WO2023001061A1

WO2023001061A1 - Cdk7 selective inhibitors as anticancer agents

Info

Publication number: WO2023001061A1
Application number: PCT/CN2022/105870
Authority: WO
Inventors: Ying Han; Dapeng Li; Yu Wang; Zhiyu Yin; Huajun LONG
Original assignee: Jingrui Biopharma Co., Ltd.
Priority date: 2021-07-17
Filing date: 2022-07-15
Publication date: 2023-01-26

Abstract

Disclosed are a compound of formula (I), a pharmaceutically acceptable composition comprising the compound of formula (I) and methods of using said compound or composition in the treatment of various diseases or conditions.

Description

CDK7 SELECTIVE INHIBITORS AS ANTICANCER AGENTS

FIELD OF THE INVENTION

The present invention is directed to novel compounds of formula I which are CDK7 selective inhibitors, their synthesis and their use for treating diseases or conditions.

BACKGROUND OF THE INVENTION

Cyclin-dependent kinases (CDKs) are a major class of kinases and are important in cancer cell proliferation and deregulated oncogenic transcription. CDK7 binds to cyclin H and MATI to form a trimeric cyclin-activating kinase (CAK) that performs its function by phosphorylating other CDKs involved in cell-cycle control. These complexes control specific transitions between two subsequent phases in the cell cycle. CDK7 is implicated in both temporal control of the cell cycle and transcriptional activity. CDK7 is implicated in the transcriptional initiation process by phosphorylation of Rbpl subunit of RNA Polymerase II (RNAPII) . Uncontrolled cell proliferation and deregulated transcription is a cancer hallmark. Targeting CDK7 selectively may offer an advantage by simultaneously inhibiting active transcription and cell-cycle progression. Therefore, CDK7 is a promising target for the treatment of cancer, in particular aggressive and hard-to-treat cancers.

The discovery of selective inhibitors of CDK7 has been hampered by the high sequence and structural similarities of the kinase domain of CDK family members. Therefore, there is a need for the discovery and development of selective CDK7 inhibitors which can be used in the treatment of cell proliferative disorders, such as cancer. Additionally, there is a need to provide CDK7 inhibitors which are selective for CDK7 compared to other CDKs. The compounds of the invention help meet this need.

SUMMARY OF THE INVENTION

The present invention provides novel compounds, their analogues including stereoisomers, or pharmaceutically acceptable salts, which are useful as CDK7 selective inhibitors.

The present invention also provides processes and intermediates for making the compounds of the present invention.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one of the compounds of the present invention or stereoisomers, or pharmaceutically acceptable salts thereof.

The compounds of the invention may be used in the treatment of diseases or conditions associated with aberrant activity of CDK7.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufacture of a medicament for the treatment of diseases or conditions associated with aberrant activity of CDK7.

In another aspect, the present invention is directed to a method of treating a cancer which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.

In yet additional aspects, the present invention is directed at pharmaceutical compositions comprising the above-mentioned compounds, processes for preparing the above-mentioned compounds and intermediates used in these processes.

These and other features of the invention will be set forth in expanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

In the first aspect of the present invention, there is provided a compound of the formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

wherein:

R ₁ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;

R ₂ is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl and phenyl;

R ₃ is selected from H, C _1-6 alkyl, C _1-6 haloalkyl and halogen;

B is selected from C and N, provided that when B is N, R ₃ is absent;

A is a bond or selected from O, N, S and SO ₂;

L is selected from

R ₄, at each occurrence, is independently selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, CN, NR ₅R ₅, OR ₅, COOR ₅, SR ₅, SO ₂R ₅, optionally substituted phenyl, optionally substituted pyridyl and C _3-6 cycloalkyl;

R ₅, at each occurrence, is independently selected from H and C _1-6 alkyl,

R, at each occurrence, is independently selected from H, C _1-6 alkyl, optionally substituted phenyl, optionally substituted pyridyl and C _3-6 cycloalkyl;

X, at each occurrence, is independently selected from C and N;

Q is selected from

R ₆, at each occurrence, is independently selected from H, C _1-6 alkyl, optionally substituted phenyl, and optionally substituted pyridyl; and

denotes a single bond or C _1-6 alkylene.

In some embodiments of the first aspect, R ₁ is selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl and C ₃ cycloalkyl. In some embodiments of the first aspect, R ₁ is selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl and C ₃ cycloalkyl. In some embodiments of the first aspect, R ₁ is selected from C _1-3 deuterated alkyl, preferably, CD ₃. In some embodiments of the first aspect, R ₁ is C ₃ cycloalkyl. In some embodiments of the first aspect, R ₁ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, n-pentyl, neopentyl, n-hexyl and sec hexyl. In some embodiments of the first aspect, R ₁ is selected from H, methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, R ₁ is selected from H, methyl and ethyl. In some preferred embodiments of the first aspect, R ₁ is H.

In some embodiments of the first aspect, R ₂ is selected from C _1-3 alkyl and C _1-3 haloalkyl. In some embodiments of the first aspect, R ₂ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, n-pentyl, neopentyl, n-hexyl, sec hexyl and phenyl. In some embodiments of the first aspect, R ₂ is selected from methyl, ethyl, n-propyl, isopropyl and n-butyl. In some preferred embodiments of the first aspect, R ₂ is isopropyl. In some embodiments of the first aspect, R ₂ is selected from C _1-3 haloalkyl. In some embodiments of the first aspect, R ₂ is phenyl.

In some embodiments of the first aspect, R ₃ is selected from H, C _1-3 alkyl, C _1-3 haloalkyl and halogen. In some embodiments of the first aspect, R ₃ is selected from H, and C _1-3 alkyl. In some embodiments of the first aspect, R ₃ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, n-pentyl, neopentyl, n-hexyl, sec hexyl, F, Cl, Br and I. In some embodiments of the first aspect, R ₃ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, n-pentyl, neopentyl, n-hexyl and sec hexyl. In some embodiments of the first aspect, R ₃ is selected from H, methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, R ₃ is H.

In some embodiments of the first aspect, B is selected from C and N. In some embodiments of the first aspect, B is C. In some embodiments of the first aspect, B is N. In some embodiments of the first aspect, when B is N, R ₃ is absent. In some embodiments of the first aspect, when B is C, R ₃ is selected from H, and C _1-3 alkyl, preferably H.

In some embodiments of the first aspect, A is selected from O, S and SO ₂. In some embodiments of the first aspect, A is O or S. In some embodiments of the first aspect, A is O. In some embodiments of the first aspect, A is N. In some embodiments of the first aspect, A is a single bond.

In some embodiments of the first aspect, Q is selected from

and R ₆, at each occurrence, is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, Q is selected from

and R ₆, at each occurrence, is independently selected from H and methyl. In some embodiments of the first aspect, Q is selected from

and R ₆, at each occurrence, is independently selected from H and methyl. In some embodiments of the first aspect, Q is

and R ₆ is selected from H and methyl. In some embodiments of the first aspect, Q is

and R ₆ is H. In some embodiments of the first aspect, Q is selected from

and R ₆, is selected from H and C _1-6 alkyl. In some embodiments of the first aspect, Q is selected from

and R ₆, is selected from H and methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, Q is selected from

and R ₆, is selected from H and methyl. In some embodiments of the first aspect, when A is O, Q is selected from

and R ₆ is independently selected from H and C _1-3 alkyl. In some embodiments of the first aspect, when A is N, Q is

wherein R ₆ is selected from H and C _1-3 alkyl, preferably H.

In some embodiments of the first aspect, L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CF ₃, halogen, NR ₅R ₅, OR ₅, SR ₅, C _3-5 cycloalkyl, and halogen substituted phenyl; R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl, R, at each occurrence, is independently selected from C _1-3 alkyl and C _3-6 cycloalkyl; X, at each occurrence, is independently selected from C and N.

In some embodiments of the first aspect, L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CF ₃, halogen, NR ₅R ₅, OR ₅, SR ₅, C _3-5 cycloalkyl, and halogen substituted phenyl; R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl, R, at each occurrence, is independently selected from C _1-3 alkyl; and X is C. In some embodiments of the first aspect, L is selected from

R ₄ is selected from NR ₅R ₅, R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl. In some embodiments of the first aspect, L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl and halogen, and R, at each occurrence, is independently selected from H, C _1-3 alkyl and C ₃ cycloalkyl. In some embodiments of the first aspect, L is

In some embodiments of the first aspect, L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl and halogen In some embodiments of the first aspect, L is selected from

R ₄ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, OR ₅, SR ₅ and C ₃ cycloalkyl; R ₅, at each occurrence, is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, L is selected from

wherein R ₄ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, CN, NR ₅R ₅, OR ₅ and SR ₅; R ₅, at each occurrence, is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl and halogen. In some embodiments of the first aspect, L is selected from

wherein R ₄ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl and halogen. In some embodiments of the first aspect, L is selected from

wherein R ₄ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen and NR ₅R ₅; R ₅, at each occurrence, is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, L is selected from

In some embodiments of the first aspect, L is selected from

wherein R ₄ is selected from NR ₅R ₅; R ₅, at each occurrence, is independently selected from H and C _1-6 alkyl, X is C. In some embodiments of the first aspect, L is selected from

In some embodiments of the first aspect, L is selected from

In some embodiments of the first aspect,

denotes a single bond (i.e., a connection site) . In some embodiments of the first aspect,

denotes C1-6 alkylene. In some embodiments of the first aspect,

denotes methylene. In some embodiments of the first aspect,

denotes ethylene. In some embodiments of the first aspect,

denotes n-propylene or isopropylidene.

In some embodiments of the first aspect, wherein R ₁ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl and C _1-6 haloalkyl; R ₂ is selected from C _1-6 alkyl and C _1-6 haloalkyl; R ₃ is selected from H, C _1-6 alkyl, C _1-6 haloalkyl and halogen; B is selected from C and N, provided that when B is N, R ₃ is absent; A is a bond or selected from O, N and S; L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CF ₃, halogen, NR ₅R ₅, OR ₅, SR ₅, C _3-5 cycloalkyl, and halogen substituted phenyl; R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl, R, at each occurrence, is independently selected from C _1-3 alkyl; and X is C, and Q is selected from

R ₆, at each occurrence, is independently selected from H and C _1-6 alkyl,

denotes a single bond.

In some embodiments of the first aspect, wherein R ₁ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl and C _1-6 haloalkyl; R ₂ is selected from C _1-6 alkyl and C _1-6 haloalkyl; R ₃ is selected from H, C _1-6 alkyl, C _1-6 haloalkyl and halogen; B is selected from C and N, provided that when B is N, R ₃ is absent; A is selected from O, N and S; L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CF ₃, halogen, NR ₅R ₅, OR ₅, SR ₅, C _3-5 cycloalkyl, and halogen substituted phenyl; R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl, and Q is selected from

R ₆, at each occurrence, is independently selected from H and C _1-6 alkyl,

denotes a single bond.

R ₆, at each occurrence, is independently selected from H and C _1-6 alkyl,

denotes a single bond.

In some preferred embodiments of the first aspect, wherein R ₁ is selected from H, and C _1-3 alkyl; R ₂ is selected from C _1-3 alkyl; R ₃ is selected from H, C _1-3 alkyl, C _1-3 haloalkyl and halogen;

B is C; A is N; L is selected from

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CF ₃, halogen, NR ₅R ₅, OR ₅ and C ₃ cycloalkyl; R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl, and Q is selected from

R ₆, at each occurrence, is independently selected from H and C _1-3 alkyl,

denotes a single bond.

In some preferred embodiments of the first aspect, wherein R ₁ is selected from H, and C _1-3 alkyl; R ₂ is selected from C _1-3 alkyl; R ₃ is selected from H, C _1-3 alkyl, C _1-3 haloalkyl and halogen; B is C; A is N; L is

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CF ₃, halogen, and C ₃ cycloalkyl; and Q is

R ₆, at each occurrence, is independently selected from H and C _1-3 alkyl,

denotes a single bond.

wherein R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CN, CF ₃, halogen, NR ₅R ₅ and OR ₅; R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl, and Q is

R ₆, at each occurrence, is independently selected from H and C _1-3 alkyl,

denotes a single bond.

The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of alternative aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements (including individual variable definitions) of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.

In some embodiments of the first aspect, the compound is selected from:

In the second aspect of the present invention, there is provided a pharmaceutical composition which comprises a compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof and one or more pharmaceutically acceptable excipients.

In the third aspect of the present invention, there is provided the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in the manufacture of a medicament for the treatment of diseases or conditions associated with aberrant activity of CDK7. In the third aspect of the present invention, the diseases or conditions are cancer, preferably breast cancer and colorectal cancer.

In the fourth aspect of the present invention, there is provided a method of treating cancer in a patient comprising administering a therapeutically effective amount of one or more compounds of the present invention or a pharmaceutically acceptable salt thereof or stereoisomer thereof to the patient. In the fourth aspect of the present invention, the cancer is breast cancer or colorectal cancer.

In the fifth aspect of the present invention, there is provided a method for making a compound of the present invention or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

THERAPEUTIC APPLICATIONS

The compounds of the invention, pharmaceutically acceptable salts thereof or stereoisomers thereof are CDK7 selective inhibitors and have potential utility in the treatment of diseases and conditions associated with aberrant activity of CDK7.

In one embodiment, there is provided a method for the treatment of a disease or condition associated with aberrant activity of CDK7, in a subject in need thereof which comprises administering a therapeutically effective amount of compound of the present invention or a pharmaceutically acceptable salt thereof.

While it is possible that for use in therapy, a compound of the present invention as well as pharmaceutically acceptable salts thereof may be administered as the compound itself, it is more commonly presented as a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a compound of formula I, a pharmaceutically acceptable salt thereof or stereoisomer thereof and one or more pharmaceutically acceptable excipients.

As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting it development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state. As used herein, the terms “condition” , “disease” and “disorder” are used interchangeably.

A “therapeutically effective amount” of a compound of formula (I) is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.

As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers. By “early stage cancer” or “early stage tumor” is meant a cancer that is not advanced or metastatic or is classified as a Stage 0, 1, or II cancer.

As used herein, the term “inhibitor” refers to biological or chemical substance that interferes with or otherwise reduces the physiological and/or biochemical action of another biological or chemical molecule. In some embodiments, the inhibitor or antagonist specifically binds to the other molecule.

A “subject, ” “patient” or “individual” includes a mammal, such as a human or other animal, and typically is human. In some embodiments, the subject, e.g., patient, to whom the therapeutic agents and compositions are administered, is a mammal, typically a primate, such as a human. In some embodiments, the primate is a monkey or an ape. The subject can be male or female and can be any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects. In some embodiments, the subject is a non-primate mammal, such as a rodent, a dog, a cat, a farm animal, such as a cow or a horse, etc.

DEFINITIONS

Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.

When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error) , and thus the number or numerical range, in some instances, will vary between 1%and 15%of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including” ) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) ) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.

Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched. ” “Optically-enriched, ” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90%by weight of a preferred enantiomer. In other embodiments the preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Wilen, et al., Tetrahedron 33: 2725 (1977) ; Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) ; Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972) .

The term “stereoisomer” as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and configuration isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.

As used herein, the term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C ₁-C ₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , and pentyl (e.g., n-pentyl, isopentyl, neopentyl) .

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Whenever it appears herein, a numerical range such as “C ₁- ₆ alkylene” means that the alkylene consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated. In some embodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula -OR _a where R _a is an alkyl radical as defined.

“Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C ₃-C ₁₅ cycloalkyl) , from three to ten carbon atoms (C ₃-C ₁₀ cycloalkyl) , from three to eight carbon atoms (C ₃-C ₈ cycloalkyl) , from three to six carbon atoms (C ₃-C ₆ cycloalkyl) , from three to five carbon atoms (C ₃-C ₅ cycloalkyl) , or three to four carbon atoms (C ₃-C ₄ cycloalkyl) . In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In some embodiments, the cycloalkyl is optionally substituted with halogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like. Examples of optionally substituted 5-to 6-membered heterocycles represented by

may include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl, all of which may be substituted by group R, wherein R is as defined herein. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. When a substituent is keto (i.e., =O) , then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N) . As used herein, the term “optionally substituted” means that at least one hydrogen atom is optionally replaced with C _1-6 alkyl, C _1-6 deuterated alkyl, C _1- ₆ haloalkyl and halogen.

When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Additionally, for purposes of clarity, where a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent. For example, -CONH ₂ is attached through the carbon atom.

Additionally, for purposes of clarity, when there is no substituent shown at the end of a solid line, this indicates that there is a methyl (CH ₃) group connected to the bond.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.

METHODS OF PREPARATION

The compounds in the present invention can be synthesized in a number of ways well to one skilled in the art of organic synthesis described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods are not limited as those described below. The references cited here are incorporated by reference in their entirety.

The methods of synthesis described hereinafter are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis. Compounds of formula I may be synthesized by reference to methods illustrated in the following schemes. As shown herein, the end compound is a product having the same structural formula depicted as formula I. It will be understood that any compound of formula I may be prepared by the selection of reagents with appropriate substitution. Solvents, temperature, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley &Sons) . These groups are removed at certain stage of the compound synthesis using the methods that are apparent to those skilled in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined herein or elsewhere in the specification.

Scheme 1

Scheme 2

Scheme 3

EXAMPLES

The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather is defined by the claims appended hereto. Although only some of the Example compounds are specifically synthesized as below, the other Example compounds can be synthesized similarly, which is obvious to one skilled in the art.

The following table shows the part abbreviation of the present invention:

Intermediate preparation

Unless otherwise stated, starting materials for the preparation of intermediates and Examples are commercially available.

Intermediate-1

Two intermediates 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (I) and 8-isopropyl-2-mercaptopyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol (II) were purchased from Huaian Laurel Pharma.

Intermediate-2

8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol

Step 1: 8-Isopropyl-2- (methylthio) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol

To a solution of 8-isopropyl-2-mercaptopyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol (10 g, 47.6 mmol) in EtOH (150 mL) and 2 M aq. NaOH (50 mL) was added MeI (7.1 g, 50 mmol) at 0 ℃, the resulting mixture was stirred at 20 ℃ overnight. The mixture was acidified to pH = 6～7 with aq. HCl (4 M) , then concentrated under reduced pressure. The remaining solid was suspended in water (100 mL) . The mixture was filtered and washed with water (20 mL) . The cake was collected and dried to afford the title product (9.0 g, crude) . LCMS: (ES ⁺) : m/z = 225.1 [M+1] ⁺.

Step 2: 8-Isopropyl-2- (methylsulfonyl) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol

To a solution of 8-isopropyl-2- (methylthio) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol (9.0 g, crude) in DCM (500 mL) was added m-CPBA (22.1 g, 3.0 eq. ) in portions, the mixture was stirred at 20 ℃ overnight. The mixture was extracted with 2 M NaOH/brine (1: 1, 50 mL x 3) . The aqueous phase was adjusted to pH = 1～2, extracted with EtOAc (100 mL x 3) . The combined organic layer was dried over Na ₂SO ₄ and filtered. The filtrates were concentrated under reduced pressure. The residue was purified by silica column chromatography to afford the title product (4.0 g, 40%yield) . LCMS: (ES ⁺) : m/z = 257.1 [M+1] ⁺.

Step 3: 8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol

A solution of 8-isopropyl-2- (methylsulfonyl) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol (4.0 g, 15.6 mmol) in DMF (10 mL) was added to a solution of 1-methylpiperidin-4-ol (5.4 g, 46.8 mmol) and NaH (1.7 g, 46.8 mmol, 65 w%) in DMF (10 mL) , the mixture was stirred at 60 ℃ for 2 h. The reaction was quenched by MeOH, acidified to pH = 5～6 with aq. HCl (2 M) . The resulting mixture was concentrated, and the residue was purified by silica column chromatography to afford the title product (2.1 g, 47%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) δ10.53 (s, 1H) , 4.92 -5.18 (m, 1H) , 3.58 -4.01 (m, 1H) , 2.81 -3.33 (m, 7H) , 2.62 -2.78 (m, 5 H) , 1.85 -2.02 (m, 3 H) , 1.58 -1.80 (m, 3H) .

Intermediate 3

(5-Chlorobenzo [d] thiazol-2-yl) methanamine

Step 1: Tert-butyl ( (5-chlorobenzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 5-chloro-2-iodoaniline (5.0 g, 20 mmol) in CH ₃CN (100 mL) was added tert-butyl (2-amino-2-thioxoethyl) carbamate (4.5 g, 23 mmol) , CaO (1.6 g, 28 mmol) , Pd ₂ (dba) ₃ (3.6 g, 3.9 mmol) and DPPF (4.4 g, 7.9 mmol) . The resulting mixture was stirred at 60 ℃ for 6 h under nitrogen. To the mixture was added water (40 mL) and extracted with EtOAc (30 mL x 3) . The organic phase was dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (4.2 g, 71.2%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.95 (d, J = 1.8 Hz, 1H) , 7.76 (d, J = 8.5 Hz, 1H) , 7.35 (dd, J = 8.5, 1.8 Hz, 1H) , 5.42 (s, 1H) , 4.72 (d, J = 5.6 Hz, 2H) , 1.49 (s, 9H) .

Step 2: (5-Chlorobenzo [d] thiazol-2-yl) methanamine

To a solution of tert-butyl ( (5-chlorobenzo [d] thiazol-2-yl) methyl) carbamate (400 mg, 1.2 mmol) in dioxane (2 mL) was added HCl/dioxane (4 M, 4 mL) at r. t., the mixture was stirred at 25 ℃for 1 h. The reaction mixture was concentrated to obtain the title product (300 mg, 95.3%yield) as a white solid. LCMS: (ES ⁺) : m/z = 199.1 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.07 (d, J = 1.9 Hz, 1H) , 8.03 (d, J = 8.6 Hz, 1H) , 7.50 (dd, J = 8.6, 2.0 Hz, 1H) , 4.66 (s, 2H) .

Intermediate 4

2- (Aminomethyl) benzo [d] thiazole-5-carbonitrile

Step 1: Tert-butyl ( (5-cyanobenzo [d] thiazol-2-yl) methyl) carbamate

To a solution of tert-butyl ( (5-chlorobenzo [d] thiazol-2-yl) methyl) carbamate (1.5 g, 5.0 mmol) in DMF (40 mL) was added Zn (CN) ₂ (0.7 g, 6.0 mmol) , DPPF (0.27 g, 0.48 mmol) , Pd ₂ (dba) ₃ (225 mg, 0.24 mmol) and Zn (30 mg, 0.4 mmol) . The resulting mixture was stirred at 120 ℃for 12 h under nitrogen. To the mixture was added water (40 mL) and extracted with EtOAc (30 mL x 3) . The organic phase was dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (250 mg, 17.2%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 8.27 (s, 1H) , 7.97 (d, J = 8.3 Hz, 1H) , 7.62 (d, J = 8.3 Hz, 1H) , 5.39 (s, 1H) , 4.76 (d, J = 5.8 Hz, 2H) , 1.49 (s, 9H) .

Step 2: 2- (Aminomethyl) benzo [d] thiazole-5-carbonitrile

To a solution of tert-butyl ( (5-cyanobenzo [d] thiazol-2-yl) methyl) carbamate (250 mg, 0.86 mmol) in dioxane (2 mL) was added HCl/1, 4-dioxane (4 M, 4 mL) at r. t, . the mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated to obtain the title product (90 mg, 55%yield) as a white solid. LCMS: (ES ⁺) : m/z = 190.0 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.45 (s, 1H) , 8.25 (d, J = 8.4 Hz, 1H) , 7.79 (d, J = 8.4 Hz, 1H) , 4.71 (s, 2H) .

Intermediate 5

(5- (Trifluoromethyl) benzo [d] thiazol-2-yl) methanamine hydrochloride

Step 1: Tert-butyl ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 2-iodo-5- (trifluoromethyl) aniline (5.0 g, 15 mmol) in CH ₃CN (100 mL) was added tert-butyl (2-amino-2-thioxoethyl) carbamate (3.6 g, 19 mmol) , CaO (1.3 g, 24 mmol) , Pd ₂ (dba) ₃ (2.8 g, 3.1 mmol) and DPPF (3.4 g, 6.1 mmol) . The resulting mixture was stirred at 60 ℃ for 6 h under nitrogen. To the mixture was added water (40 mL) and extracted with EtOAc (40 mL x 3) . The organic phase was dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (4.0 g, 76.7%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 8.23 (s, 1H) , 7.98 (d, J = 8.4 Hz, 1H) , 7.62 (d, J = 8.3 Hz, 1H) , 5.43 (s, 1H) , 4.76 (d, J = 5.8 Hz, 2H) , 1.49 (s, 9H) .

Step 2: (5-Chlorobenzo [d] thiazol-2-yl) methanamine

To a solution of tert-butyl ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) carbamate (400 mg, 1.2 mmol) in dioxane (2 mL) was added HCl/1, 4-dioxane (4 M, 4 mL) at r. t., the mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated to obtain the title product (270 mg, 83.5%yield) as a white solid. LCMS: (ES ⁺) : m/z = 233.1 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.35 (s, 1H) , 8.26 (d, J = 8.5 Hz, 1H) , 7.77 (d, J = 8.5 Hz, 1H) , 4.71 (s, 2H) .

Intermediate 6

Thiazolo [4, 5-c] pyridin-2-ylmethanamine

Step 1: Tert-butyl (thiazolo [4, 5-c] pyridin-2-ylmethyl) carbamate

To a solution of 4-iodopyridin-3-amine (0.9 g, 4.1 mmol) in CH ₃CN (18 mL) was added tert-butyl (2-amino-2-thioxoethyl) carbamate (0.92 g, 4.8 mmol) , CaO (0.34 g, 6.1 mmol) , Pd ₂ (dba) ₃ (0.75 g, 0.82 mmol) and DPPF (0.91 g, 1.63 mmol) . The resulting mixture was stirred at 60 ℃for 8 h under nitrogen. To the mixture was added water (40 mL) and extracted with EtOAc (30 mL x 3) . The organic phase was dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (1.0 g, 88.2%yield) as a brown solid. ¹H NMR (400 MHz, CDCl ₃) δ 9.29 (s, 1H) , 8.54 (d, J = 4.6 Hz, 1H) , 7.83 (d, J = 5.2 Hz, 1H) , 5.44 (s, 1H) , 4.77 (d, J = 5.8 Hz, 2H) , 1.49 (s, 9H) .

Step 2: Thiazolo [4, 5-c] pyridin-2-ylmethanamine

To a solution of tert-butyl (thiazolo [4, 5-c] pyridin-2-ylmethyl) carbamate (1.0 g, 3.9 mmol) in dioxane (4 mL) was added HCl/dioxane (4 M, 8 mL) at r.t., the mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure to give the title product (790 mg, 99.2%yield) as a brown solid. LCMS: (ES ⁺) : m/z = 166.1 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.55 (s, 1H) , 8.91 (s, 3H) , 8.70 (d, J = 5.7 Hz, 1H) , 8.54 (d, J = 5.5 Hz, 1H) , 4.73 (s, 2H) .

Intermediate 7

Thiazolo [5, 4-b] pyridin-2-ylmethanamine

Step 1: Tert-butyl (thiazolo [5, 4-b] pyridin-2-ylmethyl) carbamate

To a solution of 2-iodopyridin-3-amine (1.0 g, 1.5 mmol) in CH ₃CN (20 mL) was added tert-butyl (2-amino-2-thioxoethyl) carbamate (1.3 g, 6.8 mmol) , CaO (0.38 g, 6.8 mmol) , Pd ₂ (dba) ₃ (0.82 g, 0.9 mmol) and DPPF (1.1 g, 2.0 mmol) . The resulting mixture was stirred at 60 ℃ for 6 h under nitrogen. To the mixture was added water (40 ml) and extracted with EtOAc (20 mL x 3) . The organic phase was dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (0.5 g, 41.5%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 8.57 (d, J = 4.1 Hz, 1H) , 8.20 (d, J = 8.2 Hz, 1H) , 7.42 (dd, J = 8.1, 4.6 Hz, 1H) , 5.45 (s, 1H) , 4.74 (d, J = 5.5 Hz, 2H) , 1.49 (s, 9H) .

Step 2: Thiazolo [5, 4-b] pyridin-2-ylmethanamine

To a solution of tert-butyl (thiazolo [5, 4-b] pyridin-2-ylmethyl) carbamate (0.5 g, 1.8 mmol) in dioxane (2 mL) was added HCl/1, 4-dioxane (4 M, 4 mL) at r. t., the mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated to give the title product (300 mg, 95.3%yield) as a white solid. LCMS: (ES ⁺) : m/z = 166.2 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.91 (s, 3H) , 8.68 (dd, J = 4.6, 1.4 Hz, 1H) , 8.47 (dd, J = 8.2, 1.4 Hz, 1H) , 7.66 (dd, J = 8.2, 4.6 Hz, 1H) , 4.65 (d, J = 5.4 Hz, 2H) .

Intermediate 8

(S) -1- (4-Chlorothiazol-2-yl) ethan-1-amine

Step 1: 4-Chlorothiazole

To a solution of 2, 4-dichlorothiazole (6.0 g, 0.039 mol) in AcOH (60 mL) was added Zn power (9.0 g, 0.14 mol) , and the reaction mixture was stirred at 120 ℃ for 1 h. The reaction mixture was filtered and poured into iced water (100 mL) , then aq. NaOH (50 w%) was added (pH =9) . Then the mixture was extracted with EtOAc (50 mL x 3) . The combined organic layer was dry over anhydrous Na ₂SO ₄ and evaporated under reduced pressure to afford the crude title product (4.0 g, 85.8%yield) as yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ 8.74 (d, J = 2.1 Hz, 1H) , 7.17 (d, J = 2.3 Hz, 1H) .

Step 2: 1- (4-Chlorothiazol-2-yl) ethan-1-one

To a solution of 4-chlorothiazole (2.0 g, 16.8 mmol) in THF (20 mL) was added n-BuLi (7.3 mL, 2.5 M) at -70 ℃, and stirred for 0.5 h under an atmosphere of N ₂, then N-methoxy-N-methylacetamide (1.7 g, 20.1 mmol) was added. The reaction mixture was stirred at -70 ℃ for 1 h. To the reaction mixture was added aq. NaHCO ₃ and extracted with EtOAc (20 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 20/1) to afford the title product (1.0 g, 37.0%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ7.46 (s, 1H) , 2.71 (s, 3H) .

Step 3: (S, E) -N- (1- (4-chlorothiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide

To a solution of 1- (4-chlorothiazol-2-yl) ethan-1-one (700 mg, 4.3 mmol) in THF (7 mL) was added (S) -2-methylpropane-2-sulfinamide (1.0 g, 8.6 mmol) and Ti (OiPr) ₄ (6.1 g, 21.7 mmol) . The reaction mixture was stirred at 70 ℃ for 16 h. To the reaction mixture was added H ₂O (20 mL) and filtered. And the aqueous phase was extracted with EtOAc (30 mL x 2) . The combined organics layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 10/1) to afford the title product (1.1 g, 93.9%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.28 (s, 1H) , 2.84 (s, 3H) , 1.32 (s, 9H)

Step 4: (S) -N- ( (S) -1- (4-chlorothiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide

To a solution of LiAlH (O ^tBu) ₃ (2.1 g, 8.2 mmol) in THF (20 mL) was added (S, E) -N- (1- (4-chlorothiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide (1.1 g, 4.1 mmol) at -70 ℃ under an atmosphere of N ₂. The reaction mixture was stirred at -70 ℃ for 3 h. To the reaction mixture was added ice water (20 mL) and diluted with EtOAc (30 mL) . The mixture was filtered. Separate the organic layer, and the aqueous layer was extracted with EtOAc (30 mL x 2) . The combined organic layer was dry over anhydrous Na ₂SO ₄ and evaporate solvent under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 10/1 ～ 2/1) to afford the title product (1.0 g) as yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ 7.05 (s, 1H) , 4.86 –4.74 (m, 1H) , 4.10 (d, J = 6.5 Hz, 1H) , 1.67 (d, J = 6.7 Hz, 3H) , 1.26 (s, 9H) .

Step 5: (S) -1- (4-Chlorothiazol-2-yl) ethan-1-amine

To a solution of (S) -N- ( (S) -1- (4-chlorothiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide (1.0 g, 3.7 mmol) in DCM (5 mL) was added HCl/dioxane (4 M, 10 mL) at r.t.. The mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated. The residue was triturated with petroleum ether to offer the title product (636 mg, HCl salt, 84.8%yield) as a white solid. LCMS: (ES+) : m/z = 163.1 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.79 (s, 3H) , 7.86 (s, 1H) , 4.84 (q, J = 6.8 Hz, 1H) , 1.60 (d, J = 6.8 Hz, 3H)

Intermediate 9

(S) -1- (4-Methylthiazol-2-yl) ethan-1-amine

Step 1: 1- (4-Methylthiazol-2-yl) ethan-1-one

To a solution of 4-methylthiazole (1.0 g, 10.0 mmol) in THF (20 mL) was added n-BuLi (2 M, 4.4 mL) at -70 ℃ and stirred for 0.5 h under an atmosphere of N ₂. Then N-methoxy-N-methylacetamide (1.2 g, 12.1 mmol) was added, and the reaction mixture was stirred at -70 ℃for 1 h. To the reaction mixture was added aq. NaHCO ₃ and extract with EtOAc (10 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 20/1) to afford the title product (980 mg, 68.8%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.25 (s, 1H) , 2.70 (s, 3H) , 2.54 (s, 3H) .

Step 2: (S, E) -2-Methyl-N- (1- (4-methylthiazol-2-yl) ethylidene) propane-2-sulfinamide

To a solution of 1- (4-methylthiazol-2-yl) ethan-1-one (800 mg, 5.6 mmol) in THF (10 mL) was added (S) -2-methylpropane-2-sulfinamide (1.4 g, 11.3 mmol) and Ti (OiPr) ₄ (8.1 g, 28.3 mmol) . The reaction mixture was stirred at 70 ℃ for 8 h. To the reaction mixture was added H ₂O (10 mL) and filtered. And aqueous phase was extracted with EtOAc (10 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 10/1) to afford the title product (1.2 g, 86.6%yield) as a yellow solid. LCMS: (ES+) : m/z = 245.1 [M+1] ⁺.

Step 3: (S) -2-Methyl-N- ( (S) -1- (4-methylthiazol-2-yl) ethyl) propane-2-sulfinamide

To a solution of LiAlH (O ^tBu) ₃ (2.5 g, 9.8 mmol) in THF (20 mL) was added (S, E) -2-methyl-N- (1- (4-methylthiazol-2-yl) ethylidene) propane-2-sulfinamide (1.2 g, 4.9 mmol) at -70 ℃under an atmosphere of N ₂, and the reaction mixture was stirred at -70 ℃ for 3 h. To the reaction mixture was added ice water (10 mL) , and extract with EtOAc (20 mL x 3) . The combined organic was dried over anhydrous Na ₂SO ₄ and evaporate under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 1/1) to afford the title product (1.1 g, 90.9%yield) as yellow oil. LCMS: (ES+) : m/z = 247.1 [M+1] ⁺.

Step 4: (S) -1- (4-Methylthiazol-2-yl) ethan-1-amine

To a solution of (S) -2-methyl-N- ( (S) -1- (4-methylthiazol-2-yl) ethyl) propane-2-sulfinamide (1.1 g, 4.5 mmol) in dioxane (5 mL) was added HCl/1, 4-dioxane (4 M, 10 mL) at r. t.. The mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated. The residue was slurred in petroleum ether to obtain the title product (800 mg, 95.3%yield) as a white solid. LCMS: (ES+) : m/z = 143.1 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.89 (s, 3H) , 7.39 (s, 1H) , 4.75 (d, J = 5.5 Hz, 1H) , 2.39 (s, 3H) , 1.61 (d, J = 6.8 Hz, 3H) . e. e: 99.4% (retention time: intermediate 9: 17.98 min, the R isomer: 21.70 min) . The R isomer of intermediate 9 was synthesized using the same procedure. The chiral purity of intermediate 9 was determined by chiral HPLC method. Chiral HPLC method: Column: CHIRALPAK AD-H 4.6*250mm, 5um; Mobile Phase: A: Hexanes, B: EtOH (0.2%DEA) , A: B = 95: 5; Flow Rate: 0.6 mL/min; Oven Temperature: 30 ℃.

Intermediate 10

(S) -1- (5-Methylthiazol-2-yl) ethan-1-amine

Step 1: 1- (5-Methylthiazol-2-yl) ethan-1-one

To a solution of 4-methylthiazole (1.0 g, 10.0 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 4.4 mL) at -70 ℃ and stirred for 0.5 h under an atmosphere of N ₂. Then N-methoxy-N-methylacetamide (1.2 g, 12.1 mmol) was added, and the reaction mixture was stirred at -70 ℃for 1 h. To the reaction mixture was added aq. NaHCO ₃ and extract with EtOAc (10 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 20/1) to afford the title product (1.1 g, 77.5%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ7.66 (d, J = 0.9 Hz, 1H) , 2.67 (s, 3H) , 2.56 (d, J = 1.0 Hz, 3H) .

Step 2: (S, E) -2-Methyl-N- (1- (5-methylthiazol-2-yl) ethylidene) propane-2-sulfinamide

To a solution of 1- (5-methylthiazol-2-yl) ethan-1-one (1.1 g, 7.8 mmol) in THF (11 mL) was added (S) -2-methylpropane-2-sulfinamide (1.9 g, 15.6 mmol) and Ti (OiPr) ₄ (8.1 g, 28.3 mmol) . The reaction mixture was stirred at 70 ℃ for 8 h. To the reaction mixture was added H ₂O (10 mL) , filtered and aqueous phase was extracted with EtOAc (10 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 20/1) to afford the title product (1.2 g, 64.6%yield) as a yellow solid. LCMS: (ES+) : m/z = 245.1 [M+1] ⁺.

Step 3: (S) -2-Methyl-N- ( (S) -1- (5-methylthiazol-2-yl) ethyl) propane-2-sulfinamide

To a solution of LiAlH (O ^tBu) ₃ (2.5 g, 9.8 mmol) in THF (20 mL) was added (S, E) -2-methyl- N- (1- (5-methylthiazol-2-yl) ethylidene) propane-2-sulfinamide (1.2 g, 5.0 mmol) at -70 ℃under an atmosphere of N ₂, and the reaction mixture was stirred at -70 ℃ for 3 h. To the reaction mixture was added ice water (20 g) and extracted with EtOAc (20 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 1/1) to afford the title product (740 mg, 59.7%yield) as a white solid. LCMS: (ES+) : m/z = 247.1 [M+1] ⁺.

Step 4: (S) -1- (5-Methylthiazol-2-yl) ethan-1-amine

To a solution of (S) -2-methyl-N- ( (S) -1- (5-methylthiazol-2-yl) ethyl) propane-2-sulfinamide (740 mg, 3.01 mmol) in dioxane (5 mL) was added HCl/dioxane (4 M, 10 mL) at r. t.. The mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated. The residue was slurred in petroleum ether to give the title product (470 mg) as a white solid. LCMS: (ES+) : m/z = 143.1 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.59 (s, 3H) , 7.56 (s, 1H) , 4.75 (d, J =5.5 Hz, 1H) , 2.46 (s, 3H) , 1.56 (d, J = 6.8 Hz, 3H) .

Intermediate 11

(S) -1- (4-Isopropylthiazol-2-yl) ethan-1-amine

Step 1: 4-Isopropylthiazole

To a solution of 1-bromo-3-methylbutan-2-one (2.0 g, 12.2 mmol) in EtOH (10 mL) was added methanethioamide (1.2 g, 19.6 mmol) , and the reaction mixture was stirred at 80 ℃ for 2 h. To the reaction mixture was added aq. NaHCO ₃ (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 20/1) to afford the title product (700 mg, 45.4%yield) as yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ8.76 (d, J = 1.8 Hz, 1H) , 6.93 (d, J = 1.2 Hz, 1H) , 3.16 (dq, J = 13.7, 6.9 Hz, 1H) , 1.34 (d, J =6.9 Hz, 6H) .

Step 2: 1- (4-Isopropylthiazol-2-yl) ethan-1-one

To a solution of 4-isopropylthiazole (0.7 g, 5.5 mmol) in THF (10 mL) was added n-BuLi (2.5 M, 3.7 mL) at -70 ℃, and stirred for 0.5 h under an atmosphere of N ₂. Then N-methoxy-N-methylacetamide (900 mg, 8.7 mmol) was added. And the reaction mixture was stirred at -70 ℃for 1 h. To the reaction mixture was added aq. NaHCO ₃ (10 mL) and extract with EtOAc (10 mL x 3) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography column on silica gel (PE/EtOAc = 100/1) to afford the title product (300 mg, 32.2%yield) . ¹H NMR (400 MHz, CDCl ₃) δ 7.24 (s, 1H) , 3.23 –3.11 (m, 1H) , 2.71 (s, 3H) , 1.35 (d, J = 6.9 Hz, 6H) .

Step 3: (S, E) -N- (1- (4-isopropylthiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide

To a solution of 1- (4-isopropylthiazol-2-yl) ethan-1-one (0.3 g, 1.7 mmol) in THF (6 mL) was added (S) -2-methylpropane-2-sulfinamide (0.4 g, 3.5 mmol) and Ti (OiPr) ₄ (2.5 g, 8.8 mmol) . The reaction mixture was stirred at 70 ℃ for 3 h. The reaction mixture was added H ₂O (20 mL) , filtered and the aqueous phase was extracted with EtOAc (20 mL x 3) . The combined organic was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 5/1) to afford the title product (340 mg, 70.6%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.07 (s, 1H) , 3.13 (dt, J = 13.8, 6.9 Hz, 1H) , 2.86 (s, 3H) , 1.33 (s, 3H) , 1.32 (s, 12H)

Step 4: (S) -N- ( (S) -1- (4-isopropylthiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide

To a solution of LiAlH (O ^tBu) ₃ (635 mg, 2.5 mmol) in THF (3 mL) was added (S, E) -N- (1- (4-isopropylthiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide (340 mg, 1.2 mmol) at -70 ℃ under an atmosphere of N ₂, and the reaction mixture was stirred at -70 ℃ for 3 h. To the reaction mixture was added ice water (10 mL) and diluted with EtOAc (20 mL) . The mixture was filtered. Separate the organic layer, and extract the aqueous layer with EtOAc (20 mL x 2) . The combined organic layer was dried over anhydrous Na ₂SO ₄ and evaporated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 1/1) to afford the title product (240 mg, 69.9%yield) as yellow oil. LCMS: (ES+) : m/z 275.1 [M+1] ⁺.

Step 5: (S) -1- (4-Isopropylthiazol-2-yl) ethan-1-amine

To a solution of (S) -N- ( (S) -1- (4-isopropylthiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide (240 mg, 0.88 mmol) in DCM (2 mL) was added HCl/dioxane (4 M, 4 mL) at 25 ℃. The mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with petroleum ether to obtain the title product (115 mg, 98%HPLC purity) as a white solid. LC-MS: (ES+) : m/z = 170.2 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.78 (s, 3H) , 7.37 (s, 1H) , 4.76 (dt, J = 12.1, 6.0 Hz, 1H) , 3.05 (dt, J = 13.7, 6.9 Hz, 1H) , 1.61 (d, J = 6.8 Hz, 3H) , 1.26 (d, J = 6.9 Hz, 6H) . e. e: 98.5% (retention time: intermediate 11: 10.5 min; R isomer: 11.3 min) . The R isomer of intermediate 11 was synthesized using the same procedure. The chiral purity of intermediate 11 was determined by chiral HPLC method. Chiral HPLC method: Column: CHIRALPAK AD-H 4.6*250mm, 5um; Mobile Phase: A: Hexanes, B: IPA, C: DEA, A: B: C = 98: 2: 0.1; Flow Rate: 0.7 ml/min; Oven Temperature: 30 ℃.

Example 1

N- (2- (Dimethylamino) benzyl) -3-isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-amine

Step 1: 5-Chloro-N- (2- (dimethylamino) benzyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (80 mg, 0.35 mmol) in EtOH (1.0 mL) was added 2- (aminomethyl) -N, N-dimethylaniline (104 mg, 0.69 mmol) , the resulting mixture was stirred at 70 ℃ for 1 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluent: PE/EA =8/1) to obtain the title product (100 mg, yield 83.6%) as a white solid. LCMS: (ES ⁺) : m/z =344.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.84 (s, 1H) , 7.31 (t, J = 7.0 Hz, 3H) , 7.22 (d, J = 7.6 Hz, 1H) , 7.08 (t, J = 7.2 Hz, 1H) , 6.01 (s, 1H) , 4.63 (d, J = 5.9 Hz, 2H) , 3.34 -3.18 (m, 1H) , 2.75 (s, 6H) , 1.30 (t, J = 14.4 Hz, 6H) .

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (2- (dimethylamino) benzyl) carbamate

To a solution of 5-chloro-N- (2- (dimethylamino) benzyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine (80.0 mg, 0.23 mmol) in THF (3.0 mL) was added Boc ₂O (101.0 mg, 0.46 mmol) and DMAP (23.0 mg, 0.02 mmol) . The mixture was stirred at 25℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluent: PE/EA =10/1) to obtain the title product (100 mg, yield 96.8%) as a white solid. LCMS: (ES ⁺) : m/z =444.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.01 (s, 1H) , 7.43 (s, 1H) , 7.22 (s, 1H) , 7.03 (d, J = 5.2 Hz, 2H) , 6.43 (s, 1H) , 5.17 (s, 2H) , 3.32 (dd, J = 13.7, 6.9 Hz, 1H) , 2.38 (s, 6H) , 1.40 (s, 9H) , 1.36 (d, J = 6.9 Hz, 6H) .

Step 3: Tert-butyl (2- (dimethylamino) benzyl) (3-isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-yl) carbamate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (2- (dimethylamino) benzyl) carbamate (100.0 mg, 0.22 mmol) in toluene (2.0 mL) was added 1-methylpiperidin-4-ol (31.0 mg, 0.27 mmol) , Pd ₂ (dba) ₃ (14.4 mg, 0.015 mmol) , rac-BINAP (21.0 mg, 0.033 mmol) and t-BuONa (32.0 mg, 0.33 mmol) , the resulting mixture was stirred at 95 ℃ for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluent: DCM/MeOH = 15/1) to obtain the title product (60 mg, yield 50.9%) as yellow oil. LCMS: (ES ⁺) : m/z = 523.3 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.83 (s, 1H) , 7.46 (d, J = 7.6 Hz, 1H) , 7.21 (t, J = 7.6 Hz, 1H) , 7.04 (t, J = 7.6 Hz, 2H) , 5.99 (s, 1H) , 5.11 (s, 3H) , 3.14 (dt, J = 13.8, 6.9 Hz, 1H) , 2.66 (s, 2H) , 2.44 (s, 6H) , 2.31 (s, 5H) , 2.04 (s, 3H) , 1.83 (d, J = 8.8 Hz, 2H) , 1.39 (s, 9H) , 1.34 (d, J = 6.9 Hz, 6H) .

Step 4: N- (2- (Dimethylamino) benzyl) -3-isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of tert-butyl (2- (dimethylamino) benzyl) (3-isopropyl-5- ( (1-methyl piperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-yl) carbamate (60.0 mg, 0.11 mmol) in methanol (2.0 mL) was added HCl/MeOH (4 M 6.0 mL) , the resulting mixture was stirred at 25 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC to obtain the title product (23.3 mg, 48%yield) as a white solid. LCMS: (ES ⁺) : m/z = 423.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.29 (t, J = 6.3 Hz, 1H) , 8.18 (s, 1H) , 7.80 (s, 1H) , 7.29 (d, J = 7.4 Hz, 1H) , 7.26 –7.13 (m, 2H) , 7.00 (t, J = 7.2 Hz, 1H) , 5.32 (s, 1H) , 4.99 (d, J = 4.0 Hz, 1H) , 4.54 (d, J = 6.2 Hz, 2H) , 3.00 (dt, J = 13.8, 6.8 Hz, 1H) , 2.70 (s, 6H) , 2.63 (s, 2H) , 2.30 (d, J = 9.0 Hz, 2H) , 2.23 (s, 3H) , 1.94 (s, 2H) , 1.66 (d, J = 8.8 Hz, 2H) , 1.27 (d, J = 6.9 Hz, 6H) .

Example 2

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methylpyrrolidin-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (1-methylpyrrolidin-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (180.0 mg, 0.78 mmol) in EtOH (2.0 mL) was added (1-methylpyrrolidin-2-yl) methanamine (178.0 mg, 1.56 mmol) . The mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 20/1) to give the title product (190.0 mg, 79.2%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 308.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.86 (s, 1H) , 6.88 (s, 1H) , 5.86 (s, 1H) , 3.54 –3.08 (m, 4H) , 2.60 (s, 1H) , 2.48 –2.24 (m, 4H) , 1.99 (s, 2H) , 1.76 (dd, J = 18.6, 9.5 Hz, 3H) , 1.33 (d, J = 6.2 Hz, 6H) .

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methylpyrrolidin-2-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-methylpyrrolidin-2yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (190.0 mg, 0.62 mmol) in THF (5.0 mL) was added Boc ₂O (190.0 mg, 0.87 mmol) and DMAP (23.0 mg, 0.19 mmol) . The mixture was stirred at 25 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH = 60/1) to afford the title product (250 mg, 99.6%yield) as yellow solid. LCMS: (ES ⁺) : m/z = 408.2 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methylpyrrolidin-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methylpyrrolidin-2-yl) methyl) carbamate (80.0 mg, 0.20 mmol) in toluene (4.0 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (56.0 mg, 0.24 mmol) , Pd ₂ (dba) ₃ (16.0 mg, 0.017 mmol) , rac-BINAP (20.0 mg, 0.032 mmol) and t-BuONa (29.0 mg, 0.30 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH =10/1) to give the title product (54.0 mg, 45.7%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 602.3 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.64 (s, 1H) , 5.99 (s, 1H) , 5.24 (s, 1H) , 4.26 –3.87 (m, 4H) , 3.66 –3.48 (m, 1H) , 3.03 (dd, J = 52.0, 46.2 Hz, 4H) , 2.67 –2.43 (m, 3H) , 2.33 (s, 3H) , 2.22 (s, 1H) , 1.86 (s, 1H) , 1.65 (s, 2H) , 1.46 (d, J = 16.3 Hz, 4H) , 1.35 (s, 19H) , 1.27 –1.20 (m, 6H) .

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methylpyrrolidin-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methylpyrrolidin-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (54.0 mg, 0.090 mmol) in MeOH (2.0 mL) was added HCl/MeOH (4.0 M, 4.0 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the product (10.2 mg, yield 28%) as yellow gum. LCMS: (ES ⁺) : m/z = 402.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.23 (s, 3H) , 7.61 (s, 1H) , 6.88 (s, 2H) , 5.29 (s, 1H) , 3.40 (d, J = 154.3 Hz, 6H) , 2.99 (d, J = 36.4 Hz, 3H) , 2.28 (d, J = 47.3 Hz, 6H) , 1.77 (d, J = 93.5 Hz, 7H) , 1.23 (s, 6H) .

Example 4

(3R, 4R) -4- ( ( (7- ( ( (5- (Dimethylamino) benzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5- (Dimethylamino) benzo [d] thiazole-2-carbaldehyde

To a solution of n-BuLi (1.8 mL, 2.5 M) in dry THF (20.0 mL) was added a solution of N, N-dimethylbenzo [d] thiazol-5-amine (500.0 mg, 2.81 mmol) in THF (50.0 mL) at -70 ℃ dropwise under N ₂ atmosphere, and the temperature was kept between -60 ℃ and -50 ℃ for 1 h. Then DMF (1.2 mL) was added dropwise, and the resulting mixture was stirred at -50 ℃ for 1 h. Water (20.0 ml) was added to the mixture at 0 ℃, the aqueous layer was extracted with EtOAc (20 mL x 2) . The organic layers were washed with brine, dried over Na ₂SO ₄ and filtered. The filters were concentrated under reduced pressure to afford the title product (500.0 mg, 86.4%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 10.05 (s, 1H) , 8.02 (d, J = 9.9 Hz, 1H) , 7.11 –7.01 (m, 2H) , 3.11 (s, 6H) .

Step 2: (E) -5- (Dimethylamino) benzo [d] thiazole-2-carbaldehyde oxime

To a solution of 5- (dimethylamino) benzo [d] thiazole-2-carbaldehyde (200.0 mg, 0.97 mmol) in MeOH (5 mL) and H ₂O (2 mL) was added hydroxylamine hydrochloride (100.0 mg, 1.4 mmol) , followed by NaOH (63.0 mg, 1.2 mmol) in H ₂O (3 mL) . The resulting mixture was stirred at 20 ℃ for 1 h. The precipitate was filtered and washed with H ₂O to afford the title product (200.0 mg, 93.2%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 222.1 [M+1] ⁺.

Step 3: 2- (Aminomethyl) -N, N-dimethylbenzo [d] thiazol-5-amine

To a solution of (E) -5- (dimethylamino) benzo [d] thiazole-2-carbaldehyde oxime (0.2 g, 0.90 mmol) in AcOH (3 mL) and H ₂O (3 mL) was added Zn powder (0.47 g, 7.3 mmol) . The resulting mixture was stirred at 20 ℃ for 12 h. Then the mixture was concentrated under reduced pressure to give the title product (250 mg, crude) . LCMS: (ES ⁺) : m/z = 208.2 [M+1] ⁺.

Step 4: Tert-butyl ( (5- (dimethylamino) benzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 2- (aminomethyl) -N, N-dimethylbenzo [d] thiazol-5-amine (250.0 mg, crude, 1.2 mmol) in THF (4 mL) and H ₂O (4 mL) was added Boc ₂O (320.0 mg, 1.4 mmol) and K ₂CO ₃ (400.0 mg, 2.9 mmol) . The mixture was stirred at 25 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA = 2/1) to afford the title product (170 mg, 61.2%yield overall 2 steps) as a yellow solid. LCMS: (ES ⁺) : m/z = 308.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.79 (d, J = 9.0 Hz, 1H) , 7.07 (s, 1H) , 6.93 (d, J = 7.1 Hz, 1H) , 5.30 (s, 1H) , 4.66 (d, J = 5.4 Hz, 2H) , 3.01 (s, 6H) , 1.48 (s, 9H) .

Step 5: 2- (Aminomethyl) -N, N-dimethylbenzo [d] thiazol-5-amine hydrochloride

To a solution of tert-butyl ( (5- (dimethylamino) benzo [d] thiazol-2-yl) methyl) carbamate (170.0 mg, 0.55 mmol) in dioxane (2.0 mL) was added HCl/1, 4-dioxane (4 M, 4.0 mL) , The resulting mixture was stirred at 25 ℃ for 2 h. Then the mixture was concentrated under reduced pressure to afford the title product (140 mg, 99%yield) as a white solid. LCMS: (ES ⁺) : m/z = 208.1 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.43 (d, J = 2.0 Hz, 1H) , 8.24 (d, J = 8.9 Hz, 1H) , 7.83 (dd, J = 8.9, 2.3 Hz, 1H) , 4.71 (s, 2H) , 3.37 (s, 6H) .

Step 6: 2- ( ( (5-Chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) -N, N-dimethylbenzo [d] thiazol-5-amine

To a solution of 2- (aminomethyl) -N, N-dimethylbenzo [d] thiazol-5-amine hydrochloride (140.0 mg, 0.57 mmol) in EtOH (2 mL) was added DIPEA (185.0 mg, 1.4 mmol) and stirred at 25 ℃for 10 min. Then 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (110 mg, 0.48 mmol) was added, the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (PE/EA = 2/1) to give the title product (140.0 mg, 73.0 %yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 401.1 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.90 (s, 1H) , 7.86 (d, J = 9.1 Hz, 1H) , 7.22 (m, 1H) , 7.03 (d, J = 2.3 Hz, 1H) , 6.96 (dd, J = 9.1, 2.5 Hz, 1H) , 6.03 (s, 1H) , 4.91 (d, J = 6.0 Hz, 2H) , 3.28 (dt, J = 13.8, 6.9 Hz, 1H) , 3.02 (s, 6H) , 1.34 (d, J = 6.9 Hz, 6H) .

Step 7: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5- (dimethylamino) benzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 2- ( ( (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) -N, N-dimethylbenzo [d] thiazol-5-amine (140.0 mg, 0.35 mmol) in THF (5.0 mL) was added Boc ₂O (190.0 mg, 0.87 mmol) and DMAP (42.7 mg, 0.35 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 2/1) to afford the title product (150 mg, 85.7%yield) as yellow solid. LCMS: (ES ⁺) : m/z = 501.1 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.01 (s, 1H) , 7.77 (d, J = 9.1 Hz, 1H) , 7.08 (d, J = 2.1 Hz, 1H) , 6.93 (dd, J = 9.0, 2.3 Hz, 1H) , 6.79 (s, 1H) , 5.34 (s, 2H) , 3.31 (dt, J = 13.7, 6.9 Hz, 1H) , 3.02 (s, 6H) , 1.44 (s, 9H) , 1.36 (d, J = 6.9 Hz, 6H) .

Step 8: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5- (dimethylamino) benzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5- (dimethylamino) benzo [d] thiazol-2-yl) methyl) carbamate (80.0 mg, 0.16 mmol) in toluene (2.0 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (44.0 mg, 0.19 mmol) , Pd ₂ (dba) ₃ (10.2 mg, 0.01 mmol) , rac-BINAP (15.0 mg, 0.02 mmol) and t-BuONa (14.5 mg, 0.23 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 20/1) to give the title product (30.0 mg, 31.6%yield) as yellow oil. LCMS: (ES ⁺) : m/z =595.3 [M+1-100] ⁺.

Step 9: (3R, 4R) -4- ( ( (7- ( ( (5- (Dimethylamino) benzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5- (dimethylamino) benzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (30.0 mg, 0.043 mmol) in dioxane (1.0 mL) was added HCl/1, 4-dioxane (4 M, 2 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC to afford the title product (5.0 mg, 23.4%yield) as a yellow solid. Chemical Formula: C ₂₅H ₃₄N ₈OS; Molecular Weight: 494.66. LCMS: (ES ⁺) : m/z = 495.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.74 (d, J = 9.1 Hz, 1H) , 7.70 (s, 1H) , 7.18 (d, J = 2.3 Hz, 1H) , 7.02 (dd, J = 9.1, 2.4 Hz, 1H) , 5.25 (s, 1H) , 4.82 –4.70 (m, 2H) , 3.98 (m, 1H) , 3.46 (m, 1H) , 3.37 –3.34 (m, 1H) , 3.28 –3.24 (m, 1H) , 3.15 (m, 1H) , 3.04 (m, 1H) , 2.99 (s, 6H) , 2.91-2.96 (m, 1H) , 2.76 (t, J = 11.4 Hz, 1H) , 1.88 (d, J = 11.6 Hz, 1H) , 1.72 –1.55 (m, 2H) , 1.29 (t, J = 7.5 Hz, 6H) .

Example 5

(3R, 4R) -4- ( ( (7- ( ( (8- (Dimethylamino) quinolin-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (E) -8- (Dimethylamino) quinoline-2-carbaldehyde oxime

To a solution of 8- (dimethylamino) quinoline-2-carbaldehyde (200.0 mg, 1.0 mmol) in MeOH (5 mL) and H ₂O (2 mL) was added Hydroxylamine hydrochloride (83.0 mg, 1.2 mmol) and the aqueous solution of Na ₂CO ₃ (63.0 mg, 0.6 mmol) in H ₂O (1.5 mL) . The resulting mixture was stirred at 20 ℃ for 1 h. The precipitate was filtered and washed with H ₂O to afford the title product (180 mg, 83.7%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 216.1 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.47 (s, 1H) , 8.09 (d, J = 8.6 Hz, 1H) , 7.91 (d, J = 8.6 Hz, 1H) , 7.86 (s, 1H) , 7.45 (t, J = 7.8 Hz, 1H) , 7.37 (d, J = 7.2 Hz, 1H) , 7.12 (d, J = 7.0 Hz, 1H) , 3.13 (s, 6H) .

Step 2: 2- (Aminomethyl) -N, N-dimethylquinolin-8-amine

To a solution of (E) -8- (dimethylamino) quinoline-2-carbaldehyde oxime (150.0 mg, 0.70 mmol) in AcOH (2.5 mL) and H ₂O (1 mL) was added Zn powder (228.0 mg, 3.4 mmol) . The resulting mixture was stirred at 20 ℃ for 12 h. Then the mixture was concentrated under reduced pressure to give the title product (250 mg, crude) . LCMS: (ES ⁺) : m/z = 202.2 [M+1] ⁺.

Step 3: Tert-butyl ( (8- (dimethylamino) quinolin-2-yl) methyl) carbamate

To a solution of 2- (aminomethyl) -N, N-dimethylquinolin-8-amine (250.0 mg, 1.24 mmol) in THF (3 mL) and H ₂O (3 mL) was added Boc ₂O (406.0 mg, 1.8 mmol) and K ₂CO ₃ (515.0 mg, 3.7 mmol) . The mixture was stirred at 25 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA =20/1) to afford the title product (200 mg, 95.2%yield overall 2 steps) as yellow solid. LCMS: (ES ⁺) : m/z = 302.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.08 (d, J = 8.0 Hz, 1H) , 7.41 -7.33 (m, 3H) , 7.11 (d, J = 8.0 Hz, 1H) , 5.84 (s, 1H) , 4.64 (d, J = 4.0 Hz, 2H) , 3.13 (s, 6H) , 1.48 (s, 9H) .

Step 4: 2- (Aminomethyl) -N, N-dimethylquinolin-8-amine hydrochloride

To a solution of tert-butyl ( (8- (dimethylamino) quinolin-2-yl) methyl) carbamate (120.0 mg, 0.33 mmol) in MeOH (0.5 mL) was added HCl/MeOH (4 M, 4 mL) . The resulting mixture was stirred at 25 ℃ for 12 h. Then the mixture was concentrated under reduced pressure to afford the title product (80.0 mg, 84.5%yield) as a white solid. LCMS: (ES ⁺) : m/z = 202.2 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.61 (d, J = 8.5 Hz, 1H) , 8.32 (d, J = 7.9 Hz, 1H) , 8.23 (d, J =8.3 Hz, 1H) , 7.87 (t, J = 8.0 Hz, 1H) , 7.78 (d, J = 8.5 Hz, 1H) , 7.17 (dd, J = 21.7, 7.9 Hz, 2H) , 4.66 (s, 2H) , 3.51 (s, 6H) .

Step 5: 2- ( ( (5-Chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) -N, N-dimethylquinolin-8-amine

To a solution of 2- (aminomethyl) -N, N-dimethylquinolin-8-amine hydrochloride (80.0 mg, 0.33 mmol) in EtOH (2.0 mL) was added DIPEA (67.0 mg, 0.52 mmol) and stirred at 25 ℃ for 10 min. Then 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (48.0 mg, 0.21 mmol) was added, the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (PE/EA = 3/1) to give the title product (70.0 mg, 84.9%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 395.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.15 (d, J = 8.4 Hz, 1H) , 8.00 (s, 1H) , 7.93 (s, 1H) , 7.46 (t, J = 7.8 Hz, 1H) , 7.38 (d, J = 8.4 Hz, 2H) , 7.15 (d, J = 7.0 Hz, 1H) , 6.00 (s, 1H) , 4.85 (d, J = 5.0 Hz, 2H) , 3.30 (dt, J = 13.9, 6.9 Hz, 1H) , 3.19 (s, 6H) , 1.35 (d, J = 6.9 Hz, 6H) .

Step 6: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (8- (dimethylamino) quinolin-2-yl) methyl) carbamate

To a solution of 2- ( ( (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) -N, N-dimethylquinolin-8-amine (70.0 mg, 0.18 mmol) in THF (4.0 mL) was added Boc ₂O (77.0 mg, 0.35 mmol) and DMAP (2.2 mg, 0.02 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA = 5/1) to afford the title product (70.0 mg, 79.8%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 495.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.10 (d, J = 8.4 Hz, 1H) , 7.99 (s, 1H) , 7.52 (d, J = 8.4 Hz, 1H) , 7.44 –7.31 (m, 2H) , 7.19 (s, 1H) , 7.08 (d, J = 6.4 Hz, 1H) , 5.28 (s, 2H) , 3.31 (dt, J = 13.9, 7.0 Hz, 1H) , 3.00 (s, 6H) , 1.35 (d, J = 7.7 Hz, 15H) .

Step 7: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (8- (dimethylamino) quinolin-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (8-(dimethylamino) quinolin-2-yl) methyl) carbamate (50.0 mg, 0.10 mmol) in toluene (2.0 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (28.0 mg, 0.12 mmol) , Pd ₂ (dba) ₃ (6.5 mg, 0.007 mmol) , rac-BINAP (9.5 mg, 0.015 mmol) and t-BuONa (14.5 mg, 0.15 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM/MeOH = 10/1) to give the title product (30.0 mg, 43.1%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 689.3 [M+1] ⁺.

Step 8: (3R, 4R) -4- ( ( (7- ( ( (8- (Dimethylamino) quinolin-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (8- (dimethylamino) quinolin-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (30.0 mg, 0.043 mmol) in dioxane (1.0 mL) was added HCl/dioxane (4.0 M, 2 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (3.8 mg, yield 17.8%) as yellow solid. Chemical Formula: C ₂₇H ₃₆N ₈O; Molecular Weight: 488.64. LCMS: (ES ⁺) : m/z = 489.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.40 (s, 1H) , 8.23 (d, J = 8.4 Hz, 1H) , 7.72 (s, 1H) , 7.58 –7.40 (m, 3H) , 7.25 (d, J = 6.5 Hz, 1H) , 5.26 (s, 1H) , 4.84 (s, 2H) , 3.96 (d, J = 14.7 Hz, 1H) , 3.48 (m, 1H) , 3.34 (m, 1H) , 3.16 (d, J = 14.8 Hz, 1H) , 3.04 (m, 7H) , 2.98 –2.84 (m, 2H) , 2.76 (t, J = 11.0 Hz, 1H) , 1.89 (d, J = 11.9 Hz, 1H) , 1.64 (m, 2H) , 1.29 (t, J = 7.4 Hz, 6H) .

Example 6

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-pyrazol-5-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (1-methyl-1H-pyrazol-5-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (180.0 mg, 0.78 mmol) in EtOH (2 mL) was added (1-methyl-1H-pyrazol-5-yl) methanamine (173.0 mg, 1.5 mmol) . The mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (DCM/MeOH = 20/1) to give the title product (190 mg, 79.8%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 305.1 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ) ( (1-methyl-1H-pyrazol-5-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-methyl-1H-pyrazol-5-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (190.0 mg, 0.63 mmol) in THF (5 mL) was added Boc ₂O (192.0 mg, 0.88 mmol) and DMAP (23 mg, 0.19 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM/MeOH = 60/1) to afford the title product (250 mg, 99.2% yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 405.2 [M+1] ⁺.

Step 3: (3R, 4R) -Tert-butyl 4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ) ( (1-methyl-1H-pyrazol-5-yl) methyl) carbamate (125.0 mg, 0.31 mmol) in toluene (4.0 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (80.0 mg, 0.37 mmol) , Pd ₂ (dba) ₃ (25.0 mg, 0.021 mmol) , rac-BINAP (28.0 mg, 0.042 mmol) and t-BuONa (54.0 mg, 0.46 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (DCM/MeOH = 10/1) to give the title product (21 mg, 11.7%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 599.3 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.76 (s, 1H) , 7.34 (s, 1H) , 6.03 (s, 1H) , 5.64 (s, 1H) , 5.05 -5.05 (m, 3H) , 4.26 -4.21 (m, 2H) , 3.78 (s, 3H) , 3.18 -3.09 (m, 3H) , 2.66 -2.55 (m, 2H) , 1.46 -1.42 (m, 4H) , 1.42 (s, 18H) , 1.33 -1.25 (m, 6H) .

To a solution of (3R, 4R) -tert-butyl4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (21.0 mg, 0.035 mmol) in MeOH (2 mL) was added HCl/MeOH (4 M, 4 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the product (8.1 mg, 57.8%yield) as yellow gum. Chemical Formula: C ₂₁H ₃₅N ₇O; Molecular Weight: 398.52. LCMS: (ES ⁺) : m/z = 399.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.29 (s, 1H) , 7.84 -7.81 (t, J = 5.6 Hz, 1H) , 7.63 (s, 1H) , 7.31 -7.31 (d, J = 1.2 Hz, 1H) , 6.87 -6.83 (m, 1H) , 6.22 (s, 1H) , 5.28 (s, 1H) , 4.49 -4.48 (d, J = 6.0 Hz, 2H) , 3.84 (s, 3H) , 3.56 -3.49 (m, 1H) , 3.32 -3.25 (m, 2H) , 3.09 -2.91 (m, 3H) , 2.59 -2.54 (m, 2H) , 2.45 -2.38 (m, 2H) , 1.73 -1.69 (m, 1H) , 1.54 -1.45 (m, 1H) , 1.37 -1.21 (m, 7H) .

Example 7

3-Isopropyl-N- ( (1-methyl-1H-pyrazol-5-yl) methyl) -5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-amine

Step 1: Tert-butyl (3-isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-pyrazol-5-yl) methyl) carbamate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ) ( (1-methyl-1H-pyrazol-5-yl) methyl) carbamate (100 mg, 0.29 mmol) in Toluene (4 mL) was added 1-methylpiperidin-4-ol (42 mg, 0.36 mmol) , Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) , rac-BINAP (30 mg, 0.048 mmol) and t-BuONa (42 mg, 0.43 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 10/1) to give the title product (25 mg, 25.4%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 384.3 [M+1] ⁺.

Step 2: 3-Isopropyl-N- ( (1-methyl-1H-pyrazol-5-yl) methyl) -5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of tert-butyl (3-isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-pyrazol-5-yl) methyl) carbamate (25 mg, 0.051 mmol) in MeOH (2 mL) was added HCl/MeOH (4 M, 4 mL) . The mixture was stirred at 30 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (11.2 mg, 98%HPLC purity) as yellow gum. LCMS: (ES ⁺) : m/z = 384.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.22 -8.18 (m, 2H) , 7.82 (s, 1H) , 7.29 (s, 1H) , 6.17 (s, 1H) , 5.52 (s, 1H) , 5.00 (s, 1H) , 4.60 (d, J = 6.0 Hz, 2H) , 3.28 (s, 3H) , 3.03 –3.00 (m, 2H) , 2.69 -2.67 (m, 2H) , 2.66 (s, 3H) , 2.25 –2.21 (m, 5H) , 2.02 -2.00 (m, 2H) , 1.69 -1.66 (m, 2H) , 1.27 (d, J = 7.2 Hz, 6H) .

Example 8

3-Isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) -N- ( (1-methylpyrrolidin-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

Step 1: Tert-butyl (3-isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methylpyrrolidin-2-yl) methyl) carbamate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methylpyrrolidin-2-yl) methyl) carbamate (120.0 mg, 0.29 mmol) in toluene (4.0 mL) was added 1-methylpiperidin-4-ol (42.0 mg, 0.36 mmol) , Pd ₂ (dba) ₃ (24.0 mg, 0.026 mmol) , rac-BINAP (30.0 mg, 0.048 mmol) and t-BuONa (42.0 mg, 0.44 mmol) . The mixture was stirred at 95 ℃for 16 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 10/1) to give the title product (65.0 mg, 45.4%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 487.3 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ7.72 (s, 1H) , 6.16 (s, 1H) , 5.12 (s, 1H) , 3.98 (d, J = 13.0 Hz, 1H) , 3.63 –3.46 (m, 1H) , 3.15 –3.02 (m, 1H) , 2.95 (s, 1H) , 2.69 (s, 2H) , 2.35 (dd, J = 47.9, 19.4 Hz, 8H) , 2.10 (d, J = 8.3 Hz, 3H) , 1.87 (s, 3H) , 1.61 (s, 2H) , 1.42 (s, 1H) , 1.26 (dd, J = 30.7, 24.3 Hz, 15H) .

Step 2: 3-Isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) -N- ( (1-methylpyrrolidin-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of tert-butyl (3-isopropyl-5- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methylpyrrolidin-2-yl) methyl) carbamate (65.0 mg, 0.13 mmol) in MeOH (2 mL) was added HCl/MeOH (4 M, 4 mL) . The mixture was stirred at 30 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (23.5 mg, 45.5%yield) as yellow gum. Chemical Formula: C ₂₁H ₃₄N ₆O; Molecular Weight: 386.28. LCMS: (ES ⁺) : m/z = 387.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.18 (s, 2H) , 7.79 (s, 1H) , 7.15 (s, 1H) , 5.51 (s, 1H) , 5.06 (s, 1H) , 3.43 (s, 1H) , 3.30 (s, 1H) , 3.12 –2.93 (m, 2H) , 2.77 (s, 2H) , 2.59 (s, 1H) , 2.42 –2.22 (m, 8H) , 2.03 (s, 2H) , 1.90 (s, 1H) , 1.70 –1.50 (m, 5H) , 1.28 (d, J = 6.8 Hz, 6H) .

Example 9

(3R, 4R) -4- ( ( (7- ( ( (1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanamine

To a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-5-carboxamide (130 mg, 0.67 mmol) in THF (2 mL) was added LiAlH ₄ (100 mg, 2.68 mmol) , the mixture was stirred at 70 ℃for 2 h. Then the mixture was cooled, H ₂O (0.15 mL) and 15%NaOH (0.15 mL) was added, the resulting mixture was stirred at 20 ℃ for 15 min. Then H ₂O (0.45 mL) was added and stirred for 15 min. The mixture was dried over Mg ₂SO ₄ and filtered. The filtrates were concentrated to give the title product (113 mg, 94.2%yield) as off-white oil. ¹H NMR (400 MHz, CDCl ₃) δ7.52 (dd, J = 26.5, 9.0 Hz, 1H) , 6.17 (s, 1H) , 5.25 (d, J = 9.3 Hz, 1H) , 4.01 (d, J = 9.3 Hz, 1H) , 3.71 -3.52 (m, 1H) , 2.20 -1.79 (m, 4H) , 1.71 -1.44 (m, 4H) .

Step 2: 5-Chloro-3-isopropyl-N- ( (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (70 mg, 0.30 mmol) in EtOH (2 mL) was added (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanamine (113 mg, 0.62 mmol) , the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: PE/EA = 3/1) to give the title product (87 mg, 73.3%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 375.2 [M+1] ⁺.

Step 3: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (87 mg, 0.23 mmol) in THF (5 mL) was added Boc ₂O (100 mg, 0.46 mmol) and DMAP (30 mg, 0.25 mmol) . The mixture was stirred at 25 ℃for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: PE/EA = 3/1) to afford the title product (95 mg, 86.3%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 475.3 [M+1] ⁺.

Step 4: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin -5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methyl) carbamate (95 mg, 0.20 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (57.6 mg, 0.25 mmol) , Pd ₂ (dba) ₃ (13.3 mg, 0.01mmol) , rac-BINAP (19.4 mg, 0.03 mmol) and Cs ₂CO ₃ (135 mg, 0.41 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE/EA =0/1) to give the title product (98 mg, 73.3%yield) as yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ7.73 (s, 1H) , 7.52 (s, 1H) , 6.31 (s, 1H) , 5.84 (s, 1H) , 5.29 (d, J = 9.8 Hz, 1H) , 4.93 (s, 1H) , 4.83 (s, 1H) , 4.36 –4.10 (m, 3H) , 4.02 (s, 1H) , 3.67 (s, 1H) , 3.25 –2.93 (m, 3H) , 2.56 (s, 2H) , 2.02 (d, J = 20.2 Hz, 3H) , 1.58 (s, 8H) , 1.42 (s, 14H) , 1.29 (dd, J = 14.5, 7.7 Hz, 9H) .

Step 5: (3R, 4R) -4- ( ( (7- ( ( (1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (98 mg, 0.14 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 25 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (47.3 mg, 97%HPLC purity) as a white solid. Chemical Formula: C ₁₉H ₂₈N ₈O; Molecular Weight: 384.49. LCMS: (ES ⁺) : m/z = 385.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.80 (s, 1H) , 7.63 (s, 1H) , 6.36 (s, 1H) , 5.50 (s, 1H) , 4.66 (s, 2H) , 3.64 (s, 2H) , 3.54 –3.33 (m, 3H) , 3.03 (ddd, J = 34.0, 18.4, 9.5 Hz, 2H) , 2.81 (t, J = 11.3 Hz, 1H) , 2.05 (d, J = 12.5 Hz, 1H) , 1.84 (s, 1H) , 1.71 –1.55 (m, 1H) , 1.38 –1.15 (m, 6H) .

Example 10

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-isopropyl-1H-pyrazol-5-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (1-Isopropyl-1H-pyrazol-5-yl) methanamine

To a solution of 1-isopropyl-1H-pyrazole-5-carboxamide (150 mg, 0.98 mmol) in THF (2 mL) was added LiAlH ₄ (150 mg, 3.94 mmol) , and the mixture was stirred at 70 ℃ for 2 h. Then the mixture was cooled, H ₂O (0.15 mL) and 15%NaOH (0.15 mL) was added, stirred at 20 ℃ for 15 min. Then H ₂O (0.45 mL) was added and stirred for 15 min. The mixture was dried over Mg ₂SO ₄ and filtered. The filtrates were concentrated to give the title product (90 mg, 66.0%yield) as off-white oil. ¹H NMR (400 MHz, CDCl ₃) δ 7.45 (s, 1H) , 6.10 (s, 1H) , 4.52 -4.45 (m, 1H) , 3.90 (s, 1H) , 1.49 (d, J = 6.4 Hz, 6H) .

Step 2: 5-Chloro-3-isopropyl-N- ( (1-isopropyl-1H-pyrazol-5 yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (70 mg, 0.30 mmol) in EtOH (2 mL) was added (1-isopropyl-1H-pyrazol-5-yl) methanamine (90 mg, 0.64 mmol) , and the mixture was stirred at 70 ℃ for 2 h. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA = 3/1) to give the title product (90 mg, 53.7%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 333.2 [M+1] ⁺.

Step 3: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1 isopropyl-1H-pyrazol-5-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-isopropyl-1H-pyrazol-5-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (90 mg, 0.27 mmol) in THF (5 mL) was added Boc ₂O (117 mg, 0.54 mmol) and DMAP (32.4 mg, 0.27 mmol) . The mixture was stirred at 25℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 8/1) to afford the title product (90 mg, 76.8%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 433.2 [M+1] ⁺.

Step 4: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-isopropyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-isopropyl-1H-pyrazol-5-yl) methyl) carbamate (90 mg, 0.20 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (57.6 mg, 0.25 mmol) , Pd ₂ (dba) ₃ (13.3 mg, 0.01 mmol) , rac-BINAP (19.4 mg, 0.03 mmol) and Cs ₂CO ₃ (135 mg, 0.41 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 0/1) to give the title product (60 mg, 46.0%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 627.4 [M+1] ⁺.

Step 5: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-isopropyl-1H-pyrazol-5-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-isopropyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (60 mg, 0.09 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 25 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (30.2 mg, 99%HPLC purity) as white solid. Chemical Formula: C ₂₂H ₃₄N ₈O; Molecular Weight: 426.57. LCMS: (ES ⁺) : m/z = 427.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.83 (s, 1H) , 7.47 (s, 1H) , 6.37 (s, 1H) , 5.52 (s, 1H) , 4.77 (s, 2H) , 4.69 (dd, J = 12.9, 6.3 Hz, 1H) , 3.60 (m, 3H) , 3.47 –3.34 (m, 2H) , 3.09 (dt, J = 13.6, 6.8 Hz, 1H) , 2.96 (t, J = 11.9 Hz, 1H) , 2.79 (t, J = 11.3 Hz, 1H) , 2.06 (d, J = 13.5 Hz, 1H) , 1.85 (s, 1H) , 1.63 (d, J = 12.3 Hz, 1H) , 1.52 –1.38 (m, 6H) , 1.29 (d, J = 6.6 Hz, 6H) .

Example 11

(3R, 4R) -4- ( ( (7- ( ( (1-Cyclopropyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (1-Cyclopropyl-1H-pyrazol-5-yl) methanamine

To a solution of 1-cyclopropyl-1H-pyrazole-5-carboxamide (140 mg, 0.92 mmol) in THF (2 mL) was added LiAlH ₄ (140 mg, 3.68 mmol) , and the mixture was stirred at 70 ℃ for 2 h. Then the mixture was cooled, H ₂O (0.15 mL) and 15%NaOH (0.15 mL) was added and stirred at 20 ℃ for 15 min. Then H ₂O (0.45 mL) was added and stirred for 15 min. The mixture was dried over Mg ₂SO ₄ and filtered. The filtrates were concentrated to give the title product (100 mg, 79.3%yield) as off-white oil. ¹H NMR (400 MHz, CDCl ₃) δ 7.35 (s, 1H) , 6.15 (s, 1H) , 4.01 (s, 2H) , 3.41 (dt, J = 10.8, 3.7 Hz, 1H) , 1.19 (s, 2H) , 1.04 (d, J = 5.8 Hz, 2H) .

Step 2: 5-Chloro-N- ( (1-cyclopropyl-1H-pyrazol-5-yl) methyl) -3isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (80 mg, 0.35 mmol) in EtOH (2 mL) was added (1-cyclopropyl-1H-pyrazol-5-yl) methanamine (100 mg, 0.72 mmol) , and the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 3/1) to give the title product (90 mg, 78.2%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 331.1 [M+1] ⁺.

Step 3: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-cyclopropyl-1H-pyrazol-5-yl) methyl) carbamate

To a solution of 5-chloro-N- ( (1-cyclopropyl-1H-pyrazol-5-yl) methyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine (90 mg, 0.27 mmol) in THF (5 mL) was added Boc ₂O (117 mg, 0.54 mmol) and DMAP (32.4 mg, 0.27 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 8/1) to afford the title product (80 mg, 76.7%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 431.2 [M+1] ⁺.

Step 4: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-cyclopropyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-cyclopropyl-1H-pyrazol-5-yl) methyl) carbamate (80 mg, 0.18 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (51.2 mg, 0.22 mmol) , Pd ₂ (dba) ₃ (11.8 mg, 0.01mmol) , rac-BINAP (17.2 mg, 0.03 mmol) and Cs ₂CO ₃ (120 mg, 0.37 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: PE/EA = 0/1) to give the title product (50 mg, 44.5%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 625.4 [M+1] ⁺.

Step 6: (3R, 4R) -4- ( ( (7- ( ( (1-Cyclopropyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-cyclopropyl-1H-pyrazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3- hydroxypiperidine-1-carboxylate (50 mg, 0.08 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 30 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the product (20.4 mg, 99%HPLC purity) as white solid. Chemical Formula: C ₂₂H ₃₂N ₈O; Molecular Weight: 424.55. LCMS: (ES ⁺) : m/z =425.3 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.69 (s, 1H) , 7.35 (s, 1H) , 6.26 (s, 1H) , 5.30 (s, 1H) , 4.73 (s, 2H) , 3.92 (d, J = 11.9 Hz, 1H) , 3.60 -3.51 (m, 2H) , 3.38 -3.25 (m, 3H) , 3.05 -2.96 (m, 2H) , 2.84 -2.75 (m, 1H) , 1.96 (d, J = 11.7 Hz, 1H) , 1.80 -1.61 (m, 2H) , 1.28 (t, J =6.7 Hz, 6H) , 1.18 –1.07 (m, 4H) .

Example 13

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-imidazol-5-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (1-methyl-1H-imidazol-5-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (80.0 mg, 0.35 mmol) in EtOH (2.0 mL) was added (1-methylpyrrolidin-2-yl) methanamine (76.0 mg, 0.68 mmol) . The mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 20/1) to give the title product (85 mg, 80.9%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 305.2 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ7.91 (d, J = 13.3 Hz, 2H) , 7.16 (s, 1H) , 6.22 (s, 1H) , 4.71 (s, 2H) , 3.77 (s, 3H) , 3.19 (dt, J =13.8, 7.0 Hz, 1H) , 1.31 (d, J = 6.9 Hz, 6H) .

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-imidazol-5-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-methyl-1H-imidazol-5-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (85.0 mg, 0.28 mmol) in THF (5.0 mL) was added Boc ₂O (91.4 mg, 0.42 mmol) and DMAP (34.0 mg, 0.28 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 20/1) to give the title product (87.0 mg, 76.9%yield) as yellow solid. LCMS: (ES ⁺) : m/z = 405.1 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.02 (s, 1H) , 7.72 (s, 1H) , 6.93 (s, 1H) , 6.76 (s, 1H) , 5.12 (s, 2H) , 3.79 (s, 3H) , 3.24 –3.18 (m, 1H) , 1.33 (t, J = 3.4 Hz, 15H) .

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-imidazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-imidazol-5-yl) methyl) carbamate (85.0 mg, 0.21 mmol) in Toluene (2.0 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (58.0 mg, 0.25 mmol) , Pd ₂ (dba) ₃ (14.0 mg, 0.015 mmol) , rac-BINAP (18.0 mg, 0.029 mmol) and t-BuONa (31.0 mg, 0.32 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH =10/1) to give the title product (40.0 mg, 32%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 599.4 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.22 (s, 1H) , 7.66 (s, 1H) , 7.08 (s, 1H) , 6.04 (s, 1H) , 5.49 (s, 1H) , 5.02 (s, 2H) , 4.14 (s, 1H) , 4.03 (d, J = 15.1 Hz, 1H) , 3.82 (s, 3H) , 3.72 (s, 1H) , 3.44 (d, J = 10.7 Hz, 2H) , 3.21 (d, J = 5.0 Hz, 1H) , 3.06 (dd, J = 13.8, 6.9 Hz, 1H) , 2.64 (d, J =60.4 Hz, 4H) , 1.75 (d, J = 13.0 Hz, 1H) , 1.62 (s, 2H) , 1.43 (s, 9H) , 1.30 (dd, J = 19.4, 13.7 Hz, 15H) .

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-imidazol-5-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-imidazol-5-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (48.0 mg, 0.067 mmol) in DCM (2.0 mL) was added TFA (4 M, 4 mL) . The mixture was stirred at 25 ℃ for 1 h, and then the solution was adjusted to pH =7 with con. NH ₃·H ₂O. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (25.5 mg, 80.0%yield) as yellow gum. Chemical Formula: C ₂₀H ₃₀N ₈O; Molecular Weight: 398.25. LCMS: (ES ⁺) : m/z = 399.2 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.79 (s, 1H) , 7.77 (s, 1H) , 7.57 (s, 1H) , 5.51 (s, 1H) , 4.75 (s, 2H) , 3.93 (s, 3H) , 3.75 (s, 1H) , 3.61 (d, J = 3.7 Hz, 1H) , 3.41 (dt, J = 17.3, 14.4 Hz, 3H) , 3.15 –2.92 (m, 2H) , 2.81 (t, J = 11.4 Hz, 1H) , 2.04 (d, J = 11.1 Hz, 1H) , 1.80 (s, 1H) , 1.72 –1.58 (m, 1H) , 1.28 (dd, J = 6.8, 4.3 Hz, 6H) .

Example 14

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-imidazol-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (1-methyl-1H-imidazol-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (80.0 mg, 0.35 mmol) in EtOH (2.0 mL) was added (1-methyl-1H-imidazol-2-yl) methanamine (77.0 mg, 0.70 mmol) , and the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (PE/EA = 3/1) to give the title product (100.0 mg, 94.3%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 305.1 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.86 (s, 1H) , 7.05 (s, 1H) , 6.92 (s, 1H) , 6.07 (s, 1H) , 4.60 (d, J = 4.9 Hz, 2H) , 3.27 (dt, J = 13.8, 6.8 Hz, 1H) , 1.33 (d, J = 6.9 Hz, 6H) .

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-imidazol-2-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-methyl-1H-imidazol-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (90.0 mg, 0.30 mmol) in THF (5.0 mL) was added Boc ₂O (120.0 mg, 0.55 mmol) and DMAP (40.0 mg, 0.30 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 0/1) to afford the title product (100.0 mg, 83.6%yield) as yellow solid. LCMS: (ES ⁺) : m/z = 405.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.93 (s, 1H) , 6.88 (s, 1H) , 6.81 (s, 1H) , 6.75 (s, 1H) , 5.07 (s, 2H) , 3.75 (s, 3H) , 3.29 (dt, J = 13.8, 6.9 Hz, 1H) , 1.34 (d, J = 7.0 Hz, 6H) , 1.32 (s, 9H) .

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-imidazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-imidazol-2-yl) methyl) carbamate (70.0 mg, 0.17 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (47.6 mg, 0.20 mmol) , Pd ₂ (dba) ₃ (11.1 mg, 0.01 mmol) , rac-BINAP (16.1 mg, 0.02 mmol) and Cs ₂CO ₃ (112 mg, 0.34 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM/MeOH = 20/1) to give the title product (40.0 mg, 38.6%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 599.3 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-imidazol-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-imidazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (40 mg, 0.06 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 25 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC to afford the title product (8.4 mg, 31.4%yield) as yellow solid. Chemical Formula: C ₂₀H ₃₀N ₈O; Molecular Weight: 398.52. LCMS: (ES ⁺) : m/z =399.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.09 (s, 1H) , 7.76 (s, 1H) , 7.44 (s, 1H) , 7.31 (s, 1H) , 5.44 (s, 1H) , 4.91 (s, 2H) , 3.90 (s, 3H) , 3.76 -3.80 (m, 1H) , 3.56 -3.58 (dd, J = 9.4, 5.9 Hz, 1H) , 3.46 –3.34 (m, 3H) , 3.15 –2.90 (m, 2H) , 2.80 (t, J = 11.3 Hz, 1H) , 2.01 (d, J = 12.4 Hz, 1H) , 1.74-1.78 (s, 1H) , 1.61-1.69 (m, 1H) , 1.28 (dd, J = 6.7, 5.2 Hz, 6H) .

Example 15

(3R, 4R) -4- ( ( (7- ( ( (2- (Dimethylamino) pyridin-3-yl) methyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 2- (Dimethylamino) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (500.0 mg, 4.67 mmol) in CH ₃CN (10.0 mL) was added dimethylamine hydrochloride (0.57 g, 7.0 mmol) and K ₂CO ₃ (1.29 g, 9.34 mmol) , then the mixture was stirred at 80 ℃ for 12 h. Water (50 mL) was added to the mixture and extracted with EtOAc (20 mL x 2) . The organic layers were washed with brine, dried over Na ₂SO ₄ and filtered. The filtrates were concentrated under reduced pressure to afford the title product (300.0 mg, 49.8%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 8.29 (dd, J = 4.7, 1.8 Hz, 1H) , 7.72 (dd, J = 7.6, 1.9 Hz, 1H) , 6.62 (dd, J = 7.6, 4.7 Hz, 1H) , 3.29 (s, 6H) .

Step 2: 3- (Aminomethyl) -N, N-dimethylpyridin-2-amine

To a solution of 2- (dimethylamino) nicotinonitrile (300.0 mg, 1.70 mmol) in THF (2.0 mL) was added LiAlH ₄ (130.0 mg, 3.42 mmol) , and the mixture was stirred at 70 ℃ for 1 h. To the mixture was added EtOAc (30.0 mL) , H ₂O (0.2 mL) and 15%aq. NaOH (0.2 mL) and stirred for 10 min. Then H ₂O (0.6 mL) was added, stirred for 30 min. The mixture was dried over Mg ₂SO ₄ and concentrated under reduced pressure to afford the title product (250.0 mg, crude) as yellow oil. LCMS: (ES ⁺) : m/z = 152.2 [M+1] ⁺.

Step 3: Tert-butyl ( (2- (dimethylamino) pyridin-3-yl) methyl) carbamate

To a solution of 3- (aminomethyl) -N, N-dimethylpyridin-2-amine (250.0 mg, 1.6 mmol) in THF (4 mL) was added Boc ₂O (430.0 mg, 1.9 mmol) and TEA (250.0 mg, 2.4 mmol) . The mixture was stirred at 25 ℃ for 12 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 10/1) to afford the title product (300.0 mg, 58.6%yield overall two steps) as yellow solid. LCMS: (ES ⁺) : m/z = 252.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.20 (dd, J = 7.4, 4.9 Hz, 1H) , 7.54 (d, J = 7.4 Hz, 1H) , 6.89 (dd, J = 4.9, 1.6 Hz, 1H) , 5.06 (s, 1H) , 4.37 (d, J = 5.2 Hz, 2H) , 2.83 (s, 6H) , 1.47 (s, 9H) .

Step 4: 3- (Aminomethyl) -N, N-dimethylpyridin-2-amine hydrochloride

To a solution of tert-butyl ( (2- (dimethylamino) pyridin-3-yl) methyl) carbamate (0.3 g, 0.55 mmol) in 1, 4-dioxane (2 mL) was added HCl/dioxane (4 M, 4 mL) , the resulting mixture was stirred at 25 ℃ for 2 h. Then the mixture was concentrated under reduced pressure to afford the title product (0.2 g, 89.2%yield) as a white solid. ¹H NMR (400 MHz, MeOD) δ 8.24 (d, J =9.6 Hz, 1H) , 8.13 (d, J = 5.4 Hz, 1H) , 7.28 (t, J = 6.1 Hz, 1H) , 4.40 (s, 2H) , 3.28 (s, 6H) .

Step 5: 5-Chloro-N- ( (2- (dimethylamino) pyridin-3-yl) methyl) -3-isopropylpyrzaolo [1, 5-a] pyrimidin-7-amine

To a solution of 3- (aminomethyl) -N, N-dimethylpyridin-2-amine hydrochloride (130.0 mg, 0.69 mmol) in EtOH (2 mL) was added DIPEA (134.0 mg, 1.0 mmol) , and was stirred at 25 ℃ for 10 min. Then 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (80.0 mg, 0.35 mmol) was added. The mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 3/1) to give the title product (110.0 mg, 91.7%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 345.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 8.15 (d, J = 3.4 Hz, 1H) , 7.72 (s, 1H) , 7.44 (d, J = 6.8 Hz, 1H) , 6.94 (s, 1H) , 6.78 (dd, J = 7.4, 4.9 Hz, 1H) , 5.76 (s, 1H) , 4.44 (d, J = 5.9 Hz, 2H) , 3.10-3.17 (dt, J = 13.8, 6.9 Hz, 1H) , 2.77 (s, 6H) , 1.20 (d, J = 6.9 Hz, 6H) .

Step 6: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (2- (dimethylamino) pyridin-3-yl) methyl) carbamate

To a solution of 5-chloro-N- ( (2- (dimethylamino) pyridin-3-yl) methyl) -3-isopropyl pyrzaolo [1, 5-a] pyrimidin-7-amine (110.0 mg, 0.32 mmol) in THF (5.0 mL) was added Boc ₂O (139.0 mg, 0.64 mmol) and DMAP (39.0 mg, 0.32 mmol) . The mixture was stirred at 25 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 5/1) to afford the title product (140.0 mg, 98.6%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 445.2 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ8.18 (d, J = 3.3 Hz, 1H) , 8.00 (s, 1H) , 7.72 (d, J = 6.6 Hz, 1H) , 6.87 (dd, J = 7.4, 4.9 Hz, 1H) , 6.47 (s, 1H) , 5.08 (s, 2H) , 3.30 (dt, J = 13.8, 6.8 Hz, 1H) , 2.63 (s, 6H) , 1.36 (d, J = 7.0 Hz, 15H) .

Step 7: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (2- (dimethylamino) pyridin-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (2- (dimethylamino) pyridin-3-yl) methyl) carbamate (80.0 mg, 0.18 mmol) in toluene (2.0 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (49.0 mg, 0.21 mmol) , Pd ₂ (dba) ₃ (11.5 mg, 0.01 mmol) , rac-BINAP (16.8 mg, 0.02 mmol) and Cs ₂CO ₃ (117 mg, 0.36 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 1/1) to give the title product (40.0 mg, 34.8%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 639.4 [M+1] ⁺.

Step 8: (3R, 4R) -4- ( ( (7- ( ( (2- (Dimethylamino) pyridin-3-yl) methyl) amino) -3-isopro pylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (2- (dimethylamino) pyridin-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (40.0 mg, 0.063 mmol) in DCM (3.0 mL) was added TFA (3.0 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the title product (27.1 mg, 98.9%yield) as a yellow solid. Chemical Formula: C ₂₂H ₃₄N ₈O; Molecular Weight: 438.58. LCMS: (ES ⁺) : m/z = 439.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.14 (d, J = 3.8 Hz, 1H) , 7.82 (s, 1H) , 7.76 (d, J = 6.8 Hz, 1H) , 7.00 (dd, J = 7.5, 5.1 Hz, 1H) , 5.18 (s, 1H) , 4.68 (s, 2H) , 3.63 –3.52 (m, 2H) , 3.46 –3.33 (m, 3H) , 3.03 -3.10 (dt, J = 13.8, 6.9 Hz, 1H) , 2.92 -2.98 (m, 7H) , 2.73 -2.78 (dd, J = 14.5, 8.1 Hz, 1H) , 1.99 (d, J = 11.9 Hz, 1H) , 1.72-1.79 (m, 1H) , 1.54 -1.62 (dd, J = 22.9, 11.1 Hz, 1H) , 1.28 (dd, J = 6.9, 2.8 Hz, 6H) .

Example 17

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (pyridin-3-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (pyridin-3-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (200 mg, 0.87 mmol) in EtOH (5 mL) was added pyridin-3-ylmethanamine (141 mg, 1.3 mmol) , and the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 3/1) to give the title product (232 mg, 88.5%yield) as a yellow solid. LCMS: (ES ⁺) m/z: 302.40 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (pyridin-3-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (pyridin-3-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (115 mg, 0.38 mmol) in DCM (5 mL) was added Boc ₂O (167 mg, 0.77 mmol) and DMAP (9 mg, 0.08 mmol) . The mixture was stirred at 25 ℃ for 4 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title product (107 mg, 70%yield) as a yellow solid. LCMS: (ES ⁺) m/z: 402.50 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (pyridin-3-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (pyridin-3-ylmethyl) carbamate (107 mg, 0.27 mmol) in toluene (10 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (41.3 mg, 0.32 mmol) , Pd ₂ (dba) ₃ (12.2 mg, 0.013 mmol) , race-BINAP (24.8 mg, 0.04 mmol) and Cs ₂CO ₃ (182 mg, 0.56 mmol) under N ₂. The mixture was stirred at 110 ℃ for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 0/1) to give the title product (127 mg, 79.9%yield) as a yellow oil. LCMS: (ES ⁺) m/z: 596.90 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( (pyridin-3-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (pyridin-3-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxy piperidine-1-carboxylate (127 mg, 0.21 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 30 ℃for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (36 mg, 99.8%HPLC purity) as a white solid. LCMS: (ES ⁺) m/z: 396.60 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.62 (d, J = 2.2 Hz, 1H) , 8.49 (dd, J = 4.8, 1.6 Hz, 1H) , 8.17 (s, 1H) , 8.02 (t, J = 6.5 Hz, 1H) , 7.78 (dt, J = 7.9, 2.0 Hz, 1H) , 7.68 (s, 1H) , 7.39 (dd, J = 7.9, 4.7 Hz, 1H) , 6.88 (t, J = 6.2 Hz, 1H) , 5.21 (s, 1H) , 4.49 (d, J = 6.4 Hz, 2H) , , 3.29 –3.16 (m, 5H) , 3.00 -2.81 (m, 2H) , 2.81 (td, J = 12.3, 3.3 Hz, 1H) , 2.66 (dd, J = 11.9, 10.1 Hz, 1H) , 1.83 (dd, J = 14.3, 3.7 Hz, 1H) , 1.62 (s, 1H) , 1.52 -1.38 (m, 1H) , 1.25 (dd, J = 6.9, 4.9 Hz, 6H) .

Example 19

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (oxazol-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (oxazol-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (131 mg, 0.57 mmol) in EtOH (5 mL) was added oxazol-2-ylmethanamine hydrochloride (100 mg, 0.74 mmol) and TEA (173 mg 1.71 mmol) , the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 3/1) to give the title product (97 mg, 64.7%yield) as a yellow solid. LCMS: (ES ⁺) m/z: 292.30 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (oxazol-2-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (oxazol-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (97 mg, 0.33 mmol) in DCM (5 mL) was added Boc ₂O (167 mg, 0.67 mmol) and DMAP (4 mg, 0.03 mmol) . The mixture was stirred at 25 ℃ for 4 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title product (110 mg, 84.6%yield) as a yellow solid. LCMS: (ES ⁺) m/z: 392.50 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (oxazol-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (oxazol-2-ylmethyl) carbamate (55 mg, 0.14 mmol) in toluene (10 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (38.9 mg, 0.17 mmol) , Pd ₂ (dba) ₃ (6.5 mg, 0.007 mmol) , race-BINAP (13.1 mg, 0.02 mmol) and Cs ₂CO ₃ (96.5 mg, 0.30 mmol) under N ₂. The mixture was stirred at 110 ℃ for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC PE/EA = 0/1) to give the title product (50 mg, 61%yield) as yellow oil. LCMS: (ES ⁺) m/z: 586.80 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( (oxazol-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (oxazol-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxy piperidine-1-carboxylate (50 mg, 0.086 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 30 ℃for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (25 mg, 99.0%HPLC purity) as a white solid. LCMS: (ES ⁺) m/z: 386.50 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.26 -8.07 (m, 2H) , 7.84 (t, J =6.4 Hz, 1H) , 7.67 (s, 1H) , 7.20 (d, J = 0.9 Hz, 1H) , 6.93 (s, 1H) , 5.28 (s, 1H) , 4.60 (d, J = 6.3 Hz, 2H) , 3.60 -3.51 (m, 2H) , 3.32 -3.05 (m, 4H) , 3.00 -2.90 (m, 1H) , 2.70 –2.61 (m, 2H) , 1.82 -1.73 (m, 1H) , 1.57 (s, 1H) , 1.39 –1.30 (m, 1H) , 1.25 (dd, J = 6.9, 4.4 Hz, 6H) .

Example 23

8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) -N- ( (1-methylpyrrolidin-2-yl) methyl) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-amine

Step 1: 8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) -N- ( (1-methylpyrrolidin-2-yl) methyl) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-amine

To a solution of 4-chloro-8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazine (50.0 mg, crude) in MeCN (1 mL) was added DIEA and adjust the pH to 8. Then (1-methylpyrrolidin-2-yl) methanamine (20 mg, 0.17 mmol) was added. The mixture was stirred at 40 ℃ for 1 h. Then the mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (eluent: DCM/MeOH = 5/1) and prep-HPLC to give the title product (0.92 mg, 1.35%yield) as white solid. LCMS: (ES ⁺) : m/z = 388.3 [M+1] ⁺.

Example 25

2- ( ( (8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-yl) amino) methyl) -N, N-dimethylbenzo [d] thiazol-5-amine

Step 1: 2- ( ( (8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-yl) amino) methyl) -N, N-dimethylbenzo [d] thiazol-5-amine

To a solution of 4-chloro-8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazine (50.0 mg, crude) in MeCN (1 mL) was added DIEA to adjust the pH of the mixture to 8. A solution of 2- (aminomethyl) -N, N-dimethylbenzo [d] thiazol-5-amine hydrochloride (65.0 mg, 0.27 mmol) in MeCN (1 mL) was adjusted to pH = 8 with DIEA. Then the solution was added to the reaction mixture. The mixture was stirred at 40 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM/MeOH = 10/1) and purified further by prep-HPLC (TFA) to give the title product (1.2 mg, 0.9%yield, 98%HPLC purity) as colorless gum. LCMS: (ES ⁺) : m/z = 481.2 [M+1] ⁺.

Example 26

8-Isopropyl-N- ( (1-methyl-1H-pyrazol-5-yl) methyl) -2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-amine

Step 1: 4-Cloro-8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazine

To a solution of 8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-ol (200.0 mg, 0.69 mmol) in POCl ₃ (3.2 mL) was added N, N-diethylaniline (304.0 mg, 2.0 mmol) . The mixture was stirred at 90 ℃ for 6 h. Then the mixture was concentrated under reduced pressure to give the title product (350 mg, crude) as brown oil. LCMS: (ES ⁺) : m/z = 310.2 [M+1] ⁺.

Step 2: 8-Isopropyl-N- ( (1-methyl-1H-pyrazol-5-yl) methyl) -2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-amine

To a solution of 4-chloro-8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazine (100.0 mg, crude) in MeCN (2 mL) was added DIEA and adjust the pH to 8, then (1-methyl-1H-pyrazol-5-yl) methanamine (64 mg, 0.58 mmol) was added. The mixture was stirred at 40 ℃ for 1 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluent: DCM/MeOH = 10/1) and purified further by prep-HPLC to give the title product (12.0 mg, 9.7%yield) as a yellow solid. LCMS: (ES ⁺) : m/z =385.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.85 (s, 1H) , 7.37 -7.37 (d, J = 1.6 Hz, 1H) , 6.28 -6.27 (d, J = 1.6 Hz, 1H) , 5.29 (s, 1H) , 4.82 (s, 2H) , 3.92 (s, 3H) , 3.35 –3.30 (m, 4H) , 3.07 -3.04 (t, J = 6.8 Hz, 1H) , 2.85 (s, 3H) , 2.23 -2.17 (m, 4H) , 1.31 -1.29 (d, J = 8.0 Hz, 6H) .

Example 27

2- ( ( (8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-yl) amino) methyl) -N, N-dimethylquinolin-8-amine

Step 1: 2- ( ( (8-Isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-yl) amino) methyl) -N, N-dimethylquinolin-8-amine

To a solution of 4-chloro-8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazine (50.0 mg, crude) in MeCN (1 mL) was added DIEA to adjust the pH of the reaction mixture to 8. A solution of 2- (aminomethyl) -N, N-dimethylquinolin-8-amine hydrochloride (60.0 mg, 0.25 mmol) in MeCN (1 mL) was adjusted to pH = 8 with DIEA. Then the solution was added to the reaction mixture. The mixture was stirred at 40 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM/MeOH = 10/1) and purified further by Prep-HPLC (TFA) to give the title product (2.3 mg, 2.0%yield, 99%HPLC purity: ) as a white solid. LCMS: (ES ⁺) : m/z = 475.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.23 (d, J = 8.5 Hz, 1H) , 7.91 (s, 1H) , 7.48 (dd, J = 19.7, 7.8 Hz, 3H) , 7.21 (d, J = 5.6 Hz, 1H) , 5.15 -5.03 (m, 3H) , 3.20 -3.03 (m, 4H) , 3.00 -2.75 (m, 7H) , 2.63 (s, 3H) , 2.05 -1.90 (m, 4H) , 1.32 (d, J = 6.9 Hz, 6H) .

Example 28

N- ( (1-cyclopropyl-3-methyl-1H-pyrazol-5-yl) methyl) -8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-amine

Step 1: N- ( (1-Cyclopropyl-3-methyl-1H-pyrazol-5-yl) methyl) -8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazin-4-amine

To a solution of 4-chloro-8-isopropyl-2- ( (1-methylpiperidin-4-yl) oxy) pyrazolo [1, 5-a] [1, 3, 5] triazine (50.0 mg, crude) in MeCN (1 mL) was added DIEA to adjust the pH of the mixture to pH = 8. Then (1-cyclopropyl-3-methyl-1H-pyrazol-5-yl) methanamine (20.0 mg, 0.13 mmol) was added to the mixture, and the mixture was stirred at 40 ℃ for 1 h. Then the mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (eluent: DCM/MeOH = 5/1) and purified further by prep-HPLC to give the title product (1.0 mg, 1.9%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 425.3 [M+1] ⁺.

Example 29

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-pyrazol-3-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (1-methyl-1H-pyrazol-3-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (80 mg, 0.35 mmol) in EtOH (2 mL) was added (1-methyl-1H-pyrazol-3-yl) methanamine (77.2 mg, 0.70 mmol) , the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE/EA = 1/1) to give the title product (90 mg, 84.9%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 305.1 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-pyrazol-3-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-methyl-1H-pyrazol-3-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (90 mg, 0.30 mmol) in THF (5 mL) was added Boc ₂O (120 mg, 0.55 mmol) and DMAP (40.0 mg, 0.30 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 2/1) to afford the title product (80 mg, 66.9%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 405.2 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-pyrazol-3-yl) methyl) carbamate (80 mg, 0.19 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (53.6 mg, 0.23 mmol) , Pd ₂ (dba) ₃ (12.6 mg, 0.01 mmol) , rac-BINAP (18.4 mg, 0.02mmol) and Cs ₂CO ₃ (128 mg, 0.39 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the title product (40 mg, 38.6%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 599.4 [M+1] ⁺.

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-pyrazol-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (40 mg, 0.06 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 25 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the product (16.4 mg, 99%HPLC purity) as a white solid. LCMS: (ES ⁺) : m/z = 399.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.73 (s, 1H) , 8.14 (s, 1H) , 7.76 (s, 1H) , 7.62 (s, 1H) , 6.18 (s, 1H) , 5.38 (s, 1H) , 4.43 (s, 2H) , 3.80 (s, 3H) , 3.60 -3.42 (m, 3H) , 3.05 –2.90 (m, 1H) , 2.89 –2.72 (m, 1H) , 2.71 -2.60 (m, 1H) , 1.90 -1.80 (m, 1H) , 1.70 -1.61 (m, 1H) , 1.50 –1.40 (m, 1H) , 1.28 –1.17 (m, 6H) .

Example 30

(3R, 4R) -4- ( ( (7- ( (Benzo [d] thiazol-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: N- (Benzo [d] thiazol-2-ylmethyl) -5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (60 mg, 0.26 mmol) in EtOH (2 mL) was added benzo [d] thiazol-2-ylmethanamine hydrochloride (104.7 mg, 0.52 mmol) , DIPEA (84 mg, 0.65 mmol) , the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: PE/EA = 5/1) to give the title product (70 mg, 75%yield) as a white solid. LCMS: (ES ⁺) : m/z = 358.1 [M+1] ⁺.

Step 2: Tert-butyl (benzo [d] thiazol-2-ylmethyl) (5-chloro-3isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) carbamate

To a solution of N- (benzo [d] thiazol-2-ylmethyl) -5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine (70 mg, 0.20 mmol) in THF (5 mL) was added Boc ₂O (86 mg, 0.40 mmol) and DMAP (23.8 mg, 0.20 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 8/1) to afford the title product (80 mg, 89.3%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 458.1 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (benzo [d] thiazol-2-ylmethyl) (tertbutoxy-carbonyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3- hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (benzo [d] thiazol-2-ylmethyl) (5-chloro-3-isopropyl-pyrazolo [1, 5-a] pyrimidin-7-yl) carbamate (80 mg, 0.17 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (48.0 mg, 0.20 mmol) , Pd ₂ (dba) ₃ (11.2 mg, 0.01mmol) , rac-BINAP (16.3 mg, 0.02 mmol) and Cs ₂CO ₃ (113 mg, 0.38 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: DCM/MeOH = 20/1) to give the title product (40 mg, 35.1%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 652.2 [M+1] ⁺.

To a solution of Tert-butyl (3R, 4R) -4- ( ( (7- ( (benzo [d] thiazol-2-ylmethyl) (tertbutoxy-carbonyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (40 mg, 0.06 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 25 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (8.9 mg, 99%HPLC purity) as a white solid. LCMS: (ES ⁺) : m/z = 451.2 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.00 –7.89 (m, 2H) , 7.71 (s, 1H) , 7.52 (t, J = 7.7 Hz, 1H) , 7.42 (t, J = 7.6 Hz, 1H) , 5.25 (s, 1H) , 4.97 (s, 2H) , 3.97 (d, J = 12.9 Hz, 1H) , 3.45 (dd, J = 12.8, 6.6 Hz, 1H) , 3.35 (d, J = 4.0 Hz, 1H) , 3.27 (s, 1H) , 3.15 (d, J = 14.0 Hz, 1H) , 3.04 (dt, J = 13.5, 6.7 Hz, 1H) , 2.92 (t, J = 10.8 Hz, 1H) , 2.76 (t, J = 11.3 Hz, 1H) , 1.88 (d, J = 13.1 Hz, 1H) , 1.62 (dd, J = 22.4, 11.3 Hz, 2H) , 1.29 (t, J = 7.5 Hz, 6H) .

Example 31

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (thiazol-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (thiazol-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (80 mg, 0.34 mmol) in EtOH (2 mL) was added thiazol-2-ylmethanamine (79 mg, 0.69 mmol) , the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE/EA = 2/1) to give the title product (80 mg, 74.7%yield) as a white solid. LCMS: (ES ⁺) : m/z = 308.1 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazol-2-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (thiazol-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (80 mg, 0.26 mmol) in THF (5 mL) was added Boc ₂O (112 mg, 0.52 mmol) and DMAP (31.0 mg, 0.26 mmol) . The mixture was stirred at 25 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 5/1) to afford the product (100 mg, 94.3%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 408.1 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazol-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine -1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazol-2-ylmethyl) carbamate (80 mg, 0.22 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (60.3 mg, 0.26 mmol) , Pd ₂ (dba) ₃ (14.2 mg, 0.01 mmol) , rac-BINAP (20.7 mg, 0.02 mmol) and Cs ₂CO ₃ (144 mg, 0.44 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE/EA = 1/1) to give the title product (50 mg, 37.6%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 602.4 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( (thiazol-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazol-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxy piperidine-1-carboxylate (50 mg, 0.08 mmol) in DCM (4 mL) was added TFA (4 mL) , the mixture was stirred at 25 ℃for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (23.9 mg, 99%HPLC purity) as a white solid. LCMS: (ES ⁺) : m/z = 402.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.77 (d, J = 3.2 Hz, 2H) , 7.57 (d, J = 3.1 Hz, 1H) , 5.38 (s, 1H) , 4.92 (s, 2H) , 3.80 (s, 1H) , 3.55 (s, 1H) , 3.44 –3.33 (m, 3H) , 3.06 (dt, J = 13.7, 6.7 Hz, 1H) , 2.97 (t, J = 11.2 Hz, 1H) , 2.79 (t, J = 11.3 Hz, 1H) , 1.98 (d, J = 12.9 Hz, 1H) , 1.76 (m, 1H) , 1.70 –1.54 (m, 1H) , 1.35 –1.22 (m, 6H) .

Example 35

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-indazol-3-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (1-methyl-1H-indazol-3-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (60 mg, 0.26 mmol) in EtOH (2 mL) was added (1-methyl-1H-indazol-3-yl) methanamine (84 mg, 0.52 mmol) , the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE/EA = 3/1) to give the title product (70 mg, 75.6%yield) as a white solid. LCMS: (ES ⁺) : m/z = 355.1 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-indazol-3-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-methyl-1H-indazol-3-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (70 mg, 0.20 mmol) in THF (5 mL) was added Boc ₂O (86.1 mg, 0.40 mmol) and DMAP (24.1 mg, 0.20 mmol) . The mixture was stirred at 25 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: PE/EA = 6/1) to afford the title product (80 mg, 89.1%yield) as a yellow solid. LCMS: (ES ⁺) : m/z = 455.2 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-indazol-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-indazol-3-yl) methyl) carbamate (80 mg, 0.17 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (50.3 mg, 0.20 mmol) , Pd ₂ (dba) ₃ (11.2 mg, 0.01 mmol) , rac-BINAP (16.3 mg, 0.02 mmol) and Cs ₂CO ₃ (113 mg, 0.34 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE/EA = 1/1) to give the title product (50 mg, 43.8%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 649.2 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-indazol-3-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-indazol-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (50 mg, 0.08 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (14.7 mg, 99%HPLC purity) as a white solid. LCMS: (ES ⁺) : m/z = 449.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.85 (d, J = 8.1 Hz, 1H) , 7.67 (s, 1H) , 7.51 (d, J = 8.4 Hz, 1H) , 7.41 (t, J = 7.7 Hz, 1H) , 7.13 (t, J = 7.4 Hz, 1H) , 5.39 (s, 1H) , 4.91 (s, 2H) , 4.05 (s, 3H) , 3.94 (d, J = 14.1 Hz, 1H) , 3.50 (m, 1H) , 3.36 (d, J = 7.0 Hz, 2H) , 3.20 (d, J = 14.5 Hz, 1H) , 3.00 (ddd, J = 27.1, 17.4, 9.4 Hz, 2H) , 2.78 (t, J = 11.4 Hz, 1H) , 1.93 (d, J = 11.2 Hz, 1H) , 1.66 (d, J = 20.1 Hz, 2H) , 1.27 (t, J = 7.2 Hz, 6H) .

Example 36

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (60 mg, 0.26 mmol) in EtOH (2 mL) was added (1-methyl-1H-benzo [d] imidazol-2-yl) methanamine (84 mg, 0.52 mmol) , the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: PE/EA = 3/1) to give the title product (60 mg, 64.8%yield) as white solid. LCMS: (ES ⁺) : m/z = 355.2 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (60 mg, 0.17 mmol) in THF (5 mL) was added Boc ₂O (74 mg, 0.34 mmol) and DMAP (20.7 mg, 0.17 mmol) . The mixture was stirred at 25 ℃for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA = 2/1) to afford the title product (60 mg, 78.0%yield) as yellow solid. LCMS: (ES ⁺) : m/z = 455.2 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) carbamate (60 mg, 0.13 mmol) in toluene (2 mL) was added tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (36 mg, 0.15 mmol) , Pd ₂ (dba) ₃ (8.4 mg, 0.01 mmol) , rac-BINAP (12.2 mg, 0.02 mmol) and Cs ₂CO ₃ (85.2 mg, 0.26 mmol) . The mixture was stirred at 95 ℃ for 16 h under N ₂. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE/EA = 1/1) to give the title product (30 mg, 35.0%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 649.5 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (1-methyl-1H-benzo [d] imidazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (30 mg, 0.046 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the product (17.2 mg, 99%HPLC purity) as a white solid. LCMS: (ES ⁺) : m/z = 449.3 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.68 (s, 1H) , 7.63 (d, J = 7.8 Hz, 1H) , 7.51 (d, J = 7.7 Hz, 1H) , 7.29 (dt, J = 15.0, 7.3 Hz, 2H) , 5.39 (s, 1H) , 4.87 (s, 2H) , 4.02 –3.86 (m, 4H) , 3.46 (s, 1H) , 3.40 -3.32 (m, 2H) , 3.18 (d, J = 14.8 Hz, 1H) , 3.02 (dt, J = 13.5, 6.6 Hz, 1H) , 2.93 (t, J = 12.1 Hz, 1H) , 2.74 (t, J = 11.3 Hz, 1H) , 1.91 (d, J =11.3 Hz, 1H) , 1.63 (m, 2H) , 1.27 (t, J = 7.0 Hz, 6H) .

Example 37

2- ( ( (5- ( ( ( (3R, 4R) -3-Hydroxypiperidin-4-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) benzo [d] thiazole-5-carbonitrile

Step 1: 2- ( ( (5-Chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) benzo [d] thiazole-5-carbonitrile

To a solution of 2- (aminomethyl) benzo [d] thiazole-5-carbonitrile (70 mg, 0.30 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (60.5 mg, 0.31 mmol) in EtOH (2 mL) was added TEA (153.9 mg, 1.5 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was used in the next step without further purification. LCMS: (ES ⁺) : m/z = 383.3 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5-cyanobenzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 2- ( ( (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) benzo [d] thiazole-5-carbonitrile (110 mg, 0.28 mmol) in THF (5.5 mL) was added Boc ₂O (313.5 mg, 1.4 mmol) and DMAP (70.2 mg, 0.57 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was concentrated under reduced pressure 45 ℃. The residue was purified by prep-TLC to give the title product (43 mg, 33.1%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 483.5 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5-cyanobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3- hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5-cyanobenzo [d] thiazol-2-yl) methyl) carbamate (43 mg, 0.089 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (24.6 mg, 0.10 mmol) in toluene (2.5 mL) was added Cs ₂CO ₃ (58 mg, 0.17 mmol) , BINAP (6 mg, 0.0089 mmol) and Pd ₂ (dba) ₃ (10 mg, 0.0089 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (20 mg, 33.2%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 677.8 [M+1] ⁺.

Step 4: 2- ( ( (5- ( ( ( (3R, 4R) -3-Hydroxypiperidin-4-yl) methyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) benzo [d] thiazole-5-carbonitrile

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5-cyanobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (20 mg, 0.030 mmol) in DCM (2 mL) was added TFA (0.4 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (6 mg, 91.9 %HPLC purity) as a white solid. Chemical Formula: C ₂₁H ₂₉N ₇O ₂; Molecular Weight: 476.6. LCMS: (ES+) : m/z = 477.6 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.56 (d, J = 1.5 Hz, 1H) , 8.32 (d, J = 3.2 Hz, 1H) , 8.30 (s, 1H) , 8.29 (s, 1H) , 7.86 (dd, J = 8.3, 1.6 Hz, 1H) , 7.73 (s, 1H) , 6.86 (s, 1H) , 5.27 (s, 1H) , 4.96 (d, J = 6.1 Hz, 2H) , 3.32 (d, J = 4.5 Hz, 2H) , 3.28 –3.19 (m, 2H) , 3.08 (d, J = 10.1 Hz, 2H) , 2.98 (q, J = 6.1, 5.5 Hz, 2H) , 2.41 (t, J = 10.7 Hz, 1H) , 1.70 (d, J = 13.2 Hz, 1H) , 1.49 (s, 1H) , 1.29 (d, J = 4.2 Hz, 3H) , 1.27 (d, J = 4.0 Hz, 3H) .

Example 38

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methanamine hydrochloride (60 mg, 0.26 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (75.6 mg, 0.27 mmol) in EtOH (1.5 mL) was added TEA (158.3 mg, 1.56 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. Then the reaction mixture was concentrated under reduced pressure. The residue was used for next step without further purification. LCMS: (ES ⁺) : m/z = 426.4 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) pyrazolo [1, 5-a] pyrimidin-7-amine (110 mg, 0.25 mmol) in THF (5.5 mL) was added Boc ₂O (281.9 mg, 1.3 mmol) and DMAP (63.1 mg, 0.51 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC to give the title product (60 mg, 44.2%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 526.6 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) carbamate (60 mg, 0.11 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (31.5 mg, 0.13 mmol) in toluene (3 mL) was added Cs ₂CO ₃ (74.3 mg, 0.22 mmol) , BINAP (7 mg, 0.011 mmol) and Pd ₂ (dba) ₃ (11 mg, 0.011 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC to give the title product (35 mg, 42.6%yield) as yellow oil. LCMS: (ES ⁺) : m/z 720.3 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (35 mg, 0.065 mmol) in DCM (3 mL) was added TFA (0.6 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (6 mg, 90.7 %HPLC purity) as a white solid. Chemical Formula: C ₂₁H ₂₉N ₇O ₂; Molecular Weight: 519.59. LCMS: (ES+) : m/z = 520.7 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.33 (s, 1H) , 8.31 (s, 1H) , 8.18 (d, J = 6.0 Hz, 1H) , 7.77 (dd, J = 8.4, 1.8 Hz, 1H) , 7.70 (s, 1H) , 6.75 (t, J = 6.1 Hz, 1H) , 5.29 (s, 1H) , 4.96 (d, J = 5.4 Hz, 2H) , 3.09 (dd, J = 11.9, 4.1 Hz, 2H) , 2.99 (dt, J = 11.6, 5.9 Hz, 2H) , 2.58 (t, J = 7.1 Hz, 2H) , 2.43 (t, J = 10.9 Hz, 2H) , 1.77 -1.67 (m, 1H) , 1.51 (s, 1H) , 1.31 (s, 1H) , 1.27 (dd, J = 6.9, 3.5 Hz, 6H) .

Example 39

(3R, 4R) -4- ( ( (7- ( ( (5-Chlorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-N- ( (5-chlorobenzo [d] thiazol-2-yl) methyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (5-chlorobenzo [d] thiazol-2-yl) methanamine (70 mg, 0.30 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (75.1 mg, 0.31 mmol) in EtOH (2 mL) was added TEA (184.7 mg, 1.8 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃ to give the crude title product, which was used in next step without further purification. LCMS: (ES ⁺) : m/z =392.4 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5-chlorobenzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 5-chloro-N- ( (5-chlorobenzo [d] thiazol-2-yl) methyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine (120 mg, 0.30 mmol) in THF (6.5 mL) was added Boc ₂O (333.8 mg, 1.5 mmol) and DMAP (74.7 mg, 0.61 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC to give the title product (50 mg, 33.2%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 492.5 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5-chlorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5-chlorobenzo [d] thiazol-2-yl) methyl) carbamate (50 mg, 0.10 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (28.1 mg, 0.12 mmol) in toluene (2.5 mL) was added Cs ₂CO ₃ (66.2 mg, 0.20 mmol) , BINAP (6 mg, 0.010 mmol) and Pd ₂ (dba) ₃ (10 mg, 0.010 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (50 mg, 71.8%yield) as yellow oil. LCMS: (ES ⁺) : m/z = 686.9 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (7- ( ( (5-Chlorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5-chlorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (50 mg, 0.073 mmol) in DCM (5 mL) was added TFA (1 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (5 mg, 96.1%HPLC purity) as a white solid. Chemical Formula: C ₂₁H ₂₉N ₇O ₂; Molecular Weight: 486.04. LCMS: (ES ⁺) : m/z = 486.5 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.21 (s, 1H) , 8.16 (s, 1H) , 8.12 -8.03 (m, 2H) , 7.70 (s, 1H) , 7.49 (dd, J = 8.6, 2.1 Hz, 1H) , 6.80 (t, J = 6.1 Hz, 1H) , 5.27 (s, 1H) , 4.91 (d, J = 5.9 Hz, 2H) , 3.53 -3.49 (m, 2H) , 3.39 –3.29 (m, 3H) , 3.15 (dd, J = 11.9, 4.2 Hz, 1H) , 3.11 -3.04 (m, 1H) , 2.99 (p, J = 6.9 Hz, 1H) , 2.67 (d, J = 3.2 Hz, 1H) , 1.77 (dd, J = 14.4, 3.7 Hz, 1H) , 1.56 (s, 1H) , 1.44 -1.32 (m, 1H) , 1.27 (dd, J = 6.9, 3.4 Hz, 6H) .

Example 42

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (thiazolo [4, 5-c] pyridin-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (thiazolo [4, 5-c] pyridin-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of thiazolo [4, 5-c] pyridin-2-ylmethanamine hydrochloride (159 mg, 0.74 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (150 mg, 0.65 mmol) in DMSO (2 mL) was added TEA (132 mg, 1.3 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃ to offer the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₆H ₁₅ClN ₆S; Molecular Weight: 358.08. LCMS: (ES ⁺) : m/z 359.3 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazolo [4, 5-c] pyridin-2-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (thiazolo [4, 5-c] pyridin-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (163 mg, 0.45 mmol) in THF (10 mL) was added Boc ₂O (500 mg, 2.3 mmol) and DMAP (126 mg, 0.91 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC (EtOAc/PE = 1/5) to give the title product (125 mg, 60%yield) as yellow oil. Chemical Formula: C ₂₁H ₂₃ClN ₆O ₂S; Molecular Weight: 458.97. LCMS: (ES ⁺) : m/z 459.4 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazolo [4, 5-c] pyridin-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazolo [4, 5-c] pyridin-2-ylmethyl) carbamate (125 mg, 0.27 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (86 mg, 0.32 mmol) in toluene (5 mL) was added Cs ₂CO ₃ (200 mg, 0.54 mmol) , BINAP (20 mg, 0.027 mmol) and Pd ₂ (dba) ₃ (30 mg, 0.027 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc/PE = 1/1) to give the title product (90 mg, 51%yield) as yellow oil. Chemical Formula: C ₃₂H ₄₄N ₈O ₅S; Molecular Weight: 652.82. LCMS: (ES ⁺) : m/z 653.9 [M+1] ⁺.

Step 4: (3R, 4S) -4- ( ( (3-Isopropyl-7- ( (thiazolo [4, 5-c] pyridin-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazolo [4, 5-c] pyridin-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (90 mg, 0.14 mmol) in DCM (10 mL) was added TFA (4 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (34 mg, 54.5 %yield) as a white solid. LCMS: (ES ⁺) : m/z 453.5 [M+1] ⁺.

Example 44

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (thiazolo [5, 4-b] pyridin-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (thiazolo [5, 4-b] pyridin-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of thiazolo [5, 4-b] pyridin-2-ylmethanamine hydrochloride (159 mg, 0.74 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (150 mg, 0.65 mol) in DMSO (2 mL) was added TEA (132 mg, 1.3 mol) at 25 C. The reaction mixture was stirred at 70 C for 3 h. Then the mixture was concentrated under reduced pressure to offer the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₆H ₁₅ClN ₆S. Molecular Weight: 358.08. LCMS: (ES ⁺) : m/z 359.3 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazolo [5, 4-b] pyridin-2-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (thiazolo [5, 4-b] pyridin-2-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (155 mg, 0.43 mmol) in THF (10 mL) was added Boc ₂O (465 mg, 2.2 mmol) and DMAP (122 mg, 0.87 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC (EtOAc/PE = 1/5) to give the title product (109 mg, 55%yield) as yellow oil. Chemical Formula: C ₂₁H ₂₃ClN ₆O ₂S; Molecular Weight: 458.97. LCMS: (ES ⁺) : m/z 459.4 [M+1] ⁺.

Step 3: Tert-butyl tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazolo [5, 4-b] pyridin-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazolo [5, 4-b] pyridin-2-ylmethyl) carbamate (109 mg, 0.24 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (80 mg, 0.24 mmol) in toluene (5 mL) was added Cs ₂CO ₃ (170 mg, 0.47 mmol) , BINAP (17 mg, 0.024 mmol) and Pd ₂ (dba) ₃ (25 mg, 0.024 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted by EtOAc (5 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (EtOAc/PE = 1/1) to give the title product (100 mg, 65%yield) as yellow oil. Chemical Formula: C ₃₂H ₄₄N ₈O ₅S; Molecular Weight: 652.82. LCMS: (ES ⁺) : m/z 653.9 [M+1] ⁺.

Step 4: (3R, 4S) -4- ( ( (3-Isopropyl-7- ( (thiazolo [5, 4-b] pyridin-2-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazolo [5, 4-b] pyridin-2-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (100 mg, 0.15 mmol) in DCM (10 mL) was added TFA (4 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (36 mg, 52%yield) as a white solid. LCMS: (ES ⁺) : m/z 453.5 [M+1] ⁺.

Example 46

(3R, 4R) -4- ( ( (7- ( ( (4-Cyclopropylthiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5- a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 4-Cyclopropylthiazole-2-carboxamide

A solution of ethyl 4-cyclopropylthiazole-2-carboxylate (200 mg, 1.0 mmol) in NH ₃·MeOH (7 M, 3 mL, 20.2 mmol) was stirred at 95 ℃ for 16 h. The reaction was concentrated under reduced pressure to give the title product (140 mg, 82.1%yield) as a yellow solid. Chemical Formula: C ₇H ₈N ₂OS. Molecular Weight: 168.21. LCMS: (ES ⁺) : m/z 169.2 [M+1] ⁺.

Step 2: (4-Cyclopropylthiazol-2-yl) methanamine

A solution of 4-cyclopropylthiazole-2-carboxamide (130 mg, 0.77 mmol) in BH ₃-THF (1 M, 12 mL, 12 mmol) was stirred at 70 ℃ for 6 h. Then aq. HCl (2 M) was added to the reaction mixture, and stirred at 75 ℃ for 1 h. The mixture was adjusted pH = 10 by aq. NaOH (8 M) , and extracted with EtOAc (8 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the title product (31 mg, 26%yield) as a yellow oil. Chemical Formula: C ₇H ₁₀N ₂S; Molecular Weight: 154.23. LCMS: (ES ⁺) : m/z 155.2 [M+1] ⁺.

Step 3: 5-Chloro-N- ( (4-cyclopropylthiazol-2-yl) methyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (4-cyclopropylthiazol-2-yl) methanamine (31 mg, 0.21 mmol) and 5, 7-dichloro- 3-isopropylpyrazolo [1, 5-a] pyrimidine (45 mg, 0.20 mmol) in EtOH (1 mL) was added TEA (40 mg, 0.39 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude title product, which was used for next step without further purification. Chemical Formula: C ₁₆H ₁₈ClN ₅S. Molecular Weight: 347.87. LCMS: (ES ⁺) : m/z 348.4 [M+1] ⁺.

Step 4: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (4-cyclopropylthiazol-2-yl) methyl) carbamate

To a suspension of 5-chloro-N- ( (4-cyclopropylthiazol-2-yl) methyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine (60 mg, crude) in THF (3 mL) was added DMAP (42.1 mg, 0.34 mmol) and Boc ₂O (188.2 mg, 0.86 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted with EtOAc (5 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 10/1) to give the title product (10 mg, 12.9%yield) as yellow oil. Chemical Formula: C ₂₁H ₂₆ClN ₅O ₂S. Molecular Weight: 447.98. LCMS: (ES ⁺) : m/z 448.5 [M+1] ⁺.

Step 5: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (4-cyclopropylthiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a suspension of 5-chloro-N- ( (4-cyclopropylthiazol-2-yl) methyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine (10 mg, 0.022 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (6.2 mg, 0.027 mmol) in toluene (0.5 mL) was added Cs ₂CO ₃ (15 mg, 0.045 mmol) , Pd ₂ (dba) ₃ (2 mg, 0.0022 mmol) and BINAP (1 mg, 0.002 mmol) under N ₂ at 25 ℃. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was diluted with H ₂O (5 mL) and extracted with EtOAc (5 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 2/1) to afford the title product (10 mg, 69.8 %yield) as yellow oil. Chemical Formula: C ₃₂H ₄₇N ₇O ₅S. Molecular Weight: 641.83. LCMS: (ES ⁺) : m/z 642.8 [M+1] ⁺.

Step 6: (3R, 4R) -4- ( ( (7- ( ( (4-Cyclopropylthiazol-2-yl) methyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (4-cyclopropyl thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (10 mg, 0.016 mmol) in DCM (1 mL) was added TFA (75.6 mg, 0.78 mmol) . The reaction mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (5 mg, 92 %HPLC purity) as a white solid. Chemical Formula: C ₂₂H ₃₁N ₇OS. Molecular Weight: 441.6. LCMS: (ES+) : m/z 442.5 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.56 (s, 1H) , 8.30 (s, 1H) , 7.64 (s, 1H) , 7.04 (s, 1H) , 5.20 (s, 1H) , 4.58 (s, 2H) , 3.35 –3.20 (m, 2H) , 3.10 (t, J = 13.6 Hz, 2H) , 3.02 –2.94 (m, 1H) , 2.89 –2.75 (m, 1H) , 2.68 (d, J = 11.8 Hz, 1H) , 2.55 –2.49 (m, 2H) , 1.99 –1.84 (m, 1H) , 1.73 (d, J = 13.9 Hz, 1H) , 1.54 (s, 1H) , 1.30 (d, J =13.3 Hz, 1H) , 1.12 (dd, J = 6.9, 3.2 Hz, 6H) , 0.85 –0.61 (m, 4H) .

Example 48

(3R, 4R) -4- ( ( (7- ( ( (S) -1- (4-Cyclopropylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (S, E) -N- (1- (4-cyclopropylthiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide

To a solution of 1- (4-cyclopropylthiazol-2-yl) ethan-1-one (650 mg, 3.89 mmol) and (S) -2-methylpropane-2-sulfinamide (942.2 mg, 7.7 mmol) in THF (13 mL) was added Ti (OiPr) ₄ (5.5 g, 19.4 mmol) at 25 ℃. The mixture was stirred at 70 ℃ for 16 h. The reaction was cooled to 25 ℃ and quenched with ice water. The precipitate was dissolved in EtOAc (10 mL) and filtered through celite. The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (900 mg, 85.6%yield) as yellow oil. Chemical Formula: C ₁₂H ₁₈N ₂OS ₂; Molecular Weight: 270.41. LCMS: (ES ⁺) : m/z 271.3 [M+1] ⁺.

Step 2: (S) -N- ( (S) -1- (4-cyclopropylthiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide

To a solution of (S, E) -N- (1- (4-cyclopropylthiazol-2-yl) ethylidene) -2-methyl propane-2-sulfinamide (900 mg, 3.3 mmol) in THF (10 mL) at 25 ℃. The reaction mixture was cooled to -78 ℃. To the mixture was added LiAlH (O ^tBu) ₃ (1 M, 5 mL, 4.9 mmol) dropwise at -78 ℃. And the resulting mixture was stirred at 0 ℃ for 1 h. The reaction mixture was quenched by water (5 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (800 mg, 88.2%yield) as yellow oil. Chemical Formula: C ₁₂H ₂₀N ₂OS ₂. Molecular Weight: 272.43. LCMS: (ES ⁺) : m/z 273.2 [M+1] ⁺.

Step 3: (S) -1- (4-Cyclopropylthiazol-2-yl) ethan-1-amine hydrochloride

To a solution of (S) -N- ( (S) -1- (4-cyclopropylthiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide (800 mg, 2.9 mmol) in EtOAc (20 mL) was added HCl/1, 4-dioxanc (4 M, 11 mL, 44.0 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the title product (525 mg, 87.3%yield) as yellow oil. Chemical Formula: C ₈H ₁₂N ₂S. Molecular Weight: 168.26. LCMS: (ES ⁺) : m/z 169.2 [M+1] ⁺.

Step 4: (S) -5-Chloro-N- (1- (4-cyclopropylthiazol-2-yl) ethyl) -3-isopropylpyrazolo [1, 5- a] pyrimidin-7-amine

To a solution of (S) -1- (4-cyclopropylthiazol-2-yl) ethan-1-amine hydrochloride (525 mg, 2.56 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (560 mg, 2.43 mmol) in EtOH (16 mL) was added TEA (1.4 g, 14.6 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃for 2 h. The reaction mixture was concentrated under reduced pressure to give crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₇H ₂₀ClN ₆S; Molecular Weight: 361.89. LCMS: (ES ⁺) : m/z 362.3 [M+1] ⁺.

Step 5: Tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-cyclopropylthiazol-2-yl) ethyl) carbamate

To a suspension of (S) -5-chloro-N- (1- (4-cyclopropylthiazol-2-yl) ethyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine (880 mg, crude) in THF (45 mL) was added DMAP (891 mg, 7.3 mmol) and Boc ₂O (2.65 g, 12.1 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (600 mg, 53.4%yield) as yellow oil. Chemical Formula: C ₂₂H ₂₈ClN ₅O ₂S; Molecular Weight: 462.01. LCMS: (ES ⁺) : m/z 462.5 [M+1] ⁺.

Step 6: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-cyclopro pylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a suspension of tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-cyclopropylthiazol-2-yl) ethyl) carbamate (50 mg, 0.11 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (30 mg, 0.13 mmol) in Toluene (0.5 mL) was added Cs ₂CO ₃ (70.5 mg, 0.22 mmol) , Pd ₂ (dba) ₃ (10 mg, 0.011 mmol) and BINAP (7 mg, 0.011 mmol) under N ₂ at 25 ℃. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was diluted with H ₂O (5 mL) and extracted with EtOAc (8 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the crude title product, which was used in the next step without further purification. Chemical Formula: C ₃₃H ₄₉N ₇O ₅S. Molecular Weight: 655.86. LCMS: (ES ⁺) : m/z 656.8 [M+1] ⁺.

Step 7: (3R, 4R) -4- ( ( (7- ( ( (S) -1- (4-Cyclopropylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-cyclopropylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (71 mg, crude, 0.11 mmol) in DCM (10 mL) was added TFA (2.1 g, 21.6 mmol) . The reaction mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (12.9 mg, 91.2 %HPLC purity) as a white solid. Chemical Formula: C ₂₃H ₃₃N ₇OS. Molecular Weight: 455.63. LCMS: (ES+) : m/z 456.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 7.72 –7.58 (m, 2H) , 7.12 (s, 1H) , 6.91 (s, 1H) , 5.24 (s, 1H) , 4.91 (t, J = 6.9 Hz, 1H) , 3.49 (s, 1H) , 3.36 -3.25 (m, 3H) , 3.22 –3.05 (m, 3H) , 3.01 -2.91 (m, 1H) , 2.75 –2.64 (m, 1H) , 2.09 –2.00 (m, 1H) , 1.78 (d, J = 13.8 Hz, 1H) , 1.66 (d, J = 6.8 Hz, 3H) , 1.58 (s, 1H) , 1.40 (t, J = 12.1 Hz, 1H) , 1.24 (dd, J = 6.9, 4.8 Hz, 6H) , 0.93 –0.86 (m, 2H) , 0.85 –0.76 (m, 2H) .

Example 49

(3R, 4R) -4- ( ( (7- ( ( (R) -1- (4-Cyclopropylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: Ethyl 4-cyclopropylthiazole-2-carboxylate

A solution of 2-bromo-1-cyclopropylethan-1-one (8.0 g, 49.1 mmol) and ethyl 2-amino-2-thioxoacetate (7.8 g, 58.9 mmol) in MeOH (70 mL) was stirred at 65 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (7.0 g, 72.3%yield) as a colorless oil. Chemical Formula: C ₉H ₁₁NO ₂S. Molecular Weight: 197.25, LCMS: (ES ⁺) : m/z 198.2 [M+1] ⁺.

Step 2: 4-Cyclopropylthiazole

To a solution of ethyl 4-cyclopropylthiazole-2-carboxylate (7.0 g, 35.5 mmol) in MeOH (60 mL) was added aq. NaOH (2 M, 35.5 mL, 71 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (50 mL) and extracted with EtOAc (10 mL x 3) . The aqueous layer was adjusted to pH = 4 ～ 5 by aq. HCl (1 M) and extracted with EtOAc (30 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the title product (3.3 g, 74.3%yield) as a white solid. Chemical Formula: C ₆H ₇NS; Molecular Weight: 125.19. LCMS: (ES ⁺) : m/z = 126.3 [M+1] ⁺.

Step 3: 1- (4-Cyclopropylthiazol-2-yl) ethan-1-one

To a solution of 4-cyclopropylthiazole (3.3 g, 26.4 mmol) in THF (150 mL) was added n-BuLi (2.5 M in hexane, 14.8 mL, 36.9 mmol) at -78 ℃, and the mixture was stirred at -78 ℃ for 15 min. Then N-methoxy-N-methylacetamide (5.4 g, 52.7 mmol) was added to the reaction mixture. The mixture was warmed to 0 ℃ and stirred for 1 h. The reaction was diluted with H ₂O (20 mL) and extracted by EtOAc (20 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (1.4 g, 30.6%yield) as colorless oil. Chemical Formula: C ₈H ₉NOS; Molecular Weight: 167.23. LCMS: (ES ⁺) : m/z =168.2 [M+H] ⁺.

Step 4: (R, E) -N- (1- (4-cyclopropylthiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide

To a solution of 1- (4-cyclopropylthiazol-2-yl) ethan-1-one (650 mg, 3.89 mmol) and (R) -2-methylpropane-2-sulfinamide (942.2 mg, 7.7 mmol) in THF (13 mL) was added Ti (OiPr) ₄ (5.52 g, 19.4 mmol) at 25 ℃. The mixture was stirred at 70 ℃ for 16 h. The reaction was cooled to 25 ℃ and quenched by ice water. The precipitate was dissolved in EtOAc (10 mL) and filtered through celite. The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (900 mg, 85.6%yield) as yellow oil. Chemical Formula: C ₁₂H ₁₈N ₂OS ₂; Molecular Weight: 270.41. LCMS: (ES ⁺) : m/z = 271.2 [M+1] ⁺.

Step 5: (R) -N- ( (R) -1- (4-cyclopropylthiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide

To a solution of (R, E) -N- (1- (4-cyclopropylthiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide (900 mg, 3.33 mmol) in THF (10 mL) at 25 ℃. The reaction mixture was cooled to -78 ℃. The mixture was dropwise added LiAlH (O ^tBu) ₃ (1 M, 5 mL, 4.99 mmol) at -78 ℃and stirred at 0 ℃ for 1 h. The reaction mixture was quenched by water (5 mL) and extracted with EtOAc (10 mL x 2) . The organic was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (800 mg, 88.2%yield) as yellow oil. Chemical Formula: C ₁₂H ₂₀N ₂OS ₂. Molecular Weight: 272.43. LCMS: (ES ⁺) : m/z = 273.3 [M+1] ⁺.

Step 6: (R) -1- (4-Cyclopropylthiazol-2-yl) ethan-1-amine hydrochloride

To a solution of (R) -N- ( (R) -1- (4-cyclopropylthiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide (800 mg, 2.94 mmol) in EtOAc (20 mL) was added HCl/dioxanc (4 M, 11 mL, 44.0 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the title product (420 mg, 69.9%yield) as yellow oil. Chemical Formula: C ₈H ₁₂N ₂S. Molecular Weight: 168.26. LCMS: (ES ⁺) : m/z =169.2 [M+1] ⁺.

Step 7: (R) -5-Chloro-N- (1- (4-cyclopropylthiazol-2-yl) ethyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (R) -1- (4-cyclopropylthiazol-2-yl) ethan-1-amine hydrochloride (420 mg, 2.1 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (450 mg, 1.9 mmol) in EtOH (13.5 mL) was added TEA (1.2 g, 11.7 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the title crude product, which was used for next step without further purification. Chemical Formula: C ₁₇H ₂₀ClN ₆S. Molecular Weight: 361.89. LCMS: (ES ⁺) : m/z = 362.3 [M+1] ⁺.

Step 8: Tert-butyl tert-butyl tert-butyl (R) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-cyclopropylthiazol-2-yl) ethyl) carbamate

To a suspension of (R) -5-chloro-N- (1- (4-cyclopropylthiazol-2-yl) ethyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine (700 mg, crude, 1.9 mmol) in THF (35 mL) was added DMAP (709 mg, 5.8 mmol) and Boc ₂O (3.4 g, 15.5 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted with EtOAc (5 mL x 3) . The organic was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel to give the title product (550 mg, 61.5%yield) as yellow oil. Chemical Formula: C ₂₂H ₂₈ClN ₅O ₂S. Molecular Weight: 462.01. LCMS: (ES ⁺) : m/z = 462.5 [M+1] ⁺.

Step 9: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (R) -1- (4-cyclopropyl thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a suspension of tert-butyl tert-butyl tert-butyl (R) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-cyclopropylthiazol-2-yl) ethyl) carbamate (50 mg, 0.11 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (30 mg, 0.13 mmol) in toluene (0.5 mL) was added Cs ₂CO ₃ (70.5 mg, 0.22 mmol) , Pd ₂ (dba) ₃ (10 mg, 0.011 mmol) and BINAP (7 mg, 0.011 mmol) under N ₂ at 25 ℃. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was diluted with H ₂O (5 mL) and extracted with EtOAc (5 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the title crude product, which was used in the next step without further purification. Chemical Formula: C ₃₃H ₄₉N ₇O ₅S; Molecular Weight: 655.86. LCMS: (ES ⁺) : m/z = 656.8 [M+1] ⁺.

Step 10: (3R, 4R) -4- ( ( (7- ( ( (R) -1- (4-Cyclopropylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (R) -1- (4-cyclopropylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (90 mg, crude, 0.14 mmol) in DCM (10 mL) was added TFA (2.7 g, 27.4 mmol) . The reaction mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (19.8 mg, 99.9%HPLC purity) as a white solid. Chemical Formula: C ₂₃H ₃₃N ₇OS. Molecular Weight: 455.63. LCMS: (ES ⁺) : m/z = 456.3 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 7.65 (d, J = 13.1 Hz, 2H) , 7.12 (s, 1H) , 6.89 (t, J = 6.1 Hz, 1H) , 5.23 (s, 1H) , 4.90 (t, J =7.1 Hz, 1H) , 3.32 (s, 1H) , 3.19 –3.06 (m, 4H) , 2.97 –2.91 (m, 2H) , 2.68 (t, J = 12.0 Hz, 1H) , 2.09 –2.02 (m, 1H) , 1.77 (d, J = 13.9 Hz, 1H) , 1.66 (d, J = 6.8 Hz, 3H) , 1.56 (s, 1H) , 1.37 (q, J = 11.7 Hz, 1H) , 1.24 (dd, J = 6.9, 3.7 Hz, 6H) , 0.93 -0.89 (m, 2H) , 0.84 –0.75 (m, 2H) .

Example 51

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (thiazol-5-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (thiazol-5-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of thiazol-5-ylmethanamine hydrochloride (0.64 g, 2.8 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (0.5 g, 3.3 mmol) in EtOH (14 mL) was added TEA (1.3 g, 11.3 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃ to offer the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₃H ₁₄ClN ₅S; Molecular Weight: 307.8. LCMS: (ES ⁺) : m/z = 308.4 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazol-5-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (thiazol-5-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (0.65 g, 2.4 mmol) in THF (45 mL) was added Boc ₂O (2.7 g, 12.2 mmol) and DMAP (0.59 g, 4.8 mmol) . The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC (EtOAc/PE = 1/5) to give the title product (780 mg, 78%yield) as yellow oil. Chemical Formula: C ₁₈H ₂₂ClN ₅O ₂S; Molecular Weight: 407.92. LCMS: (ES ⁺) : m/z = 408.5 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazol-5-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazol-5-ylmethyl) carbamate (100 mg, 0.24 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (68 mg, 0.29 mmol) in toluene (3 mL) was added Cs ₂CO ₃ (160 mg, 0.49 mmol) , BINAP (15 mg, 0.024 mmol) and Pd ₂ (dba) ₃ (22 mg, 0.024 mmol) under N ₂.The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted by EtOAc (5 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (EtOAc/PE = 1/1) to give the title product (90 mg, 61%yield) as yellow oil. Chemical Formula: C ₂₉H ₄₃N ₇O ₅S; Molecular Weight: 601.77. LCMS: (ES+) : m/z = 602.8 [M+1] ⁺.

Step 4: (3R, 4S) -4- ( ( (3-Isopropyl-7- ( (thiazol-5-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazol-5-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxy piperidine-1-carboxylate (90 mg, 0.15 mmol) in DCM (10 mL) was added TFA (6 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (37 mg, 61.5%yield) as a white solid. LCMS: (ES ⁺) : m/z = 402.5 [M+1] ⁺.

Example 52

(3R, 4S) -4- ( ( (3-Isopropyl-7- ( (thiazol-4-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5- yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (thiazol-4-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of thiazol-4-ylmethanamine hydrochloride (128 mg, 0.6 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (100 mg, 0.67 mmol) in EtOH (11 mL) was added TEA (378 mg, 2.6 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃ to give the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₃H ₁₄ClN ₅S; Molecular Weight: 307.8. LCMS: (ES ⁺) : m/z = 308.4 [M+1] ⁺.

Step 2: Tert-butyl tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazol-4-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (thiazol-4-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (140 mg, 0.46 mmol) in THF (8 mL) was added Boc ₂O (540 mg, 2.4 mmol) and DMAP (120 mg, 0.96 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC (EtOAc/PE = 1/5) to give the title product (160 mg, 85%yield) as yellow oil. Chemical Formula: C ₁₈H ₂₂ClN ₅O ₂S; Molecular Weight: 407.92. LCMS: (ES ⁺) : m/z = 408.5 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4S) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazol-4-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (thiazol-4-ylmethyl) carbamate (80 mg, 0.19 mmol) and compound (54 mg, 0.23 mmol) in toluene (3 mL) was added Cs ₂CO ₃ (128 mg, 0.39 mmol) , BINAP (12 mg, 0.019 mmol) and Pd ₂ (dba) ₃ (22 mg, 0.024 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted by EtOAc (5 mL x 3) . The organic was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (EtOAc/PE =1:1) to give the title product (80 mg, 68%yield) as yellow oil. Chemical Formula: C ₂₉H ₄₃N ₇O ₅S; Molecular Weight: 601.77. LCMS: (ES ⁺) : m/z = 602.8 [M+1] ⁺.

Step 4: (3R, 4S) -4- ( ( (3-Isopropyl-7- ( (thiazol-4-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (thiazol-4-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxy piperidine-1-carboxylate (80 mg, 0.13 mmol) in DCM (10 mL) was added TFA (6 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (28 mg, 53%yield) as a white solid. LCMS: (ES ⁺) : m/z = 402.5 [M+1] ⁺.

Example 54

(S) -2- (1- (3-Isopropyl-7- ( (pyridin-3-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) piperidin-2-yl) ethan-1-ol

To a solution of 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (200 mg, 0.87 mmol) in EtOH (5 mL) was added pyridin-3-ylmethanamine (141 mg, 1.31 mmol) , and the mixture was stirred at 70 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 3/1) to give the title product (232 mg, 88.5%yield) as a yellow solid. LCMS: (ES ⁺) m/z = 302.40 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (pyridine -3-ylmethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (pyridin-3-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (115 mg, 0.38 mmol) in DCM (5 mL) was added Boc ₂O (167 mg, 0.77 mmol) and DMAP (9 mg, 0.08 mmol) . The mixture was stirred at 25 ℃ for 4 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title product (107 mg, 70%yield) as a yellow solid. LCMS: (ES ⁺) m/z = 402.50 [M+1] ⁺.

Step 3: Tert-butyl (S) - (5- (2- (2-hydroxyethyl) piperidin-1-yl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (pyridin-3-ylmethyl) carbamate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (pyridine-3-ylmethyl) carbamate (107 mg, 0.27 mmol) in toluene (10 mL) was added (S) -2- (piperidin-2-yl) ethan-1-ol (41.3 mg, 0.32 mmol) , Pd ₂ (dba) ₃ (12.2 mg, 0.013 mmol) , race-BINAP (24.8 mg, 0.04 mmol) and Cs ₂CO ₃ (182 mg, 0.56 mmol) under N ₂. The mixture was stirred at 95 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA = 0/1) to give the title product (45 mg, 37.1%yield) as yellow oil. LCMS: (ES ⁺) m/z = 495.70 [M+1] ⁺.

Step 4: (S) -2- (1- (3-Isopropyl-7- ( (pyridin-3-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) piperidin-2-yl) ethan-1-ol

To a solution of tert-butyl (S) - (5- (2- (2-hydroxyethyl) piperidin-1-yl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (pyridin-3-ylmethyl) carbamate (45 mg, 0.09 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 30 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (7.1 mg, 97%HPLC purity) as a white solid. LCMS: (ES ⁺) m/z = 395.60 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.65 (d, J = 2.2 Hz, 1H) , 8.48 (dd, J = 4.7, 1.6 Hz, 1H) , 8.40 (t, J = 6.6 Hz, 1H) , 7.83 -7.77 (m, 1H) , 7.38 (dd, J = 7.9, 4.7 Hz, 1H) , 5.47 (s, 1H) , 4.60 (d, J = 6.5 Hz, 2H) , 4.35 (q, J = 6.3 Hz, 2H) , 3.12 -2.99 (m, 3H) , 1.91 -1.68 (m, 5H) , 1.59 (s, 1H) , 1.38 (q, J =10.9, 10.1 Hz, 2H) , 1.30 (d, J = 6.9 Hz, 6H) , 1.29 -1.20 (m, 3H) .

Example 55

2- (4- (7- ( ( (1-Cyclopropyl-1H-pyrazol-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) -1-methylpiperazin-2-yl) ethan-1-ol

Step 1: Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate

To a solution of methyl 1H-pyrazole-3-carboxylate (2.0 g, 15.8 mmol) and cyclopropylboronic acid (2.7 g, 31.7 mmol) and 2, 2-bipyridine (2.4 mg, 15.8 mmol) in DCE (122 mL) was added Cu(OAc) ₂ (2.8 g, 15.8 mmol) and Na ₂CO ₃ (3.3 g, 31.7 mmol) at 25 ℃. The mixture was stirred at 70 ℃ for 16 h. The mixture was filtered. The filtrate was diluted with H ₂O (20 mL) and extracted with EtOAc (20 mL x 3) . The organic layer was dried over Mg ₂SO ₄ and filtered. The filtrates were concentrated. The residue was purified by column chromatography to give the title product (1.2 g, 45.5%yield) as red oil. LCMS: (ES ⁺) m/z = 167.2 [M+1] ⁺.

Step 2: 1-Cyclopropyl-1H-pyrazole-3-carboxamide

A solution of methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (1.2 g, 7.2 mmol) in NH ₃·MeOH (7 M, 15 mL) was stirred at 95 ℃ for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (450 mg, 41.2%yield) as a white solid. LCMS: (ES ⁺) m/z = 152.3 [M+1] ⁺.

Step 3: (1-Cyclopropyl-1H-pyrazol-3-yl) methanamine

To a solution of 1-cyclopropyl-1H-pyrazole-3-carboxamide (330 mg, 2.2 mmol) in dioxane (10 mL) was added LiAlH ₄ (830 mg, 21.8 mmol) at 0 ℃. The mixture was stirred at 80 ℃ for 2 h. The mixture was quenched by aq. NaOH (5 M, 0.5 mL) and H ₂O (0.5 mL) . The mixture was filtered, and the filtrates were dried over Mg ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (220 mg, 73.4%yield) as yellow oil. LCMS: (ES ⁺) m/z = 138.3 [M+1] ⁺.

Step 4: 5-Chloro-N- ( (1-cyclopropyl-1H-pyrazol-3-yl) methyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (1-cyclopropyl-1H-pyrazol-3-yl) methanamine (300 mg, 1.3 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine in EtOH (5 mL) was added TEA (357.7 mg, 2.61 mmol) at 25 ℃. The mixture was stirred at 70 ℃ for 3 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (340 mg, 78.8%yield) as a white solid. LCMS: (ES ⁺) m/z = 331.4 [M+1] ⁺.

Step 5: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-cyclopropyl-1H-pyrazol-3-yl) methyl) carbamate

To a solution of 5-chloro-N- ( (1-cyclopropyl-1H-pyrazol-3-yl) methyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine (350 mg, 0.75 mmol) in THF (15 mL) was added Boc ₂O (1.2 g, 5.2 mmol) and DMAP (258.5 mg, 2.1 mmol) at 25 ℃. The mixture was stirred at 40 ℃ for 2 h. Then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (450 mg, 98.7%yield) as yellow oil. LCMS: (ES ⁺) m/z = 431.6 [M+1] ⁺.

Step 6: Tert-butyl ( (1-cyclopropyl-1H-pyrazol-3-yl) methyl) (5- (3- (2-hydroxyethyl) -4-methylpiperazin-1-yl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) carbamate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (1-cyclopropyl-1H-pyrazol-3-yl) methyl) carbamate (120 mg, 0.28 mmol) and 2- (1-methylpiperazin-2-yl) ethan-1-ol (49 mg, 0.33 mmol) in toluene (3 mL) was added Cs ₂CO ₃ (180 mg, 0.55 mmol) , BINAP (20 mg, 0.27 mmol) and Pd ₂ (dba) ₃ (25 mg, 0.27 mmol) under N ₂. The mixture was stirred at 95 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted with EtOAc (5 mL x 3) . The organic layer was dried over Mg ₂SO ₄. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH = 10/1) to give the title product (25 mg, 8.3%yield) as a yellow oil. LCMS: (ES ⁺) m/z = 539.8 [M+1] ⁺.

Step 7: 2- (4- (7- ( ( (1-Cyclopropyl-1H-pyrazol-3-yl) methyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) -1-methylpiperazin-2-yl) ethan-1-ol

To a solution of tert-butyl ( (1-cyclopropyl-1H-pyrazol-3-yl) methyl) (5- (3- (2-hydroxyethyl) -4-methylpiperazin-1-yl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) carbamate (25 mg, 0.023 mmol) in DCM (3 mL) was added TFA (3 mL) . The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (7.0 mg, 99%HPLC purity) as a white solid. LCMS: (ES+) m/z = 439.6 [M+1] ⁺.

Example 56 &57

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (S) -1- (thiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (R) -1- (thiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (1- (thiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of 1- (thiazol-2-yl) ethan-1-amine (100 mg, 0.78 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (150 mg, 0.65 mmol) in EtOH (10 mL) was added TEA (263 mg, 2.6 mmol) , the reaction mixture was stirred at 70 ℃ for 3 h. LCMS showed one main peak with desired mass. Then the reaction mixture was concentrated under reduced pressure at 45 ℃ to offer the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₄H ₁₆ClN ₅S. Molecular Weight: 321.83. LCMS: (ES ⁺) = m/z 322.4 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (thiazol-2-yl) ethyl) carbamate

To a solution of 5-chloro-3-isopropyl-N- (1- (thiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (190 mg, 0.59 mmol) in THF (6.5 mL) was added Boc ₂O (600 mg, 2.77 mmol) and DMAP (160 mg, 1.3 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC (EtOAc/PE = 1/5) to give the title product (160 mg, 64.2%yield) as yellow oil. Chemical Formula: C ₁₉H ₂₄ClN ₅O ₂S; Molecular Weight: 421.94. LCMS: (ES ⁺) : m/z = 422.5 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4S) -4- ( ( (tert-butoxycarbonyl) (7- ( (tert-butoxycarbonyl) (1- (thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (thiazol-2-yl) ethyl) carbamate (160 mg, 0.5 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (140 mg, 0.6 mmol) in toluene (6 mL) was added Cs ₂CO ₃ (325 mg, 1 mmol) , BINAP (32 mg, 0.05 mmol) and Pd ₂ (dba) ₃ (46 mg, 0.05 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted by EtOAc (5 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by TLC (EtOAc/PE = 1/2) to give the title product (80 mg, 29.5%yield) as yellow oil. Chemical Formula: C ₃₅H ₅₃N ₇O ₇S; Molecular Weight: 615.79. LCMS: (ES ⁺) : m/z = 616.8 [M+1] ⁺.

Step 4: (3R, 4S) -4- ( ( (3-Isopropyl-7- ( (1- (thiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4S) -4- ( ( (tert-butoxycarbonyl) (7- ( (tert-butoxycarbonyl) (1- (thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (70 mg, 0.1 mmol) in DCM (10 mL) was added TFA (8 mL) . The reaction mixture was stirred at 25 ℃ for 3 h. LCMS showed one main peak with desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (40 mg, 96 %purity) as a white solid. Chemical Formula: C ₂₀H ₂₉N ₇OS. Molecular Weight: 415.56. LCMS: (ES ⁺) : m/z = 416.6 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.66 (s, 1H) , 8.39 (s, 1H) , 7.86 –7.72 (m, 2H) , 7.67 (d, J = 3.2 Hz, 1H) , 5.34 -5.25 (m, 1H) , 5.10 (s, 1H) , 3.15 –2.91 (m, 3H) , 2.87 –2.75 (m, 2H) , 2.69 –2.55 (m, 2H) , 2.03 -1.93 (m, 1H) , 1.91 –1.82 (m, 1H) , 1.75 (d, J = 6.8 Hz, 3H) , 1.67 –1.60 (m, 1H) , 1.40 –1.31 (m, 1H) , 1.26 (d, J = 3.4 Hz, 6H) .

Example 58 and 59

(3R, 4R) -4- ( ( (7- ( ( (S) -1- (2- (Dimethylamino) pyridin-3-yl) ethyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

(3R, 4R) -4- ( ( (7- ( ( (R) -1- (2- (Dimethylamino) pyridin-3-yl) ethyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 3-Bromo-N, N-dimethylpyridin-2-amine

To a solution of 3-bromo-2-fluoropyridine (4.5 g, 25.5 mmol) and dimethylamine (3.5 g, 76.7 mmol) in DMSO (45 mL) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 2 h. Then the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The organic layer was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (3.5 g, 68.0%yield) as a colorless oil. Chemical Formula: C ₇H ₉BrN ₂. Molecular Weight: 201.07. LCMS: (ES ⁺) : m/z = 201.1 [M+1] ⁺.

Step 2: 1- (2- (Dimethylamino) pyridin-3-yl) ethan-1-one

To a solution of 3-bromo-N, N-dimethylpyridin-2-amine (3.5 g, 17.4 mmol) and tributyl (1-ethoxyvinyl) stannane (7.5 g, 20.9 mmol) in dioxane (60 mL) was added Pd (dppf) Cl ₂ (1.1 g, 1.7 mmol) at 25 ℃. The reaction mixture was stirred at 100 ℃ for 8 h. Then the reaction mixture was cooled to room temperature. Then aq. HCl (2 M, 15 mL) was added to the mixture. Then the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (1.9 g, 66.5%yield) as yellow oil. Chemical Formula: C ₉H ₁₂N ₂O; Molecular Weight: 164.21. LCMS: (ES ⁺) : m/z = 165.2 [M+1] ⁺.

Step 3: (R, E) -N- (1- (2- (dimethylamino) pyridin-3-yl) ethylidene) -2-methylpropane-2-sulfinamide

To a solution of 1- (2- (dimethylamino) pyridin-3-yl) ethan-1-one (850 mg, 5.2 mmol) and (R) -2-methylpropane-2-sulfinamide (1.25 g, 10.3 mmol) in Ti (OiPr) ₄ (2.2 g) at 25 ℃. The reaction mixture was stirred at 120 ℃ for 24 h. The reaction mixture was diluted with water (10 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (1.0 g, 50%purity, 36.1%yield) as yellow oil. Chemical Formula: C ₁₃H ₂₁N ₃OS. Molecular Weight: 267.39. LCMS: (ES ⁺) : m/z = 268.2 [M+1] ⁺.

Step 5: (R) -N- (1- (2- (dimethylamino) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide

To a solution of (S, E) -N- (1- (2- (dimethylamino) pyridin-3-yl) ethylidene) -2-methylpropane-2-sulfinamide (1.0 g, 50%purity, 1.8 mmol) in THF (6 mL) at 25 ℃. The reaction mixture was cooled to -78 ℃. The mixture was dropwise added LiAlH (O ^tBu) ₃ (2.3 mL, 1 M) at -78 ℃ and stirred at 25 ℃ for 4 h. The reaction mixture was diluted with water (10 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (0.2 g, 80%HPLC purity, 31.8%yield) as yellow oil. Chemical Formula: C ₁₃H ₂₃N ₃OS; Molecular Weight: 269.41. LCMS: (ES ⁺) : m/z = 270.3 [M+1] ⁺.

Step 7: N- (1- (2- (dimethylamino) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide

To a solution of (R) -N- (1- (2- (dimethylamino) pyridin-3-yl) ethyl) -2-methyl propane-2-sulfinamide (0.2 g, 80%purity, 0.6 mmol) in DCM (3 mL) was added HCl/dioxane (4 M, 5 mL) , the resulting mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated under reduced pressure to give the title product (0.4 g, 80%purity) as yellow oil.

Step 9: 5-Chloro-N- (1- (2- (dimethylamino) pyridin-3-yl) ethyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of N- (1- (2- (dimethylamino) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (0.22 g, 1.3 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (0.3 g, 1.3 mmol) in EtOH (9 mL) was added TEA (264 mg, 2.6 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude title product, which was used in next step without further purification. Chemical Formula: C ₁₈H ₂₃ClN ₆; Molecular Weight: 358.87. LCMS: (ES ⁺) : m/z = 359.3 [M+1] ⁺.

Step 10: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (2- (dimethylamino) pyridin-3-yl) ethyl) carbamate

To a suspension of 5-chloro-N- (1- (2- (dimethylamino) pyridin-3-yl) ethyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine (0.46 g, 1.3 mmol) in THF (23 mL) was added DMAP (313.2 mg, 2.6 mmol) and Boc ₂O (1.4 g, 6.4 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (320 mg, 54.4%yield) as yellow oil. Chemical Formula: C ₂₃H ₃₁ClN ₆O ₂; Molecular Weight: 458.99. LCMS: (ES ⁺) : m/z = 459.5 [M+1] ⁺.

Step 11: Tert-butyl tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (1- (2- (dimethylamino) pyridin-3-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a suspension of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (2- (dimethylamino) pyridin-3-yl) ethyl) carbamate (0.32 g, 0.7 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (0.193 g, 0.84 mmol) in Toluene (2.5 mL) was added Cs ₂CO ₃ (454.3 mg, 1.39 mmol) , Pd ₂ (dba) ₃ (65 mg, 0.07 mmol) and BINAP (43.5 mg, 0.07 mmol) at 25 ℃. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the title crude product, which was used in the next step without further purification. Chemical Formula: C ₃₄H ₅₂N ₈O ₅; Molecular Weight: 652.84. LCMS: (ES ⁺) : m/z = 653.9 [M+1] ⁺.

Step 12: (3R, 4R) -4- ( ( (7- ( (1- (2- (Dimethylamino) pyridin-3-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (1- (2- (dimethylamino) pyridin-3-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (500 mg, crude) in DCM (25 mL) was added TFA (10 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the racemic product (20 mg, 98.2%purity) as a white solid, which was separated by SFC to give the Example 60 and Example 61 (7.6 mg, 98.7%HPLC purity and 97.7%ee; 7.7 mg, 99.2%HPLC purity and 98.1%ee) , which share the same MS signal and ¹H NMR spectrum. Chemical Formula: C ₂₄H ₃₆N ₈O; Molecular Weight: 452.61. LCMS: (ES+) : m/z = 453.7 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.17 (dd, J = 4.7, 1.8 Hz, 1H) , 7.89 (dd, J = 7.6, 1.7 Hz, 1H) , 7.61 (s, 1H) , 7.41 -7.32 (m, 1H) , 7.00 (dd, J = 7.6, 4.7 Hz, 1H) , 6.59 –6.48 (m, 1H) , 5.40 -5.25 (m, 1H) , 5.16 (s, 1H) , 4.99 -4.81 (m, 1H) , 3.15 -3.05 (m, 3H) , 3.02 -2.89 (m, 2H) , 2.83 (s, 6H) , 2.36 (t, J = 11.1 Hz, 1H) , 2.25 -2.18 (m, 1H) , 2.05 –1.95 (m, 1H) , 1.63 (d, J = 12.0 Hz, 3H) , 1.37 –1.13 (m, 10H) .

Example 62

(3R, 4R) -4- ( ( (7- ( ( (S) -1- (5-Chlorobenzo [d] thiazol-2-yl) ethyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 1- (5-Chlorobenzo [d] thiazol-2-yl) ethan-1-one

To a solution of 5-chlorobenzo [d] thiazole (500 mg, 2.9 mmol) and N-methoxy-N-methylacetamide (608 mg, 5.9 mmol) in THF (18 mL) was added n-BuLi (2.5 M, 1.65 mL, 4.1 mmol) at -78 ℃, and the mixture was stirred at 0 ℃ for 0.5 h. The reaction was quenched with H ₂O (5 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (350 mg, 56.1%yield) as a yellow oil. Chemical Formula: C ₉H ₆ClNOS. Molecular Weight: 211.66. LCMS: (ES ⁺) : m/z =212.1 [M+1] ⁺.

Step 2: (S, E) -N- (1- (5-chlorobenzo [d] thiazol-2-yl) ethylidene) -2-methylpropane-2-sulfinamide

To a solution of 1- (5-chlorobenzo [d] thiazol-2-yl) ethan-1-one (350 mg, 1.6 mmol) and (S) -2-methylpropane-2-sulfinamide (401 mg, 3.3 mmol) in THF (6 mL) was added Ti (OiPr) ₄ (2.35 g, 8.2 mmol) , the mixture was stirred at 70 ℃ for 16 h. The reaction was quenched with ice water (5 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (350 mg, 67.2%yield) as yellow oil. Chemical Formula: C ₁₃H ₁₅ClN ₂OS ₂; Molecular Weight: 314.85. LCMS: (ES ⁺) : m/z = 315.3 [M+1] ⁺.

Step 3: (S) -N- (1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide

A solution of (S, E) -N- (1- (5-chlorobenzo [d] thiazol-2-yl) ethylidene) -2-methyl propane-2-sulfinamide (350 mg, 1.11 mmol) in THF (5.5 mL) was cooled to -78 ℃. LiAlH (O ^tBu) ₃ (1 M,1.67 mL, 1.67 mmol) was added dropwise at -78 ℃, and resulting mixture was stirred at 0 ℃ for 1 h. The reaction mixture was quenched with water (5 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (300 mg, 85.2%yield) as yellow oil. Chemical Formula: C ₁₃H ₁₇ClN ₂OS ₂; Molecular Weight: 316.86. LCMS: (ES ⁺) : m/z = 317.3 [M+1] ⁺.

Step 4: (S) -1- (5-Chlorobenzo [d] thiazol-2-yl) ethan-1-amine hydrochloride

To a solution of (S) -N- (1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide (300 mg, 0.95 mmol) in EtOAc (7 mL) was added HCl/MeOH (4 M, 13.5 mL) , the reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the title product (220 mg, 84.8%yield) as yellow solid. Chemical Formula: C ₉H ₉ClN ₂S; Molecular Weight: 212.7. LCMS: (ES ⁺) : m/z = 213.1 [M+1] ⁺.

Step 5: (S) -5-Chloro-N- (1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (S) -1- (5-chlorobenzo [d] thiazol-2-yl) ethan-1-amine hydrochloride (220 mg, 0.91 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (200 mg, 0.87 mmol) in EtOH (6 mL) was added TEA (528 mg, 5.22 mmol) , the reaction mixture was stirred at 70 ℃for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₈H ₁₇Cl ₂N5S; Molecular Weight: 406.33. LCMS: (ES ⁺) : m/z = 406.3 [M+1] ⁺.

Step 6: Tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) carbamate

To a suspension of (S) -5-Chloro-N- (1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-7-amine (350 mg, crude, 0.86 mmol) in THF (17 mL) was added DMAP (315.7 mg, 2.58 mmol) and Boc ₂O (940 mg, 4.31 mmol) , the reaction mixture was stirred at 40 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (130 mg, 29.8%yield) as yellow oil. Chemical Formula: C ₂₃H ₂₅Cl ₂N ₅O ₂S; Molecular Weight: 506.45. LCMS: (ES ⁺) : m/z = 506.4 [M+1] ⁺.

Step 7: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a suspension of (S) -5-chloro-N- (1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine (130 mg, 0.26 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (71 mg, 0.31 mmol) in Toluene (1.5 mL) was added Cs ₂CO ₃ (168 mg, 0.51 mmol) , Pd ₂ (dba) ₃ (23.5 mg, 0.026 mmol) and BINAP (16 mg, 0.026 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (75 mg, 41.7%yield) as a white solid. Chemical Formula: C ₃₄H ₄₆ClN ₇O ₅S; Molecular Weight: 700.30. LCMS: (ES ⁺) : m/z = 700.6 [M+1] ⁺.

Step 8: (3R, 4R) -4- ( ( (7- ( ( (S) -1- (5-Chlorobenzo [d] thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (5-chlorobenzo [d] thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (75 mg, 0.11 mmol) in DCM (3 mL) was added HCl/dioxane (4 M, 0.27 mL, 1.1 mmol) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the title product (55 mg, 98.2 %purity) as a white solid. Chemical Formula: C ₂₄H ₃₀ClN ₇OS; Molecular Weight: 500.06. LCMS: (ES+) : m/z = 500.6 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.60 (s, 1H) , 9.09 –8.95 (m, 2H) , 8.38 (s, 1H) , 8.23 –7.95 (m, 3H) , 7.53 (dd, J = 8.6, 2.1 Hz, 1H) , 6.00 -5.82 (m, 1H) , 3.70 -3.51 (m, 2H) , 3.40 –3.02 (m, 4H) , 2.81 –2.55 (m, 3H) , 1.96 –1.90 (m, 1H) , 1.87 (d, J = 6.7 Hz, 3H) , 1.74 (s, 1H) , 1.47 (q, J = 11.5 Hz, 1H) , 1.28 (d, J = 6.9 Hz, 6H) .

Example 63

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (naphthalen-1-ylmethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-3-isopropyl-N- (naphthalen-1-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of naphthalen-1-ylmethanamine (100.5 mg, 0.64 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (140 mg, 0.61 mmol) in EtOH (4 mL) was added TEA (123 mg, 1.22 mmol) . The reaction mixture was stirred at 70 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give crude title product, which was used in the next step without further purification. Chemical Formula: C ₂₀H ₁₉ClN ₄; Molecular Weight: 350.85. LCMS: (ES ⁺) : m/z = 351.5 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (naphthalen-1-ylmethyl) carbamate

To a suspension of 5-chloro-3-isopropyl-N- (naphthalen-1-ylmethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (210 mg, crude, 0.6 mmol) in THF (12 mL) was added DMAP (220 mg, 1.8 mmol) and Boc ₂O (653.2 mg, 2.9 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (5 mL) and extracted with EtOAc (5 mL x 3) . The organic was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (270 mg, 99%yield) as yellow oil. Chemical Formula: C ₂₅H ₂₇Cl ₂N ₄O ₂S; Molecular Weight: 450.97. LCMS: (ES ⁺) : m/z = 451.6 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (naphthalen-1-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a suspension of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (naphthalen-1-ylmethyl) carbamate (270 mg, 0.60 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (165.5 mg, 0.72 mmol) in Toluene (3.5 mL) was added Cs ₂CO ₃ (390 mg, 1.2 mmol) , Pd ₂ (dba) ₃ (55 mg, 0.06 mmol) and BINAP (37.3 mg, 0.06 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (200 mg, 51.8 %yield) as white solid. Chemical Formula: C ₃₆H ₄₈N ₆O ₅; Molecular Weight: 644.82. LCMS: (ES ⁺) : m/z = 646.0 [M+1] ⁺.

Step 4: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (naphthalen-1-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) (naphthalen-1-ylmethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (200 mg, 0.31 mmol) in DCM (9 mL) was added HCl/dioxane (4 M, 0.78 mL, 3.1 mmol) . The reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the title product (115 mg, 97.5%HPLC purity) as a white solid. Chemical Formula: C ₂₆H ₃₂N ₆O; Molecular Weight: 444.58. LCMS: (ES+) : m/z = 445.7 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.54 (s, 1H) , 9.20 –8.95 (m, 2H) , 8.32 (d, J = 8.2 Hz, 1H) , 8.03 –8.00 (m, 1H) , 7.99 (d, J = 1.5 Hz, 1H) , 7.91 (d, J =8.2 Hz, 1H) , 7.67 –7.51 (m, 4H) , 5.58 (s, 1H) , 5.16 (s, 2H) , 3.52 –3.20 (m, 6H) , 3.09 (s, 1H) , 2.83 –2.68 (m, 1H) , 2.62 (t, J = 10.8 Hz, 1H) , 1.85 (d, J = 13.8 Hz, 1H) , 1.69 (s, 1H) , 1.45 (q, J = 12.0 Hz, 1H) , 1.26 (d, J = 6.9 Hz, 6H) .

Example 64

(3R, 4R) -4- ( ( (7- ( ( (S) -1- (4-Chlorothiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (S) -5-Chloro-N- (1- (4-chlorothiazol-2-yl) ethyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (S) -1- (4-chlorothiazol-2-yl) ethan-1-amine (500 mg, 3.1 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (760 mg, 3.2 mmol) in EtOH (15 mL) was added TEA (2.5 mL, 18.4 mmol) . The mixture was stirred at 70 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₄H ₁₅Cl ₂N ₅S. Molecular Weight: 356.27. LCMS: (ES ⁺) : m/z = 356.2 [M+1] ⁺.

Step 2: Tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-chlorothiazol-2-yl) ethyl) carbamate

To a solution of (S) -5-chloro-N- (1- (4-chlorothiazol-2-yl) ethyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine (1.7 g, 4.8 mmol) in THF (70 mL) was added Boc ₂O (15.3 mL, 24.1 mmol) and DMAP (1.2 g, 9.7 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (0.81 g, 57.6%yield) as a yellow solid. Chemical Formula: C ₁₉H ₂₃Cl ₂N ₅O ₂S. Molecular Weight: 456.39. LCMS: (ES ⁺) : m/z = 456.4 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-chlorothiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-chlorothiazol-2-yl) ethyl) carbamate (197 mg, 0.43 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (119 mg, 0.52 mmol) in toluene (1.5 mL) was added Cs ₂CO ₃ (281 mg, 0.86 mmol) , BINAP (27 mg, 0.04 mmol) and Pd ₂ (dba) ₃ (39 mg, 0.04 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (90 mg, 32.7%yield) as yellow oil. Chemical Formula: C ₃₀H ₄₄ClN ₇O ₅S. Molecular Weight: 650.24. LCMS: (ES ⁺) : m/z = 650.6 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (7- ( ( (S) -1- (4-Chlorothiazol-2-yl) ethyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-chloro thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (90 mg, 0.14 mmol) in MeOH (1.5 mL) was added HCl/MeOH (4 M, 1 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure to give the title product (54.3 mg, 99 %HPLC purity) as a white solid. Chemical Formula: C ₂₀H ₂₈ClN ₇OS. Molecular Weight: 450.00. LCMS: (ES ⁺) : m/z = 450.5 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.50 (s, 1H) , 9.05 (s, 1H) , 8.95 (s, 1H) , 8.11 –7.92 (m 2H) , 7.72 (s, 1H) , 5.71 –5.32 (m, 2H) , 3.35 -3.15 (m, 4H) , 3.10 (s, 1H) , 2.83 –2.74 (m, 1H) , 2.65 (t, J = 10.7 Hz, 1H) , 1.94 (t, J = 14.8 Hz, 1H) , 1.76 (d, J = 6.7 Hz, 4H) , 1.49 (q, J = 11.9 Hz, 1H) , 1.27 (d, J = 7.0 Hz, 6H) .

Example 66

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (S) -1- (4-methylthiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (S) -5-Chloro-3-isopropyl-N- (1- (4-methylthiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (S) -1- (4-methylthiazol-2-yl) ethan-1-amine (0.2 g, 1.4 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (0.3 g, 1.3 mmol) in EtOH (6 mL) was added TEA (0.52 mL, 3.9 mmol) , the mixture was stirred at 70 ℃ for 3 h The mixture was concentrated under reduced pressure to give the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₅H ₁₈ClN ₅S. Molecular Weight: 335.85. LCMS: (ES ⁺) : m/z = 336.3 [M+1] ⁺.

Step 2: Tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-methylthiazol-2-yl) ethyl) carbamate

To a solution of (S) -5-chloro-3-isopropyl-N- (1- (4-methylthiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (823 mg, 2.5 mmol) in THF (40 mL) was added Boc ₂O (2.6 mL, 12.2 mmol) and DMAP (600 mg, 4.9 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (326 mg, 55.8%yield) as a yellow solid. Chemical Formula: C ₂₀H ₂₆ClN ₅O ₂S. Molecular Weight: 435.97. LCMS: (ES ⁺) : m/z = 436.4 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-methylthiazol-2- yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-methylthiazol-2-yl) ethyl) carbamate (178 mg, 0.40 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (113 mg, 0.49 mmol) in toluene (2 mL) was added Cs ₂CO ₃ (266 mg, 0.81 mmol) , BINAP (25 mg, 0.037 mmol) and Pd ₂ (dba) ₃ (37 mg, 0.037 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (159 mg, 84%yield) as yellow oil. Chemical Formula: C ₃₁H ₄₇N ₇O ₅S. Molecular Weight: 629.82. LCMS: (ES ⁺) : m/z = 630.8 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (S) -1- (4-methylthiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-methylthiazol-2-yl)ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (159.5 mg, 0.25 mmol) in dioxane (1.5 mL) was added HCl/dioxane (4 M, 0.65 mL, 2.5 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure to give the title product (107 mg, 99 %purity) as a white solid. Chemical Formula: C ₂₁H ₃₁N ₇OS. Molecular Weight: 429.59. LCMS: (ES ⁺) : m/z = 430.5 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.43 –9.15 (m, 3H) , 8.44 (s, 1H) , 8.05 (s, 1H) , 7.26 (s, 1H) , 5.77 (s, 1H) , 5.54 (m, 1H) , 3.58 -3.70 (m, 2H) , 3.40 (s, 1H) , 3.30 –3.20 (m 2H) , 3.15 –3.05 (m 1H) , 2.85 –2.75 (m, 1H) , 2.65 –2.55 (m, 1H) , 2.38 (d, J = 2.7 Hz, 3H) , 1.95 (d, J = 13.6 Hz, 1H) , 1.76 (d, J = 6.8 Hz, 4H) , 1.60 –1.45 (m, 1H) , 1.27 (d, J = 7.1 Hz, 6H) .

Example 67

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (S) -1- (5-methylthiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (S) -5-Chloro-3-isopropyl-N- (1- (5-methylthiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (S) -1- (5-methylthiazol-2-yl) ethan-1-amine (100 mg, 0.78 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (160 mg, 0.70 mmol) in DMSO (2 mL) was added TEA (213 mg, 2.1 mmol) at 25 ℃. The reaction mixture was stirred at 70 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted by EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC to give the title product (100 mg, 42%yield) as yellow oil. Chemical Formula: C ₁₅H ₁₈ClN ₅S. Molecular Weight: 335.85. LCMS: (ES ⁺) : m/z = 336.3 [M+1] ⁺.

Step 2: Tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (5-methylthiazol-2-yl) ethyl) carbamate

To a solution of (S) -5-chloro-3-isopropyl-N- (1- (5-methylthiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (100 mg, 0.30 mmol) in THF (1.5 mL) was added Boc ₂O (100 mg, 0.45 mmol) and DMAP (73 mg, 0.6 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by prep-TLC to give the title product (80 mg, 61.2%yield) as yellow oil. Chemical Formula: C ₂₀H ₂₆ClN ₅O ₂S. Molecular Weight: 435.95. LCMS: (ES ⁺) : m/z = 436.4 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (5-methylthiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3- hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (5-methylthiazol-2-yl) ethyl) carbamate (80 mg, 0.18 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (51 mg, 0.22 mmol) in toluene (4 mL) was added Cs ₂CO ₃ (107 mg, 0.32 mmol) , BINAP (11.5 mg, 0.02 mmol) and Pd ₂ (dba) ₃ (17 mg, 0.02 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (40 mg, 34.2%yield) as yellow oil. Chemical Formula: C ₃₁H ₄₇N ₇O ₅S. Molecular Weight: 629.82. LCMS: (ES ⁺) : m/z = 630.8 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (S) -1- (5-methylthiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

A solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (5-methyl thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (40 mg, 0.065 mmol) in HCl/MeOH (4 mL) was stirred at 40 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give the title product (22 mg, 96 %HPLC purity) as a white solid. Chemical Formula: C ₂₁H ₃₁N ₇OS. Molecular Weight: 429.59. LCMS: (ES ⁺) : m/z = 430.5 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.36 (s, 1H) , 9.08 (s, 1H) , 8.98 (s, 1H) , 8.27 (s, 1H) , 8.08 (s, 1H) , 7.51 (s, 1H) , 5.80 (d, J = 5.6 Hz, 1H) , 5.49 (s, 1H) , 3.28 –3.17 (m, 4H) , 3.15 (s, 2H) , 2.86 (d, J = 11.8 Hz, 1H) , 2.67 (d, J = 10.9 Hz, 1H) , 2.47 (s, 3H) , 1.97 (d, J = 13.6 Hz, 1H) , 1.79 (d, J = 6.8 Hz, 4H) , 1.61 –1.45 (m, 1H) , 1.31 (d, J = 7.2 Hz, 6H) .

Example 68

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (S) -1- (4-isopropylthiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: (S) -5-Chloro-3-isopropyl-N- (1- (4-isopropylthiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (S) -1- (4-isopropylthiazol-2-yl) ethan-1-amine (110 mg, 0.65 mmol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (142 mg, 0.62 mmol) in EtOH (3 mL) was added TEA (0.7 mL, 2.5 mmol) , the mixture was stirred at 70 ℃ for 3 h. The mixture was concentrated under reduced pressure to give the crude title product, which was used in the next step without further purification. Chemical Formula: C ₁₇H ₂₂ClN ₅S. Molecular Weight: 363.91. LCMS: (ES ⁺) : m/z = 364.5 [M+1] ⁺.

Step 2: Tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-isopropylthiazol-2-yl) ethyl) carbamate

To a solution of (S) -5-chloro-3-isopropyl-N- (1- (4-isopropylthiazol-2-yl) ethyl) pyrazolo [1, 5-a] pyrimidin-7-amine (416 mg, 1.1 mmol) in THF (20 mL) was added Boc ₂O (1.3 mL, 5.7 mmol) and DMAP (279 mg, 2.3 mmol) at 25 ℃. The reaction mixture was stirred at 40 ℃ for 2 h. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column on silica gel (PE/EtOAc) to give the title product (137 mg, 45.7%yield) as a yellow solid. Chemical Formula: C ₂₂H ₃₀ClN ₅O ₂S. Molecular Weight: 464.03. LCMS: (ES ⁺) : m/z = 464.5 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-isopropyl thiazol-2-yl) ethyl) amino) -3-isopropyl-4l3-pyrazolo [5, 1-b] [1, 3] oxazin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl (S) - (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) (1- (4-isopropylthiazol-2-yl) ethyl) carbamate (37 mg, 0.29 mmol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (82 mg, 0.35 mmol) in toluene (1.5 mL) was added Cs ₂CO ₃ (192 mg, 0.59 mmol) , BINAP (18 mg, 0.03 mmol) and Pd ₂ (dba) ₃ (27 mg, 0.03 mmol) under N ₂. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (124 mg, 63.6%yield) as yellow oil. Chemical Formula: C ₃₃H ₅₁N ₇O ₅S. Molecular Weight: 657.88. LCMS: (ES ⁺) : m/z = 658.7 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (3-Isopropyl-7- ( ( (S) -1- (4-isopropylthiazol-2-yl) ethyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (S) -1- (4-isopropyl thiazol-2-yl) ethyl) amino) -3-isopropyl-4l3-pyrazolo [5, 1-b] [1, 3] oxazin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylate (124 mg, 0.18 mmol) in dioxane (1 mL) was added HCl/1, 4-dioxane (0.5 mL, 1.87 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure to give the title product (81 mg, 99%HPLC purity) as a white solid. Chemical Formula: C ₂₃H ₃₅N ₇OS. Molecular Weight: 457.64. LCMS: (ES+) : m/z = 458.6 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.61 –9.28 (m, 3H) , 8.49 (s, 1H) , 8.04 (s, 1H) , 7.26 (s, 1H) , 5.86 (s, 1H) , 5.60 (s, 1H) , 3.70 -3.55 (m, 2H) , 3.28 –3.15 (m, 2H) , 3.10 –3.05 (m, 2H) , 2.85 –2.70 (m, 1H) , 2.65 –2.55 (m, 1H) , 1.96 (d, J = 3.4 Hz, 1H) , 1.76 (d, J = 6.8 Hz, 4H) , 1.60 –1.47 (m, 1H) , 1.32 -1.16 (m, 12H) .

Example 69

2- ( ( (5- ( ( ( (3R, 4R) -3-Hydroxypiperidin-4-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) thiazole-4-carboxylic acid

Example 69 was obtained following the general synthetic route 1 with methyl 2- (aminomethyl) thiazole-4-carboxylate as the starting material. Chemical Formula: C ₂₀H ₂₇N ₇O ₃S; MW:445.54. LCMS: (ES+) : M/Z = 446.2 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.20-8.10 (m, 1H) , 7.85 (s, 1H) , 7.67 (s, 1H) , 7.05 (s, 1H) , 5.33 (s, 1H) , 4.73 (d, J = 4.0 Hz, 2H) , 3.25 -3.14 (m, 4H) , 3.03 -2.89 (m, 2H) , 2.60 -2.54 (m, 1H) , 1.79 -1.29 (m, 3H) , 1.26 -1.20 (m, 6H) .

Example 70

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (1- (4-methylthiazol-2-yl) cyclopropyl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Example 70 was obtained following the general synthetic route 1 with 1- (4-methylthiazol-2-yl)cyclopropan-1-amine as the starting material. Chemical Formula: C ₂₂H ₃₁N ₇OS; MW: 441.60. LCMS: (ES ⁺) : m/z = 442.6 [M+1] ⁺. ¹H NMR: (400 MHz, CDCl ₃) δ 7.40 (s, 1H) , 6.87 (s, 1H) , 6.71 (s, 1H) , 5.20 (s, 1H) 4.75-4.67 (m, 1H) , 4.37-4.28 (m, 1H) , 3.23 -3.18 (m, 2H) , 3.12 -3.08 (m, 1H) , 3.03 -2.99 (m, 1H) , 2.92 (dd, J = 5.2, 14.4 Hz, 1H) , 2.61 -2.55 (m, 1H) , 2.48 (t, J =10.4 Hz, 1H) , 2.38 (s, 3H) , 2.83 -2.82 (m, 2H) , 1.48 -1.38 (m, 4H) , 1.32 -1.25 (m, 8H) .

Example 71

(3R, 4R) -4- ( ( (3-Isopropyl-7- (prop-2-yn-1-ylamino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Example 71 was obtained following the general synthetic route 1 with prop-2-yn-1-amine as the starting material. Chemical Formula: C ₁₈H ₂₆N ₆O; MW: 342.45. LCMS: (ES ⁺) : m/z = 343.8 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) : δ 7.65 (s, 1H) , 5.15 (s, 1H) , 4.95 -4.92 (m, 1H) , 4.37 -4.28 (m, 1H) , 4.04 -4.03 (m, 1H) , 3.32 -3.19 (m, 2H) , 3.13 -3.05 (m, 2H) , 2.97 (dd, J = 5.2, 14.8 Hz, 1H) , 2.64 -2.58 (m, 1H) , 2.51 (t, J = 10.8 Hz, 1H) , 2.30 (m, 1H) , 1.61 -1.42 (m, 3H) , 1.30 -1.28 (m, 4H) , 1.26 -1.23 (m, 4H) .

Example 73

(3R, 4R) -4- ( ( (3-Isopropyl-7- ( (2- (4-methylthiazol-2-yl) propan-2-yl) amino) pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Example 73 was obtained following the general synthetic route 1 with 2- (4-methylthiazol-2-yl) propan-2-amine as the starting material. Chemical Formula: C ₂₂H ₃₃N ₇OS; MW: 443.61. LCMS: (ES ⁺) : m/z = 444.4 [M+1] ⁺. ¹H NMR: (400 MHz, CDCl ₃) δ 7.66 (s, 1H) , 6.87 (s, 1H) , 6.65 (s, 1H) , 4.67 (s, 1H) , 4.57 -4.54 (m, 1H) , 4.28 -4.23 (m, 1H) , 3.35 -3.29 (m, 1H) , 3.27 -3.23 (m, 1H) , 3.12 -3.03 (m, 2H) , 2.93 -2.88 (m, 1H) , 2.67 -2.60 (m, 1H) , 2.56 -2.51 (m, 1H) , 2.46 (s, 3H) , 1.87 (d, J = 8.0 Hz, 6H) , 1.58 -1.48 (m, 3H) , 1.31 -1.27 (m, 6H) .

Example 74

(3R, 4R) -4- ( ( (7- ( ( (5, 5-Dimethyl-5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazol-3-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Example 74 was obtained following the general synthetic route 1 with (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazol-3-yl) methanamine as the starting material. Chemical Formula: C ₂₅H ₃₈N ₈O ₃; MW: 452.61. LCMS: (ES ⁺) : m/z 453.3 [M+1] ⁺. ¹H NMR: (400 MHz, CDCl ₃) δ 7.62 (s, 1H) , 7.52 (s, 1H) , 6.33 (s, 1H) , 5.28 (s, 1H) , 4.27 (s, 2H) , 4.02 (s, 1H) , 3.82 (s, 2H) , 3.67 (s, 1H) , 3.47 -3.37 (m, 2H) , 3.21 (s, 1H) , 3.07 -3.04 (m, 1H) , 2.80 -2.70 (m, 2H) , 2.62 (s, 2H) , 2.00 -1.67 (m, 3H) , 1.24 (s, 12H) .

Example 78

(3R, 4R) -4- ( ( (7- ( ( (S) -1- (4, 5-Dimethylthiazol-2-yl) ethyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Example 78 was obtained following the general synthetic route 1 with (S) -1- (4, 5-dimethylthiazol-2-yl) ethan-1-amine as the starting material. Chemical Formula: C ₂₂H ₃₃N ₇OS; MW: 443.61. LCMS: (ES ⁺) : m/z = 444.5 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) : δ 7.66 (s, 1H) , 6.38 (s, 1H) , 5.01 (s, 1H) , 4.85 -4.78 (m, 1H) , 4.73 -4.69 (m, 1H) , 4.69 -4.65 (m, 1H) , 4.35 -4.29 (m, 1H) , 3.29 -3.18 (m, 2H) , 3.12 -3.03 (m, 2H) , 2.93 (dd, J = 5.2, 14.0 Hz, 1H) , 2.65 -2.56 (m, 1H) , 2.51-2.46 (m, 1H) , 2.35 -2.29 (m, 6H) , 1.73 (d, J = 6.8 Hz, 3H) , 1.58 -1.42 (m, 3H) , 1.32 -1.26 (m, 6H) .

Example 79

(3R, 4R) -4- ( ( (7- ( ( (S) -1- (5-Fluoro-4-methylthiazol-2-yl) ethyl) amino) -3-isopropyl pyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Example 79 was obtained following the general synthetic route 1 with (S) -1- (5-fluoro-4-methylthiazol-2-yl) ethan-1-amine as the starting material. Chemical Formula: C ₂₂H ₃₂FN ₇O ₃S; MW: 447.58. LCMS: (ES ⁺) : m/z = 448.3 [M+1] ⁺. ¹H NMR: (400 MHz, CDCl ₃) δ 7.68 (s, 1H) , 6.44 (d, J = 6.0 Hz, 1H) , 5.16 (s, 1H) , 4.77 -4.74 (m, 1H) , 4.25 -4.21 (m, 1H) , 3.55 -3.53 (m, 3H) , 3.40 -3.30 (m, 4H) , 3.09 -3.03 (m, 2H) , 2.77 -2.62 (m, 2H) , 2.28 (d, J = 2.4 Hz, 3H) , 1.72 (d, J = 6.4 Hz, 3H) , 1.30 -1.27 (m, 6H) .

Example 80

(3R, 4R) -4- ( ( (7- ( ( (5-Fluorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Step 1: 5-Chloro-N- ( (5-fluorobenzo [d] thiazol-2-yl) methyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine

To a solution of (5-fluorobenzo [d] thiazol-2-yl) methanamine (200 mg, 912.6 umol) and 5, 7-dichloro-3-isopropylpyrazolo [1, 5-a] pyrimidine (200 mg, 869.2 umol) in EtOH (4 mL) was added TEA (351.8 mg, 3.5 mmol) at 25 ℃. The reaction mixture was stirred at 70℃ for 3 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by flash chromatography on silica gel column (gradient: 0～30%EtOAc in PE) to give the title product (210 mg, 64.3%yield) as a yellow solid. Chemical Formula: C ₁₇H ₁₅ClFN ₅S; Molecular Weight: 375.1. LCMS: (ES ⁺) : m/z = 376.3 [M+1] ⁺.

Step 2: Tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5-fluorobenzo [d] thiazol-2-yl) methyl) carbamate

To a solution of 5-chloro-N- ( (5-fluorobenzo [d] thiazol-2-yl) methyl) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-amine (210 mg, 558.7 umol) in THF (6 mL) was added Boc ₂O (610 mg, 2.8 mmol) and DMAP (34.1 mg, 279.4 umol) at 25℃. The reaction mixture was stirred at 40 ℃for 1 h. Then the reaction mixture was concentrated under reduced pressure at 45 ℃. The residue was purified by flash chromatography on silica gel column (gradient: 0～25%EtOAc in PE) to give the title product (160 mg, 60.3%yield) as yellow oil. Chemical Formula: C ₂₂H ₂₃ClfN ₅O ₂S; Molecular Weight: 475.12. LCMS: (ES ⁺) : m/z = 476.4 [M+1] ⁺.

Step 3: Tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5-fluorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylatetert-butyl

To a solution of tert-butyl (5-chloro-3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) ( (5-fluorobenzo [d] thiazol-2-yl) methyl) carbamate (120 mg, 252.1 umol) and tert-butyl (3R, 4R) -4- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (70 mg, 302.5 umol) in THF (2.5 mL) was added Pd ₂ (dba) ₃ (23 mg, 25.2 umol) , BrettPhos (13.5 mg, 25.1 umol) under N ₂, then LiHMDS (302 uL, 302.5 umol) was added. The reaction mixture was stirred at 60 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂O and extracted by EtOAc. The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (60 mg, 35.5%yield) as yellow oil. Chemical Formula: C ₃₃H ₄₄FN ₇O ₅S; Molecular Weight: 669.31. LCMS: (ES ⁺) : m/z = 670.9 [M+1] ⁺.

Step 4: (3R, 4R) -4- ( ( (7- ( ( (5-Fluorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

To a solution of tert-butyl (3R, 4R) -4- ( ( (7- ( (tert-butoxycarbonyl) ( (5-fluorobenzo [d] thiazol-2-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) -3-hydroxypiperidine-1-carboxylatetert-butyl (60 mg, 89.6 umol) in DCM (5 mL) was added HCl/1, 4-dioxane (0.5 mL) . The reaction mixture was stirred at 40 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure to give the title product (45 mg, 96.5%HPLC purity) as a yellow solid. Chemical Formula: C ₂₂H ₂₃FN ₇OS; Molecular Weight: 469.21. LCMS: (ES+) : m/z = 470.5 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.03 (s, 1H) , 8.94 (s, 1H) , 8.14 (dd, J = 8.8, 5.3 Hz, 1H) , 8.04 (s, 1H) , 7.87 (dd, J = 9.9, 2.5 Hz, 1H) , 7.38 (td, J = 9.1, 2.6 Hz, 1H) , 5.17 (s, 1H) , 3.41 (s, 2H) , 3.20 (d, J = 11.7 Hz, 1H) , 2.74 (d, J = 14.6 Hz, 1H) , 1.86 (d, J = 13.7 Hz, 1H) , 1.70 (s, 1H) , 1.51 –1.39 (m, 1H) , 1.28 (d, J = 6.9 Hz, 6H) .

Example 84

(3R, 4R) -4- ( ( (7- ( ( (S) -1- (4- (3-Chlorophenyl) thiazol-2-yl) ethyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) methyl) piperidin-3-ol

Example 84 was obtained following the general synthetic route 1 with (S) -1- (4- (3-chlorophenyl) thiazol-2-yl) ethan-1-amine as the starting material. Chemical Formula: C ₂₆H ₃₂ClN ₇OS, MW: 526.10. LCMS: (ES ⁺) : m/z = 527.1 [M+1] ⁺. ¹H NMR (400 MHz, CDCl ₃) : δ 7.94 (s, 1H) , 7.76 (d, J = 7.6 Hz, 1H) , 7.69 (s, 1H) , 7.47 (s, 1H) , 7.39 -7.26 (m, 2H) , 6.50 (d, J = 6.0 Hz, 1H) , 5.03 -4.95 (m, 2H) , 4.73 -4.69 (m, 1H) , 4.34 -4.26 (m, 1H) , 3.22 -3.13 (m, 2H) , 3.11-3.06 (m, 1H) , 2.97 -2.93 (m, 1H) , 2.92 -2.88 (m, 1H) , 2.58 -2.52 (m, 1H) , 2.44 (t, J =10.4 Hz, 1H) , 1.84 (d, J = 6.8 Hz, 3H) , 1.53 -1.34 (m, 3H) , 1.33 -1.28 (m, 6H) .

Example 85

2- ( ( (5- ( ( ( (3R, 4R) -3-Hydroxypiperidin-4-yl) methyl) amino) -3-isopropylpyrazolo [1, 5-a] pyrimidin-7-yl) amino) methyl) -N, N-dimethylthiazole-4-carboxamide

Example 85 was obtained following the general synthetic route 1 with methyl 2- (aminomethyl) thiazole-4-carboxylate as the starting material. Chemical Formula: Chemical Formula: C ₂₂H ₃₂N ₈O ₂S, MW: 472.61. LCMS: (ES+) : m/z = 473.1 [M+1] ⁺. ¹H NMR (400 MHz, CDCl3) : δ 7.78 (s, 1H) , 7.67 (d, J = 7.6 Hz, 1H) , 6.92 (s, 1H) , 5.08 (s, 1H) , 4.99 -4.95 (m, 1H) , 4.78 -4.77 (m, 2H) , 4.31 -4.25 (m, 1H) , 3.22 -3.16 (m, 5H) , 3.12 -3.10 (m, 3H) , 3.05 -3.01 (m, 1H) , 2.96 -2.92 (m, 1H) , 2.62 -2.45 (m, 2H) , 1.59 -1.40 (m, 4H) , 1.27 -1.31 (m, 6H) .

Pharmacological testing

1. In Vitro Kinase assay (CDK7) and IC ₅₀ determination:

The kinase assay was carried out by Sundia MediTech Co., Ltd.

Materials and suppliers:

Reagents	Supplier	Item number	Batch
CDK7/CycH/MAT1	Cama	04-108	13CBS-0015U
Kinase substrate CTD3	GL	346885	P191226-MJ346885
DMSO	Sigma	D8418-1L	SHBG3288V
384-well plate	Corning	3573	12619003
PHA-793887	Selleckchem	S1487	Lot01

Instruments:

Centrifuge (Manufacturer: Eppendorf, Type: 5430)

ELIASA (Manufacturer: Perkin Elmer, Type: Caliper EZ ReaderII)

Echo 550 (Manufacturer: Labcyte, Type: 550)

General assay procedure:

Sample preparation

The compound has been received by the compound manager and dissolved in 100%DMSO to prepare a 10 mM stock solution which was stored in a nitrogen cabinet away from light.

Kinase reaction process

(1) Prepare 1×Kinase buffer.

(2) Preparation of sample concentration gradient: the initial concentration of test compound is 1000 nM, 3 times dilution, 10 concentrations, single or double holes detection. Dilute in a 384-source plate to a 100%DMSO solution of 100 times the final concentration.

Use a dispenser Echo 550 to transfer 250 nL 100 times the final concentration of the compound to the target 384-well-plate.

(3) Use 1×Kinase buffer to prepare 2.5 times the final concentration of kinase solution.

(4) Add 10 μl of 2.5 times the final concentration of kinase solution to the compound well and the positive control well;

Add 10 μl of 1×Kinase buffer to the negative control well.

(5) Centrifuge at 1000 rpm for 30 seconds, shake and mix the reaction plate, and incubate at room temperature for 60 minutes.

(6) Prepare a mixed solution of 5/3 times the final concentration of ATP and Kinase substrate with 1×Kinase buffer.

(7) Add 15 μl of a mixed solution of 5/3 times the final concentration of ATP and substrate to start the reaction.

(8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 120 minutes.

(9) Add 30 μl to stop the detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, shake and mix.

(10) Use Caliper EZ Reader to read the conversion rate.

Data analysis: The inhibition percentage in the presence of the compound was calculated based on the following formula:

Among them:

Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the average value of the negative control wells, representing the conversion rate readings of the wells without enzyme activity; Conversion%_max: the average value of the positive control wells, representing the conversion rate readings of the wells without compound inhibition.

Fitting the data in GrphaPad Prism V5.0 software with log (inhibitor) vs. response -Variable slope, the IC50 was obtained.

In vitro kinase inhibition data are summarized in the following Table 1.

Table 1: The Result of In Vitro Kinase Assay (CDK7)

Example #	IC ₅₀	Example #	IC ₅₀	Example #	IC ₅₀	Example #	IC ₅₀
Example 1	A	Example 11	A	Example 21	-	Example 31	A
Example 2	A	Example 12	-	Example 22	-	Example 32	-
Example 3	-	Example 13	A	Example 23	C	Example 33	-
Example 4	A	Example 14	A	Example 24	-	Example 34	-
Example 5	A	Example 15	A	Example 25	B	Example 35	A
Example 6	A	Example 16	-	Example 26	A	Example 36	A
Example 7	A	Example 17	-	Example 27	A	Example 38	A
Example 8	C	Example 18	-	Example 28	A	Example 39	A
Example 9	A	Example 19	-	Example 29	A	Example 48	A
Example 10	A	Example 20	-	Example 30	A

A means < 50 nM, B means > 50 nM and < 500 nM, C means > 500 nM, -means no data available

2. Cell proliferation assay

1) . Materials and Reagents:

Consumables	Vendor	Catalog
96-well cell culture plate	Corning	3610

2) . Experimental procedure

Day 0: Cell seeding

a) . Trypsinize cells and count cell density with the automated cell counter.

b) . Dilute cell suspensions in growth medium to desired density.

c) . Seed 100 uL cells into 96-well plate in growth medium according to the plate map.

Medium only is used as background control (Min) .

d) . Incubate at 37℃, overnight.

Day 1: Compounds treatment

a) . Make 200X cpd solution in DMSO

b) . Dilute compounds with growth medium to 3x final concentration.

Add 3 uL 200x cpds to 197 ul growth medium.

c) . Add 50 uL diluted cpds solution to cells and incubate at 37℃, 5%CO ₂ for 72 h.

Day 4: Measurement

a) . Equilibrate the assay plate to room temperature before measurement.

b) . Add 40 uL of

Reagent into each well.

c) . Mix contents for 2 minutes on an orbital shaker to induce cell lysis.

d) . Incubate at room temperature for 60 minutes to stabilize luminescent signal.

e) . Record luminescence on Envision.

Table 2: The Results of Cell Proliferation Assay

A means < 1 uM, B means > 1 uM and < 3 uM, C means > 3 uM.

3. Inhibition of CDK kinase activity

3.1. Materials and suppliers:

Reagents	Supplier	Item number	Batch
CDK7	Cama	04-108	13CBS-0015U
CDK1	Cama	04-102	20CBS-0607C
CDK2	Cama	04-103	09CBS-1176L
CDK6	Cama	04-107	09CBS-0622L
CDK4	Cama	04-105	14CBS-0306G
CDK9	Cama	04-110	14CBS-0084G
Caliper substrate CTD3	GL	346885	P171207-MJ346885
Caliper substrate 18	GL	114202	P171207-MJ114202
Caliper substrate 8	GL	112396	P171207-MJ112396
DMSO	Sigma	D8418-1L	SHBG3288V
384-well plate	Corning	3573	12619003
Dinaciclib	Selleckchem	S2768	lot03
Palbociclib	Selleckchem	S1116	S111612
PHA-793887	Selleckchem	S1487	Lot01

3.2. Instruments:

Centrifuge (Manufacturer: Eppendorf, Type: 5430)

ELIASA (Manufacturer: Perkin Elmer, Type: Caliper EZ ReaderII)

Echo 550 (Manufacturer: Labcyte, Type: 550)

3.3. General assay procedure:

Sample preparation

Kinase reaction process

(1) Prepare 1×Kinase buffer.

(2) Preparation of sample concentration gradient: the initial concentration of test compound is 3000 nM, 3 times dilution, 10 concentrations, single or double holes detection. Dilute in a 384-source plate to a 100%DMSO solution of 100 times the final concentration.

Use a dispenser Echo 550 to transfer 250 nL 100 times the final concentration of the compound to the target 384-well-plate. Add 250nL DMSO to positive and negative control wells.

(4) Add 10 μl of 2.5 times the final concentration of kinase solution to the compound well and the positive control well; Add 10 μl of 1×Kinase buffer to the negative well.

(5) Centrifuge at 1000 rpm for 30 seconds, shake and mix the reaction plate, and incubate at room temperature for 10 minutes.

(6) Prepare a mixed solution of 25/15 times the final concentration of ATP and Kinase substrate with 1×Kinase buffer.

(7) Add 15 μl of a mixed solution of 25/15 times the final concentration of ATP and substrate to start the reaction.

(10) Use Caliper EZ Reader to read the conversion rate.

Among them:

Taking the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the dose-response curve was fitted by the log (inhibitor) vs. response -Variable slope of the analysis software GraphPad Prism 5 to obtain the IC ₅₀ value of each compound on the enzyme activity.

Formulation: Y=Bottom+ (Top-Bottom) / (1+10^ ( (LogIC50-X) *Hillslope) ) .

Table 3: Inhibitory activity of the compounds of the present invention on CDK1, CDK2,

CDK4, CDK6, CDK7 and CDK9

	CDK1	CDK2	CDK4	CDK6	CDK7	CDK9
Example 39	1760	77.46	598.40	>3000	16.45	83.10
Example 48	>3000	2109.0	>3000	>3000	1.86	743.6

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention. The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

Claims

A compound of the formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

wherein:

R ₁ is selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;

R ₂ is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl and phenyl;

R ₃ is selected from H, C _1-6 alkyl, C _1-6 haloalkyl and halogen;

B is selected from C and N, provided that when B is N, R ₃ is absent;

A is a bond or selected from O, N, S and SO ₂;

L is selected from

R ₄, at each occurrence, is independently selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, CN, NR ₅R ₅, OR ₅, COOR ₅, SR ₅, SO ₂R ₅, optionally substituted phenyl, optionally substituted pyridyl and C _3-6 cycloalkyl;

R ₅, at each occurrence, is independently selected from H and C _1-6 alkyl,

R, at each occurrence, is independently selected from H, C _1-6 alkyl, optionally substituted phenyl, optionally substituted pyridyl and C _3-6 cycloalkyl;

X, at each occurrence, is independently selected from C and N;

Q is selected from

R ₆, at each occurrence, is independently selected from H, C _1-6 alkyl, optionally substituted phenyl, and optionally substituted pyridyl; and

denotes a single bond or C _1-6 alkylene.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, wherein R ₁ is selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl and C ₃ cycloalkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1 or 2, wherein R ₁ is selected from H, methyl, ethyl, n-propyl and isopropyl, preferably H.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-3, wherein R ₂ is selected from C _1-3 alkyl and C _1-3 haloalkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-4, wherein R ₂ is selected from methyl, ethyl, n-propyl, isopropyl and n-butyl, preferably isopropyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-5, wherein R ₃ is selected from H, C _1-6 alkyl, F and Cl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-6, wherein R ₃ is selected from H and C _1-3 alkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-7, wherein B is N.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-8, wherein B is C.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-9, wherein A is selected from O and N.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-10, wherein A is N.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-11, wherein Q is selected from

and R ₆, at each occurrence, is independently selected from H and C _1-6 alkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-12, wherein Q is selected from

and R ₆, at each occurrence, is independently selected from H and methyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-13, wherein Q is selected from

and R ₆, at each occurrence, is independently selected from H and methyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-14, wherein Q is
and R ₆ is selected from H and methyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-15, wherein L is selected from

R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, CF ₃, halogen, NR ₅R ₅, OR ₅, SR ₅, C _3-5 cycloalkyl, and halogen substituted phenyl;

R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl,

R, at each occurrence, is independently selected from C _1-3 alkyl and C _3-6 cycloalkyl;

X, at each occurrence, is independently selected from C and N.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-16, wherein

R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, CF ₃, F, Cl, NR ₅R ₅, OR ₅, and C ₃ cycloalkyl;

R ₅, at each occurrence, is independently selected from H and C _1-3 alkyl,

R, at each occurrence, is independently selected from C _1-3 alkyl and C ₃ cycloalkyl;

X, at each occurrence, is independently selected from C and N.
The compound of formula I, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-17, wherein L is selected from

R ₄, at each occurrence, is independently selected from H, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, halogen substituted phenyl, and C _3-6 cycloalkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-17, wherein L is selected from

R ₄, at each occurrence, is independently selected from H, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, F, Cl, and F substituted phenyl.
A compound, a pharmaceutically acceptable salt thereof or stereoisomer thereof, wherein the compound is selected from:
A pharmaceutical composition comprising the compound of formula I, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-20 and one or more pharmaceutically acceptable excipients.
Use of the compound of formula I, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-20 or the pharmaceutical composition according to claim 21 in the manufacture of a medicament for the treatment of diseases or conditions associated with aberrant activity of CDK7.
The use according to claim 22, wherein the diseases or conditions are cancer.
A method for treating a cancer in a patient, comprising administering a therapeutically effective amount of the compound of formula I, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1 to 20 or the pharmaceutical composition according to claim 21 to the patient.