Treatment of veterinary disorders associated with cd151

Abstract

The present invention relates to a method of treating a disorder associated with CD151 in a non-human animal, the method comprising administering a therapeutically effective amount of a compound of formula (I): Formula (I)

Description

Technical Field

[0001] This invention relates to the veterinary application of compounds in which the applicant has discovered that the compounds are inhibitors of CD151 in animals and are therefore capable of treating diseases associated with CD151 overexpression. Due to this activity, these compounds can be used to treat diseases associated with this transmembrane domain cell surface protein in non-human animals. Therefore, the compounds can be used to treat a wide range of diseases, such as viral infections. Background of the Invention

[0003] With rapid progress around the world and the shift from subsistence farming techniques to large-scale agriculture, the need for advancements in veterinary science has increased due to the larger numbers of animals raised and the relative population strength of modern farms. This demand has led to tremendous leaps in veterinary science over the past 200 years.

[0004] However, there remains a sustained drive to provide treatment for diseases and conditions for which no effective treatments are available. Therefore, a great deal of research continues on biological targets that may be involved in many targeted medical conditions, particularly those related to the most commonly bred farm animals.

[0005] One target is tetraspanin. Tetraspanin is a superfamily of cell surface proteins with four transmembrane domains, including the tumor suppressor KAI1 / CD82 and the tumor promoter CD151. Tetraspanin is expressed in multiple cell types and is associated with cancer progression. Specifically, tetraspanin is involved in cell adhesion, cell motility, and tumor suppression or activation. Tetraspanin is thought to regulate its activity through the architecture of its cell surface membrane microdomains, which facilitates its interactions with a range of other proteins such as integrins, immune receptors, and signaling molecules.

[0006] CD151 is a member of the four-transmembrane protein superfamily, which associates with integrins, membrane receptors, intracellular signaling molecules (such as PI4K and PKC), immunoglobulins, and other four-transmembrane proteins; such four-transmembrane protein-rich microdomains (TEMs) act as molecular promoters (Kumari S et al., Biomarkers in Cancer 2015; 7:7-11).

[0007] 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 frequently overexpressed in cancer cells associated with cancer progression and metastasis.

[0008] CD151 overexpression is associated with a range of common veterinary diseases in non-human animals, most notably porcine reproductive and respiratory syndrome virus (PRRSV).

[0009] Porcine reproductive and respiratory syndrome virus (PRRSV) is a virus that causes reproductive disorders in breeding pigs and respiratory diseases in piglets. PRRSV was first reported in North America and Central Europe in 1987. PRRSV can be subdivided into two main types; European (type 1), such as the Lelystad strain, and North American (type 2), such as the VR-2332 strain. Other strains are being discovered, including in Asia. The disease is economically significant, costing the U.S. swine industry approximately $644 million annually, and in Europe, the estimated annual cost is close to €1.5 billion.

[0010] Therefore, there is great interest in developing inhibitors of CD151, as compounds with this capability are expected to be used to treat this type of veterinary disease. Summary of the Invention

[0011] Therefore, the applicant studied the expression of CD151 with the aim of identifying inhibitors of its functional expression, which could be used to treat diseases involving overexpression.

[0012] As a result of these studies, the applicant has identified compounds that inhibit CD151.

[0013] Therefore, in one embodiment, the present invention provides a method for treating a CD151-related disease in non-human animals, the method comprising administering a therapeutically effective amount of a compound of formula (I):

[0014]

[0015] in

[0016] R 1 R 2 and R 3 Each independently selects H and C1-C 12 Groups composed of alkyl groups;

[0017] R 4 Choose freely between H and C1-C 12 The group consisting of alkyl groups,

[0018] R 5 Choose from the following groups: H, optional substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C6-C 18 Aryl C1-C 12 Alkyl- and optionally substituted C1-C 18heteroaryl C1-C 12 alkyl-;

[0019] R 6 Choose from the following groups: H, C1-C 12 Alkyl, C3-C6 cycloalkyl and C1-C5 heterocyclic alkyl;

[0020] R 7 Choose freely between H and C1-C 12 Groups composed of alkyl groups;

[0021] R 8 Choose from the following groups: H, C1-C 12 Alkyl, optionally substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C6-C 18 Aryl C1-C 12 Alkyl- and optionally substituted C1-C 18 heteroaryl C1-C 12 alkyl-;

[0022] Or R 7 and R 8 When combined with the nitrogen atoms they are attached to, they form C2-C. 12 Heterocyclic groups;

[0023] Or its pharmaceutically acceptable salt.

[0024] The compounds of the present invention have been found to have the ability to inhibit CD151, and therefore can be used to treat diseases associated with the expression of this gene. Detailed Implementation

[0025] This specification uses several terms that are well known to those skilled in the art. However, for clarity, several terms will be defined.

[0026] Throughout the description and claims of this specification, the word "comprise" and variations thereof such as "comprising" and "comprises" are not intended to exclude other additives, components, integers, or steps.

[0027] The term "inhibit" and its variations such as "inhibiting" refer to preventing, blocking, or reducing the function of the inhibited substance. Complete inhibition is not required; a reduction in activity of at least 50% is considered inhibition.

[0028] In the definitions of various 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 both the case where the group is a link between two other parts of the molecule and the case where it is a terminal part. Using the term alkyl as an example, some publications use the term "alkylene" for bridging groups, and therefore in these other publications, a distinction is made between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In this application, no such distinction is made, and most groups may be either bridging groups or terminal groups.

[0029] In this specification, terms well known to those skilled in the art are used. However, for clarity, several of these terms will be defined.

[0030] As used herein, the term "unsubstituted" means having no substituents or having only hydrogen as a substituent.

[0031] As used throughout this specification, the term "optionally substituted" means that the group may or may not be further substituted or fused (to form a fused polycyclic system) by one or more non-hydrogen substituents. If optional substituents are present, the substituents are one or more groups 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, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxyl, hydroxyalkyl, alkyloxy, alkyloxyalkyl Alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclic alkyloxy, heterocyclic alkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinylaminoalkyl, -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 fNR 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 SO2R f -SR e SO2NR e R f -OR e OC (=O)NR e R f OC(=O)R e and acyl group,

[0032] Where R e R f R g and R h Each can independently choose from the following groups: H, C1-C 12 Alkyl, C1-C 12 Haloalkyl, C2-C 12 alkenyl, C2-C 12 Alkyne group, C1-C 10 Heteroalkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, C1-C 12 Heterocyclic alkyl, C1-C 12 Heterocyclic alkenyl, C6-C 18 Aryl, C1-C 18 heteroaryl and acyl, or R a R b R c and R d Any two or more of them, together with the atoms to which they are attached, form a heterocyclic ring system with 3 to 12 ring atoms.

[0033] 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, hydroxyl, 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.

[0034] Examples of particularly suitable optional substituents include F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, and CN.

[0035] "Acyl" refers to an RC (=O)- group, where the R group can be an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group as defined herein. Examples of acyl groups include acetyl and benzoyl. 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 via a carbonyl carbon.

[0036] "Acylamino" refers to an RC(=O)-NH- group, where the R group can be an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group as defined herein. 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 via a nitrogen atom.

[0037] "Alkenyl" as a group or part of a group indicates an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and may be straight-chain or branched, preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, and most preferably 2-6 carbon atoms in the positive chain. The group may contain multiple double bonds in the positive chain, and the orientation of each double bond is independently E or Z. The alkenyl group is preferably 1-alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, and nonenyl. The group may be a terminal group or a bridging group.

[0038] "Alkenyloxy group" refers to an alkenyl-O- group, wherein the alkenyl group is as defined herein. Preferred alkenyloxy groups are C1-C6 alkenyloxy groups. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an oxygen atom.

[0039] "alkyl" as a group or part of a group refers to a straight-chain or branched aliphatic hydrocarbon group, preferably C1-C. 12 Alkyl, more preferably C1-C 10 Alkyl groups, preferably C1-C6, unless otherwise specified. Examples of suitable straight-chain and branched C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, hexyl, etc. The groups may be terminal groups or bridging groups.

[0040] “Alkylamino” includes monoalkylamino and dialkylamino, unless otherwise stated. “Monoalkylamino” refers to an alkyl-NH- group, wherein the alkyl group is as defined herein. “Dialkylamino” refers to a (alkyl)2N- group, wherein each alkyl group may be the same or different and each is as defined herein for alkyl. The alkyl group is preferably a C1-C6 alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a nitrogen atom.

[0041] "alkylaminocarbonyl" refers to the formula (alkyl) x (H) y The group is an NC(=O)- group, wherein the alkyl group is as defined herein, x is 1 or 2, and the sum of X + Y = 2. 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 via a carbonyl carbon.

[0042] "Alkyloxy group" refers to an alkyl-O- group, wherein the alkyl group is as defined herein. Preferably, the alkyloxy group is a C1-C6 alkyloxy group. Examples include, but are not limited to, methoxy and ethoxy groups. The group may be a terminal group or a bridging group.

[0043] "alkyloxyalkyl" refers to an alkyloxy-alkyl- group, wherein the alkyloxy and alkyl moiety are as defined herein. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an alkyl group. "alkyloxyaryl" refers to an alkyloxy-aryl- group, wherein the alkyloxy and aryl moiety are as defined herein. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an aryl group.

[0044] "alkyloxycarbonyl" refers to an alkyl-OC (=O)- group, wherein the alkyl group is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group 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 via the carbonyl carbon.

[0045] "alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl group, wherein the alkyloxy and cycloalkyl moieties are as defined herein. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a cycloalkyl group.

[0046] "alkyloxyheteroaryl" refers to an alkyloxy-heteroaryl- group, wherein the alkyloxy and heteroaryl moieties are as defined herein. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via the heteroaryl group.

[0047] "alkyloxyheterocyclic alkyl" refers to an alkyloxy-heterocyclic alkyl group, wherein the alkyloxy and heterocyclic alkyl moieties 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 via a heterocyclic alkyl group.

[0048] "alkyl sulfinyl" refers to an alkyl-S-(=O)- group, wherein the alkyl group is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkyl sulfinyl groups include, but are not limited to, methyl sulfinyl and ethyl sulfinyl. 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 via a sulfur atom.

[0049] "alkylsulfonyl" refers to an alkyl-S(=O)2- group, wherein the alkyl group is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methanesulfonyl and ethylsulfonyl. 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 via a sulfur atom.

[0050] "Alynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight-chain or branched, preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, and even more preferably 2-6 carbon atoms in the positive chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.

[0051] "Alkynooxy group" refers to an alkynyl-O- group, wherein the alkynyl group is as defined herein. Preferred alkynoxy groups are C1-C6 alkynoxy groups. 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 via an oxygen atom.

[0052] "Aminoalkyl" refers to an NH2-alkyl- group, wherein the alkyl group is as defined herein. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an alkyl group.

[0053] "Aminosulfonyl" refers to the NH2-S(=O)2- group. This 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 via a sulfur atom.

[0054] The term "aryl" as a group or part of a group indicates (i) a preferred, optionally substituted monocyclic or fused polycyclic aromatic carbocyclic ring (a ring structure having all ring atoms of carbon) having 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, etc.; (ii) an optionally substituted, partially saturated bicyclic aromatic carbocyclic moiety, wherein the phenyl and C atoms are... 5-7 cycloalkyl or C 5-7 Cycloalkenyl groups fuse together to form a cyclic structure, such as tetrahydronaphthyl, indenyl, or indenyl. These groups can be terminal or bridging groups. Typically, aryl groups are C6-C. 18 Aryl.

[0055] "Arylalkenyl" refers to an aryl-alkenyl-group, wherein the aryl and alkenyl groups are as defined herein. Exemplary arylalkenyl groups include phenylallyl. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via the alkenyl group;

[0056] "Arylalkyl" refers to an aryl-alkyl group, wherein the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain C0. 1-5 Alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthylmethyl, and 2-naphthylmethyl. 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 via an alkyl group.

[0057] "Arylalkyloxy" refers to an aryl-alkyl-O- group, wherein 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 via an oxygen atom.

[0058] "Arylamino" includes monoarylamino and diarylamino, unless otherwise stated. A monoarylamino is a group of the formula arylNH-, wherein the aryl group is as defined herein. A diarylamino is a group of the formula (aryl)2N-, wherein each aryl group may be the same or different, and each is as defined herein for the aryl group. 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 via a nitrogen atom.

[0059] "Arylhexaalkyl" refers to an aryl-hexaalkyl group, wherein the aryl and heteroalkyl moieties 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 via a heteroalkyl group.

[0060] "Aryloxy group" refers to an aryl-O- group, wherein the aryl group is as defined herein. Preferably, the aryloxy group is C6-C. 18 aryloxy group, more preferably C6-C 10 Aryloxy group. 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 via an oxygen atom.

[0061] "Arylsulfonyl" refers to an aryl-S(=O)2- group, wherein the aryl group is as defined herein. 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 via a sulfur atom.

[0062] A "bond" is a connection between atoms in a compound or molecule. The bond can be a single bond, a double bond, or a triple bond.

[0063] "Cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic cyclic system containing at least one carbon-carbon double bond and preferably having 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. The cycloalkenyl group may be substituted with one or more substituents. Cycloalkenyl groups are typically C3-C. 12 Alkenyl group. The group can be a terminal group or a bridging group.

[0064] "Cycloalkyl" refers to a saturated monocyclic, fused, or spiropolycyclic carbocyclic ring, preferably containing 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as naphthane, and polycyclic systems such as adamantane. Cycloalkyl groups are typically C3-C. 12 Alkyl group. The group may be a terminal group or a bridging group.

[0065] "Cycloalkylalkyl" refers to a cycloalkyl-alkyl-group, wherein the cycloalkyl and alkyl moiety are as defined herein. Exemplary 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 remainder of the molecule via an alkyl group.

[0066] "Cycloalkylalkenyl" refers to a cycloalkyl-alkenyl-group, wherein the cycloalkyl and alkenyl moieties are as defined herein. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via the alkenyl group.

[0067] "Cycloalkyl-heteroalkyl" refers to a cycloalkyl-heteroalkyl- group, wherein the cycloalkyl and heteroalkyl moieties 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 via a heteroalkyl group.

[0068] "Cycloalkyloxy" refers to a cycloalkyl-O- group, wherein the cycloalkyl group is as defined herein. Preferably, the cycloalkyloxy group is a C1-C6 cycloalkyloxy group. Examples include, but are not limited to, cyclopropoxy and cyclobutoxy groups. 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 via an oxygen atom.

[0069] "Cycloalkenyloxy group" refers to a cycloalkenyl-O- group, wherein the cycloalkenyl group is as defined herein. Preferably, the cycloalkenyloxy group is a C1-C6 cycloalkenyloxy group. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an oxygen atom.

[0070] "Haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms have been replaced by a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine. Haloalkyl groups typically have the formula C n H (2n+1-m) X m Each X is independently selected from the group consisting of F, Cl, Br, and I. In this type of group, n is typically 1 to 10, more preferably 1 to 6, and most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, and trifluoromethyl.

[0071] "Haloalkenyl" refers to an alkenyl group as defined herein, in which one or more hydrogen atoms have been replaced by halogen atoms independently selected from the group consisting of F, Cl, Br and I.

[0072] "Halogenated alkynyl" refers to an alkynyl group as defined herein, in which one or more hydrogen atoms have been replaced by halogen atoms independently selected from the group consisting of F, Cl, Br and I.

[0073] "Halogen" refers to chlorine, fluorine, bromine, or iodine.

[0074] "Heteroalkyl" refers to a straight-chain or branched alkyl group preferably having 2 to 12 carbons, more preferably 2 to 6 carbons, wherein one or more carbon atoms (and any associated hydrogen atoms) are each independently substituted with a heteroatom group selected from S, O, P and NR', wherein R' is selected from the group consisting of: H, optionally substituted C1-C 12 Alkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C6-C 18 Aryl and optionally substituted C1-C 18Heteroalkyl groups. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, etc. Examples of heteroalkyl groups also include hydroxy C1-C6 alkyl, C1-C6 alkyloxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkylamino C1-C6 alkyl, and di(C1-C6 alkyl)amino C1-C6 alkyl. The group may be a terminal group or a bridging group.

[0075] "Heteroalkyloxy group" refers to a heteroalkyl-O- group, wherein the heteroalkyl group is as defined herein. Preferably, the heteroalkyloxy group is a C2-C6 heteroalkyloxy group. The group may be a terminal group or a bridging group.

[0076] A "heteroaryl" group, either alone or as part of a group, refers to a group containing an aromatic ring (preferably a 5- or 6-membered aromatic ring) with one or more heteroatoms as ring atoms, and the remaining ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen, and sulfur. The group can be a monocyclic or bicyclic heteroaryl. Examples of heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzoisothiazole, naphtho[2,3-b]thiophene, furan, iso-indene, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazolium, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthidine, quinoxaline, cyclophosphine, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazine, phenothiazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinoline, 1-, 3-, 4- or 5-isoquinoline, 1-, 2- or 3-indole, and 2- or 3-thiophene. Heteroaryl groups are usually C1-C 18 Heteroaryl groups. The groups may be terminal groups or bridging groups.

[0077] "Heteroarylalkyl" refers to a heteroaryl-alkyl group, wherein the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moieties. Exemplary 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 remainder of the molecule via an alkyl group.

[0078] "Heteroarylene" refers to a heteroarylene-alkenyl-group, wherein the heteroarylene and alkenyl moieties are as defined herein. The group can be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via the alkenyl group.

[0079] "Heteroarylene-alkyl" refers to a heteroarylene-alkyl group, wherein the heteroarylene and heteroalkyl moieties 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 via a heteroalkyl group.

[0080] "Heteroaryloxy group" refers to a heteroaryl-O- group, wherein the heteroaryl group is as defined herein. Preferably, the heteroaryloxy group is C1-C. 18 Heteroaryloxy group. 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 via an oxygen atom.

[0081] A "heterocycle" is a cyclic system, whether monocyclic, bicyclic, or polycyclic, containing at least one heteroatom selected from the group consisting of nitrogen, sulfur, and oxygen as a ring atom, and is saturated, partially unsaturated, or fully unsaturated. Examples of heterocyclic moieties include heterocyclic alkyl groups, heterocyclic alkenyl groups, and heteroaryl groups.

[0082] "Heterocyclic alkenyl" refers to a heterocyclic alkyl group as defined herein but containing at least one double bond. Heterocyclic alkenyl groups are typically C2-C. 12 Heterocyclic alkenyl groups. These groups can be terminal groups or bridging groups.

[0083] "Heterocyclic alkyl" refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, or oxygen, preferably 1 to 3 heteroatoms. Each ring is preferably 3 to 10-membered, more preferably 4 to 7-membered. Examples of suitable heterocyclic alkyl substituents include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholino, 1,3-diazacycloheptane, 1,4-diazacycloheptane, 1,4-oxazazacycloheptane, and 1,4-oxazathiocycloheptane. Heterocyclic alkyl groups are typically C2-C 12 Heterocyclic alkyl groups. The groups may be terminal groups or bridging groups.

[0084] "Heterocyclic alkylalkyl" refers to a heterocyclic alkyl-alkyl-group, wherein the heterocyclic alkyl and alkyl moiety are as defined herein. Exemplary heterocyclic alkylalkyl groups include (2-tetrahydrofuranyl)methyl and (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 remainder of the molecule via an alkyl group.

[0085] "Heterocyclic alkyl alkenyl" refers to a heterocyclic alkyl-alkenyl-group, wherein the heterocyclic alkyl and alkenyl moieties 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 via the alkenyl group.

[0086] "Heterocyclic alkyl-heteroalkyl" refers to a heterocyclic alkyl-heteroalkyl- group, wherein the heterocyclic alkyl and heteroalkyl moieties 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 via a heteroalkyl group.

[0087] "Heterocyclic alkyloxy group" refers to a heterocyclic alkyl-O- group, wherein the heterocyclic alkyl group is as defined herein. Preferably, the heterocyclic alkyloxy group is a C1-C6 heterocyclic alkyloxy group. 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 via an oxygen atom.

[0088] "Heterocyclic alkenyloxy group" refers to a heterocyclic alkenyl-O- group, wherein the heterocyclic alkenyl group is as defined herein. Preferably, the heterocyclic alkenyloxy group is a C1-C6 heterocyclic alkenyloxy group. 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 via an oxygen atom.

[0089] "Hydroxyalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced by an OH group. Hydroxyalkyl groups typically have the formula C0. n H (2n+1-x) (OH) x In this type of group, n is typically 1 to 10, more preferably 1 to 6, and most preferably 1 to 3. x is typically 1 to 6, more preferably 1 to 3.

[0090] "Sulfinyl group" refers to an RS (=O)- group, where the R group can be OH, alkyl, cycloalkyl, heterocycloalkyl; such as aryl or heteroaryl as defined herein. 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 via a sulfur atom.

[0091] "Sulfinylamino" refers to an RS(=O)-NH- group, where the R group can be OH, alkyl, cycloalkyl, heterocycloalkyl; such as aryl or heteroaryl as defined herein. 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 via a nitrogen atom.

[0092] "Sulfonyl" refers to an RS(=O)2- group, where the R group can be OH, alkyl, cycloalkyl, heterocycloalkyl; or aryl or heteroaryl as defined herein. 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 via a sulfur atom.

[0093] "Sulfonylamino" refers to the RS(=O)2-NH- group. This 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 via a nitrogen atom.

[0094] It should be understood that the family of compounds of formula (I) includes isomers, including diastereomers, enantiomers, tautomers, and geometric isomers that are “E” or “Z” configurations or mixtures of E and Z isomers. It should also be understood that some isomers, such as diastereomers, enantiomers, and geometric isomers, can be isolated by physical and / or chemical methods and by those skilled in the art. For those compounds that may exhibit geometric isomerism, the applicant has drawn up what are considered to be the isomers of the compounds, although it should be understood that other isomers may be the correct structural assignments.

[0095] Some of the compounds in the disclosed embodiments may be present as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the described and claimed subject matter.

[0096] Furthermore, formula (I) is intended to cover (where applicable) both solvated and non-solventized forms of the compound. Therefore, each formula includes compounds having the structures shown, including both hydrated and non-hydrated forms.

[0097] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the aforementioned compounds, and includes pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of formula (I) can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxylic acids, and sulfonic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkyl sulfonic acids, and aryl sulfonic acids. Similarly, base addition salts can be prepared using organic or inorganic bases by methods well known in the art. Examples of suitable organic bases include simple amines such as methylamine, ethylamine, triethylamine, etc. Examples of suitable inorganic bases include NaOH, KOH, etc. Further information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA 1995. In the case of solid agents, those skilled in the art will understand that the compounds, agents, and salts of the present invention may exist in various crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formulas.

[0098] The term "therapeutic effective dose" or "effective dose" is a dose sufficient to achieve a beneficial or desired clinical outcome. An effective dose may be administered in one or more doses. An effective dose is generally sufficient to reduce, improve, stabilize, reverse, slow, or delay the progression of a disease state.

[0099] As described above, the compound used in this invention has formula (I):

[0100]

[0101] or its pharmaceutically acceptable salt

[0102] As with any set of structure-related compounds with a specific purpose, certain embodiments of the compounds of formula (I) are particularly useful in their end-use applications.

[0103] In the compounds used in this invention, R 1 R 2 and R 3 Each independently selects H and C1-C 12 A group composed of alkyl groups.

[0104] In some implementation schemes, R 1 It is H. In some implementations, R 1 It is C1-C 12 Alkyl group. In some embodiments, R 1 Choose 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.

[0105] In some implementation schemes, R 2 It is H. In some implementations, R 2 It is C1-C 12 Alkyl group. In some embodiments, R 2 Choose 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.

[0106] In some implementation schemes, R 3 It is H. In some implementations, R 3 It is C1-C 12 Alkyl group. In some embodiments, R 3Choose 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.

[0107] In some embodiments of the compounds used in this invention, R 1 It is H, and this provides the compound of formula (Ia):

[0108]

[0109] or its pharmaceutically acceptable salt

[0110] Where R 2 R 3 R 4 R 5 R 6 R 7 and R 8 As described above.

[0111] In some embodiments of the compounds used in this invention, R 2 It is H, and this provides the compound of formula (Ib):

[0112]

[0113]

[0114] or its pharmaceutically acceptable salt

[0115] Where R 1 R 3 R 4 R 5 R 6 R 7 and R 8 As described above.

[0116] In some embodiments of the compounds used in this invention, R 3 It is H, and this provides compounds of formula (Ic):

[0117]

[0118] or its pharmaceutically acceptable salt

[0119] Where R 1 R 2 R 4 R 5 R 6 R 7 and R 8 As described above.

[0120] In some embodiments of the compounds used in this invention, R 1 It is H, R 2 It is H, and

[0121] R 3 It is H, and this provides the compound of formula (II):

[0122]

[0123] or its pharmaceutically acceptable salt

[0124] Where R 4 R 5 R 6 R 7 and R 8 As described above.

[0125] R 4 Choose freely between H and C1-C 12 The group consisting of alkyl groups. In some embodiments, R 4 It is H. In some implementations, R 4 It is C1-C 12 Alkyl group. In some embodiments, R 4 Choose 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.

[0126] In some embodiments of the compounds used in this invention, R 1 It is H, R 2 It is H, R 3 It is H, and R 4 It is H, and this provides the compound of formula (III):

[0127]

[0128] or its pharmaceutically acceptable salt

[0129] Where R 5 R 6 R 7 and R 8 As described above.

[0130] In the compounds used in this invention, R 5 Choose from the following groups: H, optional substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C6-C 18Aryl C1-C 12 Alkyl- and optionally substituted C1-C 18 heteroaryl C1-C 12 alkyl-.

[0131] In some implementation schemes, R 5 It is H. In some implementations, R 5 It is an optional substitution of C6-C 18 Aryl. In some implementations, R 5 It is an optional substitution of C1-C 18 heteroaryl. In some implementations, R 5 It is an optional substitution of C6-C 18 Aryl C1-C 12 Alkyl-. In some embodiments, R 5 It is an optional substitution of C1-C 18 heteroaryl C1-C 12 alkyl-.

[0132] In some implementation schemes, R 5 It is an optional substitution of C6-C 18 Aryl group. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl groups. In some embodiments, R 5 It is an optional substituted phenyl group.

[0133] In some implementation schemes, R 5 The phenyl moiety of formula A is optionally substituted:

[0134]

[0135] Each R a Independently select from the following groups: H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, and optionally substituted C1-C. 12 Alkyl, optionally substituted C1-C 12 Halogenated alkyl groups, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkyne group, optionally substituted C2-C 12 Heteroalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted C2-C 12 Heterocyclic alkyl groups, optionally substituted C2-C 12 Heterocyclic alkenyl, optionally substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy group, optionally substituted C2-C12 alkenyloxy group, optionally substituted C2-C 12 alkynyloxy group, optionally substituted C2-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy group, optionally substituted C2-C 12 Heterocyclic alkyloxy groups, optionally substituted C2-C 12 Heterocyclic alkenyloxy group, optionally substituted C6-C 18 aryloxy group, optionally substituted C1-C 18 Heteroaryloxy group, optionally substituted C1-C 12 Alkylamino, SR 9 SO3H, SO2NR 9 R 10 SO2R 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 SO2R 10 NR 9 CONR 9 R 10 NR 9 R 10 and acyl group,

[0136] Where R 9 and R 10 Each independently selects H and C1-C 12 A group composed of alkyl groups.

[0137] In some implementation schemes, R 5 It is an arbitrarily substituted phenyl moiety selected from the group consisting of:

[0138]

[0139] Each R a As defined above.

[0140] In some embodiments of the compounds used in this invention, each R aChoose independently from the following groups: H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 Alkyloxy group.

[0141] In some implementations, each R a Choose independently the following groups: H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH3, Cl, Br, F, I, OH, NO2, NH2, N(CH3)2, NHCOCH3, NHSO2CH3, NHSO2CH2CH2CH3, CN, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2CH2OCH3, OC6H5, OCH2C(CH3)3, OCH2cyclopropyl, O-tetrahydropyran, piperazine, 4-methylpiperazine, 4-acyl-piperazine, morpholine, CF3, OCHF2, and OCF3

[0142] In some embodiments of the compounds used in this invention, R 1 It is H, R 2 It is H, R 3 It is H, R 4 It is H, and R 5 It is part of formula A, and this provides compound (IV):

[0143]

[0144] or its pharmaceutically acceptable salt

[0145] Where R a R 6 R 7 and R 8 As described above

[0146] In some implementations, group R 5 It is an optional substitution of C1-C 18Heteroaryl groups. Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzoisothiazole, naphtho[2,3-b]thiophene, furan, iso-indene, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazolium, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthidine, quinoxaline, cyclophosphine, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazine, phenothiazine, pyridyl, quinolinyl, isoquinolinyl, indole, and thiophene. All possible linkage sites are considered in each case where multiple substitution sites may exist on the heteroaryl ring. For example, if the heteroaryl group is a pyridyl moiety, it can be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

[0147] In some implementation schemes, R 5 Choose from the following groups:

[0148]

[0149] Each V 1 V 2 V 3 and V 4 Independently select N and CR B The group formed;

[0150] Each R B Independently select from the following groups: H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, and optionally substituted C1-C. 12 Alkyl, optionally substituted C1-C 12 Halogenated alkyl groups, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkyne group, optionally substituted C2-C 12 Heteroalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted C2-C 12 Heterocyclic alkyl groups, optionally substituted C2-C 12 Heterocyclic alkenyl, optionally substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy group, optionally substituted C2-C 12 alkenyloxy group, optionally substituted C2-C 12 alkynyloxy group, optionally substituted C2-C 10 Heteroalkyloxy, optionally substituted C3-C12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy group, optionally substituted C2-C 12 Heterocyclic alkyloxy groups, optionally substituted C2-C 12 Heterocyclic alkenyloxy group, optionally substituted C6-C 18 aryloxy group, optionally substituted C1-C 18 Heteroaryloxy group, optionally substituted C1-C 12 Alkylamino, SR 9 SO3H, SO2NR 9 R 10 SO2R 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 SO2R 10 NR 9 CONR 9 R 10 NR 9 R 10 and acyl group,

[0151] Where R 9 and R 10 Each independently selects H and C1-C 12 A group composed of alkyl groups.

[0152] Y can be selected from the following groups: S, O, and NH.

[0153] In one implementation, R 5 Choose from the following groups:

[0154]

[0155] Where R B As defined above.

[0156] In one implementation, R 5 Choose from the following groups:

[0157]

[0158] Each R B As defined above.

[0159] In some embodiments of the compounds used in this invention, each R B Choose independently from the following groups: H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 Alkyloxy group.

[0160] In some implementations, each R B Choose independently the following groups: 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.

[0161] In some embodiments of the compounds used in this invention, R 5 It is an optional substitution of C6-C 18 Aryl C1-C 12 Alkyl-. In these embodiments, the C6-C is optionally substituted. 18 Aryl groups, as mentioned above, target R. 5 The alkyl group 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.

[0162] In some embodiments of the compounds used in this invention, R 5 It is a replacement for C1-C 18 heteroaryl C1-C 12 Alkyl-. In these embodiments, the C1-C atoms are optionally substituted. 18 As mentioned above, heteroaryl compounds target R. 5 The alkyl group 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.

[0163] In the compounds used in this invention, R 6 Choose from the following groups: H, C1-C 12 Alkyl, C3-C6 cycloalkyl; C1-C5 heterocyclic alkyl. In one embodiment, R 6 It is H. In one implementation, R6 It is C1-C 12 Alkyl group. In one embodiment, R 6 It is a C3-C6 cycloalkyl group. In one embodiment, R 6 It is a C1-C5 heterocyclic alkyl group.

[0164] In one specific implementation plan, R 6 It is C1-C 12 Alkyl group. R 6 Examples of suitable values ​​for R include methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl. 6 The particularly preferred value is isopropyl.

[0165] In one specific implementation plan, R 6 It is a C3-C6 cycloalkyl group. R 6 Examples of suitable values ​​include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0166] In one specific implementation plan, R 6 It is a C1-C5 heterocyclic alkyl group. R 6 Examples of suitable values ​​include aziridine, oxadiazine, thiohexacyclobutane, pyrrolidine, oxadiazine, thiohexacyclobutane, piperidine, oxane, and thiazide.

[0167] In the compounds used in this invention, R 7 Choose freely between H and C1-C 12 The group consisting of alkyl groups, or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form monocyclic or bicyclic C2-C rings. 12 Heterocyclic alkyl groups.

[0168] In one implementation, R 7 It's H.

[0169] In one implementation, R 7 It is C1-C 12 Alkyl group. R 7 Examples of suitable values ​​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 a preferred embodiment, R 7 It is a methyl group.

[0170] In the compounds used in this invention, R 8 Choose from the following groups: H, C1-C 12Alkyl, optionally substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C6-C 18 Aryl C1-C 12 Alkyl- and optionally substituted C1-C 18 heteroaryl C1-C 12 alkyl-.

[0171] In one implementation, R 8 It's H.

[0172] In one implementation, R 8 It is C1-C 12 Alkyl group. R 8 Examples of suitable values ​​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 a preferred embodiment, R 8 It is a methyl group.

[0173] In one implementation, R 8 It is an optional substitution of C6-C 18 Aryl group. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl groups. In some embodiments, R 8 It is an optional substituted phenyl group.

[0174] In some implementation schemes, R 8 The phenyl moiety of formula B is optionally substituted:

[0175]

[0176] Each R c Independently select from the following groups: H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, and optionally substituted C1-C. 12 Alkyl, optionally substituted C1-C 12 Halogenated alkyl groups, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkyne group, optionally substituted C2-C 12 Heteroalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted C2-C 12 Heterocyclic alkyl groups, optionally substituted C2-C 12 Heterocyclic alkenyl, optionally substituted C6-C 18 aryl, optionally substituted C1-C 18Heteroaryl, optionally substituted C1-C 12 Alkyloxy group, optionally substituted C2-C 12 alkenyloxy group, optionally substituted C2-C 12 alkynyloxy group, optionally substituted C2-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy group, optionally substituted C2-C 12 Heterocyclic alkyloxy groups, optionally substituted C2-C 12 Heterocyclic alkenyloxy group, optionally substituted C6-C 18 aryloxy group, optionally substituted C1-C 18 Heteroaryloxy group, optionally substituted C1-C 12 Alkylamino, SR 9 SO3H, SO2NR 9 R 10 SO2R 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 SO2R 10 NR 9 CONR 9 R 10 NR 9 R 10 and acyl group,

[0177] Where R 9 and R 10 Each independently selects H and C1-C 12 A group composed of alkyl groups.

[0178] In some implementation schemes, R 8 It is an arbitrarily substituted phenyl moiety selected from the group consisting of:

[0179]

[0180] Each R c As defined above.

[0181] In some embodiments of the compounds used in this invention, each R cChoose independently from the following groups: H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 Alkyloxy group.

[0182] In some implementations, each R c Choose independently the following groups: 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.

[0183] In one implementation, R 8 It is an optional substitution of C1-C 18 Heteroaryl groups. Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzoisothiazole, naphtho[2,3-b]thiophene, furan, iso-indene, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazolium, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthidine, quinoxaline, cyclophosphine, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazine, phenothiazine, pyridyl, quinolinyl, isoquinolinyl, indole, and thiophene. All possible linkage sites are considered in each case where multiple substitution sites may exist on the heteroaryl ring. For example, if the heteroaryl group is a pyridyl moiety, it can be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

[0184] In some implementation schemes, R 8 Choose from the following groups:

[0185]

[0186] Each V 1 V 2 V 3 and V 4 Independently select N and CR D The group formed;

[0187] Each R D Independently select from the following groups: H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, and optionally substituted C1-C. 12Alkyl, optionally substituted C1-C 12 Halogenated alkyl groups, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkyne group, optionally substituted C2-C 12 Heteroalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted C2-C 12 Heterocyclic alkyl groups, optionally substituted C2-C 12 Heterocyclic alkenyl, optionally substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy group, optionally substituted C2-C 12 alkenyloxy group, optionally substituted C2-C 12 alkynyloxy group, optionally substituted C2-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy group, optionally substituted C2-C 12 Heterocyclic alkyloxy groups, optionally substituted C2-C 12 Heterocyclic alkenyloxy group, optionally substituted C6-C 18 aryloxy group, optionally substituted C1-C 18 Heteroaryloxy group, optionally substituted C1-C 12 Alkylamino, SR 9 SO3H, SO2NR 9 R 10 SO2R 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 SO2R 10 NR 9 CONR 9 R 10 NR 9 R 10 and acyl group,

[0188] Where R 9 and R 10Each independently selects H and C1-C 12 A group composed of alkyl groups.

[0189] Y can be selected from the following groups: S, O, and NH.

[0190] In one implementation, R 8 Choose from the following groups:

[0191]

[0192] Where R D As defined above.

[0193] In one implementation, R 8 Choose from the following groups:

[0194]

[0195] Each R D As defined above.

[0196] In some embodiments of the compounds used in this invention, each R D Choose independently from the following groups: H, halogen, OH, NO2, CN, SH, NH2, NHCOCH3, CF3, OCHF2, OCF3, C1-C 12 Alkyl and C1-C 12 Alkyloxy group.

[0197] In some implementations, each R D Choose independently the following groups: 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.

[0198] In some embodiments of the compounds used in this invention, R 8 It is an optional substitution of C6-C 18 Aryl C1-C 12 Alkyl-. In these embodiments, the C6-C is optionally substituted. 18 Aryl groups, as mentioned above, target R. *The alkyl group 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 specific embodiment, the alkyl group is methyl, such that the alkyl group is a methylene group with an aryl group attached to a nitrogen atom.

[0199] In some embodiments of the compounds used in this invention, R 8 It is a replacement for C1-C 18 heteroaryl C1-C 12 Alkyl-. In these embodiments, the C1-C atoms are optionally substituted. 18 As mentioned above, heteroaryl compounds target R. 8 The alkyl group 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.

[0200] In some implementation schemes, R 7 and R 8 When combined with the nitrogen atoms they are attached to, they form C2-C. 12 Heterocyclic group. C2-C 12 The heterocyclic group can be any suitable C2-C 12 Heterocyclic groups, and can be monocyclic or bicyclic heterocyclic groups. In one embodiment, C2-C 12 The heterocyclic group is monocyclic. In one embodiment, C2-C 12 The heterocyclic group is bicyclic.

[0201] C2-C 12 Heterocyclic groups can consist of fully saturated rings, fully unsaturated rings, or combinations thereof. For example, it can contain one saturated ring and one unsaturated ring.

[0202] In one implementation, C2-C 12 Heterocyclic groups are groups of formula C:

[0203]

[0204] Each R D Independently select from the following groups: H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, and optionally substituted C1-C. 12 Alkyl, optionally substituted C1-C 12 Halogenated alkyl groups, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkyne group, optionally substituted C2-C12 Heteroalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 Cycloalkenyl, optionally substituted C2-C 12 Heterocyclic alkyl groups, optionally substituted C2-C 12 Heterocyclic alkenyl, optionally substituted C6-C 18 aryl, optionally substituted C1-C 18 Heteroaryl, optionally substituted C1-C 12 Alkyloxy group, optionally substituted C2-C 12 alkenyloxy group, optionally substituted C2-C 12 alkynyloxy group, optionally substituted C2-C 10 Heteroalkyloxy, optionally substituted C3-C 12 Cycloalkyloxy, optionally substituted C3-C 12 Cycloalkenyloxy group, optionally substituted C2-C 12 Heterocyclic alkyloxy groups, optionally substituted C2-C 12 Heterocyclic alkenyloxy group, optionally substituted C6-C 18 aryloxy group, optionally substituted C1-C 18 Heteroaryloxy group, optionally substituted C1-C 12 Alkylamino, SR 9 SO3H, SO2NR 9 R 10 SO2R 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 SO2R 10 NR 9 CONR 9 R 10 NR 9 R 10 and acyl group,

[0205] Each R 9 and R 10 Independently select H and C1-C 12 Groups composed of alkyl groups;

[0206] n is an integer chosen from 1 and 2.

[0207] In one implementation, C2-C 12 The heterocyclic group is a group of formula D:

[0208]

[0209] In one implementation, C2-C 12 The heterocyclic group is a group of formula E:

[0210]

[0211] In some embodiments of compounds D and E, each R D Choose independently the following groups: 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.

[0212] In the present invention containing R 9 In some embodiments of compounds with the group R 9 The functional 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 The group consisting of H, methyl, and ethyl is selected. In some embodiments, R... 9 It is H. In some implementations, R 9 It is methyl. In some embodiments, R 9 It is an ethyl group.

[0213] In the present invention containing R 10 In some embodiments of compounds with the group R 10 The functional 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 The group consisting of H, methyl, and ethyl is selected. In some embodiments, R... 10 It is H. In some implementations, R 10 It is methyl. In some embodiments, R 10 It is an ethyl group.

[0214] Many (if not all) of the variables discussed above may optionally be substituted. If a variable is optionally substituted, in some embodiments, each optional substituent is independently selected from the group consisting of: halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, ynyl, haloalkyl, haloalkenyl, haloynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxyl, hydroxyalkyl, alkyloxy, alkyl alkyl alkyl, alkyloxycycloalkyl, alkyloxyheteroalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclic alkyloxy, heterocyclic alkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinylaminoalkyl, -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 SO2R f -SR e SO2NR e R f -OR e OC (=O)NR e R f OC(=O)R e and acyl group,

[0215] Where R e R f R g and R h Each can independently choose from the following groups: H, C1-C 12 Alkyl, C1-C 12 Haloalkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C1-C 10 Heteroalkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, C1-C 12 Heterocyclic alkyl, C1-C 12 Heterocyclic alkenyl, C6-C 18 Aryl, C1-C 18 heteroaryl and acyl, or R a R b R c and R d Any two or more of them, together with the atoms to which they are attached, form a heterocycle with 3 to 12 ring atoms.

[0216] In some embodiments, each optional substituent is independently selected from the group consisting of: F, Cl, Br, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxyl, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(O)OR a COOH, SH and acyl groups.

[0217] 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, NH2, -NO2, phenoxy, hydroxyl, methoxy, trifluoro-methoxy, ethoxy, and methylenedioxy.

[0218] 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.

[0219] Alternatively, two optional substituents on the same moiety may be linked together to form a fused cyclic substituent connected to the optionally substituted moiety. Therefore, the term "optionally substituted" includes fused rings, such as cycloalkyl rings, heterocycloalkyl rings, aryl rings, or heteroaryl rings.

[0220] Examples of compounds of specific formula (I) used in this invention include:

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] Or its pharmaceutically acceptable salt.

[0237] The compound has the ability to inhibit CD151. This ability to inhibit CD151 may be a result of the compound acting directly and alone on CD151 to regulate / enhance its biological activity. However, it should be understood that the compound may also act at least partially on other factors associated with CD151 activity.

[0238] Inhibition of CD151 can be carried out in any of a variety of ways known in the art. For example, if in vitro inhibition of CD151 is required, an appropriate amount of the compound can be added to a solution containing CD151. In cases where inhibition of CD151 in non-human animals is required, CD151 inhibition typically involves applying the compound to a non-human animal containing CD151. The method of the present invention can be implemented on a variety of non-human animals. In one embodiment, the non-human animal is selected from the group consisting of pigs, sheep, cattle, goats, chickens, and ducks. In one embodiment, the non-human animal is a pig.

[0239] Therefore, the compounds can be found to have a variety of applications, among which their ability to inhibit the aforementioned CD151 can be utilized.

[0240] Therefore, the compounds of the present invention are expected to have useful therapeutic properties, especially in relation to diseases such as cancer.

[0241] CD151 expression is also associated with infection by infectious agents such as viruses. Therefore, inhibition of CD151 may help treat infectious agent-mediated diseases, including PRSSV.

[0242] The compounds of formula (I) can be administered to nonhuman animals via any acceptable enteral route, such as oral or rectal, or via parenteral routes such as subcutaneous, intramuscular, intravenous, and intradermal. Injection can be a bolus or via 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 exhibit selective or greater toxicity to rapidly proliferating cells, such as cancerous tumors, compared to normal cells.

[0243] The compounds of this invention can be administered in any form or manner to ensure bioavailability. Those skilled in the art of formulation can readily select the appropriate form and manner of administration based on the specific characteristics of the selected compound, the disease to be treated, the stage of the disease to be treated, and other relevant circumstances. For further information, please refer to Remingtons Pharmaceutical Sciences, 19th edition, Mack Publishing Co. (1995).

[0244] The compounds of the present invention can be administered alone or in veterinary compositions in combination with veterinary-acceptable carriers, diluents, or excipients. While effective on their own, the compounds of the present invention are typically formulated and administered in the form of veterinary-acceptable salts because these forms are generally more stable, easier to crystallize, and have increased solubility.

[0245] However, the compound is typically used in the form of a veterinary composition, which is formulated according to the desired method of administration. Therefore, in some embodiments, the present invention provides a veterinary composition comprising a compound of formula (I) and a veterinary-acceptable carrier, diluent, or excipient. The composition is prepared in a manner well known in the art.

[0246] In other embodiments, the invention provides a drug kit or cassette comprising one or more containers filled with one or more ingredients of the veterinary composition of the invention. Containers containing unit doses are found in such kits or cassettes. The cassette may include a composition comprising an effective agent in the form of a concentrate (including lyophilized compositions), which may be further diluted prior to use or may be provided at a concentration, wherein the vial may contain one or more doses. Conveniently, in the cassette, a single dose may be provided in a sterile vial so that a physician can directly use the vial, which will contain the desired amount and concentration of agent. Associated with such containers may be various written materials such as instructions for use, or notices in the form of those prescribed by government agencies regulating the manufacture, use, or sale of drugs or biological products, reflecting approval by the manufacturing, using, or selling agency for administration to non-human animals.

[0247] The compounds of the present invention may be used or administered in combination with one or more other drugs to treat the mentioned conditions / diseases. The components may be administered in the same formulation or in separate formulations. If administered in a separate formulation, the compounds of the present invention may be administered sequentially or simultaneously with other drugs.

[0248] In addition to being able to be administered in combination with one or more other drugs, the compounds of the present invention can also be used in combination therapies. When doing so, the compounds are typically administered in combination with each other. Thus, one or more compounds of the present invention can be administered simultaneously (as a combination formulation) or sequentially to achieve the desired effect. This is particularly desirable when each compound has different therapeutic properties, allowing the combined action of the two drugs to provide improved therapeutic outcomes.

[0249] The veterinary compositions of the present invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or media include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Suitable flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0250] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. Isotonic agents, such as sugars and sodium chloride, may also be included if desired. Prolonged absorption of injectable drugs can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0251] If desired, and for more efficient distribution, the compound can be incorporated into sustained-release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

[0252] Injectable formulations may be sterilized, for example, by filtration through a bacterial trap or by incorporation of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media only before use.

[0253] 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 the following substances: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) dissolution inhibitors, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0254] Similar types of solid compositions can also use such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycol, as fillers in soft and hard filled gelatin capsules.

[0255] Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. These may optionally contain emulsifiers and may also have compositions that optionally delay or preferentially release the active ingredient in a portion of the intestine. Examples of usable encapsulation compositions include polymeric substances and waxes.

[0256] The active compound may also be in microencapsulated form, along with one or more of the excipients mentioned above, when appropriate.

[0257] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof.

[0258] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatizers.

[0259] In addition to the active composition, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum, and mixtures thereof.

[0260] Compositions for rectal or vaginal application are preferably suppositories prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at room temperature but liquid at body temperature, and thus melt and release the active compound in the rectal or vaginal cavity.

[0261] Dosage forms for topical application of the compounds of this invention include powders, patches, sprays, ointments, and inhalers. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0262] The amount of compound applied will preferably treat and alleviate or relieve the disease. The therapeutically effective amount can be readily determined by the attending physician using standard techniques and by observing results obtained in similar situations. In determining the therapeutically effective amount, many factors will be considered, including but not limited to: the species of animal; the size, age, and overall health of the animal; the specific disease involved; the severity of said disease; the patient's response to treatment; the specific compound applied; the method of administration; the bioavailability of the applied formulation; the selected dosage regimen; the use of other drugs; and other relevant circumstances.

[0263] The preferred dosage will be in the range of about 0.01 to 300 mg per kilogram of body weight per day. More preferred dosages 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. Appropriate dosages can be administered in multiple sub-dose doses per day.

[0264] Synthesis of the compounds of the present invention

[0265] The compounds used in the methods of this invention can be prepared using known organic synthesis techniques and can be synthesized using readily available starting materials according to any of a number of possible synthetic routes, including the reaction routes and synthetic schemes described below, using techniques available in the art. The preparation of the compounds of the embodiments is described in detail in the following examples; however, those skilled in the art will recognize that the described chemical reactions can be readily applied to the preparation of other agents of various embodiments.

[0266] The reactions used to prepare the compounds of this invention can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reaction takes place (e.g., temperatures in the range of the solvent's freezing temperature to its boiling temperature). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the reaction step, the solvent suitable for a particular reaction step can be selected by those skilled in the art.

[0267] The preparation of the compounds of this invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PGM Uts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which are incorporated herein by reference in their entirety.

[0268] The reaction can be monitored using any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin-layer chromatography.

[0269] As used herein, the terms “ambient temperature,” “room temperature,” and “rt” are known in the art and generally refer to a temperature (e.g., reaction temperature) that is approximately the temperature of the room in which the reaction is carried out, such as approximately 20°C to approximately 30°C.

[0270] The invention will now be illustrated by way of examples; however, these examples should not be construed as limiting the invention. As described herein, other compounds besides those described below can be prepared using methods and synthetic schemes, or suitable variations or modifications thereof.

[0271] Example

[0272] definition:

[0273] AcOH (acetic acid);

[0274] atm (atmosphere);

[0275] Boc2O (di-tert-butyl dicarbonate);

[0276] c-Hex (cyclohexane);

[0277] CDCl3 (deuterated chloroform)

[0278] CD3OD (deuterated methanol);

[0279] CHCl3 (chloroform);

[0280] conc. (concentrated);

[0281] DCM (dichloromethane);

[0282] DIPEA (N,N-diisopropylethylamine);

[0283] DMAP (4-dimethylaminopyridine);

[0284] DMSO (dimethyl sulfoxide);

[0285] DMSO-d6 (deuterated dimethyl sulfoxide);

[0286] eq (equivalent);

[0287] ES-API (Electrospray Atmospheric Pressure Ionization);

[0288] Et3N (triethylamine);

[0289] Et2O (diethyl ether);

[0290] EtOAc (ethyl acetate);

[0291] EtOH (ethanol);

[0292] g (grams);

[0293] h (hours);

[0294] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate);

[0295] HCl (hydrochloric acid / hydrogen chloride);

[0296] 1 H NMR (proton nuclear magnetic resonance);

[0297] Hz (Hertz);

[0298] L (liter);

[0299] LCMS (Liquid Chromatography-Mass Spectrometry);

[0300] LiHMDS (bis(trimethylsilyl)aminolithium);

[0301] M (moles);

[0302] MeOH (methanol);

[0303] mg (milligram);

[0304] MHz (megahertz);

[0305] min (minutes);

[0306] mL (milliliters);

[0307] mmol (millimole);

[0308] MsCl (methanesulfonyl chloride);

[0309] n-BuLi (n-Butyllithium);

[0310] NaH (sodium hydride);

[0311] NaHCO3 (sodium bicarbonate);

[0312] NaOH (sodium hydroxide);

[0313] Na2SO4 (sodium sulfate);

[0314] Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro, complexed with DCM);

[0315] PE (petroleum ether);

[0316] ppm (parts per million);

[0317] RT (room temperature);

[0318] TFA (trifluoroacetic acid);

[0319] THF (tetrahydrofuran).

[0320] Most of the materials are commercially available as reagent grade.

[0321] Nuclear magnetic resonance (NMR) spectroscopy on a Bruker Avance-400 spectrometer ( 1 H at 400.13MHz and 13 C was obtained at 100.62 MHz. Proton chemical shifts were reported in ppm using internal standards of residual chloroform (7.26 ppm), dimethyl sulfoxide (2.50 ppm), or methanol (3.31 ppm). Each resonance was specified according to the following convention: chemical shift (δ) (multiplicity, coupling constant in Hz, integral). Carbon chemical shifts were reported in parts per million (ppm) using internal standards of residual chloroform (77.16 ppm), dimethyl sulfoxide (39.52 ppm), or methanol (49.00 ppm). Chemical shifts were reported as δ values ​​in parts per million (ppm). The following abbreviations were used when reporting spectral data: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sext; sextet; m, multiplet; app, prominent; and br, broad.

[0322] Electrospray mass spectrometry (MS) was performed using the following method:

[0323] Method A: 1. Equipment information, LC model: Agilent 1200 (Pump type: binary pump, detector type: DAD) MS model: Agilent G6110A Quad Pole .

[0324] LCMS-LC parameters: Column: Xbridge-C18, 3.5μm, 2.1x50mm, Column temperature: 30℃, Wavelength acquisition: 214nm, 254nm, Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN, Run time: 5 minutes, MS: Ion source: ES+ (or ES-) MS range: 70-900m / z, Fracturing device: 60, Drying gas flow rate: 12-13L / min, Sprayer pressure: 35psi, Drying gas temperature: 350℃, Vcap: 3.5kV.

[0325] gradient table

[0326]

[0327]

[0328] Method B: 1) LC: Agilent Technologies 1290 series, binary pump, diode array detector. Column: Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 x 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. Detector: 214 nm, 254 nm.

[0329] Gradient stopping time: 3.0 minutes. Schedule:

[0330] 0.00 60 40 2.65 0 100 3.00 0 100

[0331] MS: G6120A, quadrupole LC / MS; ion source: ESI, signal: positive, TIC: 70-1000 m / z, fragmenter: 60, threshold: 5, gain: 1, dry gas flow rate: 10 L / min, nebulizer pressure: 35 psi

[0332] LCMS-P2-3 min-1) LC: Agilent Technologies 1290 series, binary pump, diode array detector. Column: Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 x 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. Detector: 214 nm, 254 nm.

[0333] Gradient stopping time: 3.0 minutes. Schedule:

[0334] 0.00 80 20 2.65 20 80

[0335] 3.00 20 80

[0336] MS: G6120A, quadrupole LC / MS; ion source: ESI, signal: positive, TIC: 70-1000 m / z, fragmenter: 60, threshold: 5, gain: 1, dry gas flow rate: 10 L / min, nebulizer pressure: 35 psi.

[0337] Method C-LC model: Waters 2695 alliance, (Pump: Quaternary pump, Detector: 2996 photodiode array detector), MS model: Micromass ZQ.LCMS-LC parameters: Column: Xbridge-C18, 2.5μm, 2.1x30mm, column temperature: 30℃. Wavelength acquisition: 214nm, 254nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 5 minutes. MS: Ion source: ES+ (or ES-), MS range: 50-900 m / z. Capillary voltage: 3.5kV, orifice voltage: 35V, extraction voltage: 3V. Drying gas flow rate: 350L / h, orifice: 50L / h. Desolvation temperature: 300℃. Source temperature: 120℃. Run time: 5 minutes.

[0338]

[0339]

[0340] Sample preparation - Dissolve the sample in methanol to a concentration of approximately 1 to 10 mg / mL, and then filter through a syringe filter at a depth of 0.22 μm. (Injection volume: 1 to 10 μL).

[0341] Method D LC model: Waters 2695 alliance. (Pump: Quaternary pump, Detector: 2996 photodiode array detector), MS model: Micromass ZQ, LCMS-LC parameters: Column: Xbridge-C18, 3.5 μm, 2.1 x 50 mm. Column temperature: 20℃. Wavelength acquisition: 214 nm, 254 nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 8 minutes. MS: Ion source: ES+ (or ES-). MS range: 100-1000 m / z. Capillary voltage: 3 kV. Orifice voltage: 40 V. Extraction voltage: 3 V. Drying gas flow rate: 800 L / h. Orifice: 50 L / h. Desolvation temperature: 500℃. Source temperature: 120℃. Run time: 8 minutes.

[0342]

[0343]

[0344] Sample preparation - Dissolve the sample in methanol to a concentration of approximately 1 to 10 mg / mL, and then filter through a syringe filter at a depth of 0.22 μm. (Injection volume: 1 to 10 μL).

[0345] Thin-layer chromatography (TLC) was used to monitor the reactions and chromatographic fractions on a Merck Kieselgel 60 F254 aluminum backing plate. Silica gel 60 F254 was used as the stationary phase for rapid chromatography. Gradient elution was performed using ethyl acetate (EtOAc) and hexane, analytical grade unless otherwise specified.

[0346] All glassware used in reactions requiring anhydrous conditions was dried (120°C) before use and then cooled under nitrogen.

[0347] A general scheme for forming many of the compounds of the present invention is shown in Schemes 1 and 2 below, which can be appropriately modified to produce many of the compounds of the present invention. As shown in Scheme 1, a typical first step is the synthesis of a heteroaromatic core molecule (in cases where this is not readily available).

[0348] Generally, a suitably protected diacid moiety (I) is reacted with a suitably functionalized acetylene in the presence of a strong base to form II. Compound II is then reacted with hydrazine to form a five-membered heterocyclic compound (III). Compound III is then reacted with a suitably substituted diacid to form amide IV, which is then cyclized to form a bicyclic heteroaromatic compound V. Finally, compound V is reacted with POCl3 to insert a chlorine group, further refining the substituents of the ring (compound VI). As those skilled in the art will understand, this scheme depicts a mode for forming higher intermediates used in the synthesis of the compounds of the present invention. Variations in the R group on the acetylene and the ester group on the starting diacid allow for the production of many different higher intermediates using this technique.

[0349]

[0350] Once the advanced intermediate VI has been produced using the procedure shown in Scheme 1, it can be purified into the compound of the present invention using the procedure shown in Scheme 2 below. Typically, compound VI is subjected to Suzuki coupling with a suitable heteroaromatic boronic acid to introduce a heteroaromatic group and form compound VII. Compound VII is reacted with a suitably substituted diamine to produce compound VIII, which is then saponified to remove the acid protecting group, yielding free acid IX. The free acid IX is then subjected to amide coupling with a suitable aromatic amine to form compound X.

[0351]

[0352] As those skilled in the art will understand, the procedures outlined in Schemes 1 and 2 can be modified using methods well known in the art to obtain a large number of the compounds of the present invention. Furthermore, in the following embodiments, modifications to the reactions described in these schemes are provided as examples of ways in which this can be done.

[0353] Compound Synthesis

[0354] Example 1 - 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (1)

[0355]

[0356] Compound 1 was synthesized using the procedure shown in Scheme 3.

[0357]

[0358] Step 1: 5-(3-ethoxy-3-oxopropamido)-1H-pyrazole-3-carboxylic acid ethyl ester (XII).

[0359] A solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (10 g, 64.40 mmol), 3-ethoxy-3-oxopropionic 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 overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH, 20 / 1) to give the title product (10.5 g, 60.7%), which was yellowish-white. LCMS (Method A): R t = 0.51 minutes; [M+H] + =270.1

[0360] Step 2: Ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (XIII)

[0361] Ethyl 5-(3-ethoxy-3-oxopropamido)-1H-pyrazole-3-carboxylate (10.5 g, 39.02 mmol) and DMAP (14.3 g, 117.2 mmol) were stirred overnight at 80 °C in ethanol (110 mL) and H₂O (110 mL). The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and H₂O (200 mL, 1 / 1). The organic matter was dried over Na₂SO₄ 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 minutes; [M+H] + =224.2

[0362] Step 3: Ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (XIV)

[0363] A solution of ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (11.3 g, 50.72 mmol) in phosphorus oxychloride (113 mL) was stirred overnight at 110 °C. The mixture was then...

[0364] The residue was concentrated under reduced pressure and extracted with Et2O (3 x 300 mL) into ice water. The combined organic matter was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title product (4.6 g, 35%) as a white solid. LCMS (Method A): R t = 1.41 minutes; [M+H] + =261.0.

[0365] Step 4: Ethyl 5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XV)

[0366] Ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (500 mg, 1.92 mmol), 1-Boc-pyrazol-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 overnight at 80 °C under N₂. The mixture was poured into water and extracted with EtOAc (100 mL x 3). The combined organic matter was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 80:1) to give the title product (137 mg, 25%) as a yellow solid. LCMS (Method A): R t = 2.34 minutes; [M+H] + =292.0

[0367] Step 5: Ethyl 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XVI)

[0368] A mixture of ethyl 5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-carboxylate (380 mg, 1.31 mmol), N-methyl-1-phenylmethylamine (316 mg, 2.61 mmol), and TEA (264 mg, 2.61 mmol) in DMF (15 mL) was stirred overnight at 80 °C. The mixture was diluted with water, and the precipitate was filtered under reduced pressure and purified by silica gel column chromatography (DCM:MeOH, 80:1) to give the desired product (400 mg, 81%) as a yellow solid. LCMS: (Method A), R t = 2.45 minutes, [M+H] + =377.1.

[0369] Step 6: 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XVII)

[0370] A solution of ethyl 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (400 mg, 1.06 mmol) in THF (8 mL) and MeOH (8 mL) was slowly added to an aqueous solution of KOH (1 M, 4 mL). The reaction mixture was stirred overnight at 90 °C. The mixture was concentrated under reduced pressure and the residue was partitioned between water (10 mL) and Et₂O (10 mL). The organic matter was discarded and the aqueous phase was acidified to pH 2 with an aqueous solution of HCl (1 M). The aqueous phase was extracted with CHCl₃ (100 mL x 3), and the combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to give the desired product (340 mg, 89%) as a yellow solid. LCMS: (Method A), R t = 2.22 minutes, [M+H] + =349.1.

[0371] Step 7: 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XVIII)

[0372] A mixture of 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (100 mg, 0.29 mmol), 3-aminophenol (34.5 mg, 0.32 mmol), HATU (142 mg, 0.37 mmol), and DIEA (931 mg, 9.20 mmol) in DMF (4 mL) was stirred overnight at room temperature. The mixture was diluted with water, and the solid was filtered under reduced pressure and purified by silica gel column chromatography (DCM:MeOH / , 30:1) to give the desired product (8 mg, 6.3%) as a yellow solid. LCMS: (Method A), R t = 2.28 minutes, [M+H] + =440.2. 1 HNMR(400MHz,DMSO-d6)δ13.51(s,1H),10.02(s,1H),9.45(s,1H),9.34(s,1H),8.70(d ,J=2.8Hz,1H),7.37-7.14(m,8H),6.53(s,2H),4.95(s,2H),3.60(s,1H),3.19(s,3H).

[0373] In step 7, the following compounds are prepared similarly from suitable starting material 1 (SM1) according to the method for synthesizing compound 1.

[0374] Example 2 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (2)

[0375]

[0376] The starting material used in step 7 of the synthesis is 1-ammonia. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.47 (s, ¹H), 9.36–9.22 (m, ¹H), 8.81–8.58 (m, ¹H), 8.05 (s, ¹H), 7.45 (s, 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 minutes; [M+H] + =348.0.

[0377] Example 3 -N-benzyl-5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (3)

[0378]

[0379] The starting material 1-benzylamine used in step 7 of the synthesis, 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 13.47 (s, ¹H), 9.27 (s, ¹H), 9.12 (s, ¹H), 8.72 (s, ¹H), 7.37–7.25 (m, ¹⁰H), 7.15 (s, ¹H), 6.42 (s, ¹H), 4.93 (s, 2H), 4.53 (d, J = 6.4 Hz, 2H), 3.17 (s, 3H). LCMS (Method A): R t = 2.34 minutes; [M+H] + =438.2;

[0380] Example 4 - 5-(benzyl(methyl)amino)-N-(4-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (4)

[0381]

[0382] The starting material used in step 7 of the synthesis was 1-4-aminophenol.1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),9.97(s,1H),9.34(s,1H),9.30(s,1H),8.71(s,1H),7.56(d,J=8 .9Hz,2H),7.37-7.24(m,5H),7.16(s,1H),6.77(d,=8.8Hz,2H),6.50(s,1H),4.94(s,2H),3.19(s,3H). LCMS (Method A): R t = 2.54 minutes; [M+H] + =440.0.

[0383] Example 5 - 5-(benzyl(methyl)amino)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (5)

[0384]

[0385] The starting material used in step 7 of the synthesis was 1-3-methoxyaniline; 1 HNMR(400MHz,DMSO-d6)δ13.53(s,1H),10.15(s,1H),9.35(s,1H),8.72(s,1H),7.54(t,J=2.4Hz,1H),7.4 3(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 minutes, [M+H] + =454.1.

[0386] Example 6 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (6)

[0387]

[0388] The starting material A used in step 7 of the synthesis was 1-pyridine-3-amine; 1HNMR (400MHz, DMSO-d6) δ13.53(d,J=8.0Hz,1H),10.40(s,1H),9.28(d,J=3.6Hz,1H),9.02(d,J=2.4Hz,1H),8.79(d,J=1.6Hz,1H),8.37(dd ,J=3.6,1.1Hz,1H),8.29-8.24(m,1H),7.47(dd,J=8.4,4.8Hz,1H),7.38-7.24(m,5H),7.20(s,1H),6.57(s,1H),4.95(s,2H),3.20(s,3H). LCMS (Method A): R t = 2.41 minutes; [M+H] + =425.0.

[0389] Example 7 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (7)

[0390]

[0391] The starting material used in step 7 of the synthesis was 1-pyridine-4-amine; 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.62–13.44 (m, 1H), 10.57 (s, 1H), 9.31 (s, 1H), 8.73 (s, 1H), 8.54 (d, J = 6.4 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 minutes; [M+H] + =425.2;

[0392] Example 8 - 5-(benzyl(methyl)amino)-N-(2-methoxypyridin-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (8)

[0393]

[0394] The starting material used in step 7 of the synthesis was 1-2-methoxypyridine-4-amine; 1HNMR (400MHz, DMSO-d6) δ 13.54 (s, 1H), 10.44 (s, 1H), 9.30 (s, 1H), 8.73 (s, 1H), 8.11 (d, J = 6.0Hz, 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 minutes; [M+H] + =455.1.

[0395] Example 9 - 5-(benzyl(methyl)amino)-N-(3,5-dimethoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (9)

[0396]

[0397] The starting material used in step 7 of the synthesis was 1-3,5-dimethoxyaniline; 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 10.07 (s, 1H), 9.33 (s, 1H), 8.70 (s, 1H), 7.37–7.25 (m, 5H), 7.17 (d, J = 3.6Hz, 3H), 6.55 (s, 1H), 6.30 (s, 1H), 4.95 (s, 2H), 3.77 (s, 6H), 3.20 (s, 3H). LCMS (Method C): R t = 3.09 minutes; [M+H] + =484.2.

[0398] Example 10-5-(benzyl(methyl)amino)-N-(3,5-dimethylisoxazol-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (10)

[0399]

[0400] The starting material used in step 7 of the synthesis was 1,3,5-dimethylisoxazole-4-amine; 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 9.81 (s, 1H), 9.33 (s, 1H), 8.70 (s, 1H), 7.37–7.25 (m, 5H), 7.20 (s, 1H), 6.51 (s, 1H), 4.95 (s, 2H), 3.19 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H). LCMS (Method C): R t= 3.68 minutes; [M+H] + =442.9.

[0401] Example 11-5-(benzyl(methyl)amino)-N,7-bis(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (11)

[0402]

[0403] The starting material used in step 7 of the synthesis was 1-1H-pyrazole-4-amine; 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 13.51 (s, ¹H), 12.64 (s, ¹H), 10.38 (s, ¹H), 9.34 (s, ¹H), 8.74 (s, ¹H), 7.92 (s, 2H), 7.37–7.25 (m, 5H), 7.17 (s, ¹H), 6.50 (s, ¹H), 4.95 (s, 2H), 3.19 (s, 3H). LCMS (Method C): R t = 1.35 minutes; [M+H] + =414.2

[0404] Example 12-5-(benzyl(methyl)amino)-N-(4-cyanophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (12)

[0405]

[0406] The starting material used in step 7 of the synthesis was 1,4-aminobenzonitrile; 1 HNMR (400MHz, DMSO-d6) δ 13.53 (s, 1H), 10.55 (s, 1H), 9.31 (s, 1H), 8.72 (s, 1H), 8.08 (d, J = 8.8Hz, 2H), 7.86 (d, J = 8.8Hz, 2H), 7.40–7.24 (m, 5H), 7.20 (s, 1H), 6.59 (s, 1H), 4.95 (s, 2H), 3.20 (s, 3H). LCMS (Method A): R t = 2.46 minutes; [M+H] + =449.0.

[0407] Example 13-5-(benzyl(methyl)amino)-N-(3-cyanophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (13)

[0408]

[0409] The starting material used in step 7 of the synthesis was 1-3-aminobenzonitrile; 1 HNMR (400MHz, DMSO-d6) δ 13.59(s, 1H), 10.52(s, 1H), 9.39(s, 1H), 8.80(s, 1H), 8.37(s, 1H), 8.26–8.23(m, 1H), 7.69(t, J = 6.4Hz, 2H), 7.43–7.31(m, 5H), 7.26(s, 1H), 6.64(s, 1H), 5.02(s, 2H), 3.26(s, 3H). LCMS (Method C): R t = 3.01 minutes; [M+H] + =449.1

[0410] Example 14 - 5-(benzyl(methyl)amino)-N-(3-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (18)

[0411]

[0412] The starting material used in step 7 of the synthesis was 1,3-isopropoxyaniline; 1 HNMR(400MHz,DMSO-d6)δ13.51(s,1H),10.09(s,1H),9.31(s,1H),8.70(s,1H),7.49(t,J=2.4Hz,1H),7.40-7.33(m,3H),7.3 2-7.24(m,4H),7.16(s,1H),6.70(d,J=8.0Hz,1H),6.55(s,1H),4.94(s,2H),4.60(s,1H),3.19(s,3H),1.30(d,J=6.0Hz,6H). LCMS (Method A): R t = 3.25 minutes; [M+H] + =482.2

[0413] Example 15-5-(benzyl(methyl)amino)-N-(3-(difluoromethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (19)

[0414]

[0415] The starting material used in step 7 of the synthesis was 1-3-(difluoromethoxy)aniline; A 1HNMR (400MHz, DMSO-d6) δ 13.53 (s, 1H), 10.32 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 7.79 (t, J = 2.4Hz, 1H), 7.75–7.70 (m, 1H), 7.46–7.41 (m, 1H), 7.38–7.33 (m, 2H), 7.32–7.26 (m, 3H), 7.24–7.04 (m, 2H), 6.96 (dd, J = 8.0Hz, 1H), 6.56 (s, 1H), 4.95 (s, 2H), 3.19 (s, 3H). LCMS (Method A): R t = 3.15 minutes; [M+H] + =489.9

[0416] Example 16-5-(benzyl(methyl)amino)-N-(3-(dimethylamino)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (20)

[0417]

[0418] The starting material used in step 7 of the synthesis was 1-N1,N1-dimethylphenyl-1,3-diamine; 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.97 (s, ¹H), 9.03 (s, ¹H), 8.42 (s, ¹H), 7.38–7.25 (m, 6H), 7.19–7.16 (m, 3H), 6.54 (s, ¹H), 4.95 (s, 2H), 3.19 (s, 3H), 2.94 (s, 6H). LCMS (Method A): R t = 3.84 minutes; [M+H] + =467.2

[0419] Example 17-5-(benzyl(methyl)amino)-N-(methanesulfonyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (21)

[0420]

[0421] The starting material used in step 7 of the synthesis was 1-methanesulfonamide; 1 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): Rt = 3.58 minutes; [M+H] + =425.1.

[0422] Example 18-5-(benzyl(methyl)amino)-N-(3-(4-methylpiperazin-1-yl)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (22)

[0423]

[0424] The starting material used in step 7 of the synthesis was 1-3-(4-methylpiperazin-1-yl)aniline; 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 9.99 (s, 1H), 9.33 (s, 1H), 8.70 (s, 1H), 7.48 (s, 1H), 7.39–7.14 (m, 8H), 6.73 (d, J = 8.2Hz, 1H), 6.53 (s, 1H), 4.95 (s, 2H), 3.33 (s, 4H), 3.19 (s, 7H), 2.26 (s, 3H). LCMS (Method A): R t = 2.97 minutes; [M+H] + =522.0.

[0425] Example 19 - 5-(benzyl(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (29)

[0426]

[0427] The starting material used in step 7 of the synthesis was 1-4-chloroaniline; 1 HNMR (400MHz, DMSO-d6) δ 13.54 (s, 1H), 10.29 (s, 1H), 9.33 (s, 1H), 8.72 (s, 1H), 7.88 (d, J = 8.8Hz, 2H), 7.45 (d, J = 8.8Hz, 2H), 7.37–7.25 (m, 5H), 7.19 (s, 1H), 6.55 (s, 1H), 4.96 (s, 2H), 3.20 (s, 3H). LCMS (Method A): R t = 3.27 minutes; [M+H] + =458.0.

[0428] Example 20 - 5-(benzyl(methyl)amino)-N-(3-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (30)

[0429]

[0430] The starting material used in step 7 of the synthesis was 1-3-chloroaniline; 1 ¹H NMR (400 MHz, DMSO-d⁶): 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 minutes; [M+H] + =458.1.

[0431] Example 21-5-(benzyl(methyl)amino)-N-(2-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (31)

[0432]

[0433] The starting material used in step 7 of the synthesis was 1-2-chloroaniline; 1 HNMR (400MHz, DMSO-d6) δ 13.56 (s, 1H), 9.98 (s, 1H), 9.18 (s, 1H), 8.70 (s, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.62 (dd, J = 6.8Hz, 1.2Hz, 1H), 7.44–7.22 (m, 8H), 6.56 (s, 1H), 4.96 (s, 2H), 3.20 (s, 3H). LCMS (Method A): R t = 4.39 minutes; [M+H] + =458.1

[0434] Example 22 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (32)

[0435]

[0436] The starting material used in step 7 of the synthesis was 1-4-(trifluoromethyl)aniline; 1HNMR (400MHz, DMSO-d6) δ 13.53 (s, 1H), 10.49 (s, 1H), 9.34 (s, 1H), 8.73 (s, 1H), 8.10 (d, J = 8.4Hz, 2H), 7.77 (d, J = 8.8Hz, 2H), 7.40–7.24 (m, 5H), 7.20 (s, 1H), 6.59 (s, 1H), 4.96 (s, 2H), 3.20 (s, 3H). LCMS (Method A): R t = 3.35 minutes; [M+H] + =492.1

[0437] Example 23 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (33)

[0438]

[0439] The starting material used in step 7 of the synthesis was 1-3-(trifluoromethyl)aniline; 1 HNMR(400MHz,DMSO-d6)δ13.53(s,1H),10.47(s,1H),9.35(s,1H),8.73(s,1H),8.30(s,1H),8.18(d,J=8.4Hz,1H), 7.64(t,J=8.0Hz,1H),7.49(d,J=7.8Hz,1H),7.39-7.23(m,5H),7.20(s,1H),6.58(s,1H),4.95(s,2H),3.20(s,3H). LCMS (Method A): R t = 3.34 minutes; [M+H] + =492.13.

[0440] Example 24 - 5-(benzyl(methyl)amino)-7-(1H-pyrazol-4-yl)-N-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (34)

[0441]

[0442] The starting material used in step 7 of the synthesis was 1-2-(trifluoromethyl)aniline; 1HNMR (400MHz, DMSO-d6) δ 13.57 (s, 1H), 9.91 (s, 1H), 9.15 (s, 1H), 8.68 (s, 1H), 8.02 (d, J = 8.0Hz, 1H), 7.85–7.74 (m, 2H), 7.49 (t, J = 7.6Hz, 1H), 7.38–7.24 (m, 5H), 7.22 (s, 1H), 6.55 (s, 1H), 4.96 (s, 2H), 3.19 (s, 3H). LCMS (Method A): R t = 4.44 minutes; [M+H] + =492.2;

[0443] Example 25 - 5-(benzyl(methyl)amino)-N-(4-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (35)

[0444]

[0445] The starting material used in step 7 of the synthesis was 1-4-fluoroaniline; 1 HNMR (400MHz, DMSO-d6) δ 13.50 (s, 1H), 10.28 (s, 1H), 9.33 (s, 1H), 8.72 (s, 1H), 7.84 (dd, J = 5.2Hz, 2.0Hz, 2H), 7.37–7.18 (m, 8H), 6.57 (s, 1H), 4.95 (s, 2H), 3.19 (s, 3H). LCMS (Method C): R t = 3.05 minutes; [M+H] + =488.1

[0446] Example 26 - 5-(benzyl(methyl)amino)-N-(3-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (36)

[0447]

[0448] The starting material used in step 7 of the synthesis was 1-3-fluoroaniline; 1HNMR (400MHz, DMSO-d6) δ13.52(s,1H),10.33(s,1H),9.32(s,1H),8.72(s,1H),7.81(d,J=11.6Hz,1H),7.67(d,J= 8.4Hz,1H),7.47-7.24(m,6H),7.19(s,1H),6.97(td,J=8.6Hz,2.4Hz,1H),6.56(s,1H),4.95(s,2H),3.19(s,3H). LCMS (Method A): R t = 3.12 minutes; [M+H] + =442.03.

[0449] Example 27 - 5-(benzyl(methyl)amino)-N-(2-fluorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (37)

[0450]

[0451] The starting material used in step 7 of the synthesis was 1-2-fluoroaniline; 1 HNMR (400MHz, DMSO-d6) δ 13.52 (s, 1H), 10.00 (s, 1H), 9.28 (s, 1H), 8.72 (s, 1H), 7.78 (td, J = 7.8, 2.1Hz, 1H), 7.39–7.22 (m, 8H), 7.19 (s, 1H), 6.53 (s, 1H), 4.95 (s, 2H), 3.19 (s, 3H). LCMS (Method A): R t = 3.10 minutes; [M+H] + =442.09.

[0452] Based on the method for synthesizing compound 1 in scheme 3 above, the following compounds are prepared similarly from the appropriate starting material in step 5 and the appropriate starting material 2 in step 7.

[0453] Example 28 -(S)-N-(3-methoxyphenyl)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (14)

[0454]

[0455] The starting material used in step 5 is (S)-N-methyl-1-phenylethyl-1-amine; the starting material used in step 7 is 3-methoxyaniline; 1HNMR(400MHz,DMSO-d6)δ13.52(s,1H),10.14(s,1H),9.35(s,1H),8.75(s,1H),7.54(d,J=2.4Hz,1H),7.45-7.27(m,7H),7 .19(s,1H),6.73(dd,J=8.2Hz,2.0Hz,1H),6.56(s,1H),6.27-6.11(m,1H),3.79(s,3H),2.90(s,3H),1.60(d,J=6.8Hz,3H). LCMS (Method A): R t = 2.53 minutes; [M+H] + =468.0

[0456] Example 29 -(S)-N-(3-hydroxyphenyl)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (15)

[0457]

[0458] The starting material used in step 5 is S)-N-methyl-1-phenylethyl-1-amine; the starting material used in step 7 is 3-aminophenol; 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 10.04 (s, 1H), 9.40 (d, J = 16Hz, 2H), 8.74 (s, 1H), 7.40–7.14 (m, 9H), 6.54 (s, 2H), 6.18 (dd, J = 2.8Hz, 1.2Hz, 1H), 2.89 (s, 3H), 1.60 (d, J = 6.8Hz, 3H). LCMS (Method A): R t = 2.34 minutes; [M+H] + =454.0.

[0459] Example 30-(S)-5-(methyl(1-phenylethyl)amino)-N-phenyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (16)

[0460]

[0461] The starting material used in step 5 is S)-N-methyl-1-phenylethyl-1-amine; the starting material used in step 7 is aniline; 1HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 10.17 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 7.84 (d, J = 7.8Hz, 2H), 7.52–7.07 (m, 9H), 6.55 (s, 1H), 6.19 (s, 1H), 2.89 (s, 3H), 1.60 (d, J = 6.4Hz, 3H). LCMS (Method A): R t = 3.15 minutes; [M+H] + =438.0.

[0462] Example 31-(S)-5-(methyl(1-phenylethyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (17)

[0463]

[0464] The starting material used in step 5 is (S)-N-methyl-1-phenylethyl-1-amine; the starting material used in step 7 is ammonia; 1 HNMR(400MHz,DMSO-d6)δ13.46(s,1H),9.30(d,J=1.6Hz,1H),8.70(d,J=2.8Hz,1H),8.04(s ,1H),7.51-7.14(m,7H),6.39(s,1H),6.30-6.06(m,1H),2.87(s,3H),1.58(d,J=6.8Hz,3H). LCMS (Method A): R t = 2.09 minutes; [M+H] + =362.0.

[0465] Example 32 - 5-(isoindoline-2-yl)-N-phenyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (23)

[0466]

[0467] The starting material used in step 5 is isoindoline; the starting material used in step 7 is aniline. 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 10.19 (s, 1H), 9.38 (s, 1H), 8.78 (s, 1H), 7.48 (d, J = 7.6Hz, 2H), 7.45–7.35 (m, 6H), 7.15 (d, J = 7.2Hz, 1H), 7.09 (s, 1H), 6.60 (s, 1H), 4.97 (s, 4H). LCMS (Method C): Rt = 3.01 minutes; [M+H] + =422.1.

[0468] Example 33-N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (24)

[0469]

[0470] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 3-aminophenol; 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 10.19 (s, 1H), 9.45 (s, 1H), 9.08 (s, 2H), 7.45 (s, 2H), 7.38 (t, J = 2.8Hz, 3H), 7.23 (s, 1H), 7.15 (d, J = 7.2Hz, 1H), 7.09 (s, 1H), 6.57 (s, 2H), 4.97 (s, 4H). LCMS (Method A): R t = 3.66 minutes; [M+H] + =438.1.

[0471] Example 34 - 5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (25)

[0472]

[0473] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 3-methoxyaniline; 1 HNMR(400MHz,DMSO-d6)δ13.53(s,1H),10.15(s,1H),9.38(s,1H),8.77(s,1H),7.54-7.36(m,6H) ,7.30(t,J=7.2Hz,1H),7.09(s,1H),6.73(d,J=7.6Hz,1H),6.60(s,1H),4.97(s,4H),3.97(s,3H). LCMS (Method C): R t = 3.01 minutes; [M+H] + =452.1

[0474] Example 35 - 5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (26)

[0475]

[0476] The starting material used in step 5 is isoindoline; the starting material used in step 7 is 3-trifluoromethoxyaniline; 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.55 (s, ¹H), 10.45 (s, ¹H), 9.37 (s, ¹H), 8.79 (d, J = 7.8Hz, ¹H), 8.01 (s, ¹H), 7.93–7.86 (m, ¹H), 7.56–7.33 (m, 5H), 7.17–7.08 (m, 2H), 6.63 (s, ¹H), 4.97 (s, 4H). LCMS (Method A): R t = 3.37 minutes; [M+H] + =506.0.

[0477] Example 36 -N-(3-ethoxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (27)

[0478]

[0479] The starting material used in step 5 is isoindoline; the starting material used in step 7 is 3-ethoxyaniline; 1 HNMR(400MHz,DMSO-d6)δ13.54(s,1H),10.14(s,1H),9.38(s,1H),8.77(s,1H),7.56-7.23(m,7H),7.1 0 (s, 1H), 6.71 (d, = 8.4Hz, 1H), 6.61 (s, 1H), 4.98 (d, J = 1.6Hz, 4H), 4.05 (d, J = 6.8Hz, 2H), 1.37 (s, 3H). LCMS (Method A): R t = 3.17 minutes; [M+H] + =466.11.

[0480] Example 37 - 5-(isoindoline-2-yl)-N-(3-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (28)

[0481]

[0482] The starting material used in step 5 is isoindoline; the starting material used in step 7 is 3-isopropoxyaniline; 1HNMR (400MHz, DMSO-d6) δ13.54(s,1H),10.12(s,1H),9.37(s,1H),8.77(s,1H),7.53-7.35(m,6H),7.27(t,J=8.2Hz ,1H),7.10(s,1H),6.70(dd,J=8.2,1.9Hz,1H),6.61(s,1H),4.98(s,4H),4.66-4.56(m,1H),1.31(d,J=6.0Hz,6H). LCMS (Method A): R t = 3.25 minutes; [M+H] + =480.11.

[0483] Example 38 -N-(4-chlorophenyl)-5-((4-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (38)

[0484]

[0485] The starting material used in step 5 is 1-(4-methoxyphenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6) δ13.50(s,1H),10.28(s,1H),9.32(s,1H),8.71(s,1H),7.88(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,2 H),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 minutes; [M+H] + =488.1.

[0486] Example 39 -N-(4-chlorophenyl)-5-((3-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (39)

[0487]

[0488] The starting material used in step 5 is 1-(3-methoxyphenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1HNMR (400MHz, DMSO-d6) δ 10.29 (s, 1H), 9.02 (s, 1H), 8.71 (s, 1H), 7.88 (d, J = 7.2Hz, 2H), 7.45 (d, J = 8.8Hz, 2H), 7.26 (t, J = 7.6Hz, 1H), 7.17 (s, 1H), 6.91 (t, J = 7.2Hz, 3H), 6.55 (s, 1H), 5.77 (s, 1H), 4.91 (s, 2H), 3.72 (s, 3H), 3.16 (s, 3H). LCMS (Method A): R t = 3.47 minutes; [M+H] + =488.2.

[0489] Example 40 -N-(4-chlorophenyl)-5-((2-methoxybenzyl)(methyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (40)

[0490]

[0491] The starting material used in step 5 is 1-(2-methoxyphenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6) δ13.50(s,1H),10.28(s,1H),9.32(s,1H),8.71(s,1H),7.88(d,J=7.2Hz,2H),7.44(d,J=8.8Hz,2H),7.2 5(t,J=6.4Hz,1H),7.17(s,1H),7.05(d,J=8.0Hz,2H),6.89(t,J=6.8Hz,1H),6.52(s,1H),4.86(s,2H),3.72(s,3H),3.16(s,3H). LCMS (Method A): R t = 4.26 minutes; [M+H] + =488.2.

[0492] Example 41 -N-(4-chlorophenyl)-5-(methyl(4-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (41)

[0493]

[0494] The starting material used in step 5 is 1-(4-trifluoromethoxyphenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1HNMR(400MHz,DMSO-d6)δ13.53(s,1H),10.30(s,1H),9.34(s,1H),8.73(s,1H),7.88(d,J=8.8Hz,2H),7. 71(d,J=8.0Hz,2H),7.48(dd,J=16.0Hz,8.0Hz,4H),7.19(s,1H),6.55(s,1H),5.04(s,2H),3.23(s,3H). LCMS (Method C): R t = 3.46 minutes; [M+H] + =525.9.

[0495] Example 42-N-(4-chlorophenyl)-5-(methyl(3-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (42)

[0496]

[0497] The starting material used in step 5 is 1-(3-trifluoromethoxyphenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1 HNMR(400MHz,DMSO-d6)δ13.52(s,1H),10.30(s,1H),9.33(s,1H),8.73(s,1H),7.88(d,J=8.8Hz,2H),7.69(s,1H),7.71 -7.63(m,1H),7.59(d,J=5.2Hz,2H),7.45(dd,J=8.80Hz,2.8Hz,2H),7.19(s,1H),6.55(s,1H),5.04(s,2H),3.23(s,3H). LCMS (Method A): R t = 4.45 minutes; [M+H] + =526.1.

[0498] Example 43 -N-(4-chlorophenyl)-5-(methyl(2-(trifluoromethyl)benzyl)amino)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (43)

[0499]

[0500] The starting material used in step 5 is 1-(2-trifluoromethoxyphenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1HNMR (400MHz, DMSO-d6) δ 13.53 (s, 1H), 10.29 (s, 1H), 9.34 (s, 1H), 8.73 (s, 1H), 7.91–7.77 (m, 3H), 7.62 (t, J = 7.6Hz, 1H), 7.53–7.41 (m, 3H), 7.33–7.17 (m, 2H), 6.53 (s, 1H), 5.11 (s, 2H), 3.24 (s, 3H). LCMS (Method A): R t = 4.62 minutes; [M+H] + =526.1.

[0501] Example 44 - 5-((4-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (44)

[0502]

[0503] The starting material used in step 5 is 1-(4-chlorophenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1 HNMR(400MHz,DMSO-d6)δ13.52(s,1H),10.30(s,1H),9.33(s,1H),8.72(s,1H),7.88(d,J=8.9Hz, 2H),7.47-7.38(m,4H),7.33(d,J=8.5Hz,2H),7.17(s,1H),6.55(s,1H),4.93(s,2H),3.19(s,3H). LCMS (Method A): R t = 4.39 minutes; [M+H] + =492.1.

[0504] Example 45 - 5-((3-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (45)

[0505]

[0506] The starting material used in step 5 is 1-(3-chlorophenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1HNMR(400MHz,DMSO-d6)δ13.53(s,1H),10.30(s,1H),9.33(s,1H),8.73(s,1H),7.88(d,J=8.9Hz,2H),7.45( d,J=8.8Hz,2H),7.41-7.31(m,3H),7.26(d,=7.4Hz,1H),7.17(s,1H),6.56(s,1H),4.95(s,2H),3.21(s,3H). LCMS (Method A): R t = 3.36 minutes; [M+H] + =492.02.

[0507] Example 46 - 5-((2-chlorobenzyl)(methyl)amino)-N-(4-chlorophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (46)

[0508]

[0509] The starting material used in step 5 is 1-(2-chlorophenyl)-N-methylmethylamine; the starting material used in step 7 is 4-chloroaniline; 1 HNMR (400MHz, DMSO-d6) δ13.52(s,1H),10.30(s,1H),9.33(s,1H),8.74(s,1H),7.88(d,J=4.4Hz,2H),7.51(d,J=6 .0Hz,1H),7.44(d,J=8.8Hz,2H),7.31(t,J=2.8Hz,2H),7.19-7.16(m,2H),6.54(s,1H),5.00(s,2H),3.24(s,3H). LCMS (Method A): R t = 4.54 minutes; [M+H] + =429.1.

[0510] Example 47 - 5-(isoindoline-2-yl)-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (47)

[0511]

[0512] The starting material used in step 5 is isoindoline; the starting material used in step 7 is 3-morpholinoaniline; 1HNMR(400MHz, DMSO-d6)δ13.52(s,1H),10.05(s,1H),9.37(s,1H),8.74(s,1H),7.48(d,J=2.0Hz,1H),7.39-7.34(m,3H),7.23(t, J=8.0Hz,1H),7.09(s,1H),6.75(dd,J=6.0Hz,2.0Hz,1H),6.60(s,1H),4.97(s,4H),3.77(t,J=5.2Hz,4H),3.13(t,J=4.8Hz,4H). LCMS (Method A): R t = 3.91 minutes; [M+H] + =507.2.

[0513] Example 48 - 5-(isoindoline-2-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (48)

[0514]

[0515] The starting material used in step 5 is isoindoline; the starting material used in step 7 is 3-(4-methylpiperazin-1-yl)aniline; 1 HNMR (400MHz, DMSO-d6) δ13.54(s,1H),10.05(s,1H),9.36(d,J=1.6Hz,1H),8.78(d,J=1.6Hz,1H),7. 54-7.20(m,7H),7.09(s,1H),6.83-6.72(m,1H),6.60(s,1H),4.97(s,4H),3.26(s,8H),2.82(s,3H). LCMS (Method A): R t = 3.09 minutes; [M+H] + =520.16.

[0516] Example 49 -N-(3-(4-acetylpiperazin-1-yl)phenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (49)

[0517]

[0518] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethyl-1-one; 1HNMR(400MHz,DMSO-d6)δ13.54(s,1H),10.05(s,1H),9.36(s,1H),8.78(s,1H),7.51(s,1H),7.45(s,2H),7.37-7.33(m ,3H),7.09(s,1H),6.76(d,J=8.0Hz,1H),6.60(s,1H),4.97(s,4H),3.61(s,4H),3.19(s,2H),3.12(s,2H),2.06(s,3H). LCMS (Method A): R t = 3.69 minutes; [M+H] + =548.2.

[0519] Example 50 -N-(3-cyclobutoxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (50)

[0520]

[0521] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 3-cyclobutoxyaniline; 1 HNMR(400MHz,DMSO-d6)δ13.54(s,1H),10.14(s,1H),9.37(d,J=2.8Hz,1H),8.77(s,1H),7.57-7.21(m,8H),7.09(s,1H ), 6.62 (d, J = 11.2Hz, 2H), 4.98 (d, J = 2.8Hz, 4H), 4.80-4.56 (m, 1H), 2.51 (s, 1H), 2.15-2.01 (m, 2H), 1.86-1.61 (m, 2H). LCMS (Method A): R t = 4.47 minutes; [M+H] + =492.2.

[0522] Example 51 -N-(3,5-dimethoxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (51)

[0523]

[0524] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 3,5-dimethoxyaniline; 1HNMR(400MHz,DMSO-d6)δ13.53(s,1H),10.05(s,1H),9.35(s,1H),8.80(s,1H),7.44(d,J=2.8Hz,2H),7. 37-7.35(m,2H),7.16(d,J=2.0Hz,2H),7.09(s,1H),6.60(s,1H),6.31(s,1H),4.97(s,4H),3.77(s,6H). LCMS (Method A): R t = 4.10 minutes; [M+H] + =482.2.

[0525] Example 52 -N-(3-chloro-5-methoxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (52)

[0526]

[0527] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 3-chloro-5-methoxyaniline; 1 HNMR(400MHz,DMSO-d6)δ13.53(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=2.8Hz,2H),7.11(s,1H),6.82(s,1H),6.62(s,1H),4.97(s,4H),3.81(s,3H). LCMS (Method A): R t = 4.49 minutes; [M+H] + =486.1.

[0528] Example 53 -N-(4-chloro-3-methoxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (53)

[0529]

[0530] The starting material used in step 5 is isoindoline; the starting material used in step 7 is 4-chloro-3-methoxyaniline. 1HNMR(400MHz,DMSO-d6)δ13.56(s,1H),10.30(s,1H),9.37(s,1H),9.00-8.59(m,1H),7.79(d, J=2.0Hz,1H),7.57-7.32(m,6H),7.10(s,1H),6.62(s,1H),4.97(d,J=1.6Hz,4H),3.89(s,3H). LCMS (Method A): R t = 4.27 minutes; [M+H] + =486.1

[0531] Example 54 - 5-(isoindoline-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (54)

[0532]

[0533] The starting material used in step 5 is isoindoline; the starting material used in step 7 is 4-methoxyaniline. 1 HNMR (400MHz, DMSO-d6) δ 13.53 (s, 1H), 10.09 (s, 1H), 9.37 (s, 1H), 8.77 (s, 1H), 7.71 (s, 2H), 7.41 (d, J = 8.0Hz, 4H), 7.08 (s, 1H), 6.97 (s, 2H), 6.58 (s, 1H), 4.97 (s, 4H), 3.71 (s, 3H). LCMS (Method A): R t = 3.93 minutes; [M+H] + =452.2.

[0534] Example 55 -N-(4-ethoxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (55)

[0535]

[0536] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 4-ethoxyaniline. 1HNMR(400MHz,DMSO-d6)δ13.52(s,1H),10.09(s,1H),9.38(s,1H),8.77(s,1H),7.70(d,J=8.8Hz,2H),7.53-7.32( m, 4H), 7.08 (s, 1H), 6.95 (d, J = 8.8Hz, 2H), 6.57 (s, 1H), 4.97 (s, 4H), 4.03 (q, J = 6.4Hz, 2H), 1.34 (t, J = 6.0Hz, 3H). LCMS (Method A): R t = 3.18 minutes; [M+H] + =466.04.

[0537] Example 56 - 5-(isoindoline-2-yl)-N-(4-isopropoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (56)

[0538]

[0539] The starting material used in step 5 is isoindoline, and the starting material used in step 7 is 4-isopropoxyaniline. 1 HNMR (400MHz, DMSO-d6) δ13.55(s,1H),10.09(s,1H),9.35(s,1H),8.77(s,1H),7.66(d,J=8.8Hz,2H),7.44(d,J=3.2Hz,2H) ,7.37-7.35(m,2H),7.07(s,1H),6.95(d,J=8.8Hz,2H),6.57(s,1H),4.97(s,4H),4.62-4.55(m,1H),1.27(t,J=6.0Hz,3H). LCMS (Method A): R t = 42.2 minutes; [M+H] + =480.2.

[0540] Example 57 - 5-(5-chloroisoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (61)

[0541]

[0542] The starting material used in step 5 is 5-chloroisoindoline, and the starting material used in step 7 is 4-methoxyaniline; 1¹H NMR (400 MHz, DMSO-d⁶) 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 minutes; [M+H] + =466.1.

[0543] Example 58 - 5-(5-chloroisoindoline-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (62)

[0544]

[0545] The starting material used in step 5 is 5-chloroisoindoline, and the starting material used in step 7 is 4-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.04(s,1H),9.43(s,1H),8.74(s,1H),7.53(s,1H),7.47(d,J=8.0Hz,1H),7.42 -7.38(m,3H),7.22(d,J=7.6Hz,1H),7.15(t,J=8.0Hz,1H),7.06(s,1H),6.59(s,1H),4.55(d,J=8.0Hz,1H),4.95(s,4H). LCMS (Method A): R t = 3.90 minutes; [M+H] + =472.1.

[0546] Example 59 - 5-(5-fluoroisoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (63)

[0547]

[0548] The starting material used in step 5 is 5-fluoroisoindoline, and the starting material used in step 7 is 4-methoxyaniline; 1HNMR (400MHz, DMSO-d6) δ 13.54 (s, 1H), 10.16 (s, 1H), 9.37 (s, 1H), 8.76 (s, 1H), 7.65–7.00 (m, 7H), 6.83–6.47 (m, 2H), 5.20–4.73 (m, 4H), 3.79 (s, 3H). LCMS (Method A): R t = 4.10 minutes; [M+H] + =470.1.

[0549] Example 60 - 5-(5-fluoroisoindoline-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (64)

[0550]

[0551] The starting material used in step 5 is 5-fluoroisoindoline, and the starting material used in step 7 is 4-aminophenol. 1 HNMR (400MHz, DMSO-d6) δ 13.53 (s, 1H), 10.06 (s, 1H), 9.53–9.29 (m, 2H), 8.75 (s, 1H), 7.49–7.43 (m, 1H), 7.38 (s, 1H), 7.32–7.12 (m, 4H), 7.06 (s, 1H), 6.65–6.50 (m, 2H), 4.94 (dd, J = 2.0Hz, 1.2Hz, 4H). LCMS (Method A): R t = 3.93 minutes; [M+H] + =456.1.

[0552] According to the method for synthesizing compound 1, the following compounds are prepared similarly from the appropriate starting materials in step 4, step 5 and step 7.

[0553] Example 61-5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (57)

[0554]

[0555] The starting material used in step 4 is 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole; the starting material used in step 5 is isoindoline; and the starting material used in step 7 is 4-methoxyaniline. 1HNMR (400MHz, DMSO-d6) δ10.05(s,1H),9.31(s,1H),8.77(s,1H),7.57(t,J=2.0Hz,1H),7.34(t,J=8.8Hz,2H),7.37-7.35(m ,2H),7.30(t,J=8.4Hz,1H),7.07(s,1H),6.73(dd,J=6.0Hz,2.0Hz,1H),6.60(s,1H),4.97(s,4H),4.00(s,3H),3.79(s,3H). LCMS (Method A): R t = 4.23 minutes; [M+H] + =466.2.

[0556] Example 62-N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (58)

[0557]

[0558] The starting material used in step 4 is 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole, the starting material used in step 5 is isoindoline, and the starting material used in step 7 is 4-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ9.95(s,1H),9.46(s,1H),9.31(s,1H),8.70(s,1H),7.44-7.36(m,5H),7.24 (t,J=7.6Hz,1H),7.16(t,J=8.0Hz,1H),7.07(s,1H),6.75(t,J=8.0Hz,2H),4.97(s,4H),4.03(s,3H). LCMS (Method A): R t = 3.81 minutes; [M+H] + =452.1.

[0559] Example 63-5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (59)

[0560]

[0561] The starting material used in step 4 is 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole, the starting material used in step 5 is isoindoline, and the starting material used in step 7 is 4-methoxyaniline. 1 HNMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 7.62-7.18 (m, 7H), 6.78-6.46 (m, 3H), 4.94 (s, 4H), 3.78 (d, J = 8.8Hz, 6H), 2.25 (d, J = 6.4Hz, 6H). LCMS (Method A): R t = 4.20 minutes; [M+H] + =494.2.

[0562] Example 64 N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (60)

[0563]

[0564] The starting material used in step 4 is 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole; the starting material used in step 5 is isoindoline; and the starting material used in step 7 is 4-aminophenol. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.68 (s, 1H), 9.41 (s, 1H), 7.49–7.31 (m, 5H), 7.18–7.07 (m, 2H), 6.61 (s, 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 minutes; [M+H] + =480.2.

[0565] Example 65 - 5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0566]

[0567] Compound 65 was synthesized using the procedure outlined in Scheme 4.

[0568]

[0569] Step 1: Ethyl 3-cyano-2-oxobutyrate (IXX)

[0570] Propanolon (0.90 g, 16.42 mmol) was added dropwise over 5 minutes to a solution of lithium bis(trimethylsilyl)amino (1.0 M in THF, 13.7 mL, 13.71 mmol) in 15 mL of THF cooled to -78 °C under N2, and the mixture was stirred at -78 °C for 1 hour. Diethyl oxalate (2.01 g, 13.72 mmol) was added dropwise over 5 minutes, and the reaction mixture was stirred at -78 °C for 45 minutes, then at 0 °C for 1 hour. H2O (100 mL) was added, and the organic phase was removed with Et2O (100 mL). The aqueous phase was adjusted to pH 5 with an aqueous solution of HCl (6 M) and extracted with Et2O (3 x 100 mL). The combined organic matter was 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 minutes; [M+H] + =157.1.

[0571] Step 2: Ethyl 5-amino-4-methyl-1H-pyrazole-3-carboxylate (XX)

[0572] Ethyl 3-cyano-2-oxobutyrate (8.8 g, 44.00 mmol) and hydrazine hydrate (4.47 g, 89.20 mmol) were mixed in AcOH (10 mL) and toluene (100 mL) and stirred overnight at 110 °C. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH, 100 / 1) to give the title product (3.6 g, 38%) as a yellow oil. LCMS (Method A): R t = 2.54 minutes; [M+H] + =170.2.

[0573] Step 3: Ethyl 5-(3-ethoxy-3-oxopropamido)-4-methyl-1H-pyrazole-3-carboxylate (XXI)

[0574] Ethyl 5-amino-4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 5.92 mmol), 3-ethoxy-3-oxopropionic 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) were stirred overnight at room temperature in a mixture of DCM (15 mL). The mixture was filtered, washed with DCM (2 x 10 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (1.46 g, 87%) as a yellow oil. LCMS (Method A): R t = 2.91 minutes; [M+H] + =284.1.

[0575] Step 4: Ethyl 5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXII)

[0576] Ethyl 5-(3-ethoxy-3-oxopropamido)-4-methyl-1H-pyrazole-3-carboxylate (1.46 g, 5.16 mmol) and DMAP (1.89 g, 15.48 mmol) were stirred overnight at 80 °C in ethanol (15 mL) and H₂O (15 mL). The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (50 mL) and H₂O (50 mL). The organic matter was dried over Na₂SO₄ 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 minutes; [M+H] + =238.1.

[0577] Step 5: Ethyl 5,7-dichloro-3-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXIII)

[0578] A mixture of ethyl 5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (2.3 g, 9.71 mmol) in phosphorus oxychloride (25 mL) was stirred overnight at 110 °C. The mixture was concentrated under reduced pressure, and the residue was poured into ice water and extracted with Et2O (3 x 300 mL). The combined organic matter was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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 minutes; [M+H] +=274.0.

[0579] Step 6: Ethyl 5-chloro-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XXIV)

[0580] Ethyl 5,7-dichloro-3-methylpyrazolo[1,5-a]pyrimidin-2-carboxylate (3 g, 11.15 mmol), 1-Boc-pyrazol-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) were stirred overnight at 80 °C under N₂. The mixture was poured into water and extracted with EtOAc (100 mL x 3). The combined organics were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (1.5 g, 45%) as a yellow solid. LCMS (Method A): R t = 3.75 minutes; [M+H] + =306.1.

[0581] Step 7: Ethyl 5-(isoindoline-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XXV)

[0582] A mixture of ethyl 5-chloro-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-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 overnight at 80 °C. The mixture was diluted with water and the solid was filtered under reduced pressure. The solid was purified by silica gel column chromatography (DCM:MeOH, 90:10) to give the desired product (1 g, 53%) as a yellow solid. LCMS: (Method A), R t = 4.97 minutes, [M+H] + =389.2

[0583] Step 8: 5-(isoindoline-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XXVI)

[0584] A solution of ethyl 5-(isoindoline-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1 g, 2.62 mmol) in THF (12 mL) and MeOH (12 mL) was slowly added to an aqueous solution of KOH (1 M, 6 mL). The reaction mixture was stirred overnight at 90 °C. The mixture was concentrated under reduced pressure, and the residue was partitioned between H₂O and Et₂O (50 mL, 1 / 1). The organic matter was discarded, and the aqueous phase was acidified to pH 2 with an aqueous solution of HCl (2 M). The aqueous phase was extracted with CHCl₃ (100 mL x 3), and the combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to give the desired product (860 mg, 93%) as a yellow solid. LCMS (Method A): R t = 4.22 minutes; [M+H] + =361.

[0585] Step 9: 5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XXVII) (Compound 65)

[0586] A mixture of 5-(isoindoline-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (200 mg, 0.56 mmol), 3-aminophenol (68 mg, 0.62 mmol), HATU (319 mg, 0.84 mmol), and DIEA (142 mg, 1.12 mmol) in DMF (2 mL) was stirred overnight at room temperature. The mixture was diluted with water and the solid was filtered under reduced pressure. The filter cake was dried and purified by silica gel column chromatography (DCM:MeOH 90:10) to give the title product (58 mg, 23%) as a yellow solid. LCMS: (Method A), R t = 4.10 minutes, [M+H] + =452.1. 1 HNMR(400MHz,DMSO-d6)δ13.47(s,1H),9.99(s,1H),9.41(s,1H),8.97(s,1H),7.46-7.35(m,6H),7.22 (t,J=8.0Hz,1H),7.14(t,J=8.0Hz,1H),7.06(s,1H),6.53(d,J=6.0Hz,1H),4.96(s,4H),2.42(s,3H).

[0587] Example 66 - 5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (66)

[0588]

[0589] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.51(s,1H),10.0(s,1H),9.36(s,1H),8.74(s,1H),7.55(s,1H),7.45-7.35( m,5H),7.28(t,J=8.0Hz,1H),7.06(s,1H),6.72(d,J=6.0Hz,1H),4.96(s,4H),3.79(s,3H),2.42(s,3H). LCMS: (Method A), R t = 4.61 minutes, [M+H] + =465.2.

[0590] Example 67 - 5-(isoindoline-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (67)

[0591]

[0592] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is 3-(trifluoromethoxy)aniline. 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 10.40 (s, 1H), 9.36 (s, 1H), 8.74 (s, 1H), 8.01 (s, 1H), 7.88 (t, J = 7.6Hz, 1H), 7.53–7.46 (m, 3H), 7.37–7.35 (m, 2H), 7.11 (t, J = 7.6Hz, 2H), 4.78 (s, 4H), 2.42 (s, 3H). LCMS: (Method A), R t = 3.54 minutes, [M+H] + =520.1.

[0593] Example 68 - 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (68)

[0594]

[0595] The starting material used in step 7 is N-methyl-1-phenylmethylamine, and the starting material used in step 9 is 3-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.46(s,1H),9.97(s,1H),9.40(s,1H),9.30(s,1H),8.68(s,1H),7.41(s,1H),7.34(s,4H),7 .27(s,1H),7.21(d,J=8.0Hz,1H),7.13(t,J=7.6Hz,2H),6.52(d,J=7.6Hz,1H),4.96(s,2H),3.21(s,3H),2.37(s,3H). LCMS: (Method A), R t = 4.13 minutes, [M+H] + =454.2.

[0596] Example 69 - 5-(benzyl(methyl)amino)-N-(3-methoxyphenyl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (69)

[0597]

[0598] The starting material used in step 7 is N-methyl-1-phenylmethylamine, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.46(s,1H),10.06(s,1H),9.32(s,1H),8.69(s,1H),7.54(t,J=2.4Hz,1H),7.43(d,J=8.0Hz,1H),7.3 5(t,J=3.2Hz,4H),7.28(t,J=8.0Hz,2H),7.15(s,1H),6.71(d,J=6.0Hz,1H),4.96(s,2H),3.78(s,3H),3.21(s,3H),2.37(s,3H). LCMS (Method A): R t = 4.62 minutes; [M+H] + =468.2.

[0599] Example 70 - 5-(benzyl(methyl)amino)-3-methyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (70)

[0600]

[0601] The starting material used in step 7 is N-methyl-1-phenylmethylamine, and the starting material used in step 9 is 3-(trifluoromethoxy)aniline. 1 HNMR(400MHz,DMSO-d6)δ13.46(s,1H),10.36(s,1H),9.32(s,1H),8.70(s,1H),8.01(s,1H),7.88(d,J=8.0Hz,1H),7.51(t, J=7.6Hz,1H),7.43(s,4H),7.27(d,J=3.2Hz,1H),7.16(s,1H),7.11(d,J=8.0Hz,1H),4.96(s,2H),3.21(s,3H),2.37(s,3H). LCMS (Method A), R t = 3.2 minutes; [M+H] + =521.2.

[0602] Example 71 -N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (71)

[0603]

[0604] Compound 71 was prepared using the procedure outlined in Scheme 5.

[0605]

[0606] Step 1: Ethyl 3-cyano-4-methyl-2-oxovalerate (XXVIII)

[0607] 3-Methylbutyronitrile (43 mL, 0.41 mol) was added dropwise over 10 minutes to a solution of LiHMDS (1.0 M in THF, 342 mL, 0.34 mol) in anhydrous THF (450 mL) at -78 °C under N2, and the mixture was stirred at -78 °C for 1 hour. Diethyl oxalate (46 mL, 0.34 mol) was added dropwise over 5 minutes, and the mixture was stirred at -78 °C for 1 hour, followed by stirring at 0 °C for 1 hour. The mixture was diluted with H2O and the organic matter was extracted with Et2O (200 mL). The aqueous phase was adjusted to pH 5 with an aqueous solution of HCl (1 M), and the organic matter was extracted with Et2O (2 x 200 mL). The organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (44.2 g, 71%) as a yellow oil.

[0608] Step 2: Ethyl 5-amino-4-isopropyl-1H-pyrazole-3-carboxylate (IXXX)

[0609] A mixture of ethyl 5-amino-4-isopropyl-1H-pyrazole-3-carboxylate (44.2 g, 0.24 mol) and N₂H₄H₂O (23 mL, 0.31 mol) in AcOH (40 mL) and toluene (400 mL) was refluxed overnight using a Dean Stark separator. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO₃ (100 mL, 1 / 1). The organic matter was dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (23 g, 51%) as a yellow solid.

[0610] Step 3: 5-(3-ethoxy-3-oxopropamido)-4-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (XXX)

[0611] 3-Ethoxy-3-oxopropionic acid (15.8 g, 0.12 mol) was added dropwise over 10 minutes to a mixture of ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropamido)-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). The reaction mixture was stirred overnight at room temperature. The solids were removed by filtration and washed with DCM. The combined organic compounds were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (35.6 g, 99.7%) as a yellow oil. LCMS: (Agilent 5 min), R t = 1.83 minutes, [M+H] + =311.8.

[0612] Step 4: Ethyl 5,7-dihydroxy-3-isopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXXI)

[0613] A mixture of ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropamido)-1H-pyrazole-3-carboxylate (1.5 g, 4.79 mmol) and DMAP (1.8 g, 14.4 mmol) in ethanol (15 mL) and H₂O (15 mL) was stirred overnight at 80 °C. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (200 mL) and water (50 mL). The organic matter was 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 minutes, [M+H] + =266.0.

[0614] Step 5: Ethyl 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XXXII)

[0615] A solution of ethyl 5,7-dihydroxy-3-isopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1.0 g, 3.76 mol) in phosphorus oxychloride (15 mL) was stirred overnight at 110 °C. The mixture was concentrated under reduced pressure, and the residue was poured into ice water, extracted with DCM (3 x 20 mL), and the combined organic matter was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the desired product (700 mg, 62%) as a white solid. LCMS: (Agilent 5 min), R t = 4.54 minutes, [M+H] + =302.0.

[0616] Step 6: Ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XXXIII)

[0617] Ethyl 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidin-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) were stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was poured into water and extracted with DCM (20 mL x 3). The organic matter was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (525 mg, 61%) as a yellow solid. LCMS (Method A): R t = 4.20 minutes; [M+H] + =334.1.

[0618] Step 7: 5-(isoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester (XXXIV)

[0619] A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-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 overnight at 80 °C. The mixture was diluted with H₂O and filtered to give a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 75 / 1) to give the desired product (862 mg, 86%) as a yellow solid. LCMS: (Method A), R t = 3.70 minutes, [M+H] + =417.1.

[0620] Step 8: 5-(isoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XXXV)

[0621] A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-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 hours. The mixture was concentrated under vacuum, then poured into H₂O, and the aqueous phase was adjusted to pH 3 to 4 with HCl. The mixture was filtered and dried to give the desired product (750 mg, 93%) as a yellow solid. LCMS: (Method A), R t = 23.20 minutes, [M+H] + =389.1.

[0622] Step 9: N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XXXVI)

[0623] A mixture of ethyl 5-chloro-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-carboxylate (200 mg, 0.52 mmol), 3-aminophenol (62 mg, 0.57 mmol), HATU (294 mg, 0.77 mmol), and DIEA (134 mg, 1.04 mmol) in DMF (5 mL) was stirred overnight at room temperature. The mixture was diluted with H2O and the residue was filtered off, followed by purification by silica gel column chromatography (DCM:MeOH, 100:0 to 98:2) to give the title product (142 mg, 58%) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ13.48(s,1H),10.05(s,1H),9.40(s,1H),9.27(s,1H),8.71(s,1H),7.47-7.35(m,5H),7.22(d,J= 8.4Hz, 1H), 7.14 (t, J = 8Hz, 1H), 7.04 (s, 1H), 6.53 (d, J = 1.6Hz, 1H), 4.97 (s, 4H), 3.83-3.76 (m, 1H), 1.46 (d, J = 7.2Hz, 6H). LCMS: (Method A), R t = 4.61 minutes, [M+H] + =480.2.

[0624] According to the method for synthesizing compound 71, the following compounds are similarly prepared in steps 7 and 9 of scheme 5 using suitable starting materials.

[0625] Example 72 - 5-(isoindoline-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (72)

[0626]

[0627] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),10.45(s,1H),9.48-9.11(m,1H),8.94-8.53(m,1H),8.02(s,1H),7.87(d,J=8.0Hz,1H ),7.56-7.42(m,3H),7.36(dd,J=5.6Hz,3.2Hz,2H),7.16-7.04(m,2H),4.98(s,4H),3.88-3.74(m,1H),1.47(d,J=7.2Hz,6H). LCMS: (Method A), R t = 4.16 minutes, [M+H] + =548.1

[0628] Example 73 - 5-(isoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (73)

[0629]

[0630] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is 3-(trifluoromethoxy)aniline. 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),10.45(s,1H),9.48-9.11(m,1H),8.94-8.53(m,1H),8.02(s,1H),7.87(d,J=8.0Hz,1H ),7.56-7.42(m,3H),7.36(dd,J=5.6Hz,3.2Hz,2H),7.16-7.04(m,2H),4.98(s,4H),3.88-3.74(m,1H),1.47(d,J=7.2Hz,6H). LCMS: (Method A), R t = 4.16 minutes, [M+H] + =548.1

[0631] Example 74 - 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (74)

[0632]

[0633] The starting material used in step 7 is N-methyl-1-phenylmethylamine, and the starting material used in step 9 is 3-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.45(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, = 8.0Hz, 1.3Hz, 1H), 4.93 (s, 2H), 3.81-3.65 (m, 1H), 3.20 (s, 3H), 1.37 (d, J = 7.2Hz, 6H). LCMS (Method A): R t = 4.45 minutes; [M+H] + =482.2.

[0634] Example 75 - 5-(benzyl(methyl)amino)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (75)

[0635]

[0636] The starting material used in step 7 is N-methyl-1-phenylmethylamine, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.45(s,1H),10.10(s,1H),9.23(s,1H),8.66(s,1H),7.54(s,1H),7.43-7.39(m,1H),7.34(d,J=4.4Hz,4 H),7.27(t,J=8.0Hz,2H),7.13(s,1H),6.70(dd,J=8.0Hz,2.0Hz,1H),4.93(s,2H),3.78(s,4H),3.21(s,3H),1.37(d,J=7.2Hz,6H). LCMS (Method A): R t = 3.26 minutes, [M+H] + =496.2.

[0637] Example 76 - 5-(benzyl(methyl)amino)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (76)

[0638]

[0639] The starting material used in step 7 is N-methyl-1-phenylmethylamine, and the starting material used in step 9 is 3-(trifluoromethoxy)aniline. 1 HNMR (400MHz, DMSO-d6) δ13.48(s,1H),10.36(s,1H),9.24(s,1H),8.68(s,1H),8.0(s,1H),7.85(d,J=8.0Hz,1H),7.50(t,J=7.6 Hz,1H),7.34(s,4H),7.27(d,J=4.0Hz,1H),7.12(t,J=8.0Hz,2H),4.93(s,2H),3.78(s,1H),3.21(s,3H),1.37(d,J=6.4Hz,6H). LCMS (Method A): R t = 3.96 minutes, [M+H] + =550.1.

[0640] Example 77 - 5-(5-fluoroisoindoline-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (77)

[0641]

[0642] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR (400MHz, DMSO-d6) δ13.50(s,1H),10.15(s,1H),9.28(s,1H),8.71(s,1H),7.58-7.48(m,2H),7.44-7.31(m,2H),7.28(t,J= 8.8Hz, 1H), 7.19 (t, J = 8.0Hz, 1H), 7.04 (s, 1H), 6.71 (d, J = 6.4Hz, 1H), 4.95 (d, J = 12.0Hz, 4H), 3.79 (s, 4H), 1.46 (d, J = 7.2Hz, 6H). LCMS (Method A): R t = 3.53 minutes; [M+H] + =512.2.

[0643] Example 78 -N-(3-acetamidophenyl)-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (78)

[0644]

[0645] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is N-(3-aminophenyl)acetamide. 1 HNMR (400MHz, DMSO-d6) δ 10.17 (s, 1H), 9.99 (s, 1H), 9.02 (s, 2H), 8.13 (s, 1H), 7.67–6.98 (m, 7H), 4.93 (s, 4H), 3.80 (s, 1H), 3.21 (s, 3H), 1.46 (s, 6H). LCMS (Method A): R t = 4.42 minutes; [M+H] + =539.2.

[0646] Example 79 -N-(3-(4-acetylpiperazin-1-yl)phenyl)-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (79)

[0647]

[0648] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethyl-1-one; 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),10.03(s,1H),9.28(s,1H),8.71(s,1H),7.58-7.16(m,6H),7.02(s,1H),6.75 (d,J=1.6Hz,1H),4.93(s,4H),3.85-3.78(m,1H),3.61(s,4H),3.18-3.11(m,4H),2.06(s,3H),1.46(d,J=7.2Hz,6H). LCMS (Method A): R t = 4.54 minutes; [M+H] + =608.3.

[0649] Example 80 -N-(4-(4-acetylpiperazin-1-yl)phenyl)-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (80)

[0650]

[0651] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 1-(4-(4-aminophenyl)piperazin-1-yl)ethyl-1-one. 1 HNMR (400MHz, DMSO-d6) δ13.49(s,1H),10.0(s,1H),9.28(s,1H),8.70(s,1H),7.68(d,J=6.8Hz,1H),7.49(s,1H),7.35(s,1H),7.19(t,J=6.8Hz, 1H),6.99(t,J=6.4Hz,3H),4.94(t,J=11.2Hz,4H),3.83-3.79(m,1H),3. 61 (s, 4H), 3.14 (s, 2H), 3.08 (s, 2H), 2.05 (s, 3H), 1.46 (d, J = 7.2Hz, 6H). LCMS (Method A): R t = 4.44 minutes; [M+H] + =608.3.

[0652] Example 81 - 5-(5-chloroisoindoline-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (81)

[0653]

[0654] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.0(s,1H),9.28(s,1H),8.70(s,1H),7.54(s,3H),7.42(s,2H),7.27(t ,J=8.0Hz,1H),7.03(s,1H),6.71(d,J=6.4Hz,1H),4.94(s,4H),3.78(s,4H),1.46(d,J=7.2Hz,6H), LCMS (Method A): R t = 3.86 minutes, [M+H] + =528.2.

[0655] Example 82 -N-(3-acetamidophenyl)-5-(5-chloroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (82)

[0656]

[0657] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is N-(3-aminophenyl)acetamide. 1 HNMR(400MHz,DMSO-d6)δ13.47(s,1H),10.17(s,1H),9.99(s,1H),8.73(s,1H),8.13(s,1H),7.66-7.36(m,5H ),7.27(t,J=4.8Hz,1H),7.03(s,1H),4.94(s,4H),3.80(t,J=7.2Hz,1H),2.06(s,3H),1.46(d,J=7.2Hz,6H). LCMS (Method A): R t = 4.72 minutes; [M+H] + =555.2.

[0658] Example 83 -N-(3-(4-acetylpiperazin-1-yl)phenyl)-5-(5-chloroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (83)

[0659]

[0660] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethyl-1-one. 1 HNMR(400MHz,DMSO-d6)δ13.47(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,=6 .4Hz,1H),4.95(s,4H),3.83-3.78(m,1H),3.61(s,4H),3.18(d,J=2.4Hz,4H),2.06(d,J=7.6Hz,3H),1.46(d,J=6.8Hz,6H). LCMS (Method A): R t = 4.81 minutes; [M+H] + =623.2.

[0661] Example 84 -N-(4-(4-acetylpiperazin-1-yl)phenyl)-5-(5-chloroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (84)

[0662]

[0663] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 1-(4-(4-aminophenyl)piperazin-1-yl)ethyl-1-one. 1 HNMR(400MHz,DMSO-d6)δ13.47(s,1H),10.03(s,1H),9.27(s,1H),8.70(s,1H),7.70-7.40(m,5H),7.0(t,J=7.2Hz,3H),4.9 5 (s, 4H), 3.82 (t, J = 6.8Hz, 1H), 3.59 (d, J = 4.0Hz, 4H) 3.14 (s, 2H), 3.07 (s, 2H), 2.06 (d, J = 7.6Hz, 3H), 1.46 (d, J = 6.8Hz, 6H). LCMS (Method A): R t = 4.62 minutes, [M+H] + =624.2.

[0664] Example 85 - 5-(5-fluoroisoindoline-2-yl)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (99)

[0665]

[0666] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 3-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.49(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 = 9.2Hz, 1H), 4.95 (d, J = 11.6Hz, 4H), 3.83-3.76 (m, 1H), 3.21-3.17 (m, 1H), 1.46 (d, J = 7.0Hz, 6H). LCMS: (Method A), R t = 4.66 minutes, [M+H] + =498.2.

[0667] Example 86 - 5-(5-chloroisoindoline-2-yl)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (100)

[0668]

[0669] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 3-aminophenol. 1 HNMR(400M Hz,DMSO-d6)δ13.48(s,1H),10.04(s,1H),9.39(s,1H),9.26(s,1H),8.70(s,1H),7.57-7.40(m,4H),7.22(d,J=8.4Hz ,1H),7.14(t,J=8.0Hz,1H),7.02(s,1H),6.54(d,J=6.5Hz,1H),4.96(s,4H),3.83-3.76(m,1H),1.46(d,J=6.8Hz,6H). LCMS (Method A): R t = 4.69 minutes; [MH] +＝ 514.2.

[0670] Example 87 - 5-(5-fluoroisoindoline-2-yl)-3-isopropyl-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (101)

[0671]

[0672] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 3-morpholinoaniline. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.01(s,1H),9.27(s,1H),8.69(s,1H),7.55-7.29(m,4H),7.23-7.16(m,2H), 7.02(s,1H),6.73(d,J=1.6Hz,1H),4.94(d,J=11.6Hz,4H),3.85-3.76(m,5H),3.1-3.11(m,4H),1.45(d,J=7.0Hz,6H). LCMS: (Method A), R t = 3.42 minutes, [M+H] + =567.2.

[0673] Example 88 - 5-(5-fluoroisoindoline-2-yl)-3-isopropyl-N-(4-(2-methoxyethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (102)

[0674]

[0675] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 4-(2-methoxyethoxy)aniline. 1 HNMR(400MHz,DMSO-d6)δ13.48(s,1H),10.06(s,1H),9.29(s,1H),8.70(s,1H),7.71(d,J=8.8Hz,2H),7.49-7.16(m,3H),7.02(s,1H),6.96( d,J=9.2Hz,2H),4.94(d,J=12.0Hz,4H),4.10(t,J=4.8Hz,2H),3.85-3.78(m,1H),3.67(t,J=4.4Hz,2H),3.33(s,3H),1.45(d,J=7.0Hz,6H). LCMS: (Method A), R t = 4.81 minutes, [M+H] + =556.2.

[0676] Example 89 - 5-(5-fluoroisoindoline-2-yl)-3-isopropyl-N-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (103)

[0677]

[0678] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 7-amino-3,4-dihydroquinoline-2(1H)-one. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.14(d,J=14.8Hz,2H),9.27(s,1H),8.71(s,1H),7.57-7.35(m,3H),7.25-7.14(m, 3H), 7.02 (s, 1H), 4.95 (d, J = 11.6Hz, 4H), 3.84-3.77 (m, 1H), 2.85 (t, J = 7.2Hz, 2H), 2.47-2.44 (m, 2H), 1.45 (d, J = 6.8Hz, 6H). LCMS (Method A), R t = 4.71 minutes; [M+H] + =551.2.

[0679] Example 90 - 5-(5-fluoroisoindoline-2-yl)-N-(1H-indazol-6-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (104)

[0680]

[0681] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 1H-indazole-6-amine. 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),12.98(s,1H),10.30(s,1H),9.31(s,1H),8.72(s,1H),8.30(s,1H),8.02(s,1H),7.73(d,J= 8.8Hz,1H),7.54-7.32(m,3H),7.20(t,J=8.8Hz,1H),7.04(s,1H),4.96(d,J=11.6Hz,4H),3.86-3.79(s,1H),1.48(d,J=7.0Hz,6H). LCMS: (Method A), R t = 4.66 minutes, [M+H] + =522.2

[0682] Example 91-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-N-(3-(methylsulfonamido)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (105)

[0683]

[0684] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is N-(3-aminophenyl)methanesulfonamide. 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),10.25(s,1H),9.76(s,1H),9.27(s,1H),8.71(s,1H),7.84(s,1H),7.52(d,J=8.4Hz,2H),7.32(t ,J=8.0Hz,2H),7.19(t,J=10.8Hz,1H),7.04-6.96(m,2H),4.95(d,J=11.6Hz,4H),3.83-3.75(m,1H),3.03(s,3H),1.46(d,J=7.2Hz,6H). LCMS: (Method A), R t = 4.64 minutes, [M+H] + =575.2.

[0685] Example 92-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-N-(4-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (106)

[0686]

[0687] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 4-morpholinoaniline. 1 HNMR(400MHz,DMSO-d6)δ13.48(s,1H),9.99(s,1H),9.28(s,1H),8.70(s,1H),7.69-7.40(m,5H),7.01(s,1H),6.96(d,J=8 .4Hz, 2H), 4.94 (s, 4H), 4.10 (q, J = 5.2Hz, 1H), 3.84-3.76 (m, 5H), 3.17 (d, J = 5.6Hz, 2H), 3.09 (s, 4H), 1.45 (d, J = 7.2Hz, 6H). LCMS: (Method A), R t = 3.11 minutes, [M+H] + =567.2.

[0688] Example 93 - 5-(5-chloroisoindoline-2-yl)-3-isopropyl-N-(4-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (107)

[0689]

[0690] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 4-morpholinoaniline. 1 HNMR(400MHz,DMSO-d6)δ13.48(s,1H),9.99(s,1H),9.28(s,1H),8.70(s,1H),7.69-7.40(m,5H),7.01(s,1H),6.96(d,J=8 .4Hz, 2H), 4.94 (s, 4H), 4.10 (q, J = 5.2Hz, 1H), 3.84-3.76 (m, 5H), 3.17 (d, J = 5.6Hz, 2H), 3.09 (s, 4H), 1.45 (d, J = 7.2Hz, 6H). LCMS: (Method A), R t = 2.67 minutes, [M+H] + =583.1

[0691] Example 94 - 5-(5-chloroisoindoline-2-yl)-3-isopropyl-N-(3-morpholinophenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (108)

[0692]

[0693] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 3-morpholinoaniline. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.02(s,1H),9.27(s,1H),8.70(s,1H),7.53-7 .03(m,8H),6.74(s,1H),4.95(s,4H),3.77(s,4H),3.12(m,4H),1.45(d,J=6.0Hz,6H). LCMS: (Method A), R t = 2.96 minutes, [M+H] + =583.2.

[0694] Example 95 - 5-(5-chloroisoindoline-2-yl)-3-isopropyl-N-(4-(2-methoxyethoxy)phenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (109)

[0695]

[0696] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 4-(2-methoxyethoxy)aniline. 1 HNMR(400MHz,DMSO-d6)δ13.48(s,1H),10.06(s,1H),9.29(s,1H),8.70(s,1H),7.71(d,J=8.8Hz,2H),7.59-7.40(m, 3H),7.02-6.95(m,3H),4.95(s,4H),4.10(s,2H),3.84-3.78(m,1H),3.67(s,2H),3.33(s,3H),1.45(d,J=6.8Hz,6H). LCMS: (Method A), R t = 3.59 minutes, [M+H] + =572.2.

[0697] Example 96 - 5-(5-chloroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (117)

[0698]

[0699] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 3-((tetrahydro-2H-pyran-4-yl)oxy)aniline. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.12(s,1H),9.26(s,1H),8.70(s,1H),7.53-7.40(m,5H),7.26(t,J=8.0Hz,1H),7.03(s,1H),6.76(d,J =8.2Hz,1H),4.95(s,4H),4.59-4.53(m,1H),3.90-3.76(m,3H),3.54-3 .48(m,2H),2.02-1.98(m,2H),1.66-1.57(m,2H),1.45(d,J=7.0Hz,6H). LCMS: (Method A), R t = 2.70 minutes, [M+H] + =598.4

[0700] Example 97 - 5-(5-chloroisoindoline-2-yl)-N-(2-fluoro-3-methoxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (118)

[0701]

[0702] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 2-fluoro-3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.53(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=7.0Hz,6H). LCMS: (Method A), R t = 2.94 minutes, [M+H] + =546.4.

[0703] Example 98 - 5-(5-chloroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (119)

[0704]

[0705] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 4-((tetrahydro-2H-pyran-4-yl)oxy)aniline. 1 HNMR(400MHz,DMSO-d6)δ13.48(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),4.9 5(s,4H),4.55-4.58(m,1H),3.89-3.78(m,3H),3.52-3.46(m,2H),1.97(s,2H),1.63-1.55(m,2H),1.45(d,J=7.0Hz,6H). LCMS: (Method A), R t = 2.74 minutes, [M+H] + =598.2

[0706] Example 99-5-(5-chloroisoindoline-2-yl)-N-(2-fluoro-5-methoxyphenyl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (120)

[0707]

[0708] The starting material used in step 7 is 5-chloroisoindoline, and the starting material used in step 9 is 2-fluoro-5-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.52(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=7.0Hz,6H). LCMS: (Method A), R t = 4.14 minutes, [M+H] + =545.2.

[0709] Example 100-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (121)

[0710]

[0711] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 3-((tetrahydro-2H-pyran-4-yl)oxy)aniline. 1 HNMR (400MHz, DMSO-d6) δ10.12(s,1H),9.00(s,2H),7.53-7.16(m,6H),7.03(s,1H),6.76(dd,J=8.2Hz,2.0Hz,1H),4.95(d,J=11 .6Hz,4H),4.59-4.52(m,1H),3.90-3.76(m,3H),3.54-3.48(m,2H),2.06-1.93(m,2H),1.68-1.55(m,2H),1.45(d,J=7.0Hz,6H). LCMS: (Method A), R t = 2.43 minutes, [M+H] + =582.2.

[0712] Example 101-N-(2-fluoro-3-methoxyphenyl)-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (122)

[0713]

[0714] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 2-fluoro-3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.52(s,1H),9.88(s,1H),9.23(s,1H),8.71(s,1H),7 .12-7.05(m,7H),4.95(s,3H),3.89(s,4H),2.69(s,1H),1.45(d,J=7.0Hz,6H). LCMS: (Method A), R t = 2.88 minutes, [M+H] + =530.1.

[0715] Example 102-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (123)

[0716]

[0717] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 4-((tetrahydro-2H-pyran-4-yl)oxy)aniline. 1 HNMR (400MHz, DMSO-d6) δ13.49(s,1H),10.06(s,1H),9.28(s,1H),8.71(s,1H),7.71(d,J=8.2Hz,2H),7.43(m,3H),7.01(t,J=13.2Hz,3H ),4.95(d,J=10.8Hz,4H),4.55(s,1H),3.94-3.76(m,,3H),3.53-3.46(m,2H),1.98(d,J=8.8Hz,2H),1.58(s,2H),1.45(d,J=6.6Hz,6H). LCMS: (Method A), R t = 2.23 minutes; [M+H] + =582.2.

[0718] Example 103-N-(2-fluoro-5-methoxyphenyl)-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (124)

[0719]

[0720] The starting material used in step 7 is 5-fluoroisoindoline, and the starting material used in step 9 is 2-fluoro-5-methoxyaniline. 1 HNMR (400MHz, DMSO-d6) δ 13.56 (s, 1H), 9.84 (s, 1H), 7.68–6.98 (m, 7H), 6.78 (s, 1H), 4.95 (s, 4H), 3.78 (s, 5H), 1.46 (s, 6H). LCMS: (Method A), R t = 2.83 minutes, [M+H] + =530.2.

[0721] Example 104-5-(4-fluoroisoindoline-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (125)

[0722]

[0723] The starting material used in step 7 is 4-fluoroisoindoline, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.15(s,1H),9.28(s,1H),8.74(s,1H),7.55(s,1H),7.44-7.26(m,4H),7.19(t,J= 9.2Hz, 1H), 7.09 (s, 1H), 6.71 (dd, J = 6.4Hz, 2.0Hz, 1H), 5.01 (s, 4H), 3.86-3.79 (m, 1H), 3.78 (s, 3H), 1.46 (d, J = 7.2Hz, 6H). LCMS: (Method A), R t = 2.46 minutes; [M+H] + =512.2.

[0724] Example 105-5-(4-chloroisoindoline-2-yl)-3-isopropyl-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (126)

[0725]

[0726] The starting material used in step 7 is 4-chloroisoindoline, and the starting material used in step 9 is 3-methoxyaniline. 1 HNMR (400MHz, DMSO-d6) δ 13.49 (s, 1H), 10.15 (s, 1H), 9.28 (s, 1H), 8.74 (s, 1H), 7.55–7.38 (m, 5H), 7.27 (s, 1H), 7.09 (s, 1H), 6.71 (dd, J = 8.2Hz, 2.0Hz, 1H), 5.04 (d, J = 0.8Hz, 4H), 3.78 (s, 4H), 1.46 (d, J = 7.0Hz, 6H). LCMS: (Method A), Rt = 2.94 minutes, [M+H] + =528.0.

[0727] Example 106-5-(5-fluoroisoindoline-2-yl)-3-isopropyl-N-(2-methoxypyridin-4-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (127)

[0728]

[0729] The starting material used in step 7 is 4-fluoroisoindoline, and the starting material used in step 9 is 2-methoxypyridine-4-amine. 1 HNMR (400MHz, DMSO-d6) δ 13.51 (s, 1H), 10.46 (s, 1H), 9.26 (s, 1H), 8.69 (s, 1H), 8.10 (d, J = 6.0Hz, 1H), 7.52–7.36 (m, 4H), 7.19 (d, J = 7.6Hz, 1H), 7.05 (s, 1H), 4.95 (d, J = 11.6Hz, 4H), 3.86 (s, 3H), 3.82–3.74 (m, 1H), 1.46 (d, J = 7.0Hz, 6H). LCMS: (Method A), Rt = 3.28 minutes, [M+H] + =513.2.

[0730] Example 107-3-Cyclopropyl-5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (93)

[0731]

[0732] Compound 93 was prepared using the procedure outlined in Scheme 6.

[0733]

[0734] Step 1: Ethyl 3-cyano-3-cyclopropyl-2-oxopropionate (XXXVII)

[0735] 2-Cyclopropylacetonitrile (29 mL, 0.28 mol) was added dropwise over 10 minutes to a solution of LiHMDS (1.0 M in THF, 0.24 mL, 0.24 mol) in anhydrous THF (450 mL), and the mixture was stirred at -78 °C for 1 hour. Diethyl oxalate (33 mL, 0.24 mol) was added dropwise over 5 minutes, and the mixture was stirred at -78 °C for 1 hour, followed by stirring at 0 °C for 1 hour. The mixture was diluted with H₂O and the organic matter was extracted with Et₂O (200 mL). The aqueous phase was adjusted to pH 5 with an aqueous solution of HCl (1 M), and the organic matter was extracted with Et₂O (2 x 200 mL). The organic matter was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (28 g, 65%) as a yellow oil. LCMS: (Method A), R t = 3.02 minutes, [M+H] + =182.1.

[0736] Step 2: Ethyl 5-amino-4-cyclopropyl-1H-pyrazole-3-carboxylate (XXXVIII)

[0737] Ethyl 3-cyano-3-cyclopropyl-2-oxopropionate (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) were refluxed overnight using a Dean Stark separator. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between a saturated aqueous solution of EtOAc and NaHCO₃. The organic layer was dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (18 g, 60%) as a yellow solid. LCMS: (Method A), R t = 3.80 minutes, [M+H] + =196.1.

[0738] Step 3: 4-Cyclopropyl-5-(3-ethoxy-3-oxopropamido)-1H-pyrazole-3-carboxylic acid ethyl ester (XXXIX)

[0739] 3-ethoxy-3-oxopropionic acid (12.8 g, 0.10 mol) was added dropwise 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) at 0 °C. The reaction mixture was stirred overnight at room temperature. The solids were removed by filtration and washed with DCM. The combined organic compounds were concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOH, 70:1) to give the desired product (20 g, 71%) as a yellow solid. LCMS: (Agilent 5 min), R t = 4.17 minutes, [M+H] + =543.2.

[0740] Step 4: Ethyl 3-cyclopropyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (XL)

[0741] A mixture of ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropamido)-1H-pyrazole-3-carboxylate (20 g, 64.70 mmol) and DMAP (23.7 g, 0.194 mmol) in ethanol (200 mL) and H₂O (200 mL) was stirred overnight at 80 °C. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (200 mL) and water (200 mL). The organic matter was 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), Rt = 2.60 min, [M+H] + =264.1.

[0742] Step 5: Ethyl 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (XLI)

[0743] A solution of ethyl 3-cyclopropyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (17.0 g, 0.06 mol) in phosphorus oxychloride (400 mL) was stirred overnight at 110 °C. The mixture was concentrated under reduced pressure, and the residue was poured into ice water, extracted with DCM (3 x 300 mL), and the combined organic matter was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the desired product (11 g, 57%) as a yellow solid. LCMS: (Agilent 5 min), R t = 4.27 minutes, [M+H]+ =300.0.

[0744] Step 6: Ethyl 5-chloro-3-cyclopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XLII)

[0745] A mixture of ethyl 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-2-carboxylate (2 g, 6.7 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazol-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was poured into water and extracted with DCM (100 mL x 3). The organic matter was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (1.4 g, 61%) as a yellow solid. LCMS (Method A): R t = 4.05 minutes; [M+H] + =332.2.

[0746] Step 7: Ethyl-3-cyclopropyl-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (XLIII)

[0747] A mixture of ethyl 5-chloro-3-cyclopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-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 overnight at 80 °C. The mixture was diluted with H₂O and filtered to give a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to give the desired product (2.4 g, 96%) as a yellow solid. LCMS: (Method A), R t = 4.66 minutes, [M+H] + =465.2.

[0748] Step 8: 3-Cyclopropyl-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (XLIV)

[0749] A mixture of ethyl 3-cyclopropyl-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (2.4 g, 5.8 mmol) and aqueous KOH solution (2 M, 29 mL, 58.0 mmol) in THF (30 mL) and MeOH (30 mL) was stirred at 80 °C for 3 hours. The mixture was concentrated under vacuum and then poured into H₂O. The aqueous phase was adjusted to pH 3 to 4 with 2 M HCl, and the precipitate formed 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 minutes, [M+H] + =387.1.

[0750] Step 9: 3-Cyclopropyl-5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XLV)

[0751] A mixture of 3-cyclopropyl-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (200 mg, 0.52 mmol), 3-methoxyaniline (70 mg, 0.57 mmol), HATU (296 mg, 0.78 mmol), and DIEA (134 mg, 1.04 mmol) in DMF (8 mL) was stirred overnight at room temperature. The mixture was diluted with H2O and the residue was filtered off, followed by purification by silica gel column chromatography (DCM:MeOH, 100:0 to 98:2) to give the title product (85 mg, 33%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ13.50(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=6Hz,1.6Hz,1H),4.93(s,4H),3.78(s,3H),2.61-2.55(m,1H),1.49-1.45(m,2H),0.85-0.81(m,2H). LCMS: (Method A), R t = 3.19 minutes, [M+H] + =492.2.

[0752] According to the method for synthesizing compound 93, the following compounds are similarly prepared in steps 7 and 9 of scheme 6 using appropriate starting materials.

[0753] Example 108-3-Cyclopropyl-N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (94)

[0754]

[0755] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is 3-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.02(s,1H),9.41(s,1H),9.28(s,1H),8.70(s,1H),7.46-7.35(m,5H),7.23-7.1 2(m,2H),7.02(s,1H),6.53(d,J=6.4Hz,1.6Hz,1H),4.93(s,4H),2.60-2.50(m,1H),1.47-1.45(m,2H),0.84-0.82(m,2H). LCMS: (Method A), R t = 4.29 minutes; [M+H] + =478.2.

[0756] Example 109-N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-cyclopropyl-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (95)

[0757]

[0758] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethyl-1-one; 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),10.01(s,1H),9.28(s,1H),8.70(s,1H),7.55-7.31(m,6H),7.23(t,J=8Hz,1H),7.03(s,1H),6 .75(d,J=8Hz,1H)4.94(s,4H),3.61(s,4H),3.20-3.11(m,4H),2.63-2.56(m,1H),2.06(s,3H),1.49-1.46(m,2H),0.85-0.81(m,2H). LCMS: (Method A), R t = 4.42 minutes, [M+H] + =588.3.

[0759] Example 110-3-cyclopropyl-5-(isoindoline-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (96)

[0760]

[0761] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is 4-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.48(s,1H),10.04(s,1H),9.30(s,1H),8.71(s,1H),7.73(d,J=8Hz,2H),7.47(s,2H),7.37-7.34(m, 4H),7.01(s,1H),6.96(d,J=8.8Hz,2H),4.93(s,4H),3.77(s,3H),2.69-2.58(m,1H),1.47(d,J=3.2Hz,2H),0.87-0.77(m,2H). LCMS: (Method A), R t = 4.56 minutes, [M+H] + =492.2.

[0762] Example 111-N-(3-acetamidophenyl)-3-cyclopropyl-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (97)

[0763]

[0764] The starting material used in step 7 is isoindoline, and the starting material used in step 9 is N-(3-aminophenyl)acetamide. 1 HNMR(400MHz,DMSO-d6)δ13.49(s,1H),10.15(s,1H),9.99(s,1H),9.30(s,1H),8.71(s,1H),8.13(s,1H),7.47-7.35(m,6H) ,7.27(t,J=8.0Hz,1H),7.02(s,1H),4.94(s,4H),2.61-2.54(m,1H),2.06(s,3H),1.46(d,J=3.2Hz,2H),0.84-0.81(m,2H). LCMS: (Method A), R t = 4.25 minutes, [M+H] + =519.2.

[0765] Example 112-N-(3-chlorophenyl)-3-cyclopropyl-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (98)

[0766]

[0767] The starting material used in step 7 is 7-isoindoline, and the starting material used in step 9 is 3-chloroaniline. 1 HNMR (400MHz, DMSO-d6) δ 13.50 (s, 1H), 10.30 (s, 1H), 9.30 (s, 1H), 8.71 (s, 1H), 8.03 (s, 1H), 7.83 (d, J = 9.2Hz, 1H), 7.47–7.33 (m, 5H), 7.19 (d, J = 8.0Hz, 1H), 7.03 (s, 1H), 4.93 (s, 4H), 2.61–2.54 (m, 1H), 1.49–1.45 (s, 2H), 0.86–0.81 (m, 2H). LCMS (Method A): R t = 3.71 minutes; [M+H] + =496.1.

[0768] Example 113-3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (85)

[0769]

[0770] Compound 85 was prepared using the procedure outlined in Scheme 7.

[0771]

[0772] Step 1: 3,3-Dimethylbutyronitrile (XLVI)

[0773] Sodium cyanide (19.4 g, 0.297 mol) was added to a stirred solution of 1-bromo-2,2-dimethylpropane (25.0 g, 0.165 mol) in DMSO (250 mL). The resulting mixture was heated at 90 °C overnight. The reaction mixture was filtered through a diatomaceous earth stopper and the solids were washed with DCM (2 x 20 mL). The combined filtrates were concentrated under reduced pressure to give 3,3-dimethylbutyronitrile (12.48 g, 77%) as a yellow oil. 1 HNMR(400MHz, CDCl3) δ3.66-3.63(m,4H),2.14(s,2H),1.76(s,3H).

[0774] Step 2: Ethyl 3-cyano-4,4-dimethyl-2-oxovalerate (XLVII)

[0775] 3,3-Dimethylbutyronitrile (5.0 g, 51.00 mmol) was added dropwise over 5 minutes to a mixture of lithium bis(trimethylsilyl)amino (1.0 M in THF, 40 mL, 40.00 mmol) in 50 mL of THF, under N2 at -78°C, and the mixture was stirred at -78°C for 1 hour. Diethyl oxalate (6.25 g, 40.00 mmol) was added dropwise over 5 minutes, and the solution was stirred at -78°C for 45 minutes, then at 0°C for 1 hour. The mixture was diluted with 100 mL of H2O and organic matter was removed with 2 x 100 mL of Et2O. The aqueous phase was adjusted to pH 5 with 6 M HCl and extracted with 3 x 100 mL of Et2O. The combined organic matter was washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the desired product (7.5 g, 89%) as a yellow oil. LCMS (Method A): R t = 2.44 minutes; [M+H] + =198.1, 1 HNMR (400MHz, CDCl3) δ4.37 (d, J = 7.2Hz, 2H), 1.34-1.32 (m, 3H), 1.15 (s, 9H).

[0776] Step 3: Ethyl 5-amino-4-(tert-butyl)-1H-pyrazole-3-carboxylate (XLVIII)

[0777] Ethyl 3-cyano-4,4-dimethyl-2-oxovalerate (8.8 g, 44.00 mmol) and hydrazine hydrate (4.47 g, 89.20 mmol) were stirred overnight at 110 °C in AcOH (10 mL) and toluene (100 mL). 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 minutes; [M+H] + =212.1, 1 HNMR (400MHz, CDCl3) δ4.30 (d, J = 7.2Hz, 2H), 1.40-1.29 (m, 12H).

[0778] Step 4: 4-(tert-butyl)-5-(3-ethoxy-3-oxopropamido)-1H-pyrazole-3-carboxylic acid ethyl ester (XLIX)

[0779] Ethyl 5-amino-4-(tert-butyl)-1H-pyrazole-3-carboxylate (3.6 g, 17.00 mmol), 3-ethoxy-3-oxopropionic 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) were stirred overnight at room temperature in a mixture of DCM (36 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (5.5 g, 95%) as a yellow oil. LCMS (Method A): R t = 3.28 minutes; [M+H] + =326.1, 1 HNMR (400MHz, DMSO-d6) δ13.52 (s, 1H), 9.67 (s, 1H), 4.33-4.22 (m, 2H), 4.13-4.07 (m, 2H)), 3.39 (d, J = 12.0Hz, 2H), 1.35-1.21 (m, 15H).

[0780] Step 5: Ethyl 3-(tert-butyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (L)

[0781] Ethyl 4-(tert-butyl)-5-(3-ethoxy-3-oxopropamido)-1H-pyrazole-3-carboxylate (5.5 g, 17.00 mmol) and DMAP (6.2 g, 51.00 mmol) were stirred overnight at 80 °C in ethanol (112 mL) and H₂O (112 mL). The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (100 mL) and H₂O (100 mL). The organic matter was dried over Na₂SO₄ 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 minutes; [M+H] + =280.1.

[0782] Step 6: Ethyl 3-(tert-butyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (LI)

[0783] A mixture of ethyl 3-(tert-butyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (4.0 g, 14.00 mmol) in phosphorus oxychloride (200 mL) was stirred overnight at 110 °C. The mixture was concentrated under reduced pressure, and the residue was poured into ice water and extracted with Et2O (3 x 300 mL). The combined organic matter was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc, 10 / 1) to give the title product (1.0 g, 22%) as a yellow oil. LCMS (Method A): R t = 3.49 minutes; [M+H] + =316.9. 1 HNMR (400MHz, DMSO-d6) δ6.92 (s, 1H), 4.41 (q, J = 6.8Hz, 2H), 1.51 (s, 3H) 1.47 (s, 9H).

[0784] Step 7: Ethyl 3-(tert-butyl)-5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LII)

[0785] A mixture of ethyl 3-(tert-butyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (1.15 g, 3.60 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (1.07 g, 3.60 mmol), 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 overnight at 80 °C under N₂. The mixture was poured into water and extracted with EtOAc (100 mL x 3). The combined organic matter was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (600 mg, 61%) as a yellow solid. LCMS (Method A): R t = 4.36 minutes; [M+H] + =348.1. 1 HNMR (400MHz, DMSO-d6) δ 8.69 (s, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 4.41 (q, = 7.2Hz, 2H), 1.49 (s, 9H), 1.36 (t, J = 7.2Hz, 3H).

[0786] Step 8: 3-(tert-butyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester (LIIII)

[0787] A mixture of ethyl 3-(tert-butyl)-5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-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 overnight at 80 °C. The mixture was diluted with water and the solid was filtered off. The filter cake was dried and purified by silica gel column chromatography (DCM:MeOH 100:1) to give the desired product (230 mg, 49%) as a yellow solid. LCMS: (Method A), R t = 4.97 minutes, [M+H] + =431.2. 1 HNMR (400MHz, DMSO-d6) δ8.67 (s, 2H), 7.39-7.31 (m, 4H), 6.53 (s, 1H), 4.94 (s, 4H), 4.45 (q, J = 7.8Hz, 2H), 1.56 (s, 9H), 1.44 (t, J = 7.6Hz, 3H).

[0788] Step 9: 3-(tert-butyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (LIV)

[0789] A solution of 3-(tert-butyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (600 mg, 1.39 mmol) in THF (24 mL) and H₂O (24 mL) was slowly added to an aqueous solution of KOH (1 M, 12 mL) over 15 minutes at 0 °C. The reaction mixture was stirred at 90 °C overnight. The solution was concentrated under reduced pressure and the residue was partitioned between H₂O (20 mL) and Et₂O (20 mL). The organic matter was discarded and the aqueous layer was acidified to pH 2 with an aqueous solution of HCl (2 M). The aqueous phase was extracted with CHCl₃ (100 mL x 3), and the combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to give the title product (560 mg, 100%) as a yellow solid. LCMS: (Method A), R t = 4.22 minutes, [M+H] + =403.1. 1HNMR (400MHz, DMSO-d6) δ8.77(s,2H),7.55-7.38(m,4H),6.99(s,1H),4.99(s,4H),1.54(s,9H).

[0790] Step 10: 3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (LV)

[0791] A solution of 3-(tert-butyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (100 mg, 0.25 mmol), 3-aminophenol (34 mg, 0.28 mmol), HATU (142 mg, 0.37 mmol), and DIEA (931 mg, 9.20 mmol) in DMF (20 mL) was stirred overnight at room temperature. The mixture was diluted with water and the solids were removed by filtration. The combined solids were purified by silica gel column chromatography (DCM:MeOH, 99:1) to give the title product (50 mg, 39%) as a yellow solid. LCMS: (Method A), R t = 2.26 minutes, [M+H] + =508.2. 1 HNMR(400MHz,DMSO-d6)δ13.47(s,1H),10.55(s,1H),9.01(s,1H),8.63(s,1H),7.50-7.47(m,3H),7.37-7. 35(m,3H),7.26(t,J=8.0Hz,1H),7.0(s,1H),6.70(d,J=6.0Hz,1H),4.96(s,4H),3.76(s,3H),1.55(s,9H).

[0792] According to the method for synthesizing compound 85, the following compounds are similarly prepared in steps 8 and 10 of scheme 7 using suitable starting materials.

[0793] Example 114-N-(3-acetamidophenyl)-3-(tert-butyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (86)

[0794]

[0795] The starting material used in step 8 is isoindoline, and the starting material used in step 10 is N-(3-aminophenyl)acetamide. 1HNMR(400MHz,DMSO-d6)δ13.44(s,1H),10.57(s,1H),9.98(s,1H),9.01(s,1H),8.64(s,1H),8.08(s,1H),7.46 (d,J=7.6Hz,3H),7.37-7.35(m,3H),7.26(t,J=8.0Hz,1H),7.0(s,1H),4.96(s,4H),2.05(s,3H),1.55(s,9H). LCMS: (Method A), R t = 3.610 minutes, [M+H] + =535.2.

[0796] Example 115-N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(tert-butyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (87)

[0797]

[0798] The starting material used in step 8 is isoindoline, and the starting material used in step 10 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethyl-1-one. 1 HNMR (400MHz, DMSO-d6) δ13.44(s,1H),10.43(s,1H),9.00(s,1H),8.66(s,1H),7.51-7.47(m,3H),7.37-7.35(m,3H),7.27-7. 18(m,2H),7.0(s,1H),6.74(d,J=7.2Hz,1H),4.96(s,4H),3.60(t,J=4.8Hz,4H),3.17-3.08(m,4H),2.05(s,3H),1.55(s,9H). LCMS: (Method D), R t = 5.53 minutes, [M+H] + =604.3.

[0799] Example 116-3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (88)

[0800]

[0801] The starting material used in step 8 is isoindoline. The starting material used in step 10 is 3-aminophenol. 1HNMR (400MHz, DMSO-d6) δ 13.41 (s, 1H), 10.44 (s, 1H), 9.40 (s, 1H), 8.66 (s, 1H), 7.50–7.34 (m, 6H), 7.16–7.09 (m, 2H), 7.0 (s, 1H), 6.51 (d, J = 7.2Hz, 1H), 4.96 (s, 4H), 1.55 (s, 9H). LCMS: (Method A), R t = 3.67 minutes, [M+H] + =494.2.

[0802] Example 117-3-(tert-butyl)-5-(5-chloroisoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (89)

[0803]

[0804] The starting material used in step 8 is 5-chloroisoindoline, and the starting material used in step 10 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.44(s,1H),10.55(s,1H),8.94(s,1H),8.63(s,1H),7.50-7 .23(m,6H),6.98(s,1H),6.70(d,J=7.0Hz,1H),4.96(s,4H),3.76(s,3H),1.55(s,9H). LCMS: (Method A), R t = 3.88 minutes, [M+H] + =542.2.

[0805] Example 118-N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(tert-butyl)-5-(5-chloroisoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (90)

[0806]

[0807] The starting material used in step 8 is 5-chloroisoindoline, and the starting material used in step 10 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethyl-1-one. 1HNMR(400M Hz,DMSO-d6)δ13.42(s,1H),10.43(s,1H),8.81(s,2H),7.51-7.18(m,6H),6.98(s,1H),6.74(d,J =8Hz,1H),4.95(d,J=4.8Hz,4H),3.59(s,4H),3.16(s,2H),3.10(s,2H),2.05(s,3H),1.55(s,9H). LCMS (Method D): R t = 5.86 minutes; [MH] +＝ 638.3.

[0808] Example 119-3-(tert-butyl)-5-(5-fluoroisoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (91)

[0809]

[0810] The starting material used in step 8 is 5-fluoroisoindoline, and the starting material used in step 10 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.44(s,1H),10.55(s,1H),9.0(s,1H),8.63(s,1H),7.50(s,2H),7.36(d,J=8.0Hz,2H),7.26(t, J=8.0Hz,1H),7.19(t,J=9.2Hz,1H),6.98(s,1H),6.70(d,J=6.4Hz,1H),4.96(d,J=12.4Hz,4H),3.76(s,3H),1.55(s,9H). LCMS: (Method A), R t = 2.11 minutes, [M+H] + =526.2.

[0811] Example 120-N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(tert-butyl)-5-(5-fluoroisoindoline-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (92)

[0812]

[0813] The starting material used in step 8 is 5-fluoroisoindoline, and the starting material used in step 10 is 1-(4-(3-aminophenyl)piperazin-1-yl)ethyl-1-one. 1HNMR(400M Hz,DMSO-d6)δ13.45(s,1H),10.42(s,1H),8.99(s,1H),8.62(s,1H),7.5(s,2H),7.39-7.18(m,4H),6.98(s ,1H),6.74(s,1H),4.93(d,J=13.2Hz,4H),3.59(s,4H),3.16(s,2H),3.10(s,2H),2.05(s,3H),1.55(s,9H). 1 HNMR(400M Hz,DMSO-d6)δ13.45(s,1H),10.42(s,1H),8.99(s,1H),8.62(s,1H),7.5(s,2H),7.39-7.18(m,4H),6.98(s ,1H),6.74(s,1H),4.93(d,J=13.2Hz,4H),3.59(s,4H),3.16(s,2H),3.10(s,2H),2.05(s,3H),1.55(s,9H).

[0814] Example 121-N-(3-chlorophenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazol[1,5-a]pyrimidine-2-carboxamide (110)

[0815]

[0816] Compound 110 was prepared using the procedure outlined in Scheme 8.

[0817]

[0818] Step 1: 2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (LVI)

[0819] Diethyl (cyanomethyl)phosphonate (19.5 g, 0.11 mol) was added dropwise to a suspension of NaH (60% in oil, 4.4 g, 0.11 mol) cooled to 0 °C in diethyl ether (300 mL), followed by the dropwise addition of a solution of tetrahydro-4H-pyran-4-one (10 g, 0.10 mol) in diethyl ether (300 mL). The reaction mixture was stirred overnight at room temperature. The mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title product (7.0 g, 57%) as a yellow oil. LCMS (Method A): Rt = 0.34 min; [M+H] + =124.1, 1HNMR (400MHz, CDCl3) δ5.10(s,1H),3.72-3.66(m,4H),2.63-2.50(m,2H),2.36-2.27(m,2H).

[0820] Step 2: 2-(tetrahydro-2H-pyran-4-yl)acetonitrile (LVII)

[0821] Pd / C (10%, 100 mg) was added to a solution of 2-(tetrahydro-4H-pyran-4-yl)acetonitrile (2.6 g, 21.14 mmol) in PE (25 mL) and acetic acid (1 mL). The reaction mixture was purged with H2 and stirred overnight at 1 atm of hydrogen. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to provide the title product as a yellow oil. LCMS (Method A): R t = 0.71 minutes; [M+H] + =126.1. 1 HNMR (400MHz, CDCl3) δ4.02-3.98(m,2H),3.43-3.37(m,2H),2.32(d,J=8.4Hz,2H),2.08(s,1H),1.99-1.86(m,1H),1.77-1.72(m,2H).

[0822] Step 3: Ethyl 3-cyano-2-oxo-3-(tetrahydro-2H-pyran-4-yl)propionate (LVIII)

[0823] Over 5 minutes, 2-(tetrahydro-2H-pyran-4-yl)acetonitrile (2.0 g, 15.90 mmol) was added dropwise to a mixture of lithium bis(trimethylsilyl)amino (1.0 M in THF, 13.3 mL, 13.30 mmol) cooled to -78 °C under N2 in 50 mL of anhydrous THF, and the mixture was stirred at -78 °C for 1 hour. Diethyl oxalate (1.95 g, 13.30 mmol) was added dropwise over 5 minutes at -78 °C, and the solution was stirred at 0 °C for 45 minutes. The mixture was diluted with H2O (100 mL) and the organic matter was extracted with Et2O (2 x 100 mL). The aqueous layer was adjusted to pH 5 with 6 M HCl, and the organic matter was then extracted with Et2O (3 x 100 mL). The combined organic matter was washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title product (7.5 g, 89%) as a yellow oil. LCMS (Method A): R t = 0.868 minutes; [M+H] + =226.1.

[0824] Step 4: Ethyl 5-amino-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (LIX)

[0825] Ethyl 3-cyano-2-oxo-3-(tetrahydro-2H-pyran-4-yl)propionate (24.22 g, 0.11 mol) and hydrazine hydrate (10.7 g, 0.21 mol) were stirred overnight at 110 °C in a mixture of AcOH (50 mL) and toluene (500 mL). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give a product (8 g, 31%) as a yellow oil. LCMS (Method A): R t = 2.34 minutes; [M+H] + =240.1.

[0826] Step 5: Ethyl 5-(3-ethoxy-3-oxopropamido)-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (LX)

[0827] Ethyl 5-amino-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (7.0 g, 29.29 mmol), 3-ethoxy-3-oxopropionic 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) were stirred overnight at room temperature in a mixture of DCM (70 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the title product (6.6 g, 56%) as a yellow oil. LCMS (Method A): R t = 2.76 minutes; [M+H] + =354.1.

[0828] Step 6: Ethyl 5,7-dihydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LXI)

[0829] Ethyl 5-(3-ethoxy-3-oxopropamido)-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-carboxylate (5.6 g, 15.86 mmol) and DMAP (5.8 g, 47.58 mmol) were stirred overnight at 80 °C in ethanol (112 mL) and H₂O (112 mL). The mixture was concentrated and the residue was dissolved in EtOAc (200 mL) and washed with water (100 mL). The organic matter was dried over Na₂SO₄ 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 minutes; [M+H] + =308.1.

[0830] Step 7: Ethyl 5,7-dichloro-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (LXII)

[0831] A mixture of 5,7-dihydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (2.0 g, 5.83 mmol) in phosphorus oxychloride (50 mL) was stirred overnight at 110 °C. The mixture was concentrated under reduced pressure. The residue was poured into ice water, extracted with Et2O (3 x 300 mL), and the combined organic matter was washed with brine (100 mL), dried (Na2SO4), 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 HNMR(400MHz,DMSO-d6)δ7.05(s,1H),4.51(d,J=7.1Hz,2H),4.13-4.06(m,2H),3.75(tt,J=12.8Hz,3.6Hz,1H) ,3.56(d,J=1.2Hz,2H),2.47(dd,J=13.1Hz,4.4Hz,2H),1.69(dd,J=12.8Hz,2.0Hz,2H),1.47(t,J=7.2Hz,3H).

[0832] Step 8: 5-Chloro-7--(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester (LXIII)

[0833] Ethyl 5,7-dichloro-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-2-carboxylate (1.2 g, 3.49 mmol), 1-Boc-pyrazol-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) were stirred overnight at 80 °C under N₂. The mixture was poured into water and extracted with EtOAc (100 mL x 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 column chromatography (MeOH:DCM, 1:100) to give the title product (600 mg, 61%) as a yellow solid. LCMS (Method A): R t = 3.71 minutes; [M+H] + =376.1.

[0834] Step 9: 5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester (LXIV)

[0835] A mixture of ethyl 5-chloro-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-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 overnight at 80 °C. The mixture was poured into water (20 mL), and the precipitate formed 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 minutes, [M+H] + =459.2.

[0836] Step 10: 5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (LXV)

[0837] A solution of ethyl 5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (870 mg, 1.89 mmol) in THF (24 mL) and H₂O (24 mL) was slowly added to an aqueous solution of KOH (1 M, 12 mL, 48 mmol) over 15 minutes at 0 °C. The reaction mixture was stirred overnight at 70 °C. The solvent was removed under reduced pressure, and the residual aqueous solution was washed with Et₂O (2 x 30 mL) and then acidified to pH 2 with an aqueous solution of 1 M HCl. The aqueous phase was extracted with CHCl₃ (3 x 100 mL), and the combined organic matter was dried over Na₂SO₄ and concentrated under reduced pressure to give the title product as a solid (800 mg, 99%). LCMS: (Method A), R t = 3.60 minutes, [M+H] + =431.1.

[0838] Step 11: N-(3-chlorophenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazol[1,5-a]pyrimidine-2-carboxamide (LXVI)

[0839] A mixture of 5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (100 mg, 0.25 mmol), 3-chloroaniline (36 mg, 0.28 mmol), HATU (142 mg, 0.37 mmol), and DIEA (120 mg, 0.93 mmol) in DMF (20 mL) was stirred overnight at room temperature. The mixture was diluted with water to form a suspension, which was then filtered. The filter cake was dried and purified by silica gel column chromatography (MeOH / DCM = 1 / 100, v / v) to give the desired product (60 mg, 48%) as a yellow solid. LCMS: (Method D), Rt = 6.16 min, [M+H] + =540.2. 1HNMR(400MHz, DMSO-d6)δ13.50(s,1H),10.37(s,1H),9.30(s,1H),8.72(s,1H),8.03(s,1H),7.82(d,J=7.6Hz,1H)7.51-7.35(m,5H),7.19(d,J= 7.6Hz,1H),7.07(s,1H),4.98(s,4H),3.99(d,J=8.4Hz,2H),3.68(t,J= 10.0Hz, 1H), 3.44 (d, J = 7.2Hz, 2H), 2.54 (s, 2H), 1.59 (d, J = 12.0Hz, 2H).

[0840] According to the method for synthesizing compound 110, the following compounds are similarly prepared in steps 9 and 11 of scheme 8 using suitable starting materials.

[0841] Example 122-N-(3-hydroxyphenyl)-5-(isoindoline-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (111)

[0842]

[0843] The starting material used in step 9 is isoindoline, and the starting material used in step 11 is 3-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.50(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),6.5 3(d,J=8.8Hz,1H),4.98(s,4H),4.0(d,J=10.4Hz,2H),3.66(s,1H),3.44(d,J=11.6Hz,2H),3.33(s,2H),1.60(d,J=12.0Hz,2H). LCMS: (Method B),R t = 2.27 minutes, [M+H] + =522.2.

[0844] Example 123-5-(isoindoline-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (112)

[0845]

[0846] The starting material used in step 9 is isoindoline, and the starting material used in step 11 is 3-methoxyaniline. 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),10.17(s,1H),9.28(s,1H),8.72(s,1H),7.45 -7.42(m,4H),7.38-7.35(m,2H),7.28(t,J=12.0Hz,1H),7.06(s,1H),6.72(dd,J=5.6 Hz, 1.6Hz, 1H), 4.98(s, 4H), 3.98(dd, J = 7.2Hz, 3.2Hz, 2H), 3.78(s, 3H), 3.72-3.64(m, 1H), 3.44(d, J = 11.2Hz, 2H), 3.33(s, 2H), 2.57-2.53(m, 1H), 1.60(d, J = 12.0Hz, 2H). LCMS: (Method D), R t = 5.51 minutes, [M+H] + =536.2.

[0847] Example 124-5-(isoindoline-2-yl)-N-(4-methoxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (113)

[0848]

[0849] The starting material used in step 9 is isoindoline, and the starting material used in step 11 is 4-methoxyaniline. 1 HNMR(400M Hz,DMSO-d6)δ13.50(s,1H),10.09(s,1H),9.29(s,1H),8.72(s,1H),7.73(d,J=9.2Hz,2H),7.49-7.35(m,4H),7.05(s,1H),6.95(d,J=6. 8Hz, 2H), 4.97 (s, 4H), 3.99 (d, J = 7.2Hz, 2H), 3.77 (s, 3H), 3.70 (s, 1H), 3.34 (t, J = 11.2Hz, 2H), 2.57-2.53 (m, 2H), 1.60 (d, J = 12.0Hz, 2H). LCMS: (Method A), R t = 2.45 minutes, [M+H] + =536.2.

[0850] Example 125-5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazol[1,5-a]pyrimidine-2-carboxamide (114)

[0851]

[0852] The starting material used in step 9 is N-methyl-1-phenylmethylamine, and the starting material used in step 11 is 3-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.45(s,1H),10.03(s,1H),9.40(s,1H),9.22(s,1H),8.65(s,1H), 7.43(t,J=3.2Hz,1H),7.37-7.34(m,4H),7.28-7.24(m,1H),7.19(d,J=8.4Hz,1H),7.15-7.1 1(m,2H),6.52(d,J=6.4Hz,1H),4.93(s,2H),3.92(dd,J=7.6Hz,4.4Hz,2H),3.67-3.57(m,1H ), 3.38 (t, J = 11.2Hz, 2H), 3.23 (s, 3H), 2.39 (dd, J = 8.4Hz, 4.0Hz, 2H), 1.60 (d, J = 12.0Hz, 2H). LCMS: (Method A), R t = 1.91 minutes, [M+H] + =523.2.

[0853] Example 126-5-(5-fluoroisoindoline-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (115)

[0854]

[0855] The starting material used in step 9 is 5-fluoroisoindoline, and the starting material used in step 11 is 3-aminophenol. 1HNMR(400MHz,DMSO-d6)δ13.45(s,1H),10.05(s,1H),8.94(s,2H),7.41-7.12(m,7H),6.99(s,1H),6.53(d,J=6.8Hz, 1H), 4.95 (d, J = 13.2Hz, 4H), 3.98 (d, J = 7.6Hz, 2H), 3.69-3.63 (m, 2H), 3.43 (t, J = 11.6Hz, 3H), 1.60 (d, J = 12.0Hz, 2H). LCMS: (Method A), R t = 2.08 minutes, [M+H] + =540.1.

[0856] Example 127-5-(5-chloroisoindoline-2-yl)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (116)

[0857]

[0858] The starting material used in step 9 is 5-chloroisoindoline, and the starting material used in step 11 is 3-aminophenol. 1 HNMR(400MHz,DMSO-d6)δ13.50(s,1H),10.09(s,1H),9.40(s,1H),9.26(s ,1H),8.70(s,1H),7.44-7.40(m,4H),7.21-7.11(m,2H),7.03(s,1H),6.53 (d,J=7.2Hz,1H),4.96(s,4H),4.09(q,J=2.8Hz,1.6Hz,2H),4.0(d,J=4.4 Hz, 2H), 3.70-3.61 (m, 1H), 3.43 (t, J = 11.2Hz, 2H), 1.60 (d, J = 12.0Hz, 2H). LCMS: (Method A), R t = 2.37 minutes, [M+H] + =556.2.

[0859] Example 128 - Inhibition of PRRSV

[0860] The following materials are used for the biological evaluation of the compounds' capabilities.

[0861] • EMEM (Eeger's minimum required medium obtained from Sigma)

[0862] • FBS (fetal bovine serum) obtained from Life Technologies;

[0863] • Pen / Strep (penicillin-streptomycin) obtained from Gibco;

[0864] • PBS (phosphate-buffered saline) obtained from Life Technologies;

[0865] • 0.05% trypsin-EDTa obtained from Thermo Fisher;

[0866] • 384w board obtained from Perkin Elmer

[0867] • PRRs virus obtained from Iszler;

[0868] • INFα obtained from Sigma;

[0869] • DMSO obtained from Sigma;

[0870] • Methanol obtained from Merck;

[0871] • Distilled water obtained from life technologies;

[0872] Phalloid AF 488 obtained from Thermofisher;

[0873] • Triton X100 10% obtained from Sigma-Alrich.

[0874] Marc-145 cells

[0875] Culture medium preparation

[0876] Cell culture medium was prepared by combining 500 mL of EMEM, 5 mL of P / S and 50 mL of FBS.

[0877] Day 0 of cell seeding

[0878] Remove the old cell culture medium from the cells. Then wash the cells twice with 10 mL PBS. Add 2.0 mL / flask of 0.05% trypsin / EDTA and incubate the resulting flask until cells detach. Resuspend the cells in 7 mL / flask of cell culture medium. Count the cells and seed them at 1500 cells / well in 384-well plates. Then transfer the plates to a 37°C, 5% CO2 incubator.

[0879] Day 1

[0880] Compound addition

[0881] Prepare a compound dilution plate using a 1000X concentrated compound (maximum concentration 30 μM). Add 1 mL of 190 kU / mL INFa and 1 mL of DMSO to the compound dilution plate. Then add 99 mL of cell culture medium to the compound dilution plate to obtain a 10X concentrated compound (100x dilution). Then add 5 μl / w of the 10X concentrated compound to Marc-145 cells containing 40 μl / w of culture medium (10x dilution). The plate was then centrifuged at 200 g for 1 minute and incubated at 37 °C in a 5% CO2 incubator for 1 hour.

[0882] Virus addition (1 hour after compound treatment)

[0883] The virus was added to Marc-145 cells with MOI1 (5 μl / well). The plate was centrifuged at 200 g for 1 minute and then incubated at 37 °C in a 5% CO2 incubator for 72 hours.

[0884] Fixation and staining on day 4

[0885] fixed

[0886] Fix the plate with 50 μl / well of 8% formaldehyde at room temperature for 20 minutes.

[0887] Remove formaldehyde and add 50 μL of PBS to the cells. Then store the plate under refrigeration until further use.

[0888] dyeing

[0889] Dissolve phalloidin AF488 in 1.5 mL of water. Dissolve DAPI (4′,6-diamidinyl-2-phenylindole) in 2 mL of distilled water. Then mix these solutions to produce the following staining solution:

[0890] PBS - Triton X100 1∶1000 Phalloid peptide AF488 1∶150 DAPI 1∶1000

[0891] After removing the fixative, wash the plate once with 100 μl / well of PBS. Then add 40 μl / well of staining solution and incubate the plate at room temperature for 30 minutes. Wash the cells with 2 x 50 μl / well of PBS. After washing, seal the cells and image using an InCell 6000 with a 10x objective.

[0892] DAPI 0.06 11.0 AF488 0.10 11.2

[0893] The results for representative compounds are shown below:

[0894] 59 5.31 80 5.48 98 5.47 99 5.41 102 5.36 109 5.25

[0895] 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. While the invention has been described in conjunction with specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications intended to carry out the described modes of the invention will be readily apparent to those skilled in the art and are within the scope of the invention.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of porcine reproductive and respiratory syndrome virus: Formula (I) in: R 1 R 2 and R 3 Each is independently selected from the group composed of H and methyl groups. R 4 For H, R 5 C6 aryl groups optionally substituted with -OH, halogen, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, 4-acyl-piperazine, and OCH2CH2OCH3; R 6 Choose from the group consisting of: H, C1-C6 alkyl and C3-C6 cycloalkyl. R 7 and R 8 When combined with the nitrogen atoms they are attached to, they form heterocyclic groups of the following formula: ， Each R D It is independently selected from H or halogens.

2. The use according to claim 1, wherein in the compound of formula (I): R 1 and R 3 It is H.

3. The use according to claim 1, wherein in the compound of formula (I): R 2 It is H.

4. The use according to claim 1, wherein in the compound of formula (I), R 6 Choose 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.

5. The use according to claim 1, wherein in the compound of formula (I): R 6 It is isopropyl.

6. The use according to claim 1, wherein the compound of formula (I) is selected from: Or its pharmaceutically acceptable salt.

7. The use according to claim 1, wherein the compound of formula (I) is: 99 Or its pharmaceutically acceptable salt.

Images