used in step 9 is isoindoline, the starting material used in step 11 is 3-methoxyaniline. ^1H NMR (400 MHz, 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=12.0 Hz, 1H), 7.06 (s, 1H), 6.72 (dd, J=5.6 Hz, 1.6 Hz, 1H), 4.98 (s, 4H), 3.98 (dd, J=1.2 Hz, 3.2 Hz, 2H), 3.78 (s, 3H), 3.72-3.64 (m, 1H), 3.44 (d, J=11.2 Hz, 2H), 3.33 (s, 2H), 2.57-2.53 (m, 1H), 1.60 (d, J=12.0 Hz, 2H). LCMS: (Method D), R _t =5.51 min, [M+H] ⁺ =536.2.

Example 124-5-(isoindolin-2-yl)-N-{4-methoxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (113)

The starting material in step 9 is isoindoline, the starting material in step 11 is 4-methoxyaniline, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H), 10.09 (s, 1H), 9.29 (s, 1H), 8.72 (s, 1H), 7.73 (d, J=9.2 Hz, 2H), 7.49-7.35 (m, 4H), 7.05 (s, 1H), 6.95 (d, J=6.8 Hz, 2H), 4.97 (s, 4H), 3.99 (d, J=1.2 Hz, 2H), 3.77 (s, 3H), 3.70 (s, 1H), 3.34 (t, J=11.2 Hz, 2H), 2.57-2.53 (m, 2H), 1.60 (d, J=12.0 Hz, 2H). LCMS: (Method A), R _t =2.45 min, [M+H] ⁺ =536.2.

Example 125-5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrmidine-2-carboxamide (114)

The starting material for step 9 is N-methyl-1-phenylmethanamine, the starting material for step 11 is 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=3.2 Hz, 1H), 7.37-7.34 (m, 4H), 7.28-7.24 (m, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.15-7.11 (m, 2H), 6.52 (d, J=6.4 Hz, 1H), 4.93 (s, 2H), 3.92 (dd, J=7.6 Hz, 4.4 Hz, 2H), 3.67-3.57 (m, 1H), 3.38 (t, J=11.2 Hz, 2H), 3.23 (s, 3H), 2.39 (dd, J=8.4 Hz, 4.0 Hz, 2H), 1.60 (d, J=12.0 Hz, 2H). LCMS: (Method A), R _t =1.91 min, [M+H] ⁺ =523.2.

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]pyrmidine-2-carboxamide (115)

The starting material used in step 9 is 5-fluoroisoindoline, the starting material used in step 11 is 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=6.8 Hz, 1H), 4.95 (d, J=13.2 Hz, 4H), 3.98 (d, J=7.6 Hz, 2H), 3.69-3.63 (m, 2H), 3.43 (t, J=11.6 Hz, 3H), 1.60 (d, J=12.0 Hz, 2H). LCMS: (Method A), R _t = 2.08 min, [M+H] ⁺ = 540.1.

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]pyrmidine-2-carboxamide (116)

The starting material used in step 9 is 5-chloroisoindoline, the starting material used in step 11 is 3-aminophenol, ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=7.2 Hz, 1H), 4.96 (s, 4H), 4.09 (q, J=2.8 Hz, 1.6 Hz, 2H), 4.0 (d, J=4.4 Hz, 2H), 3.70-3.61 (m, 1H), 3.43 (t, J=11.2 Hz, 2H), 1.60 (d, J=12.0 Hz, 2H). LCMS: (Method A), R _t =2.37 min, [M+H] ⁺ =556.2.

Example 128 Biological activity.

1.1 Cell culture

Antibiotic and serum media were purchased from Invitrogen (rife Technologies). PC3 cells were purchased from ATCC (Granville, NSW, Australia). PC3 cells were propagated in T75 cell culture flasks with vented lids and then maintained at low passage rates. The medium used for PC3 cells is RPMI (GlutaMAX) supplemented with 10% FCS and 1% penicillin/streptomycin (culture medium). Cells were maintained at 37°C in a humidified atmosphere of 95% (v/v) air/5% (v/v) CO2 and grown to 80% confluency.

1.2 xCELLigence Tablets

The XCELLigence® Real-Time Cell Analysis (RTCA) instrument (ACEA Biosciences), ACEA CIM 16-well plates, ACEA E-Plat 16-well plates, and assembly tool were purchased from ELITechGroup empowering IVD (Braeside, Australia). Matrigel was purchased from Corning (Australia).

1.2.1 Cell seeding on CIM plates and cell invasion and proliferation on xCELLigence RTCA DP

To measure cell invasion upon compound treatment, the upper chamber of the CIM plate is coated with 5% Matrigel diluted in SF RPMI (20 μL) and incubated in a tissue culture incubator at 37°C for four hours. Using the chamber assembly tool, the lower chamber is filled with 160 μL of culture medium containing the compound at a specified concentration of 25 μM to 1 μM and two controls (0.1% DMSO and 10 μM ESFAM 4C) (see diagram in Figure 1). Once the upper chamber is positioned on top of the lower chamber, it is loaded with 40 μL of serum-free (SF) RPMI containing the compound as described previously. After one hour of calibration at 37°C, the plates are placed in the xCELLigence station and the baseline electrical impedance is measured to ensure all wells and connections are functioning properly. If connection issues occur, the program automatically informs the researcher of the nature of the problem in the message section. Cells are then trypsinized, collected and counted, diluted in SF RPMI to the desired density (3×10 ^{^4} ) and seeded (100 µl) into wells. After 30 minutes of incubation at room temperature to ensure cell attachment, the plates are loaded into the xCELLigence RTCA DP machine. Cell invasion is monitored in real time for 72 hours.

It is important to note that the same procedure, but with slight modifications, is performed to measure cell proliferation upon compound treatment, where cell proliferation is monitored in real time using the E-plate and the xCELLigence station, see Figure 1.

1.3 Software and data analysis

The xCELLigence system automatically tracks the electrical impedance of each well and expresses it as a cellular index (CI) over 72 hours. Treatment data are automatically grouped as mean ± standard deviation. Software version 1.2.1 is used for these experiments. Electronic records of experimental data are automatically saved in a file that cannot be modified or replaced by the researcher.

Statistical analysis was performed using Microsoft® Office EXCEL and GraphPad Prism 7. IC50 was calculated from a four-parameter dose-response curve (log(inhibitor) to response - variable slopes). Where row data are pasted into GraphPad Prism 7 (dose-response x - log(dose)) and analyzed for nonlinear XY regression (curve fitting), dose-response - inhibition, log(inhibitor) to variable response slope (four parameters). To calculate IC90, the equation log(IC50)=log(IC90)-(1/HillSlope)*log(9) is used in EXCEL based on raw data extracted from the xCELLigence system and the dose-response curve.

Typical inhibition data are given in the table below:

Effect of compounds of the invention on prostate cancer cells (μM)

Finally, it should be understood that various modifications and variations of the methods and compositions of the 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 claimed invention should not be unduly limited to such specific embodiments. Indeed, it is intended that various modifications of the described methods for carrying out the invention, obvious to those skilled in the art, are included within the scope of the present invention.

Claims (52)

1. Compound of formula (I): , Where R ¹ , R ² and R ³ are each independently selected from the group consisting of H and C ₁ -C ₁₂ alkyl; R ⁴ is H; R ⁵ is selected from the group consisting of H and C ₆ -C ₁₈ aryl optionally substituted with one or more ^Ra , wherein each ^Ra is independently selected from the group consisting of H, halogen, OH, CN, C ₁ -C ₁₂ alkyloxy, haloC ₁ -C ₁₂ alkyl, C ₃ -C ₆ cycloalkyloxy, diC ₁ -C ₁₂ alkylamino, OCHF ₂ , OCF ₃ , NHCOCH ₃ , NHSO ₂ CH ₃ , OCH ₂ CH ₂ OCH ₃ , -O-tetrahydropyran, piperazine, 4-methylpiperazine, 4-acylpiperazine, morpholine, or two ^Ra , taken together with the atoms to which they are attached, form a fused heterocyclic ring system comprising 9-10 ring atoms, containing one or two heteroatoms selected from nitrogen and optionally substituted with a =O group; _C3 - _C5 heteroaryl containing one or two heteroatoms selected from nitrogen and oxygen and optionally substituted with one or two groups independently selected from _C1 - _C12 alkyl and _C1 - _C12 alkyloxy; and _C6 - _C18 arylC1 _{-C12 alkyl-} ; R ⁶ is selected from the group consisting of H, C ₁ -C ₁₂ alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₅ heterocycloalkyl including one heteroatom selected from oxygen; R ⁷ is C ₁ -C ₁₂ alkyl; R ⁸ is selected from C ₆ -C ₁₈ arylC ₁ -C ₁₂ alkyl-, optionally substituted with a group independently selected from halogen, haloC ₁ -C ₁₂ alkyl and C ₁ -C ₁₂ alkyloxy; or R ⁷ and R ⁸ , taken together with the nitrogen atom to which they are attached, form a group of the formula where each R ^D is independently selected from the group consisting of H and halogen; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that R ¹ and R ³ are H. 3. The compound according to claim 1 or 2, characterized in that R ² is H. 4. Connection according to any of paragraphs. 1-3, characterized in that R ⁵ is C ₆ -C ₁₈ aryl optionally substituted with one or more ^Ra , wherein each ^{Ra is} independently selected from the group consisting of H, halogen, OH, CN, C ₁ -C ₁₂ alkyloxy, haloC ₁ -C ₁₂ alkyl, C ₃ -C ₆ cycloalkyloxy, diC ₁ -C ₁₂ alkylamino, OCHF ₂ , OCF ₃ , NHCOCH ₃ , NHSO ₂ CH ₃ , OCH ₂ CH ₂ OCH ₃ , -O-tetrahydropyran, piperazine, 4-methylpiperazine, 4-acylpiperazine, morpholine, or two ^Ra , taken together with the atoms to which they are attached, form a fused heterocyclic ring system comprising 9-10 ring atoms, containing one or two heteroatoms selected from nitrogen and optionally substituted with an =O group; _C3 - _C5 heteroaryl containing one or two heteroatoms selected from nitrogen and oxygen and optionally substituted with one or two groups independently selected from _C1 - _C12 alkyl and _C1 - _C12 alkyloxy; and _C6 - _C18 arylC1 _{-C12 alkyl-} . 5. Connection according to any of paragraphs. 1-4, characterized in that R ⁵ is phenyl optionally substituted with one or more ^Ra , wherein each ^Ra is independently selected from the group consisting of H, halogen, OH, CN, C ₁ -C ₁₂ alkyloxy, haloC ₁ -C ₁₂ alkyl, C ₃ -C ₆ cycloalkyloxy, diC ₁ -C ₁₂ alkylamino, OCHF ₂ , OCF ₃ , NHCOCH ₃ , NHSO ₂ CH ₃ , OCH ₂ CH ₂ OCH ₃ , -O-tetrahydropyran, piperazine, 4-methylpiperazine, 4-acylpiperazine, morpholine, or two ^Ra , taken together with the atoms to which they are attached, form a fused heterocyclic ring system comprising 9-10 ring atoms containing one or two heteroatom selected from nitrogen and optionally substituted with a =O group; _C3 - _C5 heteroaryl containing one or two heteroatoms selected from nitrogen and oxygen and optionally substituted with one or two groups independently selected from _C1 - _C12 alkyl and _C1 - _C12 alkyloxy; and _C6 - _C18 arylC1 _{-C12 alkyl-} . 6. A compound according to any one of paragraphs 1-5, characterized in that R ⁶ is C ₁ -C ₁₂ alkyl. 7. A compound according to any one of paragraphs 1-6, characterized in that R ⁶ is isopropyl or tert-butyl. 8. The compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 9. A compound according to any one of paragraphs 1-8, selected from the group consisting of: , or a pharmaceutically acceptable salt thereof. 10. A compound according to any one of paragraphs 1-9, which is: , or a pharmaceutically acceptable salt thereof. 11. A compound according to any one of paragraphs 1-9, which is: , or a pharmaceutically acceptable salt thereof. 12. A compound according to any one of paragraphs 1-9, which is: , or a pharmaceutically acceptable salt thereof. 13. A compound according to any one of paragraphs 1-9, which is: , or a pharmaceutically acceptable salt thereof. 14. A compound according to any one of paragraphs 1-9, which is: , or a pharmaceutically acceptable salt thereof. 15. A compound according to any one of paragraphs 1-9, which is: , or a pharmaceutically acceptable salt thereof.